Silver-catalyzed spirolactonization: first synthesis of spiroisoindole-γ-methylene-γ-butyrolactones

Article abstract of DOI:10.1016/j.tet.2008.01.137

γ-Acetylenic carboxylic acids are cyclized to spirolactones under mild conditions, in the presence of Ag₂CO₃ catalyst. The corresponding spiro-5-alkylidene-γ-butyrolactones were isolated in high yields, and this process constitutes an easy and efficient route to analogous structures of natural products of biological interest.

Full text of DOI:10.1016/j.tet.2008.01.137

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 3505e3516
www.elsevier.com/locate/tet
Silver-catalyzed spirolactonization: first synthesis of
spiroisoindole-g-methylene-g-butyrolactones
b
Mohamed M. Rammah a,d, Mohamed Othman a, , Kabula Ciamala ,
*
Carsten Strohmann c, Mohamed B. Rammah d
a URCOM, Universite´ du Havre, BP 540, 25 rue Philippe Lebon, 76058 Le Havre Cedex, France
b Institut UTINAM UMR CNRS 6213, Universite´ de Franche-Comte´, F-25030 Besanc¸on Cedex, France
c Institut fuˆr Anorganische, Chemie, Universita¨t Wu¨rzburg, D-97074, Germany
d LCOH, Universite´ de Monastir, 5000 Monastir, Tunisia
Received 12 December 2007; received in revised form 30 January 2008; accepted 31 January 2008
Available online 6 February 2008
Abstract
g-Acetylenic carboxylic acids are cyclized to spirolactones under mild conditions, in the presence of Ag2CO3 catalyst. The corresponding
spiro-5-alkylidene-g-butyrolactones were isolated in high yields, and this process constitutes an easy and efficient route to analogous structures
of natural products of biological interest.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
3-substituted dihydroisoindolin-1-ones such as pazinaclone
I8 and zoplicone II9 possess a pharmaceutical profile similar
to benzodiazepines (sedatives, hypnotics)10 and have been
commercialized as anxiolytics (Fig. 2).
In recent years, increasing attention has been focused on
spirocyclic compound synthesis due to their interesting confor-
mational features and their structural implications in biological
and environmental systems.11e13 For example, spirocyclic
isoindolin-1-one III14 was described as an aldose reductase
inhibitor and antihyperglycemic agent.
Exocyclic enol lactones (Fig. 1) are useful intermediates for
the synthesis of a variety of natural products, which display
a wide range of biological activities.1,4b,5d,7b Compounds con-
taining this moiety are reported to have cytotoxic, insecticidal,
and antibiotic properties. As a consequence, much attention
has been paid to the synthesis of g-methylene-g-butyrolactone
derivatives. Of the existing strategies for their syntheses, those
based on transition metal-catalyzed cyclization of alkynoic acids
by Au, Ag, Hg, Rh or Pd2e7 are arguably the most effective.
On the other hand, the dihydroisoindolin-1-one ring system
is present in numerous synthetic and natural compounds,
which exhibit interesting biological properties. For example,
In this context and in connection with our current research in-
terest in the preparation of biologically relevant nitrogenated
and oxygenated compounds,15,16 we wish to describe in this pa-
per a convenient silver salt catalyzed procedure as a novel and
R
O
O
O
O
cat.
N
N Me
N
OH
NH
O
R
O
O
O
O
N
Cl
N
N R
Figure 1.
N
N
II
I
N
O
III
O
O
Cl
* Corresponding author. Tel.: þ33 02 32 74 44 01; fax: þ33 02 32 74 43 91.
E-mail address: mohamed.othman@univ-lehavre.fr (M. Othman).
Figure 2.
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.01.137

3506
M.M. Rammah et al. / Tetrahedron 64 (2008) 3505e3516
O
COOR1
COOEt
COOH
N R
O
O
i, ii
N
R
N
R
O
N
R
A
O
O
B
6a-g
6a-g R1 = CO2Et
7a-g R1 = COOH
5a-g
ii
COOEt
N R
O
COOEt
N R
O
Scheme 3. Reagents and conditions: (i) K2CO3, propargyl bromide, CH3CN,
reflux, 12 h, 80e97%; (ii) (a) NaOH, EtOH/H2O, rt, 2 h; (b) aqueous 1 M
HCl, 0 ꢀC, 72e98%.
D
C
Scheme 1. Retrosynthetic approach.
Treatment of lactams 5 with K2CO3 to effect enolate
formation followed by alkylation with propargyl bromide,
afforded alkylated phthalimidines esters 6aeg in good yields
(80e97%) (Scheme 3).
Esters 6aeg were then treated with a molar excess of 1 M
aqueous NaOH solution and ethanol at room temperature for
2 h, followed by acidification with diluted HCl at 0 ꢀC to give
the corresponding carboxylic acids 7aeg in 72e98% yield.
With a large variety of acetylenic carboxylic acids 7aeg in
hand, we then investigated the optimal conditions for the
spirolactone formation.
expedient entry to diversespirocyclic compounds containing the
g-methylene-g-butyrolactone and the dihydroisoindolin-1-one
moieties from commercially available homophthalic acid.
Our retrosynthetic strategy is outlined in Scheme 1. Spirolac-
tone A can be readily obtained by catalytic silver cyclization of
acid B, which in turn can be obtained by propargylation and
saponification of phthalimidine D.
2. Results and discussion
In their pioneering work on silver-catalyzed heterolactoni-
zation, Pale and co-workers4c established that acetylenic acids
could be efficiently cyclized by a catalytic amount of silver
carbonate (10 mol %). The cyclization proved to be highly
regioselective and the exocyclic a-methylene heterocycles
resulting from an exo-dig ring closure were always exclusively
isolated.
Using the same protocol on the compound 7a chosen as
model, we found that the use of just 5 mol % of Ag2CO3 in tol-
uene at 80 ꢀC cleanly afforded in a short reaction time (15 min)
the corresponding spiro-5-alkylidene-g-butyrolactone 8a in
quantitative yield (Table 1, entry 1). IR, 1H and 13C NMR spec-
troscopies unambiguously confirmed the expected cyclic struc-
ture for this compound. Particularly characteristic were the
exocyclic enol lactone data, with the methylene protons at
4.52 and 4.98 ppm, the lactone carbon at 170.5 ppm, and the
methylene carbons at 151.3 and 91.6 ppm. The reaction has
been scaled up to 5 g with no loss in yield (Scheme 4).
The reaction scope was probed by applying these optimal
conditions to the other substrates 7beg, which cyclized
smoothly to offer the spiro compounds 8beg in good yields
(Table 1). As far as we know, this is the first preparation of
g-spirobutyrolactone derivatives containing the isoindole moi-
ety starting from homophthalic acid.
2.1. Synthesis of achiral spirobutyrolactone derivatives
We started our synthesis from diethylhomophthalate 2 read-
ily available in quantitative yield, through the esterification of
commercially available homophthalic acid 1, as previously
described by our group.16 The conversion of 2 into the corre-
sponding diethyl a-bromohomophthalate 3 was accomplished
under standard conditions by treatment with N-bromosuccin-
imide and a catalytic amount of AIBN. Condensation of bromine
3 with 2 equiv of the required primary amines 4aeg in acetoni-
trile at room temperature for 8 h16 afforded the desired bicyclic
lactams 5aeg in high yields ranging from 84 to 92% (Scheme 2).
It should be noted that phthalimidines 5 could be efficiently
prepared by lithiation with LDA of isoindolinones derivatives.17
COOH
i
COOEt
COOH
COOEt
1
2
ii
COOEt
Br
iii
COOEt
N
R
O
Importantly, in all cases, the reaction seems to be highly re-
gioselective because during the cyclization process only the
exo-dig products were obtained.
COOEt
OMe
3
5a-g
R
It is worth noticing that the use of dichloromethane or tet-
rahydrofuran led to the formation of the desired spirolactone
in lower isolated yields (Table 1, entry 1). It should also be
noted that the presence of an allylic or propargylic side chains
in acids 7c and 7g was compatible with the reaction conditions
and no other competitive addition was observed.
H2N
:
H2N
NH2
H2N
4a
4b
4c
H2N
H2N
H2N
S
H2N
4g
N
O
4f
4d
4e
Scheme 2. Reagents and conditions: (i) HCl, EtOH, 0 ꢀC, 4 h then reflux, 4 h;
(ii) NBS, AIBN, CCl4, reflux, 12 h; (iii) amines 4aeg, CH3CN, rt, 8 h.
In order to study the generality of this silver-catalyzed
spirolactonization, the unsubstituted acid 11 and the methyl

M.M. Rammah et al. / Tetrahedron 64 (2008) 3505e3516
3507
Table 1
Spirocyclization produced via Scheme 3
O
COOH
Entrya,b
Substrate
Product
Yield %
O
N
N
O
N
7a
8a
O
O
COOH
N
100
74c
78d
O
1
Scheme 4. Reagents and conditions: (i) Ag2CO3, toluene, 80 ꢀC, 100%.
8a
7a
O
O
COOEt
COOEt
O
COOEt
COOH
N
i
ii
O
N
H
N
H
N
O
N
9
10
O
2
3
89
80
O
5e
7b
8b
O
O
Scheme 5. Reagents and conditions: (i) TFA, CH2Cl2, rt, 12 h, 84%; (ii)
K2CO3, propargyl bromide, CH3CN, reflux, 12 h, 80%.
OMe
OMe
O
COOH
O
BBr3)18 in dichloromethane at room temperature for 12 h
afforded the desired phthalimidine 9 in 84% yield (Scheme 5).
Alkylation of 9 with propargyl bromide under standard
conditions followed by basic saponification of the ester func-
tion of the resulting phthalimidine 10, gave the acid 11 in
52% yield after the two steps.
Acid 11 was next treated with Ag2CO3 (5 mol %) according
to the protocol given above. The examination of the TLC of
the reaction mixture indicated the presence of only one prod-
uct (less polar), which, after a classical workup, was identified
as compound 12, resulting from the thermal decarboxylation
of the acid function (Scheme 6).
N
O
N
8c
7c
O
O
N
COOH
N
O
4
5
6
78
100
98
O
O
8d
7d
O
O
O
N
COOH
O
N
O
N
N
8e
7e
O
N
H
ii
COOH
12
O
O
COOH
N
i
10
O
N
H
O
N
N
iii
11
S
S
O
O
H
7f
8f
O
O
13
O
O
Scheme 6. Reagents and conditions: (i) (a) NaOH, EtOH/H2O, rt, 2 h; (b)
aqueous 1 M HCl, 0 ꢀC, 65%; (ii) Ag2CO3, toluene, 80 ꢀC, 15 min, 100%;
(iii) Ag2CO3, CH2Cl2, reflux, 48 h, 40%.
