A convenient synthesis of novel spiroisoindolone γ- halobutyrolactones via halocyclization of γ-ethylenic acids

Article abstract of DOI:10.3987/COM-09-11787

γ-Ethylenic carboxylic acids are cyclized to spiroisoindolone γ-halomethylbutyrolactones, in the presence of NBS or NIS and K₂CO₃. The corresponding haloaspirobutyrolactones were isolated in high yields (57-95%).

Full text of DOI:10.3987/COM-09-11787

HETEROCYCLES, Vol. 78, No. 11, 2009
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HETEROCYCLES, Vol. 78, No. 11, 2009, pp. 2787 - 2798. © The Japan Institute of Heterocyclic Chemistry
Received, 1st July, 2009, Accepted, 3rd September, 2009, Published online, 7th September, 2009
DOI: 10.3987/COM-09-11787
A CONVENIENT SYNTHESIS OF NOVEL SPIROISOINDOLONE
γ_HALOBUTYROLACTONES
γ_ETHYLENIC ACIDS
VIA
HALOCYCLIZATION
OF
Mohamed M. Rammah,a,d Mohamed Othman,a,* Kabula Ciamala,b Michael
Knorr,b Carsten Strohmann,c and Mohamed B. Rammahd
aURCOM, EA 3221, FR CNRS 3038, University of Le Havre, BP 540, F-76058
b
Le Havre Cedex, France. Institut UTINAM UMR CNRS 6213, University of
Franche-Comté, F-25030 Besançon Cedex, France. cTechnical University
d
Dortmund, D-44227 Dortmund, Germany. LCOH, University of Monastir, 5000
Monastir, Tunisia
Abstract – γ-Ethylenic carboxylic acids are cyclized to spiroisoindolone
γ-halomethylbutyrolactones, in the presence of NBS or NIS and K2CO3. The
corresponding haloaspirobutyrolactones were isolated in high yields (57-95%).
INTRODUCTION
In the years since its discovery in the early 1900s, halolactonization has proven to be a versataile reaction
in organic synthesis, allowing facile formation of small or medium ring size lactones1 from
γ-unsaturated carboxylic acids,2 esters3 or amides.4 The general method used to halogenate organic
substrates has been the use of N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS) or
N-iodosuccinimide (NIS).
O
O
CO2Et
N R
Ag2CO3
N R
O
NBS
R
N
or NIS
O
O
O
III
I
O
II
X
Figure 1
In connection with our current research interest in the preparation of nitrogenated and oxygenated
compounds containing the isoindolinone moiety with promising pharmaceutical properties,5 we have

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HETEROCYCLES, Vol. 78, No. 11, 2009
recently reported a convenient access to various new spiroisoindole-γ-methylene butyrolactones of type
II5a and novel spiroisoindole γ-halobutyrolactones of type III5c when γ-acetylenic acids I are reacted with
a catalytic amount of Ag2CO3 and NBS/NIS respectively (Figure 1).
Here, we would like to report the synthesis of new spiroisoindolone γ-halobutyrolactones through
halolactonization of γ-ethylenic acids 4 with NBX (X: I, Br) as the key step to form the five membered
ring. As far as we know, this is the first preparation of γ-(halomethyl)-γ-spirobutyrolactone derivatives
containing the isoindole moiety starting from homophthalic acid.
RESULTS AND DISCUSSION
The required acids 4 were efficiently obtained, as outlined in Scheme 1, from phthalimidines 2.5a-c,h,i After
alkylation of 2a-d with allyl bromide (K2CO3, CH3CN, reflux),5a-c the resulting alkylated phthalimidines
esters 3a-d were converted to the γ-ethylenic carboxylic acids 4a-d in good yields (84-92%) as previously
described by our group. 5a-c
R :
CO2Et
CO2Et
N
i
N
O
2a
2b
R
R
OMe
3a-d
2a-d
O
ii
X = Br, I
O
N
S
R
2c
CO2Et
N
iii
O
2d
O
R
O
5-9a/b
4a-d
X
O
Scheme 1. Reagents and conditions: (i) K2CO3, allyl bromide, MeCN, reflux, 12 h; (ii) a. NaOH,
EtOH/H2O, rt, 2 h; b. aqueous 1M HCl, 0 °C; (iii) K2CO3, NBS or NIS, CH2Cl2, -30 °C
With a large variety of ethylenic carboxylic acids 4a-d in hand, we then investigated the optimal
conditions for the halocyclization. Since the diastereoselectivity in halolactonization reactions is
significantly affected by the choice of solvent and temperature, the acid 4a chosen as a model was
submitted to the halolactonization reaction with iodine (I2), N-iodosuccinimide (NIS) and
N-bromosuccinimide (NBS) under different conditions (kinetic and thermodynamic controls) and the
results are reported in Table 1.