COOH
N
O
7
74
N
7g
8g
O
O
It is noteworthy that, although a variety of reaction temper-
atures and Ag2CO3 ratios were explored, the formation of
spirolactone 13 was not accomplished. This is probably due
to the facile decarboxylation of acid 11 as well as its low
solubility in the solvent of the reaction.
a
All the reactions were conducted under Argon.
b
c
d
All the reactions were carried out using 5 mol % of Ag2CO3.
The reaction was carried out using CH2Cl2 at reflux.
The reaction was carried out using THF at reflux.
On the other hand, when the reaction was tested in various
solvents such as THF, DMF, dichloromethane, and H2O with
10 mol % of Ag2CO3 at room temperature and at reflux, only
in refluxing dichloromethane, trace amounts of the spirolactone
13 were obtained. The acetylenic acid 11 gave only 12 in
refluxing THF, DMF, or H2O, and remained unchanged at
room temperature. After optimizationof the reaction conditions,
substituted acid 15 were synthesized and then submitted to the
above conditions.
Our initial efforts on the synthesis of acid 11 started from the
phthalimidine-3-carboxylate derivative 5e, which upon treat-
ment with 4 equiv of trifluoroacetic acid (TFA less toxic than

3508
M.M. Rammah et al. / Tetrahedron 64 (2008) 3505e3516
we found that the best result was obtained with 20 mol %
Ag2CO3 in refluxing dichloromethane. This gave the desired
compound 13 in a moderate yield of 40%.
Using the same operating methods previously used to obtain
acid 7a, we then prepared the methyl substituted acid 15 to look
at the stereoselectivity of this spirolactonization (Scheme 7).
g-methylene-g-butyrolactones. The R- and S-a-methylbenzyl-
amines were chosen as examples for this study.
The conditions previously employed for the condensation of
primary amines, i.e., stirring diethyl a-bromohomophthalate 3
in acetonitrile at room temperature, with either R- or S-a-meth-
ylbenzylamine, failed to give the desired phthalimidine cycliza-
tion products, with only starting material being systematically
recovered. It was therefore apparent that the extra steric
hindrance in the system, with the addition of an extra methyl
group in the a position to the nitrogen of the amine, compared
to benzylamine, was sufficient to stop cyclization from
occurring.
After intensive screeningof thereaction conditions, forexam-
ple, reactiontemperatures, additives(K2CO3, NaH, andNaNH2),
and solvents (toluene, THF, and solvent-free), we found that
cyclizationcouldbeachievedbyusing4 equivofR- orS-a-meth-
ylbenzylamine in solvent-free conditions at room temperature
for 4 days. This gave (in the case of S-a-methylbenzylamine)
the desired compounds 18a and 18b in a 1.8/1 mixture of nonse-
parable stereoisomers in an acceptable yield of 50% (Scheme 8).
H5
1
O
COOH
2
PhMe
i
O
N
O
N
15
O
16
CH2Cl2
ii
Ha
Ha
'
1
O
H4
H4
O
4
O
O
16
+
N
3
N
+
Z-17
O
E-17
O
Scheme 7. Reagents and conditions: (i) Ag2CO3, toluene, 80 ꢀC, 1 h, 34%; (ii)
Ag2CO3, CH2Cl2, reflux, 4 h, 38%.
COOEt
N
Br
Cyclization of acid 15 using the above optimized conditions
proceeded more slowly (1 h) than the corresponding terminal
acetylenic acid 7a (15 min) and resulted in the exclusive forma-
tion of the six membered ring spirolactone 16 in 34% yield. The
structure of this product was unambiguously determined by
usual spectrometric methods (1H, 2D, and 13C NMR). For exam-
ple, in the 1H NMR spectrum, the proton H5 resonates at
4.40 ppm as a multiplet (JH5eH4¼2.0 Hz, JH5eH(CH3)¼2.3 Hz,
COOEt
COOEt
O
18a
Solvent-free
COOEt
3
NH2
N
18b
O
Scheme 8. Reagents and conditions: S-a-methylbenzylamine, rt, 4 days, 50%.
0
JH5eH4 ¼7.0 Hz). The protons of the methyl group appear
Next, alkylation of 18 followed by saponification of 19
under the same operating methods previously used to obtain
acids 7 afforded a mixture of nonseparable products in 71%
overall yield for the two stages.
Finally, the phthalimidine carboxylic acids 20a,b were
subjected to the above optimized silver-catalyzed spirolactoni-
zation conditions. We were pleased to see that the 5-exo process
was still effective with these sterically more demanding sub-
strates, giving a chromatographically separable mixture of
diastereomers (21b/21a 2/1) in 87% yield (Scheme 9).
0
as
a
multiplet (JH(CH3)eH4¼2.0 Hz, JH(CH3)eH4 ¼2.0 Hz,
JH(CH3)eH5¼2.3 Hz) at 1.68 ppm due to the coupling with the
two protons H4 and H5. Additional support was provided by
13C NMR spectroscopy, which detected a carbon at d¼13.1 ppm
(CH3) and a quaternary carbon at 143.0 ppm characteristic of
a six membered spirolactone.6b,c It should be noted that in
CH2Cl2 at reflux, the cyclization became nonselective and
lead to a mixture of nonseparable products, including the Z-17
(29%), the E-17 (58%), and the six membered ring spirolactone
1
16 (13%) in 38% over isolated yield. The H NMR spectra of
E-17 exhibits a multiplet of the methyl protons (d¼1.75 ppm,
0
JH(CH3)eH4¼2.3 Hz, JH(CH3)eH4 ¼2.3 Hz, Jvicinal¼7.0 Hz) and
O
a quartet of doublet for the vinylic proton Ha (d¼4.76 ppm,
0
O
N
JHaeH4 ¼2.3 Hz, JHaeH(CH3)¼7.0 Hz). We noticed the absence
of any coupling between H4 and Ha protons. The stereochemi-
stry of the double bond was demonstrated by performing NOE
difference experiments on lactones 17.
21a
O
COOR2
iii
i
N
O
18a,b
O
19a,b
2.2. Synthesis of chiral spirobutyrolactone derivatives
O
N
19a,b
R2 = CO2Et
R2 = COOH
ii
20a,b
O
Having established the facility of acids 7aeg to provide
interesting spirolactones in good yields and under catalytic
amount of Ag2CO3, we envisioned whether this process might
be extended for the preparation of chiral nonracemic
21b
Scheme 9. Reagents and conditions: (i) K2CO3, propargyl bromide, CH3CN,
reflux, 12 h, 86%; (ii) (a) NaOH, EtOH/H2O, rt, 2 h; (b) aqueous 1 M HCl,
0 ꢀC, 89%; (iii) Ag2CO3, toluene, 80 ꢀC, 84%.

M.M. Rammah et al. / Tetrahedron 64 (2008) 3505e3516
3509
SigmaeAldrich. Tetrahydrofuran was dried by distillation
from sodium/benzophenone. Dichloromethane was dried by
distillation from calcium hydride, toluene was distilled from
sodium and acetonitrile was dried by distillation from P2O5.
4.2. Typical procedure of primary amine condensation
To an ice chilled solution of diethyl a-bromophthalate 1
(2 g, 6.34 mmol) in dry acetonitrile (50 mL) was added under
argon, primary amines 4aeg (12.7 mmol) diluted in 10 mL of
acetonitrile. The mixture was stirred at room temperature for
8 h. The salt that formed was removed by filtration, and the
filtrate was concentrated under reduced pressure. The residue
was purified by flash column chromatography on silica gel
(dichloromethane/acetone 90/10).
Figure 3. Molecular structure of 21b. The hydrogen atoms of the aryl rings are
omitted for clarity.
4.2.1. 2-Benzyl-3-oxo-2,3-dihydro-1H-isoindole-1-
carboxylic acid ethyl ester (5a)
This product was prepared according to our previous
work.16b
Single-crystal X-ray structure elucidation19 on the major
(more polar) diastereomer 21b unambiguously established
the relative configuration and, hence, the stereochemistry of
the spirocenter C-16 as R* (Fig. 3).
4.2.2. 2-(4-Methoxybenzyl)-3-oxo-2,3-dihydro-1H-isoindole-
1-carboxylic acid ethyl ester (5b)
3. Conclusion
Yellow liquid; yield: 84%; IR (n, cmꢁ1, CHCl3) 1693, 1747;
1H NMR (200 MHz, CDCl3, 25 ꢀC) d 0.94 (t, J¼7.0 Hz, 3H),
3.50 (s, 3H), 3.92e3.99 (m, 3H), 4.61 (s, 1H), 5.15 (d,
J¼15.0 Hz, 1H), 6.56e6.60 (m, 2H), 6.90e6.94 (m, 2H),
7.23e7.28 (m, 2H), 7.54e7.65 (m, 1H); 13C NMR (50 MHz,
CDCl3, 25 ꢀC) d 14.1 (CH3), 44.4 (CH2), 55.2 (CH3), 61.0
(CH2), 62.0 (CH), 114.1 (2CH), 122.6 (CH), 124.0 (CH),
128.3 (Cq), 129.1 (CH), 129.8 (2CH), 131.7 (Cq), 131.8 (CH),
139.3 (Cq), 159.2 (Cq), 168.0 (CO), 168.5 (CO). Anal. Calcd
for C19H19NO4 (325.37): C, 70.14; H, 5.89; N, 4.30. Found:
C, 70.37; H, 6.02; N, 4.50.
In summary, a highly efficient spirocyclization reaction of
g-acetylenic carboxylic acids was developed in the isoindol-
one series by using Ag2CO3 as a simple commercially avail-
able catalyst in toluene at 80 ꢀC. The carboxylic substrates
were very easily prepared from simple precursors and the
cyclization reactions selectively afforded the corresponding
5-alkylidene-spirobutyrolactones. Further investigations will
be devoted to the synthesis of halo spiro-g-butyrolactones,
as well as applications in analogous natural product syntheses.
4. Experimental part
4.2.3. 2-Allyl-3-oxo-2,3-dihydro-1H-isoindole-1-carboxylic
acid ethyl ester (5c)
4.1. General
Thisproduct was prepared according toour previous work.16a
Allmeltingpointsweremeasuredona Boetiusmicrohotstage
and are uncorrected. 1H and 13C NMR spectra were recorded, re-
spectively, at 200 (300) and 50 (75) MHz on a Brucker AC-200
and Brucker AVANCE 300 spectrometers. The infrared spectra
were recorded on a PerkineElmer FT-IR paragon 1000 spec-
trometer. Thin-layer chromatography (TLC) was performed
with aluminum plates (0.20 mm) precoated with fluorescent
silica gel, using EtOAc/hexanes as eluent. Reaction components
were thenvisualized under UV light and dipped in a Dragendorff
solution. Silica gel (230e400 mesh) was used for flash chroma-
tography separations. Gas chromatographyemass spectrometry
(GCeMS) was performed with a GC apparatus equipped with
a 25 m capillary column, at 90 ꢀC for 2 min, then 10 ꢀC/min
up to 290 ꢀC. Some reactions were performed under an inert
atmosphere. The elemental analyses were carried out by the
microanalysis laboratory of INSA, F-76130 Mt St Aignan,
France. Abbreviations: dd¼doublet of doublet, m¼multiplet,
s¼singlet, d¼doublet, q¼quartet, t¼triplet, br s¼broad singlet,
DCM¼dichloromethane. Silver carbonate was purchased from
4.2.4. 2-(Furan-2-ylmethyl)-3-oxo-2,3-dihydro-1H-isoindole-
1-carboxylic acid ethyl ester (5d)
Yellow solid; yield: 90%; mp 98e100 ꢀC; IR (n, cmꢁ1
,
1
CHCl3) 1694, 1747; H NMR (200 MHz, CDCl3, 25 ꢀC)
d 1.28 (t, J¼7.1 Hz, 3H), 5.15e4.34 (m, 2H), 4.44 (d,
J¼15.6 Hz, 1H), 4.99 (s, 1H), 5.32 (d, J¼15.6 Hz, 1H),
6.28e6.31 (m, 2H), 7.33e7.34 (m, 1H), 7.46e7.59 (m, 3H),
13
7.82e7.86 (m, 1H); C NMR (50 MHz, CDCl3, 25 ꢀC)
d 14.1 (CH3), 37.7 (CH2), 61.5 (CH), 62.1 (CH2), 109.0
(CH), 110.4 (CH), 122.7 (CH), 124.0 (CH), 129.1 (CH),
131.4 (Cq), 131.9 (CH), 139.2 (Cq), 142.7 (CH), 149.7 (Cq),
167.9 (2CO). Anal. Calcd for C16H15NO4 (285.30): C,
67.36; H, 5.30; N, 4.91. Found: C, 67.52; H, 5.32; N, 5.02.
4.2.5. 2-(1,5-Dimethyl-1H-pyrrol-2-ylmethyl)-3-oxo-2,3-
dihydro-1H-isoindole-1-carboxylic acid ethyl ester (5e)
This product was prepared according to our previous
work.16c

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M.M. Rammah et al. / Tetrahedron 64 (2008) 3505e3516
4.2.6. 3-Oxo-2-(thiophen-2-ylmethyl)-2,3-dihydro-1H-
isoindole-1-carboxylic acid ethyl ester (5f)
This product was prepared according to our previous
work.16b
(CH2), 69.8 (Cq), 72.0 (CH), 77.0 (Cq), 121.2 (CH), 123.9
(CH), 127.5 (CH), 128.3 (2CH), 128.9 (2CH), 129.4 (CH),
129.5 (Cq), 132.2 (CH), 136.6 (Cq), 143.5 (Cq), 169.3 (2CO).
Anal. Calcd for C21H19NO3 (333.39): C, 75.66; H, 5.74; N,
4.20. Found: C, 75.92; H, 5.60; N, 4.32.
4.2.7. 3-Oxo-2-(prop-2-ynyl)-2,3-dihydro-1H-isoindole-1-
carboxylic acid ethyl ester (5g)
4.3.2. 2-(4-Methoxybenzyl)-3-oxo-1-(prop-2-ynyl)-2,3-
This product was prepared according to our previous
work.16a
dihydro-1H-isoindole-1-carboxylic acid ethyl ester (6b)
Yellow liquid; yield: 88%; IR (n, cmꢁ1, CHCl3) 1696, 1732;
1H NMR (200 MHz, CDCl3, 25 ꢀC) d 0.94 (t, J¼7.0 Hz, 3H),
1.70 (t, J¼2.3 Hz, 1H), 3.05 (dd, J¼2.3 Hz, 17.2 Hz, 1H), 3.16
(dd, J¼2.3 Hz, 17.2 Hz, 1H) 3.61e3.70 (m, 1H), 3.77 (s, 3H),
3.80e3.90 (m, 1H), 4.58 (d, J¼15.6 Hz, 1H), 4.86 (d, J¼
15.6 Hz, 1H), 6.79e6.83 (d, J¼8.6 Hz, 2H), 7.32 (d,
J¼8.6 Hz, 2H), 7.43e7.54 (m, 3H), 7.86e7.91 (m, 1H); 13C
NMR (50 MHz, CDCl3, 25 ꢀC) d 13.4 (CH3), 24.7 (CH2), 43.9
(CH2), 55.2 (CH3), 62.3 (CH2), 69.7 (Cq), 72.0 (CHþCq),
113.6 (2CH), 121.9 (CH), 123.8 (CH), 128.6 (Cq), 129.4 (CH),
129.7 (2CH), 131.8 (Cq), 132.1 (CH), 143.5 (Cq), 159.0 (Cq),
169.3 (CO), 169.4 (CO). Anal. Calcd for C22H21NO4 (363.42):
C, 72.71; H, 5.82; N, 3.85. Found: C, 72.52; H, 5.70; N, 3.74.
4.2.8. Ethyl 3-oxo-2-(1-phenylethyl) isoindoline-1-
carboxylate (18a and 18b)
The ester diastereoisomers were inseparable and character-
ized together. Yellow liquid; yield: 50%; IR (n, cmꢁ1, CHCl3)
1
1680, 1730; H NMR (200 MHz, CDCl3, 25 ꢀC).
Min: d 0.90 (t, J¼7.0 Hz, 3H), 1.72 (d, J¼7.8 Hz, 3H), 3.49e
3.75 (m, 2H), 5.10 (s, 1H), 5.40 (q, J¼7.0 Hz, 1H), 7.06e7.32
(m, 4H), 7.34e7.51 (m, 4H), 7.69e7.82 (m, 1H); 13C NMR
(50 MHz, CDCl3, 25 ꢀC) d 13.4 (CH3), 17.7 (CH3), 52.1 (CH),
61.3 (CH), 61.5 (CH2), 121.9 (CH), 123.7 (CH), 127.6 (CH),
127.9 (2CH), 128.1 (2CH), 128.9 (CH), 131.7 (CH), 132.2
(Cq), 139.6 (Cq), 139.8 (Cq), 168.6 (C]O), 168.8 (C]O).
Maj: 1H NMR (200 MHz, CDCl3, 25 ꢀC) d 1.19 (t, J¼7.0 Hz,
3H), 1.66 (d, J¼7.0 Hz, 3H), 4.07e4.18 (m, 2H), 4.68 (s, 1H),
5.68 (q, J¼7.0 Hz, 1H), 7.16e7.23 (m, 4H), 7.31e7.47 (m,
4.3.3. 2-Allyl-3-oxo-1-(prop-2-ynyl)-2,3-dihydro-1H-
isoindole-1-carboxylic acid ethyl ester (6c)
This product was prepared according to our previous
work.16a
13
4H), 7.69e7.82 (m, 1H); C NMR (50 MHz, CDCl3, 25 ꢀC)
d 13.8 (CH3), 17.2 (CH3), 51.2 (CH), 60.9 (CH), 61.8 (CH2),
121.8 (CH), 123.8 (CH), 127.3 (2CH), 127.7 (CH), 128.6
(2CH), 129.9 (CH), 131.8 (CH), 132.1 (Cq), 139.7 (Cq), 139.9
(Cq), 168.4 (C]O), 169.3 (C]O). Anal. Calcd for
C19H19NO3 (309.37): C, 73.77; H, 6.19; N, 4.53. Found: C,
73.59; H, 6.14; N, 4.62.
4.3.4. 2-(Furan-2-ylmethyl)-3-oxo-1-(prop-2-ynyl)-2,3-
dihydro-1H-isoindole-1-carboxylic acid ethyl ester (6d)
Yellow solid; yield: 93%; mp 104e106 ꢀC; IR (n, cmꢁ1
,
1
CHCl3) 1698, 1731; H NMR (300 MHz, CDCl3, 25 ꢀC)
d 0.99 (t, J¼7.0 Hz, 3H), 1.65 (t, J¼2.6 Hz, 1H), 3.17 (dd,
J¼2.6 Hz, J¼17.2 Hz, 1H), 3.28 (dd, dd, J¼2.6 Hz,
J¼17.2 Hz, 1H), 3.75e3.84 (m, 1H), 3.92e3.98 (m, 1H),
4.65 (d, J¼16.0, 1H), 4.90 (d, J¼16.0 Hz, 1H), 6.27e6.29
(m, 1H), 6.30e6.33 (m, 1H), 7.30e7.31 (m, 1H), 7.42e7.51
(m, 3H), 7.85 (d, J¼6.4 Hz, 1H); 13C NMR (75 MHz,
CDCl3, 25 ꢀC) d 13.6 (CH3), 24.6 (CH2), 36.7 (CH2), 62.5
(CH2), 69.7 (Cq), 71.8 (CH), 76.6 (Cq), 109.3 (CH), 110.6
(CH), 121.2 (CH), 123.9 (CH), 129.4 (CH), 131.6 (Cq),
132.2 (CH), 142.1 (CH), 143.2 (Cq), 149.8 (Cq), 168.7
(CO), 169.3 (CO). Anal. Calcd for C19H17NO4 (323.35): C,
70.58; H, 5.30; N, 4.33. Found: C, 70.32; H, 5.36; N, 4.32.
4.3. Alkylation with propargyl bromide (1-bromo-2-butyne)
To a mixture of 5, 9, 18 (8.23 mmol), potassium carbonate
(1.25 g, 9.05 mmol), and 50 mL of acetonitrile was added
propargyl bromide (1-bromo-2-butyne for preparing com-
pound 14) (9.87 mmol). The reaction mixture was refluxed
over-night. The cooled resulting suspension was filtered off.
The filtrate was concentrated in vaccuo, diluted with water,
and extracted with dichloromethane (3ꢂ30 mL). The organic
phase was dried over MgSO4 and evaporated under reduced
pressure. The residue was purified by flash column chromatog-
raphy on silica gel (cyclohexane/EtOAc 75/25) to give the
phthalimidines 6, 10, 14, and 19.