HETEROCYCLES, Vol. 78, No. 11, 2009
2789
O
O
CO2H
NBS
or NIS
N
O
N
+
N
O
O
O
O
5b (X=I)
9b (X=Br)
5a (X=I)
9a (X=Br)
X
X
4a
"cis"
"trans"
Scheme 2. Reagents and conditions: K2CO3, NBS or NIS, CH2Cl2, -30 °C
Table 1. Halocyclization of acid 4a
Entry
Conditions
I2/Et2O-aq.NaHCO3
I2/Et2O- aq.NaHCO3
I2/Et2O- aq.NaHCO3
NIS/CH2Cl2
T°C
rt
Time h
Yield%
57
a/b
1
2
3
3
6
3
3
3
1
1
3
3
70:30
74:26
74:26
70/30
82/18
90/10
90/10
100/0
70/30
74/26
-30
-30
rt
64
3
60
4
72
5
NIS-CH2Cl2
-30
-30
-30
-30
rt
76
6
NBS-CH2Cl2
70
7
NIS/CH2Cl2/K2CO3
NBS/CH2Cl2/K2CO3
I2/ MeCN
83
8
77
9
60
10
I2/ MeCN
-30
62
Using standard conditions involving kinetic control, iodine in a mixture of Et2O and H2O in the presence
of sat. aqueous NaHCO3 at room temperature (entry 1), a mixture of syn and anti iodo-lactones 5a/b was
isolated in 57% chemical yield, but in moderate ratio (70:30) in favor of the syn diastereomer 5a. A
similar diastereoselectivity (74:26 entry 2) was observed when the reaction was performed at -30 °C. A
prolonged reaction time (entry 3) did not improve the yield. A cleaner reaction occurred with NIS in
CH2Cl2 (entry 4) at room temperature, to give the diastereomeric mixture of lactones 5a/b in 72% yield
and 70:30 ratio. A better diastereoselectivity (82:18, entry 5) was observed when the reaction was
performed at -30 °C. Under the same operating conditions and by replacing NIS by NBS (entry 6), acid
4a gave a mixture of bromo-lactones cis-9a and trans-9b in 70% yield, in a ratio of 90:10. A dramatic
rate enhancement was observed when the reaction was carried out in the presence equimolar amount of
K2CO3 (entries 7 and 8). Within 1 h the starting material was consumed to give the iodo-lactones 5a/b
(entry 7) in 83% yield with an increase in the ratio cis:trans to 90:10. On bromocyclization, acid 4a gave
only one diastereomer 9a (entry 8) in 77% yield. Single-crystal X-ray structure elucidation6 on the
diastereomer 9a unambiguously established the relative configuration as “cis” and, hence, the relative
stereochemistry at C-3, C-5 as 3R*, 5S*.

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HETEROCYCLES, Vol. 78, No. 11, 2009
O
N
4
3
O
O
1
Br
-9a
cis
Figure 2. ORTEP drawing of structure 9a
The reaction scope was probed by applying these optimal conditions (NXS/CH2Cl2/K2CO3, 2 h, -30 °C) to
the other substrates 4b-d, which cyclized smoothly to give the corresponding γ-lactones 5-11 in good
yields, with even higher selectivities in favor of the cis-lactones. Silica gel column chromatography was
ultimately used to remove the succinimide, and the results are summarized in Table 2.
Table 2. Halocyclization produced via Scheme 1
Entry
Substrate
4a
X+
Product
5a/5b
6a/6b
7a/7b
8a/8b
Yield%
83
(a/b)dra
90/10
80/20
100/0
100/0
100/0
100/0
75/25
-
1
2
3
4
5
6
7
8
NIS
NIS
NIS
NIS
NBS
NBS
NBS
NBS
4b
4c
4d
4a
4b
4c
4d
95
71
67
77
60
73
0
9a/9b
10a/10b
11a/11b
12a/12b
a Diastereomeric ratios were determined on the crude mixture by integration of non-overlapping signals in the 1H
NMR spectra.
It is noteworthy that, although a variety of bases (NaHCO3, benzyl amine, pyrrolidine), solvent (CH2Cl2,
THF, DMF, MeCN, THF/H2O, MeCN/H2O) and NBSratios were examined, the formation of spirolactones
12a,b from 4d was not accomplished but complete decomposition occurred.
It should be noted that when conducted under Bartlett’s “thermodynamic” conditions (iodine in acetonitrile,
entries 9 and 10),8 cis to trans equilibration does not occur. Under these conditions, acid 4a gave a mixture
of cis and trans diastereoisomers, the cis diastereoisomer being again the major product. It should also be
noted that the iodo lactones 7a and 8a do not interconvert when resubjected to the reaction conditions.
The assignement of all structures reported herein was made on the basis of their X-ray (9a), IR, and NMR
13
spectroscopies (1H, C and DEPT programs). In the case of solids, their elemental analyses were also
1
performed. H NMR Spectra of 5-11 showed the methylene group of the –N-CH2- moiety as an AB
system due to the diastereotopic effect with a coupling constant of J = 15-16 Hz characteristic of gem
13
protons. Likewise, the C NMR spectra of the spiro products 5-11 reveled the presence of an additional

HETEROCYCLES, Vol. 78, No. 11, 2009
2791
secondary (δ ≈ 75 ppm) and primary (δ ≈ 30 ppm for bromine products and δ ≈ 8 ppm for iodide
products) carbons in the aliphatic region as the consequence of the cyclization process.
The formation of two diastereomers of spirobutyrolactone derivatives could be visualized to proceed
through intermediates A and B (Scheme 3) formed by the addition of iodine (bromine) on either of the
two faces of double bond. Iodonium (bromonium) ion intermediate A would result in the formation of
halolactone product with C-N and CH2I groups placed syn to each other, while halonium ion intermediate
B would result in formation of product with C-N and CH2I groups on the opposite faces of furane ring.