4.3.5. 2-(1,5-Dimethyl-1H-pyrrol-2-ylmethyl)-3-oxo-1-
(prop-2-ynyl)-2,3-dihydro-1H-isoindole-1-carboxylic
acid ethyl ester (6e)
4.3.1. 2-Benzyl-3-oxo-1-(prop-2-ynyl)-2,3-dihydro-1H-
isoindole-1-carboxylic acid ethyl ester (6a)
Brown solid; yield: 81%; mp 142e144 ꢀC; IR (n, cmꢁ1
,
1
CHCl3) 1691, 1734; H NMR (200 MHz, CDCl3, 25 ꢀC)
d 0.95 (t, J¼7.1 Hz, 3H), 1.63 (t, J¼2.3 Hz, 1H), 2.1 (s,
3H), 3.02 (dd, J¼2.3 Hz, J¼17.2, 1H), 3.25 (dd, J¼2.3 Hz,
J¼17.2, 1H), 3.45 (s, 3H), 3.54e3.70 (m, 1H), 3.78e3.94
(m, 1H), 4.49 (d, J¼15.6 Hz, 1H), 5.05 (d, J¼15.6 Hz, 1H),
5.73 (d, J¼3.1 Hz, 1H), 5.93 (d, J¼3.1 Hz, 1H), 7.31e7.38
(m, 1H), 7.45e7.56 (m, 2H), 7.83e7.87 (m, 2H); 13C NMR
(50 MHz, CDCl3, 25 ꢀC) d 12.4 (CH3), 13.5 (CH3), 23.8
(CH2), 30.5 (CH3), 35.7 (CH2), 62.2 (CH2), 68.9 (Cq), 71.3
White solid; yield: 91%; mp 86e88 ꢀC; IR (n, cmꢁ1, CHCl3)
1695, 1733; 1H NMR (300 MHz, CDCl3, 25 ꢀC) d 1.00 (t, J¼
7.1 Hz, 3H), 1.71 (t, J¼2.3 Hz, 1H), 3.08 (dd, J¼2.3 Hz,
J¼17.2, 1H), 3.21 (dd, J¼2.3 Hz, J¼17.2, 1H), 3.58e3.64 (m,
1H), 3.75e3.90 (m, 1H), 4.63 (d, J¼15.6, 1H), 4.94 (d,
J¼15.6 Hz, 1H), 7.27e7.34 (m, 3H), 7.38e7.50 (m, 3H),
7.53e7.63 (m, 2H), 7.90e7.94 (m, 1H); 13C NMR (75 MHz,
CDCl3, 25 ꢀC) d 13.5 (CH3), 24.8 (CH2), 44.3 (CH2), 62.2

M.M. Rammah et al. / Tetrahedron 64 (2008) 3505e3516
3511
(CH, Cq), 105.1 (CH), 109.2 (CH), 120.5 (CH), 123.8 (CH),
124.7 (Cq), 129.2 (CH), 130.3 (Cq), 131.7 (Cq), 132.1 (CH),
143.6 (Cq), 168.6 (CO), 168.9 (CO). Anal. Calcd for
C21H22N2O3 (350.42): C, 71.98; H, 6.33; N, 7.99. Found: C,
71.91; H, 6.36; N, 7.91.
7.05e7.16 (m, 3H), 7.21e7.43 (m, 5H), 7.75e7.78 (m, 1H);
13C NMR (75 MHz, CDCl3, 25 ꢀC) d 2.8 (CH3), 13.2 (CH3),
24.9 (CH2), 44.1 (CH2), 61.7 (CH2), 70.0 (Cq), 71.4 (Cq),
79.1 (Cq), 121.0 (CH), 123.3 (CH), 126.9 (CH), 127.7
(2CH), 128.2 (2CH), 128.8 (CH), 131.3 (Cq), 131.7 (CH),
136.5 (Cq), 143.5 (Cq), 168.9 (C]O), 169.0 (C]O). Anal.
Calcd for C21H20NO3 (334.40): C, 75.43; H, 6.03; N, 4.19.
Found: C, 75.25; H, 6.12; N, 4.08.
4.3.6. 3-Oxo-1-(prop-2-ynyl)-2-(thiophen-2-ylmethyl)-2,3-
dihydro-1H-isoindole-1-carboxylic acid ethyl ester (6f)
Yellow solid; yield: 86%; mp 113e115 ꢀC; IR (n, cmꢁ1
,
1
CHCl3) 1696, 1731; H NMR (200 MHz, CDCl3, 25 ꢀC)
d 0.98 (t, J¼7.0 Hz, 3H), 1.73 (t, J¼2.3 Hz, 1H), 3.17e3.19
(m, 2H), 3.74e3.79 (m, 2H), 4.86 (d, J¼15.6 Hz, 1H), 5.07
(d, J¼15.6 Hz, 1H), 6.87e6.91 (m, 1H), 7.03e7.05 (m, 1H),
7.18e7.21 (m, 1H), 7.43e7.53 (m, 3H), 6.82e6.89 (m, 1H);
13C NMR (50 MHz, CDCl3, 25 ꢀC) d 13.6 (CH3), 25.1
(CH2), 38.9 (CH2), 62.4 (CH2), 69.8 (Cq), 72.2 (Cq), 76.9
(CH), 121.4 (CH), 123.9 (CH), 125.8 (CH), 126.4 (CH),
127.5 (CH), 129.4 (CH), 131.5 (Cq), 132.2 (CH), 139.1
(Cq), 143.3 (Cq), 168.8 (CO), 169.1 (CO). Anal. Calcd for
C19H17NO3S (339.42): C, 67.24; H, 5.05; N, 4.13. Found: C,
67.45; H, 5.09; N, 4.32.
4.3.10. 3-Oxo-2-(1-phenyl-ethyl)-1-(prop-2-ynyl)-2,3-
dihydro-1H-isoindole-1-carboxylic acid ethyl ester
(19a and 19b)
The ester diastereoisomers were inseparable and character-
ized together. Brown solid; yield 86%; mp 67e69 ꢀC; IR (n,
cmꢁ1, CHCl3) 1696, 1730.
Min: 1H NMR (200 MHz, CDCl3, 25 ꢀC) d 1.17 (t, J¼7.0 Hz,
3H), 1.55 (t, J¼2.3 Hz, 1H), 1.98 (d, J¼7.0 Hz, 3H), 2.98e3.15
(m, 2H), 4.02e4.13 (m, 2H), 4.78 (q, J¼7.0 Hz, 1H), 7.27e7.35
(m, 4H), 7.40e7.55 (m, 4H), 7.79e7.90 (m, 1H); 13C NMR
(50 MHz, CDCl3, 25 ꢀC) d 13.8 (CH3), 20.1 (CH3), 25.7
(CH2), 54.4 (CH), 62.4 (CH2), 70.5 (Cq), 72.2 (Cq), 77.1
(CH), 121.2 (CH), 123.5 (CH), 127.2 (CH), 127.7 (2CH),
128.1 (2CH), 129.3 (CH), 131.7 (CH), 132.6 (Cq), 141.7 (Cq),
143.0 (Cq), 169.1 (CO), 169.5 (CO).
Maj: 1H NMR (200 MHz, CDCl3, 25 ꢀC) d 0.74 (t, J¼7.0 Hz,
3H), 1.78 (t, J¼2.3 Hz, 1H), 2.01 (d, J¼7.0 Hz, 3H), 3.19e3.22
(m, 2H), 3.49e3.86 (m, 2H), 4.75 (q, J¼7.0 Hz, 1H), 7.27e7.35
(m, 4H), 7.40e7.55 (m, 4H), 7.79e7.90 (m, 1H); 13C NMR
(50 MHz, CDCl3, 25 ꢀC) d 13.1 (CH3), 20.1 (CH3), 25.0
(CH2), 55.7 (CH), 62.1 (CH2), 71.8 (Cq), 72.0 (Cq), 77.3
(CH), 120.9 (CH), 123.5 (CH), 127.2 (CH), 127.6 (2CH),
128.1 (2CH), 129.2 (CH), 131.9 (CH), 132.7 (Cq), 141.7 (Cq),
143.4 (Cq), 169.3 (CO), 169.6 (CO). Anal. Calcd for
C22H21NO3 (347.42): C, 76.06; H, 6.09; N, 4.03. Found: C,
75.92; H, 6.00; N, 4.12.
4.3.7. 3-Oxo-1,2-(di-prop-2-ynyl)-2,3-dihydro-1H-isoindole-
1-carboxylic acid ethyl ester (6g)
Yellow solid; yield: 89%; mp 100e102 ꢀC; IR (n, cmꢁ1
,
1
CHCl3) 1701, 1734; H NMR (200 MHz, CDCl3, 25 ꢀC)
d 1.17 (t, J¼7.0 Hz, 3H), 1.80 (t, J¼2.35 Hz, 1H), 2.25 (t,
J¼2.3 Hz, 1H), 3.34e3.37 (m, 2H), 4.08e4.19 (m, 2H), 4.38
(dd, J¼2.3 Hz, 18.0 Hz, 1H), 4.53 (dd, J¼2.3 Hz, 18.0 Hz,
1H), 7.49e7.60 (m, 3H), 7.84e7.88 (m, 1H); 13C NMR
(50 MHz, CDCl3, 25 ꢀC) d 13.7 (CH3), 25.2 (CH2), 30.0
(CH2), 62.5 (CH2), 69.6 (Cq), 72.2 (Cq), 72.6 (Cq), 76.8 (CH),
77.7 (CH), 121.3 (CH), 123.9 (CH), 129.5 (CH), 131.2 (Cq),
132.5 (CH), 143.0 (Cq), 168.1 (C]O), 169.3 (C]O). Anal.
Calcd for C17H15NO3 (281.31): C, 72.58; H, 5.37; N, 4.98.
Found: C, 72.66; H, 5.60; N, 4.92.
4.4. Preparation of acids 7, 11, 15, and 20
4.3.8. 3-Oxo-1-(prop-2-ynyl)-2,3-dihydro-1H-isoindole-1-
carboxylic acid ethyl ester (10)
To an ice chilled solution of the esters 6, 10, 14, and 19
(4 mmol) in 20 mL of ethanol was added sodium hydroxide
solution (0.32 g, 8 mmol in 5 mL of water). The reaction mix-
ture was stirred for 15 min concentrated in vaccuo, diluted
with water, and washed with dichloromethane. The aqueous
layer was acidified with 10% hydrochloric acid solution to
pH¼1. The aqueous layer was extracted with dichloromethane
(3ꢂ30 mL). The organic phase was dried over MgSO4, filtered
then concentrated under reduced pressure to give the corre-
sponding acids 7, 11, 15, and 20 who were used without puri-
fication in the following steps.
White solid; yield: 80%; mp 169e171 ꢀC; IR (n, cmꢁ1
,
1
CHCl3) 1712, 1738; H NMR (300 MHz, CDCl3, 25 ꢀC)
d 1.20 (t, J¼7.0 Hz, 3H), 2.00 (t, J¼2.3 Hz, 1H), 2.56 (dd,
J¼2.3 Hz, J¼16.4, 1H), 3.23 (dd, J¼2.3 Hz, J¼16.4, 1H),
4.05e4.26 (m, 2H), 6.73e6.90 (br s, 1H), 7.45e7.61 (m,
3H), 7.75 (d, J¼7.0 Hz, 1H); 13C NMR (75 MHz, CDCl3,
25 ꢀC) d 13.8 (CH3), 29.5 (CH2), 62.7 (CH2), 66.7 (Cq),
72.3 (Cq), 76.6 (CH), 122.8 (CH), 124.1 (CH), 129.8 (CH),
131.0 (Cq), 131.9 (CH), 143.8 (Cq), 169.3 (CO), 169.5
(CO). Anal. Calcd for C14H13NO3 (243.26): C, 69.12; H,
5.39; N, 5.76. Found: C, 68.92; H, 5.50; N, 5.93.
4.4.1. 2-Benzyl-3-oxo-1-(prop-2-ynyl)-2,3-dihydro-1H-
isoindole-1-carboxylic acid (7a)
4.3.9. 2-Benzyl-1-(but-2-ynyl)-3-oxo-2,3-dihydro-1H-
isoindole-1-carboxylic acid ethyl ester (14)
White solid; yield: 93%; mp 86e88 ꢀC; IR (n, cmꢁ1, CHCl3)
1691, 1730, 3307; 1H NMR (300 MHz, CDCl3, 25 ꢀC) d 1.62 (t,
J¼2.3 Hz, 1H), 2.92 (dd, J¼2.3 Hz, J¼17.2, 1H), 3.14 (dd,
J¼2.3 Hz, J¼17.2 Hz, 1H), 4.62 (d, J¼15.6 Hz, 1H), 4.79 (br
s, 1H), 4.91 (d, J¼15.6 Hz, 1H), 7.09e7.24 (m, 4H),
Yellow liquid; yield 92%; IR (n, cmꢁ1, CHCl3) 1692, 1730;
1H NMR (300 MHz, CDCl3, 25 ꢀC) d 0.79 (t, J¼7.0 Hz, 3H),
1.32 (s, 3H), 2.97 (s, 2H), 3.47e3.58 (m, 1H), 3.65e3.76
(m, 1H), 4.56 (d, J¼15.4 Hz, 1H), 4.78 (d, J¼15.4 Hz, 1H),

3512
M.M. Rammah et al. / Tetrahedron 64 (2008) 3505e3516
7.32e7.36 (m, 2H), 7.46e7.60 (m, 2H), 7.84 (d, J¼6.2 Hz, 1H);
13C NMR (75 MHz, CDCl3, 25 ꢀC) d 24.9 (CH2), 45.1 (CH2),
70.4 (Cq), 72.1 (Cq), 76.7 (CH), 121.6 (CH), 124.1 (CH),
127.5 (CH), 128.2 (2CH), 128.7 (2CH), 129.6 (CH), 131.3
(Cq), 132.4 (CH), 136.0 (Cq), 143.1 (Cq), 169.9 (CO), 172.1
(CO). Anal. Calcd for C19H15NO3 (305.34): C, 74.74; H, 4.95;
N, 4.59. Found: C, 74.82; H, 5.02; N, 4.78.
(CH), 131.5 (Cq), 132.3 (Cq), 132.9 (CH), 143.8 (Cq), 169.4
(CO), 173.8 (CO). Anal. Calcd for C19H18N2O3 (322.37): C,
70.79; H, 5.63; N, 8.69. Found: C, 70.76; H, 5.71; N, 8.68.
4.4.6. 3-Oxo-1-(prop-2-ynyl)-2-(thiophen-2-ylmethyl)-2,3-
dihydro-1H-isoindole-1-carboxylic acid (7f)
Yellow solid; yield: 97%; mp 131e133 ꢀC; IR (n, cmꢁ1
,
CHCl3) 1695, 1724, 3302; 1H NMR (300 MHz, CDCl3,
25 ꢀC) d 1.68 (t, J¼2.3 Hz, 1H), 3.11 (dd, J¼2.3 Hz, J¼17.2,
1H), 3.22 (dd, J¼2.3 Hz, J¼17.2, 1H), 4.84 (d, J¼15.6 Hz,
1H), 5.12 (d, J¼15.6 Hz, 1H), 6.83e6.87 (m, 1H), 7.06e7.16
(m, 2H), 7.46e7.63 (m, 3H), 7.83e7.87 (m, 1H), 8.26 (br s,
4.4.2. 2-(4-Methoxybenzyl)-3-oxo-1-(prop-2-ynyl)-2,3-
dihydro-1H-isoindole-1-carboxylic acid (7b)
White solid; yield: 91%; mp 134e136 ꢀC; IR (n, cmꢁ1
,
CHCl3) 1692, 1730, 3308; 1H NMR (200 MHz, CDCl3,
25 ꢀC) d 1.63 (t, J¼2.3 Hz, 1H), 2.93 (dd, J¼2.3 Hz, J¼17.2,
1H), 3.18 (dd, J¼2.3 Hz, J¼17.2, 1H), 3.71 (s, 3H), 4.58 (d,
J¼14.8 Hz, 1H), 4.89 (d, J¼14.8 Hz, 1H), 6.74e6.78 (m, 2H),
7.15 (br s, 1H), 7.28e7.32 (m, 2H), 7.52e7.57 (m, 3H),
7.81e7.85 (m, 1H); 13C NMR (75 MHz, CDCl3, 25 ꢀC) d 24.5
(CH2), 43.7 (CH2), 54.6 (CH3), 69.9 (Cq), 71.3 (Cq), 77.2
(CH), 113.0 (2CH), 121.1 (CH), 122.9 (CH), 128.6 (CH),
128.7 (Cq), 128.7 (Cq), 129.5 (2CH), 131.3 (Cq), 131.5 (CH),
143.4 (Cq), 158.2 (Cq), 168.8 (CO), 170.3 (CO). Anal. Calcd
for C20H17NO4 (335.36): C, 71.63; H, 5.11; N, 4.18. Found:
C, 71.70; H, 5.12; N, 4.08.
13
1H); C NMR (75 MHz, CDCl3, 25 ꢀC) d 25.4 (CH2), 39.6
(CH2), 70.4 (Cq), 72.2 (CH), 76.6 (Cq), 121.8 (CH), 124.0
(CH), 125.8 (CH), 126.5 (CH), 127.8 (CH), 129.7 (CH), 131.3
(Cq), 132.5 (CH), 138.7 (Cq), 143.1 (Cq), 169.3 (CO), 172.0
(CO). Anal. Calcd for C17H13NO3S (311.36): C, 65.58; H,
4.21; N, 4.50. Found: C, 65.57; H, 4.31; N, 4.54.
4.4.7. 3-Oxo-1,2-(di-prop-2-ynyl)-2,3-dihydro-1H-isoindole-
1-carboxylic acid (7g)
Yellow solid; yield: 72%; mp 127e129 ꢀC; IR (n, cmꢁ1
,
CHCl3) 1701, 1730, 3308; 1H NMR (200 MHz, CDCl3,
25 ꢀC) d 1.82 (t, J¼2.3 Hz, 1H), 2.27 (t, J¼2.3 Hz, 1H), 3.34
(dd, J¼2.3 Hz, 18.0 Hz, 1H), 3.42 (dd, J¼2.3 Hz, 18.0 Hz,
1H), 5.51 (s, 2H), 6.82 (br s, 1H), 7.51e7.65 (m, 3H), 7.83e
4.4.3. 2-Allyl-3-oxo-1-(prop-2-ynyl)-2,3-dihydro-1H-
isoindole-1-carboxylic acid (7c)
This product was prepared according to our previous
work.16a
13
7.91 (m, 1H); C NMR (50 MHz, CDCl3, 25 ꢀC) d 25.3
(CH2), 30.4 (CH2), 70.1 (Cq), 72.4 (Cq), 73.0 (Cq), 76.8 (CH),
77.4 (CH), 121.7 (CH), 124.0 (CH), 129.7 (CH), 130.8 (Cq),
132.7 (CH), 143.1 (Cq), 169.0 (C]O), 171.5 (C]O). Anal.
Calcd for C15H11NO3 (253.26): C, 71.14; H, 4.38; N, 5.53.
Found: C, 71.00; H, 4.41; N, 3.32.
4.4.4. 2-(Furan-2-ylmethyl)-3-oxo-1-(prop-2-ynyl)-2,3-
dihydro-1H-isoindole-1-carboxylic acid (7d)
Yellow solid; yield: 72%; mp 104e106 ꢀC; IR (n, cmꢁ1
,
CHCl3) 1700, 1722, 3405; 1H NMR (300 MHz, CDCl3,
25 ꢀC) d 1.54 (t, J¼2.3 Hz, 1H), 3.01 (dd, J¼2.3 Hz, J¼17.2,
1H), 3.20 (dd, J¼2.3 Hz, J¼17.2, 1H), 4.59 (d, J¼14.4 Hz,
1H), 4.89 (d, J¼14.4 Hz, 1H), 6.22e6.29 (m, 2H), 6.43 (br
s, 1H), 7.37e6.51 (m, 4H), 7.76 (d, J¼7.0 Hz, 1H); 13C NMR
(75 MHz, CDCl3, 25 ꢀC) d 24.8 (CH2), 36.9 (CH2), 69.9 (Cq),
71.1 (CH), 76.1 (Cq), 108.9 (CH), 110.2 (CH), 121.4 (CH),
123.3 (CH), 128.9 (CH), 131.8 (CH), 134.6 (Cq), 141.7 (CH),
143.3 (Cq), 149.9 (Cq), 168.5 (CO), 170.6 (CO). Anal. Calcd
for C17H13NO4 (295.30): C, 69.15; H, 4.44; N, 4.74. Found:
C, 70.07; H, 4.41; N, 4.78.
4.4.8. 3-Oxo-1-(prop-2-ynyl)-2,3-dihydro-1H-isoindole-1-
carboxylic acid (11)
White solid; yield: 65%; mp 163e165 ꢀC; IR (n, cmꢁ1
,
CHCl3) 1712, 1724, 3301; 1H NMR (300 MHz, CDCl3,
25 ꢀC) d 1.96 (t, J¼2.3 Hz, 1H), 2.60 (dd, J¼2.3 Hz, J¼16.4,
1H), 3.19 (dd, J¼2.3 Hz, J¼16.4, 1H), 7.05 (br s, 1H), 7.38e
7.54 (m, 2H), 7.62 (d, J¼7.0 Hz, 1H), 7.71 (d, J¼7.0 Hz, 1H),
13
8.22 (br s, 1H); C NMR (75 MHz, CDCl3, 25 ꢀC) d 39.7
(CH2), 65.9 (Cq), 73.6 (Cq), 78.8 (CH), 122.5 (CH), 122.7
(CH), 129.1 (CH), 132.0 (CH), 132.1 (Cq), 144.6 (Cq), 169.1
(CO), 171.3 (CO). Anal. Calcd for C12H9NO3 (215.21): C,
66.97; H, 4.22; N, 6.51. Found: C, 66.80; H, 4.31; N, 6.64.