O
O
O
O
R
R
R
R
(Br)
(Br)
(Br)
I
N
A
I
N
N
N
+
I
H
H
+
(Br)
I
O
O
-
O
H
H
O
O
-
O
O
O
B
trans-lactone
cis-lactone
Scheme 3. Possible mechanisms for the formation of the cis and trans lactones
The present iodine (bromine) mediated intramolecular cyclizations of acids 4 result in formation of the
products with C-N and CH2I moieties present on same side either exclusively or predominantly and
involve the preferential participation of intermediate A. This preference arises probably due to
stabilization halonium ion intermediate by its electrostatic interactions with free pair of nitrogen in
intermediate A.
Synthesis of chiral spirobutyrolactone derivatives
Having established the facility of acids 4a-d to provide novel interesting spirolactones in good yields, we
extended the halolactonization strategy to the synthesis of chiral spirohalobutyrolactones.
S-α-Methylbenzylamine was chosen as example for this study.
CO2Et
Br
CO2R
N
ii
i
CO2Et
N
O
CO2Et
13a/b
1
14a
15a
O
14a,b
15a,b
R = Et
R = H
iii
+
O
N
CO2R
O
N
iv
N
O
+
O
O
O
14b
15b
O
16a (X=Br)
17a (X=I)
16b (X=Br)
17b (X=I)
X
X
Scheme 4. Reagents and conditions: (i) S-α-methylbenzylamine; (ii) K2CO3, allyl bromide, MeCN,
reflux, 12 h; (iii) a. NaOH, EtOH/H2O, rt, 2 h; b. aqueous 1M HCl, 0 °C; (iv) K2CO3, NBS
or NIS, CH2Cl2, -30 °C

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HETEROCYCLES, Vol. 78, No. 11, 2009
The required acids 15a,b were efficiently obtained as outlined in Scheme 3, from the bromide 1 in three
steps, following our reported procedure.5 Halocyclization of carboxylic acids 15a,b with NBS/NIS in the
presence of K2CO3, gave a 4:1 mixture of two diastereomers 16a/16b (X = Br) with NBS and a 3:1
mixture of 17a/17b (X = I) with NIS in yields of 78% and 72%, respectively. It is noteworthy that, even
on repeated chromatography and crystallization, it was not possible to isolate pure samples of the minor
diastereomers 16b and 17b just the major diastereomers 16a and 17a could be isolated.
Importantly, in all cases, the reaction seems to be highly regioselective because during the cyclization
process only the exo-dig products were obtained.
CONCLUSION
In conclusion, a highly efficient halocyclization reaction of γ-ethylenic carboxylic acids was developed in
the isoindolone series by using X+ (NBS or NIS) and K2CO3. The carboxylic substrates were very easily
prepared from simple precursors and the halogen mediated intramolecular cyclization of 4 and 15
selectively afforded the spirobutyrolactones with C-N and CH2-X moities placed syn to each other as the
major or the only product. We now envisage applying this methodology to the synthesis of analogous
natural products.
EXPERIMENTAL
General
1
13
All melting points were measured on a Boetius micro hotstage and are uncorrected. H and C NMR
spectra were recorded respectively at 200 (300) and 50 (75) MHz on a Brucker AC-200 and Brucker
AVANCE 300 spectrometers. The infrared spectra were recorded on a Perkin-Elmer FT-IR paragon 1000
spectrometer. 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 then
visualized under UV light and dipped in a Dragendorff solution. Silica gel (230-400 mesh) was used for
flash chromatography separations. 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.
Alkylation with allylyl bromide.
Products 3 are prepared according to our previous work.5
1-Allyl-2-benzyl-3-oxo-2,3-dihydro-1H-isoindole-1-carboxylic acid ethyl ester (3a). Yellow liquid;
1
yield: 90%; IR (ν, cm-1 CHCl3) 1688, 1731; H NMR (200 MHz, CDCl3, 25 °C) δ 0.84 (t, J = 7.0 Hz,
3H), 2.93 (dd, J = 15.6, J = 6.3 Hz, 1H) 3.09 (dd, J = 15.6, J = 6.3 Hz, 1H), 3.49-3.55 (m, 1H), 3.80-3.87
(m, 1H), 4.57 (d, J = 15.5 Hz, 1H), 4.68-4.90 (m, 4H), 7.15-7.51 (m, 8H), 7.81 (d, J = 8.6 Hz, 1H).

HETEROCYCLES, Vol. 78, No. 11, 2009
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1-Allyl-2-(4-methoxy-benzyl)-3-oxo-2,3-dihydro-1H-isoindole-1-carboxylic acid ethyl ester (3b).
Yellow liquid; yield: 68%; IR (ν, cm-1 CHCl3) 1690, 1732; 1H NMR (200 MHz, CDCl3, 25 °C) δ 0.93 (t,
J = 7.0 Hz, 3H), 2.99 (dd, J = 14.8, J = 6.3 Hz, 1H) 3.11 (dd, J = 14.8, J = 6.3 Hz, 1H), 3.62-3.70 (m,
1H), 3.71-3.79 (s, 3H), 3.87 (m, 1H), 4.59 (d, J = 14.8 Hz, 1H), 4.70 (d, J = 14.8 Hz, 1H), 4.71-4.96 (m,
3H), 6.81 (d, J = 8.6 Hz, 2H), 7.30-7.39 (m, 3H), 7.43-7.58 (m, 2H), 7.84-7.88 (m, 1H).
1-Allyl-3-oxo-2-thiophen-2-ylmethyl-2,3-dihydro-1H-isoindole-1-carboxylic acid ethyl ester (3c).
Yellow liquid; yield: 96%; IR (ν, cm-1 CHCl3) 1691, 1732; 1H NMR (200 MHz, CDCl3, 25 °C) δ 0.74 (t,
J = 7.1 Hz, 3H), 2.79 (dd, J = 14.9, J = 6.2 Hz, 1H), 2.91 (dd, J = 14.9, J = 6.2 Hz, 1H), 3.51-3.61 (m,
1H), 3.70-3.77 (m, 1H), 4.46-4.71 (m, 5H), 6.62-6.66 (m, 1H), 6.78-6.80 (m, 1H), 6.92-6.95 (m, 1H),
7.15-7.25 (m, 2H), 7.27-7.33 (m, 1H), 7.58-7.62 (m, 1H).
1-Allyl-2-furan-2-ylmethyl-3-oxo-2,3-dihydro-1H-isoindole-1-carboxylic acid ethyl ester (3d).
Yellow liquid; yield: 82%; IR (ν, cm-1 CHCl3) 1694, 1731; 1H NMR (200 MHz, CDCl3, 25 °C) δ 1.00 (t,
J = 7.0 Hz, 3H), 2.98 (dd, J = 14.8, J = 4.7 Hz, 1H), 3.14 (dd, J = 14.8, J = 4.7 Hz, 1H,), 3.73-3.78 (m,
2H), 4.71 (d, J = 15.6 Hz, 2H), 4.73-4.88 (m, 3H), 6.23-6.32 (m, 2H), 7.28-7.29 (m, 1H), 7.37-7.54 (m,
3H), 7.77-7.82 (m, 1H).
Preparation of acids 4 and 15.
Products 4 and 15 are prepared according to our previous work.5
1-Allyl-2-benzyl-3-oxo-2,3-dihydro-1H-isoindole-1-carboxylic acid (4a). White solid; yield: 92%; mp
123-125 °C; IR (ν, cm-1 CHCl3) 1697, 1776; 1H NMR (200 MHz, CDCl3, 25 °C) δ 2.88 (dd, J = 14.8, J =
6.2 Hz, 1H) 3.05 (dd, J = 14.8, J = 6.2 Hz, 1H), 4.50 (d, J = 15.6 Hz, 1H), 4.62-4.87 (m, 3H), 4.95 (d, J =
15.6 Hz, 1H), 6.57-6.89 (sl, 1H), 7.12-7.58 (m, 8H), 7.83 (d, J = 8.0 Hz, 1H).
1-Allyl-2-(4-methoxy-benzyl)-3-oxo-2,3-dihydro-1H-isoindole-1-carboxylic acid (4b). White solid;
1
yield: 85%; mp 120-122 °C; IR (ν, cm-1 CHCl3) 1693, 1714; H NMR (200 MHz, CDCl3, 25 °C) δ 2.90
(dd, J = 14.9, J = 6.2 Hz, 1H) 3.06 (dd, J = 14.9, J = 6.2 Hz, 1H), 3.71 (s, 3H), 4.50 (d, J = 15.6 Hz, 1H),
4.59-4.76 (m, 3H), 4.84 (d, J = 15.6 Hz, 1H), 6.75 (d, J = 8.6 Hz, 2H), 7.25-7.34 (m, 2H), 7.40-7.57 (m,
3H), 7.76-7.82 (m, 1H).
1-Allyl-3-oxo-2-thiophen-2-ylmethyl-2,3-dihydro-1H-isoindole-1-carboxylic acid (4c). White solid;
yield: 85%; mp 120-122 °C; IR (ν, cm-1 CHCl3) 1694, 1726; 1H NMR (300 MHz, CDCl3, 25 °C) δ 3.03
(dd, J = 15.3, J = 6.0 Hz, 1H), 3.14 (dd, J = 15.3, J = 6.0 Hz, 1H,), 3.72-4.04 (sl, 1H), 4.68-4.91 (m, 4H),
5.09 (d, J = 15.8 Hz, 1H), 6.84-6.87 (m, 1H), 7.05-7.07 (m, 1H), 7.15-7.17 (m, 1H), 7.48-7.60 (m, 3H),
7.84-7.87 (m, 1H).
1-Allyl-2-furan-2-ylmethyl-3-oxo-2,3-dihydro-1H-isoindole-1-carboxylic acid (4d). White solid;
yield: 74%; mp 136-138 °C; IR (ν, cm-1 CHCl3) 1694, 1725; 1H NMR (200 MHz, CDCl3, 25 °C) δ 3.03
(dd, J = 14.7, J = 4.7 Hz, 1H), 3.17 (dd, J = 14.7, J = 4.7 Hz, 1H,), 4.70 (d, J = 16.4 Hz, 1H), 4.77-4.93

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(m, 5H), 6.24-6.26 (m, 1H), 6.37-6.39 (m, 1H), 7.49-7.62 (m, 4H), 7.83-7.87 (m, 1H).
Typical procedure of the spirohalolactonization reaction.
A mixture of ethylenic acid 4 (1 mmole), K2CO3 (1.1 equiv) and NBS or NIS (1.2 equiv) in degassed
CH2Cl2 (5 mL) was stirred under argon atmosphere at -30 °C. After the completion of the reaction
indicated 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
lactones 5-11, 16 or 17.