4.4.5. 2-(1,5-Dimethyl-1H-pyrrol-2-ylmethyl)-3-oxo-1-
(prop-2-ynyl)-2,3-dihydro-1H-isoindole-1-carboxylic
acid (7e)
4.4.9. 2-Benzyl-1-(but-2-ynyl)-3-oxo-2,3-dihydro-1H-
Yellow solid; yield: 98%; mp 144e146 ꢀC; IR (n, cmꢁ1
,
isoindole-1-carboxylic acid (15)
CHCl3) 1691, 1734, 3307; 1H NMR (200 MHz, CDCl3,
25 ꢀC) d 1.64 (t, J¼2.3 Hz, 1H), 1.82 (s, 3H, CH3), 2.99 (dd,
J¼2.3 Hz, J¼17.2, 1H), 3.22 (dd, J¼2.3 Hz, J¼17.2, 1H),
3.31 (s, 3H), 4.53 (d, J¼16.4 Hz, 1H), 5.06 (d, J¼16.4 Hz,
1H), 5.53 (d, J¼3.3 Hz, 1H), 5.93 (d, J¼3.3 Hz, 1H), 7.40e
7.63 (m, 3H), 7.84 (d, J¼7.8 Hz, 1H), 8.14 (br s, 1H); 13C
NMR (50 MHz, CDCl3, 25 ꢀC) d 12.6 (CH3), 24.3 (CH2), 31.0
(CH3), 36.5 (CH2), 66.4 (Cq), 69.5 (Cq), 77.1 (CH), 105.2
(CH), 110.1 (CH), 121.4 (CH), 124.7 (CH), 124.9 (Cq), 130.2
White solid; yield: 88%; mp 98e100 ꢀC; IR (n, cmꢁ1
,
CHCl3) 1692, 1735, 3155; 1H NMR (300 MHz, CDCl3,
25 ꢀC) d 1.34 (s, 3H), 2.86 (dd, J¼2.3 Hz, 16.9 Hz, 1H), 3.00
(dd, J¼2.3 Hz, 16.9 Hz, 1H), 4.54 (d, J¼15.8 Hz, 1H), 4.91
(d, J¼15.4 Hz, 1H), 6.13 (br s, 1H), 7.05e7.19 (m, 3H),
7.26e7.32 (m, 2H), 7.40e7.53 (m, 3H), 7.75e7.78 (m, 1H);
13C NMR (75 MHz, CDCl3, 25 ꢀC) d 3.21 (CH3), 25.0 (CH2),
45.2 (CH2), 71.1 (Cq), 71.6 (Cq), 79.7 (Cq), 121.7 (CH),
123.8 (CH), 127.3 (CH), 128.0 (2CH), 128.5 (2CH), 129.4

M.M. Rammah et al. / Tetrahedron 64 (2008) 3505e3516
3513
(CH), 131.3 (Cq), 132.3 (CH), 136.5 (Cq), 143.5 (Cq), 170.0
(C]O), 172.0 (C]O). Anal. Calcd for C20H17NO3 (319.36):
C, 75.22; H, 5.37; N, 4.39. Found: C, 75.12; H, 5.32; N, 4.50.
d 2.87 (d, J¼16.4 Hz, 1H), 3.18 (dt, J¼2.3 Hz, J¼16.4 Hz,
1H), 3.78 (s, 3H), 4.19 (d, J¼15.6 Hz, 1H), 4.51 (t, J¼2.3 Hz,
1H), 5.00 (t, J¼2.3 Hz, 1H), 5.27 (d, J¼15.6 Hz, 1H), 6.80e
6.88 (m, 2H), 7.15e7.25 (m, 2H), 7.42e7.47 (m, 1H), 7.52e
7.60 (m, 2H), 7.91e7.98 (m, 1H); 13C NMR (50 MHz, CDCl3,
25 ꢀC) d 34.9 (CH2), 43.6 (CH2), 55.1 (CH3), 68.9 (Cq), 91.6
(CH2), 114.1 (2CH), 120.4 (CH), 124.3 (CH), 128.5 (Cq),
129.0 (2CH), 129.9 (CH), 130.2 (Cq), 132.9 (CH), 143.6 (Cq),
151.1 (Cq), 159.2 (Cq), 168.5 (CO), 170.7 (CO). Anal. Calcd
for C20H17NO4 (335.36): C, 71.63; H, 5.11; N, 4.18. Found:
C, 71.70; H, 5.16; N, 4.20.
4.4.10. 3-Oxo-2-(1-phenyl-ethyl)-1-(prop-2-ynyl)-2,3-
dihydro-1H-isoindole-1-carboxylic acid (20a and 20b)
The acid diastereoisomers were inseparable and character-
ized together. White solid; yield 89%; mp 83e85 ꢀC; IR (n,
cmꢁ1, CHCl3) 1694, 1730, 3308.
Min: 1H NMR (200 MHz, CDCl3, 25 ꢀC) d 1.50 (t, J¼2.3 Hz,
1H), 1.99 (d, J¼7.0 Hz, 3H), 2.94e3.26 (m, 2H), 4.74 (q,
J¼7.0 Hz, 1H), 7.18e7.25 (m, 4H), 7.43e7.58 (m, 4H),
7.76e7.80 (m, 1H), 8.41 (br s, 1H); 13C NMR (50 MHz,
CDCl3, 25 ꢀC) d 20.2 (CH3), 25.3 (CH2), 56.3 (CH), 72.1
(Cq), 72.2 (Cq), 77.1 (CH), 121.5 (CH), 123.6 (CH), 127.6
(CH), 127.8 (2CH), 128.2 (2CH), 129.5 (CH), 131.8 (CH),
132.6 (Cq), 141.6 (Cq), 142.8 (Cq), 169.6 (CO), 172.4 (CO).
4.5.3. 20-Allyl-5-methylidene-4,5-dihydrospiro[furan-10,3-
isoindol-30-one]-2-one (8c)
White solid; yield: 80%; mp 104e106 ꢀC; IR (n, cmꢁ1
,
1
CHCl3) 1684, 1703; H NMR (300 MHz, CDCl3, 25 ꢀC)
d 3.00 (d, J¼16.4 Hz, 1H), 3.51 (dt, J¼2.3 Hz, J¼16.4 Hz,
1H), 4.00 (dd, J¼16.2, J¼6.0 Hz, 1H), 4.29 (dd, J¼16.2,
J¼6.0 Hz, 1H), 4.56 (t, J¼2.3 Hz, 1H), 4.98 (t, J¼2.3 Hz,
1H), 5.13e5.21 (m, 2H), 5.77e5.90 (m, 1H), 7.37e7.40 (m,
1H), 7.45e7.54 (m, 2H), 7.80 (d, J¼7.9 Hz, 1H); 13C NMR
(75 MHz, CDCl3, 25 ꢀC) d 33.6 (CH2), 42.3 (CH2), 67.5
(Cq), 90.7 (CH2), 117.3 (CH2), 119.4 (CH), 123.3 (CH),
129.0 (CH), 129.4 (Cq), 131.8 (CH), 131.9 (CH), 142.6
(Cq), 150.0 (Cq), 167.0 (CO), 170.1 (CO). Anal. Calcd for
C15H13NO3 (255.28): C, 70.58; H, 5.13; N, 5.49. Found: C,
70.70; H, 5.21; N, 5.38.
1
Maj: H NMR (200 MHz, CDCl3, 25 ꢀC) d 1.72 (t,
J¼2.3 Hz, 1H), 1.95 (d, J¼7.0 Hz, 3H), 2.94e3.26 (m, 2H),
4.74 (q, J¼7.0 Hz, 1H), 7.18e7.25 (m, 4H), 7.43e7.58 (m,
4H), 7.76e7.80 (m, 1H), 8.41 (br s, 1H); 13C NMR
(50 MHz, CDCl3, 25 ꢀC) d 19.2 (CH3), 25.5 (CH2), 53.9
(CH), 70.7 (Cq), 72.4 (Cq), 77.2 (CH), 121.2 (CH), 123.7
(CH), 127.3 (CH), 127.9 (2CH), 128.1 (2CH), 129.4 (CH),
132.2 (CH), 132.3 (Cq), 140.5 (Cq), 143.3 (Cq), 169.5 (CO),
172.0 (CO). Anal. Calcd for C20H17NO3 (319.36): C, 75.22;
H, 5.37; N, 4.39. Found: C, 75.10; H, 5.32; N, 4.28.
4.5. Typical procedure of the spirolactonization reaction
4.5.4. 20-(Furan-2-ylmethyl)-5-methylidene-4,5-dihydrospiro-
[furan-10,3-isoindol-30-one]-2-one (8d)
A mixture of acetylenic acid 7 or 20 (1 mmol), Ag2CO3
(5 mol %) in degassed toluene (5 mL) was stirred under argon
atmosphere at 80 ꢀC. After the completion of the reaction indi-
cated by TLC analysis, solvent was evaporated under reduced
pressure and the crude mixture was purified by silica gel flash
chromatography (cyclohexane/EtOAc, 60/40) to give the
corresponding lactone 8 or 21.
Yellow solid; yield: 78%; mp 148e150 ꢀC; IR (n, cmꢁ1
,
1
CHCl3) 1681, 1708; H NMR (200 MHz, CDCl3, 25 ꢀC)
d 2.90 (d, J¼16.2 Hz, 1H), 3.30 (d, J¼16.2 Hz, 1H), 4.43 (dt,
J¼2.3 Hz, J¼16.2 Hz, 1H), 4.52 (t, J¼2.3 Hz, 1H), 4.98 (m,
2H), 6.27e6.30 (m, 2H), 7.35e7.37 (m, 1H), 7.40e7.49 (m,
13
3H), 7.81e7.83 (m, 1H); C NMR (50 MHz, CDCl3, 25 ꢀC)
d 34.5 (CH2), 36.8 (CH2), 68.4 (Cq), 91.6 (CH2), 109.8 (CH),
110.9 (CH), 120.4 (CH), 124.4 (CH), 130.0 (CHþCq), 133.0
(CH), 142.6 (CH), 143.9 (Cq), 149.0 (Cq), 151.3 (Cq), 168.2
(CO), 170.5 (CO). Anal. Calcd for C17H13NO4 (295.30): C,
69.15; H, 4.44; N, 4.74. Found: C, 70.02; H, 4.50; N, 4.68.
4.5.1. 20-Benzyl-5-methylidene-4,5-dihydrospiro[furan-10,3-
isoindol-30-one]-2-one (8a)
White solid; yield: 100%; mp 112e114 ꢀC; IR (n, cmꢁ1
,
CHCl3) 1684, 1703; 1H NMR (200 MHz, CDCl3): d 2.86 (d, J¼
16.4 Hz, 1H), 3.13 (dt, J¼2.3 Hz, 16.4 Hz, 1H), 4.19 (d,
J¼15.6 Hz, 1H), 4.49 (t, J¼2.3 Hz, 1H), 4.98 (t, J¼2.3 Hz,
1H), 5.33 (d, J¼15.6 Hz, 1H), 7.18e7.28 (m, 5H), 7.41e7.58
(m, 3H), 7.90e7.94 (m, 1H); 13C NMR (50 MHz, CDCl3)
d 35.0 (CH2), 44.3 (CH2), 69.0 (Cq), 91.7 (CH2), 120.5 (CH),
124.4 (CH), 127.5 (2CH), 127.8 (CH), 128.8 (2CH), 130.0
(CH), 130.1 (Cq), 132.9 (CH), 136.6 (Cq), 143.5 (Cq), 151.0
(Cq), 168.7 (CO), 170.6 (CO). Anal. Calcd for C19H15NO3
(305.34): C, 74.74; H, 4.95; N, 4.59. Found: C, 74.72; H, 5.02;
N, 4.70.