5-(Iodomethyl)-2’-benzyl-4,5-dihydrospiro[furan-1’,3-isoindol-3’-one]-2-one (5a/b). White solid;
yield: 83%; mp 187-189 °C; IR (, cm-1, CHCl3) 1704, 1788; dr: 90/10
Maj (5a): 1H NMR (300 MHz, CDCl3, 25 °C)  2.30 (dd, J = 14.0, J = 10.1 Hz, 1H), 2.45 (dd, J = 14.0,
J = 6.2 Hz, 1H), 3.25-3.47 (m, 2H), 4.15 (d, J = 15.6 Hz, 1H), 4.69-4.83 (m, 1H), 5.41 (d, J = 15.6 Hz,
13
1H), 7.28-7.63 (m, 7H), 7.52-7.63 (m,2H), 7.92-7.96 (m, 1H), C NMR (50 MHz, CDCl3, 25 °C) δ 7.1
(CH2), 37.5 (CH2), 44.5 (CH2), 70.6 (Cq), 75.0 (CH), 120.4 (CH), 124.7 (CH), 127.6 (2 CH), 127.7 (CH),
128.8 (2 CH), 129.9 (CH), 130.4 (Cq), 132.8 (CH), 136.9 (Cq), 143.9 (Cq), 168.7 (CO), 171.6 (CO).
Min (5b): 1H NMR (300 MHz, CDCl3, 25 °C)  2.51 (d, J = 6.2 Hz, 1H), 3.25-3.47 (m, 2H), 4.30 (d, J =
15.6 Hz, 1H), 4.69-4.83 (m, 1H), 5.25 (d, J = 15.6 Hz, 1H), 7.28-7.63 (m, 7H), 7.52-7.63 (m,2H),
13
7.92-7.96 (m, 1H), C NMR (50 MHz, CDCl3, 25 °C) δ 8.4 (CH2), 38.9 (CH2), 44.5 (CH2), 69.5 (Cq),
75.0 (CH), 121.7 (CH), 124.2 (CH), 127.5 (2 CH), 128.1 (CH), 128.9 (2 CH), 129.7 (CH), 130.9 (Cq),
132.8 (CH), 136.2 (Cq), 144.6 (Cq), 168.5 (CO), 172.6 (CO). Anal. Calcd for C19H16INO3 (433.25) : C,
52.67; H, 3.72; N, 3.23. Found: C, 52.72; H, 3.75; N, 3.18.
5-(Iodomethyl)-2’-(4-methoxy-benzyl)-4,5-dihydrospiro[furan-1’,3-isoindol-3’-one]-2-one
(6a/b).
White solid; yield: 95%; mp 131-133 °C; IR (, cm-1, CHCl3) 1702, 1789; dr: 80/20
Maj (6a) : 1H NMR (300 MHz, CDCl3, 25 °C) δ 2.36 (dd, J = 13.6, J = 10.1 Hz, 1H), 2.44 (dd, J = 13.6,
J = 6.4 Hz, 1H), 3.32 (dd, J = 10.9, J = 6.4 Hz, 1H), 3.39 (dd, J = 10.9, J = 4.1 Hz, 1H), 3.78 (s, 3H),
4.15 (d, J = 15.8 Hz, 1H), 4.73-4.83 (m, 1H), 5.33 (d, J = 15.8 Hz, 1H), 6.85 (d, J = 8.3 Hz, 2H),
13
7.23-7.25 (m,2H), 7.38-7.41 (m,1H), 7.53-7.62 (m,2H), 7.92-7.95 (m,1H), C NMR (75 MHz, CDCl3,
25 °C) δ 7.0 (CH2), 37.5(CH2), 44.0 (CH2), 55.2 (CH3), 70.6 (Cq), 75.0 (CH), 114.1 (2CH), 120.3 (CH),
124.6 (CH), 129.1 (2CH), 129.9 (CH), 130.5 (Cq), 132.8 (CH), 143.9 (Cq), 159.2 (Cq), 168.6 (CO),
171.6 (CO).
Min (6b): 1H NMR (300 MHz, CDCl3, 25 °C)  2.53 (d, J = 7.6 Hz, 2H), 3.42 (dd, J = 10.9, J = 4.1 Hz,
1H), 3.47 (dd, J = 10.9, J = 6.4 Hz, 1H), 3.78 (s, 3H), 4.30 (d, J = 15.8 Hz, 1H), 4.73-4.83 (m, 1H), 5.11
(d, J = 15.8 Hz, 1H), 6.85 (d, J = 8.3 Hz, 2H), 7.23-7.25 (m,2H), 7.38-7.41 (m,1H), 7.53-7.62 (m,2H),
13
7.92-7.95 (m,1H), C NMR (75 MHz, CDCl3, 25 °C) δ 8.4 (CH2), 39.0 (CH2), 44.0 (CH2), 55.2 (CH3),

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69.4 (Cq), 75.0 (CH), 114.2 (2CH), 121.7 (CH), 124.2 (CH), 128.9 (2CH), 129.8 (CH), 131.0 (Cq), 132.9
(CH), 144.7 (Cq), 159.4 (Cq), 168.4 (CO), 172.6 (CO). Anal. Calcd for C20H18INO4 (463.28): C, 51.85; H,
3.92; N, 3.02. Found: C, 51.82; H, 3.95; N, 3.08.
5-(Iodomethyl)-2’-thiophen-2-ylmethyl-4,5-dihydrospiro[furan-1’,3-isoindol-3’-one]-2-one
(7a).
1
White solid; yield: 71%; mp 196-198 °C; IR (, cm-1, CHCl3) 1700, 1789; H NMR (300 MHz, CDCl3,
25 °C)  2.54 (d, J = 6.8 Hz, 2H), 3.40 (dd, J = 10.2 J = 6.8 Hz, 1H), 3.48 (dd, J = 10.2, J = 3.8 Hz, 1H),
4.47 (d, J = 16.2 Hz, 1H), 4.74-4.86 (m, 1H), 5.46 (d, J = 16.2 Hz, 1H); 6.95-6.98 (m, 1H), 7.10-7.12 (m,
1H), 7.40-7.42 (m, 1H), 7.54-7.63 (m, 3H) , 7.92-7.96 (m, 1H), 13C NMR (75 MHz, CDCl3, 25 °C) δ 7.2
(CH2), 37.7 (CH2), 39.6 (CH2), 70.5 (Cq), 75.0 (CH), 120.4 (CH), 124.8 (CH), 126.0 (CH), 126.9 (CH),
127.0 (CH), 130.0 (CH), 130.3 (Cq), 132.9 (CH), 139.6 (Cq), 144.0 (Cq), 168.3 (CO), 171.5 (CO). Anal.
Calcd for C17H14INO3S (439.27): C, 46.48; H, 3.21; N, 3.19. Found: C, 46.42; H, 3.25; N, 3.18.
5-(Iodomethyl)-2’-furan-2-ylmethyl-4,5-dihydrospiro[furan-1’,3-isoindol-3’-one]-2-one (8a). White
solid; yield: 67%; mp 152-154 °C; IR (, cm-1, CHCl3) 1705, 1787; 1H NMR (300 MHz, CDCl3, 25 °C) δ
2.44 (dd, J = 14.0, J = 10.1 Hz, 1H), 2.63 (dd, J = 14.0, J = 6.0 Hz, 1H), 3.32 (dd, J = 10.1 J = 7.8 Hz,
1H), 3.51 (dd, J = 10.1, J = 3.9 Hz, 1H), 4.42 (d, J = 16.4 Hz, 1H), 4.82-4.96 (m, 1H), 5.11 (d, J = 16.4
Hz, 1H) ; 6.35-6.38 (m, 2H), 7.36-7.38 (m, 1H), 7.39-7.41 (m, 1H), 7.53-7.70 (m, 2H) , 7.86-7.89 (m, 1H),
13C NMR (75 MHz, CDCl3, 25 °C) δ 8.2 (CH2), 39.1 (2CH2), 70.1 (Cq), 76.4 (CH), 109.6 (CH), 111.0
(CH), 120.3 (CH), 124.6 (CH), 129.8 (CH), 129.9 (Cq), 133.0 (CH), 142.5 (CH), 144.1 (Cq), 149.3 (Cq),
168.2 (CO), 171.5 (CO). Anal. Calcd for C19H14BrNO3 (423.21) : C, 48.25; H, 3.33; N, 3.31. Found: C,
48.20; H, 3.35; N, 3.38.
5-(Bromomethyl)-2’-benzyl-4,5-dihydrospiro[furan-1’,3-isoindol-3’-one]-2-one (9a). White solid;
yield: 77%; mp 199-201 °C; IR (, cm-1, CHCl3) 1705, 1794; 1H NMR (300 MHz, CDCl3, 25 °C) δ 2.37
(dd, J = 14.0, J = 6.0 Hz, 1H), 2.51 (dd, J = 14.0, J = 10.1 Hz,1H), 3.49 (dd, J = 11.0, J = 3.9 Hz, 1H),
3.58 (dd, J = 11.0, J = 4.7 Hz, 1H), 4.12 (d, J = 16.4 Hz, 1H), 4.95-5.08 (m, 1H), 5.40 (d, J = 16.4 Hz,
1H), 7.27-7.43 (m, 6H), 7.52-7.63 (m, 2H), 7.92-7.96 (m, 1H), 13C NMR (50 MHz, CDCl3, 25 °C) δ 33.5
(CH2), 35.2 (CH2), 44.5 (CH2), 70.2 (Cq), 74.6 (CH), 120.3 (CH), 124.7 (CH), 127.6 (2CH), 127.7 (CH),
128.8 (2CH), 130.0 (CH), 130.5 (Cq), 132.8 (CH), 137.0 (Cq), 143.9 (Cq), 168.7 (CO), 171.4 (CO). Anal.
Calcd for C19H16BrNO3 (386.25) : C, 59.08; H, 4.18; N, 3.63. Found: C, 59.12; H, 4.15; N, 3.68.
5-(Bromomethyl)-2’-(4-methoxy-benzyl)-4,5-dihydrospiro[furan-1’,3-isoindol-3’-one]-2-one (10a).