4.5.5. 20-(1,5-Dimethyl-1H-pyrrol-2-ylmethyl)-5-methyl-
idene-4,5-dihydrospiro[furan-10,3-isoindol-30-one]-
2-one (8e)
Yellow solid; yield: 99%; mp 145e147 ꢀC; IR (n, cmꢁ1
,
1
CHCl3) 1688, 1708; H NMR (200 MHz, CDCl3, 25 ꢀC)
d 2.16 (s, 3H), 2.90 (d, J¼16.4 Hz, 1H), 3.34e3.38 (m, 4H,
1H), 4.51 (t, J¼2.3 Hz, 1H), 4.52 (d, J¼15.6 Hz, 1H), 4.93 (t,
J¼2.3 Hz, 1H), 5.10 (d, J¼15.6 Hz, 1H), 5.65 (d, J¼3.9 Hz,
1H), 5.97 (d, J¼3.9 Hz, 1H), 7.33e7.41 (m, 1H), 7.47e7.58
(m, 2H), 7.84e7.88 (m, 1H); 13C NMR (50 MHz, CDCl3,
25 ꢀC) d 12.4 (CH3), 30.2 (CH3), 33.2 (CH2), 35.7 (CH2), 67.3
(Cq), 91.1 (CH2), 105.2 (CH), 109.4 (CH), 120.28 (CH),
123.7 (Cq), 124.2 (CH), 129.8 (CH), 130.1 (Cq), 131.6 (Cq),
132.9 (CH), 144.5 (Cq), 151.0 (Cq), 167.8 (CO), 169.7 (CO).
4.5.2. 20-(4-Methoxybenzyl)-5-methylidene-4,5-dihydrospiro-
[furan-10,3-isoindol-30-one]-2-one (8b)
White solid; yield: 89%; mp 117e119 ꢀC; IR (n, cmꢁ1
,
1
CHCl3) 1683, 1702; H NMR (200 MHz, CDCl3, 25 ꢀC)

3514
M.M. Rammah et al. / Tetrahedron 64 (2008) 3505e3516
Anal. Calcd for C19H18N2O3 (322.37): C, 70.79; H, 5.63; N,
8.69. Found: C, 70.87; H, 5.61; N, 8.78.
(CH2), 41.4 (CH2), 72.1 (Cq), 112.9 (CH), 122.33 (CH), 122.6
(CH), 126.5 (CH), 127.0 (2CH), 127.4 (CH), 127.7 (2CH),
129.2 (Cq), 130.5 (CH), 131.0 (Cq), 136.0 (Cq), 143.7 (Cq),
167.5 (CO), 170.9 (CO).
4.5.6. 20-(Thiophen-2-ylmethyl)-5-methylidene-4,5-
dihydrospiro[furan-10,3-isoindol-30-one]-2-one (8f)
Yellow solid; yield: 87%; mp 148e150 ꢀC; IR (n, cmꢁ1
,
4.5.10. 20-Benzyl-5-eth-(Z)ylidene-4,5-dihydrospiro[furan-
10,3-isoindol-30-one]-2-one (E-17)
The lactone diastereoisomers were inseparable and charac-
1
CHCl3) 1686, 1704; H NMR (200 MHz, CDCl3, 25 ꢀC)
d 2.96 (d, J¼16.4 Hz, 1H), 3.33 (dt, J¼2.3 Hz, J¼15.6 Hz,
1H), 4.50 (d, J¼16.4 Hz, 1H), 4.57 (t, J¼2.3 Hz, 1H), 5.03
(t, J¼2.3 Hz, 1H), 5.38 (d, J¼15.6 Hz, 1H), 6.91e6.95 (m,
1H), 7.01e7.03 (m, 1H), 7.23e7.25 (m, 1H), 7.43e7.47 (m,
1H), 7.51e7.58 (m, 2H), 7.89e7.95 (m, 1H); 13C NMR
(50 MHz, CDCl3, 25 ꢀC) d 35.0 (CH2), 39.2 (CH2), 68.8
(Cq), 91.8 (CH2), 120.5 (CH), 124.4 (CH), 126.1 (CH),
126.8 (CH), 126.9 (CH), 129.9 (Cq), 130.0 (CH), 133.0
(CH), 139.2 (Cq), 143.6 (Cq), 151.1 (Cq), 168.1 (CO), 170.5
(CO). Anal. Calcd for C17H13NO3S (311.36): C, 65.58; H,
4.21; N, 4.50. Found: C, 65.64; H, 4.19; N, 4.48.
1
terized together. White solid; yield 38%; H NMR (300 MHz,
0
CDCl3):
d
1.75 (m, JH(CH3)eH4¼2.3 Hz, JH(CH3)eH4
¼
2.3 Hz, JH(CH3)eHa¼7.0 Hz, 1H), 2.27 (qd, JH4eH(CH3)
¼
0
0
2.3 Hz, JH4eH4 ¼15.6 Hz, 1H), 3.08 (m, JH4 eH(CH3)¼2.3 Hz,
0
0
JH4 eHa¼2.3 Hz, JH4 eH4¼15.6 Hz, 1H), 4.18 (d, J¼15.6 Hz,
0
1H), 4.76 (qd, JHaeH4 ¼2.3 Hz, JHaeH(CH3)¼7.0 Hz, 1H),
5.30 (d, J¼15.6 Hz, 1H), 7.18e7.28 (m, 5H), 7.40e7.55 (m,
3H), 7.90e7.94 (m, 1H); 13C NMR (50 MHz, CDCl3) d 9.3
(CH3), 34.0 (CH2), 43.3 (CH2), 67.9 (Cq), 101.3 (CH),
119.6 (CH), 123.4 (CH), 126.5 (2CH), 126.8 (CH), 127.7
(2CH), 128.9 (CH), 129.3 (Cq), 131.8 (CH), 135.8 (Cq),
142.7 (Cq), 148.2 (Cq), 167.7 (CO), 169.9 (CO).
4.5.7. 20-(Prop-2-ynyl)-5-methylidene-4,5-dihydrospiro-
[furan-10,3-isoindol-30-one]-2-one (8g)
White solid; yield: 74%; mp 133e135 ꢀC; IR (n, cmꢁ1
,
4.5.11. 20-Benzyl-5-eth-(Z)ylidene-4,5-dihydrospiro[furan-
10,3-isoindol-30-one]-2-one (Z-17)
1
CHCl3) 1683, 1713; H NMR (200 MHz, CDCl3, 25 ꢀC)
d 2.33 (t, J¼2.3 Hz, 1H), 3.11 (d, J¼16.4 Hz, 1H), 4.01 (dt,
J¼2.3 Hz, J¼16.4 Hz, 1H), 4.13 (dd, J¼2.3 Hz, J¼18.0, H),
4.66 (t, J¼2.3 Hz, 1H), 4.71 (dd, J¼3.1 Hz, J¼18.0 Hz, 1H),
5.08 (t, J¼2.3 Hz, 1H), 7.37e7.40 (m, 1H), 7.44e7.63 (m,
1H NMR (300 MHz, CDCl3): d 1.95e2.05 (m, J¼2.3 Hz,
J¼7.0 Hz, 3H), 2.74e2.83 (m, 2H), 4.14 (d, J¼16.4 Hz, 1H),
5.03e5.10 (m, 2.3 Hz, J¼7.0 Hz, 1H) 5.50 (d, J¼16.4 Hz,
1H), 7.23e7.29 (m, 5H), 7.53e7.64 (m, 3H), 7.92e7.97 (m,
1H); 13C NMR (50 MHz, CDCl3) d 10.3 (CH3), 30.1 (CH2),
44.6 (CH2), 66.6 (Cq), 98.5 (CH), 121.5 (CH), 124.5 (CH),
127.2 (2CH), 127.5 (CH), 128.6 (2CH), 129.9 (CH), 130.7
(Cq), 132.4 (CH), 138.0 (Cq), 143.8 (Cq), 149.6 (Cq), 165.6
(CO), 168.6 (CO).
13
3H), 7.85e7.87 (m, 1H); C NMR (50 MHz, CDCl3, 25 ꢀC)
d 29.7 (CH2), 34.6 (CH2), 68.4 (Cq), 73.8 (Cq), 77.4 (CH),
92.0 (CH2), 120.4 (CH), 124.4 (CH), 129.6 (Cq), 130.1
(CH), 133.2 (CH), 143.6 (Cq), 151.1 (Cq), 167.6 (CO),
170.6 (CO). Anal. Calcd for C15H11NO3 (253.26): C, 71.14;
H, 4.38; N, 5.53. Found: C, 71.00; H, 4.35; N, 5.58.
4.5.12. 20-(1-Phenyl-ethyl)-5-methylidene-4,5-dihydrospiro-
[furan-10,3-isoindol-30-one]-2-one (21a and 21b)
Yield: 84%.
4.5.8. 20-H-5-Methylidene-4,5-dihydrospiro[furan-10,3-
isoindol-30-one]-2-one (13)
The CH2Cl2 was used as solvent for this reaction. White
solid; yield: 40%; mp 136e138 ꢀC; IR (n, cmꢁ1, CHCl3)
4.5.12.1. 20-(1-Phenyl-ethyl)-5-methylidene-4,5-dihydrospiro-
1
1696, 1722; H NMR (200 MHz, CDCl3, 25 ꢀC) d 3.3 (d,
[furan-10,3-isoindol-30-one]-2-one (21a). White solid; mp
1
J¼16.4 Hz, 1H), 3.43 (dt, J¼2.3 Hz, J¼16.4, 1H), 4.66 (t,
J¼2.3 Hz, 1H), 5.08 (t, J¼2.3 Hz, 1H), 6.65 (br, 1H), 7.46e
7.50 (m, 1H), 7.57e7.63 (m, 2H), 7.86e7.92 (m, 1H); 13C
NMR (50 MHz, CDCl3, 25 ꢀC) d 37.5 (CH2), 68.22 (Cq),
92.1 (CH2), 120.9 (CH), 124.6 (CH), 130.2 (CH), 133.4
(CH), 134.0 (Cq), 143.4 (Cq), 151.3 (Cq), 169.3 (CO), 171.4
(CO). Anal. Calcd for C12H9NO3 (215.21): C, 66.97; H,
4.22; N, 6.51. Found: C, 66.94; H, 4.19; N, 6.48.
123e125 ꢀC; IR (n, cmꢁ1, CHCl3) 1678.6, 1704.4; H NMR
(200 MHz, CDCl3, 25 ꢀC) d 1.97 (d, J¼7.0 Hz, 3H), 2. 89 (d,
J¼16.4 Hz, 1H), 3.31 (dt, J¼2.3 Hz, 16.4 Hz, 1H), 4.46 (q,
J¼7.0 Hz, 1H), 4.49 (t, J¼2.3 Hz, 1H), 4.96 (t, J¼2.3 Hz,
1H), 7.18e7.28 (m, 3H), 7.33e7.38 (m, 3H), 7.44e7.52 (m,
13
2H), 7.78e7.81 (m, 1H); C NMR (50 MHz, CDCl3, 25 ꢀC)
d 20.0 (CH3), 34.8 (CH2), 55.8 (CH), 70.5 (Cq), 91.9 (CH2),
120.3 (CH), 124.1 (CH), 126.6 (2CH), 127.5 (CH), 128.7
(2CH), 130.0 (CH), 131.5 (Cq), 132.7 (CH), 141.6 (Cq), 143.2
(Cq), 151.0 (Cq), 168.5 (C]O), 171.2 (C]O). Anal. Calcd
for C20H17NO3 (319.36): C, 75.22; H, 5.37; N, 4.39. Found:
C, 75.12; H, 5.34; N, 4.44.
4.5.9. 20-Benzyl-6-methyl-3,4-dihydrospiro[furan-10,3-
isoindol-30-one]-2-one (16)
Gummy solid; yield: 34%; IR (n, cmꢁ1, CHCl3) 1682, 1709;
1H NMR (300 MHz, CDCl3): d 1.68 (m, JH(CH3)eH4¼2.0 Hz,
JH(CH3)eH4 ¼2.0 Hz, JH(CH3)eH5¼2.3 Hz, 3H), 2.45e2.85 (m,
4.5.12.2. 20-(1-Phenyl-ethyl)-5-methylidene-4,5-dihydrospiro-
0
2H), 4.27 (d, J¼15.6 Hz, 1H), 4.40 (m, JH5eH4¼2.0 Hz,
[furan-10,3-isoindol-30-one]-2-one (21b). White solid; mp
1
JH5eH(CH3)¼2.3 Hz, JH5eH4 ¼7.0 Hz, 1H), 5.39 (d, J¼
160e162 ꢀC; IR (n, cmꢁ1, CHCl3) 1691.1, 1702.0; H NMR
0
15.6 Hz, 1H), 7.16e7.28 (m, 5H), 7.41e7.56 (m, 3H), 7.90e
7.93 (m, 1H); 13C NMR (50 MHz, CDCl3) d 13.1 (CH3), 31.2
(200 MHz, CDCl3, 25 ꢀC) d 1.73 (d, J¼7.0 Hz, 3H), 2.68 (d,
J¼16.4 Hz, 1H), 3.03 (dt, J¼2.3 Hz, 16.4 Hz, 1H), 4.39 (t,

M.M. Rammah et al. / Tetrahedron 64 (2008) 3505e3516
3515
Haga, Y.; Okazaki, M.; Shuto, Y. Biosci. Biotechnol. Biochem. 2003, 67,
2183; (n) Oh, C. O.; Yi, H. J.; Lee, J. H. New J. Chem. 2007, 31, 835.
5. For the use of mercury catalysts, see: (a) Ref. 1e. (b) Rollinson, S. W.;
Amos, R. A.; Katzenellenbogen, J. A. J. Am. Chem. Soc. 1981, 103,
4114; (c) Amos, R. A.; Katzenellenbogen, J. A. J. Am. Chem. Soc.
1981, 103, 5459; (d) Yamamoto, M. J. Chem. Soc., Perkin Trans. 1
1981, 582; (e) Ref. 1h; (f) Sofia, M. J.; Katzenellenbogen, J. A. J. Org.
Chem. 1984, 50, 2331; (g) Spencer, R. W.; Tam, T. F.; Thomas, E.;
Robinson, W. J.; Krantz, A. J. Am. Chem. Soc. 1986, 108, 5589.
J¼2.3 Hz, 1H), 4.92 (t, J¼2.3 Hz, 1H), 5.75 (q, J¼7.0 Hz,
1H), 7.19e7.34 (m, 6H), 7.46e7.52 (m, 2H), 7.84e7.87 (m,
13
1H); C NMR (50 MHz, CDCl3, 25 ꢀC) d 17.1 (CH3), 34.4
(CH2), 50.0 (CH), 67.8 (Cq), 91.5 (CH2), 120.1 (CH), 124.4
(CH), 126.7 (2CH), 127.7 (CH), 128.7 (2CH), 129.9 (CH),
130.3 (Cq), 132.9 (CH), 140.8 (Cq), 144.4 (Cq), 151.2 (Cq),
168.6 (C]O), 172.0 (C]O). Anal. Calcd for C20H17NO3
(319.36): C, 75.22; H, 5.37; N, 4.39. Found: C, 75.09; H,
5.33; N, 4.34.
6. For the use of rhodium catalysts, see: (a) Marder, T. B.; Chan, D. M.-T.;
Fultz, W. C.; Calabrese, J. C.; Mibtein, D. J. Chem. Soc., Chem. Commun.
1987, 1885; (b) Chan, D. M.-T.; Marder, T. B.; Mibtein, D.; Taylor, N. J.
J. Am. Chem. Soc. 1987, 109, 6385; (c) Elgafi, S.; Field, L. D.; Messerle,
B. A. J. Organomet. Chem. 2000, 607, 97.
4.5.12.3.3-(Prop-2-ynyl)-2,3-dihydro-isoindol-1-one(12). White
solid, yield 100%; mp 179e181 ꢀC; IR (n, cmꢁ1, CHCl3) 1700;
1H NMR (300 MHz, CDCl3, 25 ꢀC) d 2.04 (t, J¼2.3 Hz, 1H),
2.42 (ddd, J¼2.3 Hz, J¼7.8 Hz, J¼17.1 Hz, 1H), 2.70 (ddd,
J¼2.3 Hz, J¼5.4 Hz, J¼17.1 Hz, 1H), 4.67 (dd, J¼5.4 Hz, J¼
7.8, 1H), 6.66 (br s, 1H), 7.39e7.55 (m, 3H), 7.79 (d,
7. For the use of palladium catalysts, see: (a) Lambert, C.; Utimoto, K.;
Nozaki, H. Tetrahedron Lett. 1984, 25, 5323; (b) Yanagihara, N.;
Lambert, C.; Iritani, K.; Utimoto, K.; Nozaki, H. J. Am. Chem. Soc.
1986, 108, 2753; (c) Negishi, E. I.; Kotora, M. Synthesis 1997, 121; (d)
Tsuda, T.; Ohashi, Y.; Nagahama, N.; Sumiya, R.; Saegusa, T. J. Org.
Chem. 1988, 53, 2650; (e) Arcadi, A.; Burini, A.; Cacchi, S.; Delmastro,
M.; Marinelli, F.; Pietroni, B. R. J. Org. Chem. 1992, 57, 967; (f) Mandai,
T.; Ohta, K.; Baba, N.; Kawada, M.; Tsuji, J. Synlett 1992, 671; (g)
13
J¼7.0 Hz, 1H); C NMR (50 MHz, CDCl3, 25 ꢀC) d 13C
NMR (75 MHz, CDCl3, 25 ꢀC) d 25.2 (CH2), 55.1 (CH), 71.3
(Cq), 77.2 (CH), 122.5 (CH), 124.0 (CH), 128.8 (CH), 132.1
(CH), 133.6 (Cq), 146.3 (Cq), 171.8 (C]O). Anal. Calcd for
C11H9NO (171.20): C, 77.17; H, 5.30; N, 8.18. Found: C,
77.09; H, 5.33; N, 8.34.
´
Bouyssi, D.; Gore, J.; Balme, G. Tetrahedron Lett. 1992, 33, 2811; (h)
´
Bouyssi, D.; Gore, J.; Balme, G.; Louis, D.; Wallach, J. Tetrahedron
Lett. 1993, 34, 3129; (i) Wakabayashi, T.; Ishii, Y.; Ishikawa, K.; Hidai,
M. Angew. Chem., Int. Ed. 1996, 35, 2123; (j) Cavicchioli, M.; Bouyssi,
´
D.; Gore, J.; Balme, G. Tetrahedron Lett. 1996, 37, 1429.
8. Takahashi, I.; Kawakami, T.; Hirano, E.; Yokota, H.; Kitajima, H. Synlett
1996, 353.
Acknowledgements
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The authors are grateful to Dr. V. Dalla for many fruitful
discussions throughout the course of this work.
10. Goa, K. I.; Heel, R. C. Drugs 1986, 32, 48.
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3516
M.M. Rammah et al. / Tetrahedron 64 (2008) 3505e3516
Fousse, A.; Bousquet, T.; Othman, M.; Dalla, V. Org. Lett. 2005, 7, 2825;
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18. Phthalimidine 9 could be prepared by using BBr3 (more toxic then TFA)
according to our previous work (see Ref. 16c).
´
´
7, 5335; (d) Akue-Gedu, R.; Al Akoum Ebrik, S.; Witczak-Legrand, A.;
Fasseur, D.; El Ghammarti, S.; Couturier, D.; Decroix, B.; Othman, M.;
Debacker, M.; Rigo, B. Tetrahedron 2002, 58, 9239.
19. Crystaldatafor21bC20H17NO3 (193 K):orthorombic, P212121, a¼6.963(2),
b¼13.324(5), c¼17.853(6) A, a¼b¼g¼90ꢀ, wavelength: 0.71073 A,
˚
˚
3
3
˚
V¼1656.3(10) A , Z¼4, Dc¼1.281 Mg/m , 14435 reflections, 2921 unique
reflections; 2422 with I>2s(I); structure refined by full-matrix least-squares
on F2 to give final indices R1¼0.0588 and wR2¼0.1493 (all data). Full crys-
tallographic data have been deposited to the Cambridge Crystallographic
Data Center (CCDC reference number 646997 for compound 21b. Copies
of the data can be obtained free of charge at http://www.ccdc.cam.ac.uk.
16. (a) Ben Othman, R.; Othman, M.; Decroix, B. Tetrahedron 2008, 64, 559;
(b) Othman, M.; Pigeon, P.; Decroix, B. Tetrahedron 1998, 54, 8737; (c)
Othman, M.; Decroix, B. Synth. Commun. 1996, 26, 2803.
17. Couture, A.; Deniau, E.; Ionescu, D.; Grandclaudon, P. Tetrahedron Lett.
1998, 39, 2319.