1
White solid; yield: 60%; mp 118-120 °C; IR (, cm-1, CHCl3) 1704, 1794; H NMR (300 MHz, CDCl3,
25 °C) δ 2.38 (dd, J = 14.2, J = 6.2 Hz, 1H) 2.58 (dd, J = 14.2, J = 10.2 Hz, 1H), 3.53 (dd, J = 11.0, J =
3.9 Hz, 1H) 3.62 (dd, J = 11.0, J = 5.5 Hz, 1H), 3.79 (s, 3H), 4.12 (d, J = 15.7 Hz, 1H), 4.98-5.11 (m, 1H),
5.34 (d, J = 15.7 Hz, 1H), 6.85 (d, J = 8.6 Hz, 2H), 7.27-7.31 (m, 2H), 7.36-7.45 (m, 1H), 7.53-7.64 (m,

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13
2H), 7.91-7.97 (m, 1H), C NMR (75 MHz, CDCl3, 25 °C) δ 33.6 (CH2), 35.1 (CH2), 43.9 (CH2), 55.2
(CH3), 70.2 (Cq), 74.6 (CH), 114.1 (2CH), 120.3 (CH), 124.6 (CH), 128.1 (Cq), 129.0 (2CH), 129.9 (CH),
130.5 (Cq), 132.8 (CH), 143.9 (Cq), 159.1 (Cq), 168.7 (CO), 171.5 (CO). Anal. Calcd for C20H18BrNO4
(416.27) : C, 57.71; H, 4.36; N, 3.36. Found: C, 57.72; H, 4.35; N, 3.38.
5-(Bromomethyl)-2’-thiophen-2-ylmethyl-4,5-dihydrospiro[furan-1’,3-isoindol-3’-one]-2-one
(11a/b). White solid; yield: 73%; mp 181-183 °C; IR (, cm-1, CHCl3) 1710, 1795; dr: 75/25
Maj (11a): 1H NMR (300 MHz, CDCl3, 25 °C) δ 2.49 (dd, J = 13.7, J = 6.4 Hz, 1H), 2.74 (dd, J = 13.7,
J = 9.8 Hz, 1H), 3.61 (dd, J = 11.3, J = 3.9 Hz, 1H), 3.69 (dd, J = 11.3, J = 5.1 Hz, 1H), 4.44 (d, J =
Hz, 1H), 5.03-5.12 (m, 1H), 5.45 (d, J = 16.2 Hz, 1H), 6.94-6.97 (m, 1H), 7.08-7.10 (m, 1H), 7.40-7.42
13
(m, 1H), 7.55-7.61 (m, 3H), 7.92-7.95 (m, 1H), C NMR (75 MHz, CDCl3, 25 °C) δ 33.7 (CH2), 35.3
(CH2), 39.5 (CH2), 70.0 (Cq), 74.7 (CH), 120.3 (CH), 124.8 (CH), 126.0 (CH), 126.9 (2CH), 130.0 (CH),
130.3 (Cq), 132.9 (CH), 140.0 (Cq), 144.0 (Cq), 168.3 (CO), 171.4 (CO).
Min (11b): 1H NMR (300 MHz, CDCl3, 25 °C) δ 2.39 (dd, J = 14.2, J = 10.2 Hz, 1H), 2.66 (dd, J = 14.2,
J = 5.1 Hz, 1H,), 3.79 (dd, J = 11.3, J = 4.9 Hz, 1H), 3.87 (dd, J = 11.3, J = 3.7 Hz, 1H), 4.54 (d, J =
Hz, 1H), 4.73-4.81 (m, 1H), 5.33 (d, J = 15.4 Hz, 1H), 6.94-6.97 (m, 1H), 7.08-7.10 (m, 1H), 7.40-7.42
13
(m, 1H), 7.55-7.61 (m, 3H), 7.92-7.95 (m, 1H), C NMR (75 MHz, CDCl3, 25 °C) δ 34.3 (CH2), 36.5
(CH2), 39.6 (CH2), 69.1 (Cq), 75.0 (CH), 121.6 (CH), 124.4 (CH), 126.3 (CH), 127.0 (2CH), 129.9 (CH),
130.4 (Cq), 133.1 (CH), 139.0 (Cq), 144.0 (Cq), 168.3 (CO), 171.4 (CO). Anal. Calcd for C19H14BrNO3
(392.27) : C, 52.05; H, 3.60; N, 3.57. Found: C, 52.12; H, 3.65; N, 3.68.
5-(Bromomethyl)-2’-((S)-1-phenylethyl)-4,5-dihydrospiro[furan-1’,3-isoindol-3’-one]-2-one (16a/b):
Yield: 68%; d.r = 80/20
Maj (16a): White solid; mp 156-158°C; IR (ν, cm-1 CHCl3) 1705, 1795; 1H NMR (300 MHz, CDCl3,
25 °C) δ 1.25 (d, J = 7.2 Hz, 3H), 1.55 (dd, J = 14.7, J = 5.9 Hz, 1H) 1.58 (dd, J = 14.7, J = 10.1 Hz,
1H), 1.91 (dd, J = 11.0, J = 3.9 Hz, 1H) 2.00 (dd, J = 11.0, J = 5.3 Hz, 1H), 5.52-5.60 (m, 1H), 5.96 (q, J
= 7.3, 1H), 7.16-7.25 (m, 1H), 7.27-7.34 (m, 2H), 7.47-7.54 (m, 2H), 7.55-7.51 (m, 1H), 7.65-7.72 (m,
1H), 7.78-7.82 (m, 1H), 7.83-7.93 (m, 1H), 13C NMR (75 MHz, CDCl3, 25 °C) δ 17.5 (CH3), 30.9 (CH2),
37.5 (CH2), 57.7 (CH), 75.4 (Cq), 78.4 (CH), 123.4 (CH), 127.7 (CH), 128.1 (2CH), 128.4 (2CH), 130.3
(CH), 131.4 (CH), 132.7 (CH), 140.5 (Cq), 143.0 (Cq), 148.8 (Cq), 168.7 (CO), 168.9 (CO).
Min (16b): 1H NMR (300 MHz, CDCl3, 25 °C) δ 1.25 (d, J = 7.2 Hz, 3H), 1.44 (dd, J = 14.9, J = 10.3
Hz, 1H) 1.49 (dd, J = 14.9, J = 6.2 Hz, 1H), 1.91 (dd, J = 11.0, J = 5.5 Hz, 1H) 2.00 (dd, J = 11.0, J =
3.9 Hz, 1H), 5.52-5.60 (m, 1H), 5.86 (q, J = 7.3, 1H), 7.16-7.25 (m, 1H), 7.27-7.34 (m, 2H), 7.47-7.54 (m,
13
2H), 7.55-7.51 (m, 1H), 7.65-7.72 (m, 1H), 7.78-7.82 (m, 1H), 7.83-7.93 (m, 1H), C NMR (75 MHz,
CDCl3, 25 °C) δ 17.1 (CH3), 29.6 (CH2), 37.6 (CH2), 54.1 (CH), 75.3 (Cq), 79.6 (CH), 123.6 (CH), 127.6
(CH), 128.0 (2CH), 128.3 (2CH), 129.4 (CH), 131.9 (CH), 133.2 (CH), 140.7 (Cq), 142.8 (Cq), 148.9

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(Cq), 168.2 (CO), 169.8 (CO). Anal. Calcd for C20H18BrNO3 (400.28): C, 60.01; H, 4.53; N, 3.50. Found:
C, 60.02; H, 4.55; N, 3.38.
5-(Iodomethyl)-2’-((S)-1-phenylethyl)-4,5-dihydrospiro[furan-1’,3-isoindol-3’-one]-2-one (17a/b):
Yield: 57%; d.r = 75/25
Maj (17a): White solid; mp 138-140 °C; IR (ν, cm-1 CHCl3) 1704, 1785; 1H NMR (300 MHz, CDCl3,
25 °C) δ 1.23 (d, J = 7.2 Hz, 3H), 1.41 (dd, J = 14.8, J = 10.0 Hz, 1H) 1.56 (dd, J = 14.8, J = 6.1 Hz,
1H), 1.98 (dd, J = 11.4, J = 5.7 Hz, 1H) 2.16 (dd, J = 11.4, J = 4.3 Hz, 1H), 4.00-4.19 (m, 1H), 5.85 (q, J
13
= 7.3, 1H), 7.37-7.53 (m, 4H), 7.54-7.70 (m, 2H), 7.72-7.90 (m, 2H), 7.91-7.96 (m, 1H), C NMR (75
MHz, CDCl3, 25 °C) δ 7.9 (CH2), 17.0 (CH3), 30.9 (CH2), 60.4 (CH), 74.0 (Cq), 76.2 (CH), 123.5 (CH),
124.7 (CH), 127.4 (2CH), 128.2 (2CH), 128.8 (CH), 130.2 (Cq), 131.8 (CH), 133.9 (CH), 140.5 (Cq),
147.2 (Cq), 167.2 (CO), 176.5 (CO).
Min (17b): 1H NMR (300 MHz, CDCl3, 25 °C) δ 1.20 (d, J = 7.2 Hz, 3H), 1.39 (dd, J = 14.8, J = 6.1 Hz,
1H) 1.53 (dd, J = 14.8, J = 10.1 Hz, 1H), 1.95 (dd, J = 11.4, J = 3.9 Hz, 1H) 2.11 (dd, J = 11.4, J = 5.7
Hz, 1H), 3.59-3.84 (m, 1H), 4.64 (q, J = 7.3, 1H), 7.37-7.53 (m, 4H), 7.54-7.70 (m, 2H), 7.72-7.90 (m,
13
2H), 7.91-7.96 (m, 1H), C NMR (75 MHz, CDCl3, 25 °C) δ 9.3 (CH2), 14.2 (CH3), 29.7 (CH2), 57.9
(CH), 74.5 (Cq), 76.1 (CH), 123.1 (CH), 126.1 (CH), 127.9 (2CH), 128.4 (CH), 128.7 (2CH), 129.7 (Cq),
132.5 (CH), 133.6 (CH), 136.1 (Cq), 150.8 (Cq), 167.7 (CO), 177.0 (CO). Anal. Calcd for C20H18INO3
(447.28): C, 53.71; H, 4.06; N, 3.13. Found: C, 53.82; H, 4.05; N, 3.18.
REFERENCES AND NOTES
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3. For a example see: (a) M. Pattarozzi, C. Zonta, Q. B. Broxterman, B. Kaptein, R. De Zorzi, L.
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A. Macritchie, T. M. Peakman, A. Silcock, and C. L. Willis, Tetrahedron Lett., 1998, 39, 7415.
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5. (a) M. M. Rammah, M. Othman, K. Ciamala, C. Strohmann, and M. B. Rammah, Tetrahedron,
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Rammah, M. Othman, M. Msaddek, and M. B. Rammah, Heterocycles, 2008, 75, 1971; (d) M. J.
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Synth. Commun.,1996, 26, 2803.
6. Full crystallographic data have been deposited to the Cambridge Crystallographic Data Center
(CCDC reference number 716551 for product 9a. Copies of the data can be obtained free of charge
at http://www.ccdc.cam.ac.uk
7. (a) P. A. Bartlet and J. Myerson, J. Am. Chem., Soc., 1978, 100, 3950; (b) P. A. Bartlett and J.
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175.