Regio- and stereoselective synthesis of isoindolin-1-ones via electrophilic cyclization

Article abstract of DOI:10.1021/jo048007c

(Chemical Equation Presented) A variety of substituted isoindolin-1-ones are readily prepared in good to excellent yields under very mild reaction conditions by the reaction of o-(1-alkynyl)benzamides with ICl, I₂, and NBS. In a few cases, subs

Full text of DOI:10.1021/jo048007c

Regio- and Stereoselective Synthesis of Isoindolin-1-ones via
Electrophilic Cyclization
Tuanli Yao and Richard C. Larock*
Department of Chemistry, Iowa State University, Ames, Iowa 50011
larock@iastate.edu
Received November 10, 2004
A variety of substituted isoindolin-1-ones are readily prepared in good to excellent yields under
very mild reaction conditions by the reaction of o-(1-alkynyl)benzamides with ICl, I2, and NBS. In
a few cases, substituted isoquinolin-1-ones were obtained as the major product instead. This
methodology accommodates various alkynyl amides and functional groups and has been successfully
extended to heterocyclic starting materials. This chemistry has been successfully applied to the
synthesis of a biologically interesting alkaloid, cepharanone B.
SCHEME 1
Introduction
The isoindolin-1-one ring system represents a key
structural subunit in numerous natural and synthetic
products that exhibit a wide range of biological activities,
including antihypertensive,1 antiinflammatory,2 antiul-
cer,3 and antileukemic4 properties. For example, magal-
lanesine (I), an isoindolobenzazocine, has been isolated
from various Berberis species (Scheme 1).5 Aristolactams
(II) are found exclusively among the plants of the family
Aristolochiaceae.6 The current interest elicited by these
fused phenanthrene lactams arises from their varied
pharmaceutical and biological activities reported in folk
medicine7 and as immunostimulant and anticancer
agents.6
nones have been prepared via Grignard8 or lithiation9
procedures, as well as by Wittig,10 Diels-Alder,4,11 rear-
rangement,12 and photochemical reactions.13 The reduc-
tion of N-substituted phthalimides14 and the condensa-
Considerable efforts have been directed toward the
synthesis of isoindolinones (phthalimidines). Isoindoli-
(8) (a) Heidenbluth, V. K.; Tonjes, H.; Scheffier, R. J. Prakt. Chem.
1965, 30, 204. (b) Ang, W. S.; Halton, B. B. Aust. J. Chem. 1971, 24,
851.
(9) (a) Watanabe, H.; Mao, C.-L.; Barnish, I. T.; Hauser, C. R. J.
Org. Chem. 1969, 34, 919. (b) Parham, W. E.; Jones, L. D. J. Org. Chem.
1976, 41, 1188. (c) Couture, A.; Deniau, E.; Grandclaudon, P. Tetra-
hedron 1997, 53, 10313. (d) Couture, A.; Deniau, E.; Ionescu, D.;
Grandclaudon, P. Tetrahedron Lett. 1998, 39, 2319.
(10) (a) Flitsch, W.; Peters, H. Tetrahedron Lett. 1969, 1161. (b) Mali,
R. S.; Yeola, S. Synthesis 1986, 755. (c) Epsztajn, J.; Grzelak, R.;
Jozwiak, A. Synthesis 1996, 1212.
(1) Ferland, J.-M.; Demerson, C. A.; Humber, L. G. Can. J. Chem.
1985, 63, 361.
(2) Li, S.; Wang, X.; Guo, H.; Chen, L. Yiyao Gongye 1985, 16, 543;
Chem. Abstr. 1985, 105, 3788.
(3) Lippmann, W. U.S. Patent 4 267 189, 1981; Chem. Abstr. 1981,
95, 61988m.
(4) Taylor, E. C.; Zhou, P.; Jenning, L. D.; Mao, Z.; Hu, B.; Jun, J.-
G. Tetrahedron Lett. 1997, 38, 521.
(11) Gutierrez, A. J.; Shea, K. J.; Svoboda, J. J. J. Org. Chem. 1989,
54, 4335.
(5) Valencia, E.; Fajardo, V.; Freyer, A. J.; Shamma, M. Tetrahedron
Lett. 1985, 26, 993.
(12) Guillaumel, J.; Boccara, N.; Demersemann, P.; Royer, R. J.
Chem. Soc., Chem. Commun. 1988, 1604.
(6) (a) Chang, Z.-L.; Zhu, D.-Y. In The Alkaloids; Brossi, A., Ed.;
Academic Press: New York, 1987; Vol. 31, p 29. (b) Han, D. S.; Cheng,
B. S.; Chi, H. J.; Lee, H. S. Korean J. Pharmacogn. 1989, 20, 1. (c)
Lee, H. S.; Han, D. S.; Won, D. K. Korean J. Pharmacogn. 1990, 21,
52.
(13) (a) Freccero, M.; Fasani, E.; Albini, A. J. Org. Chem. 1993, 58,
1740. (b) Weidner-Wells, M. A.; Oda, K.; Mazzocchi, P. H. Tetrahedron
1997, 53, 3475.
(14) (a) Brewster, J. H.; Fusco, A. M.; Carosino, L. E.; Corman, B.
G. J. Org. Chem. 1963, 28, 498. (b) Milewska, M. J.; Bytner, T.;
Polonski, T. Synthesis 1996, 1485.
(7) Kijjoa, A.; Pinto, M. M. M.; Tantisewie, B.; Herz, W. Planta Med.
1989, 55, 193.
10.1021/jo048007c CCC: $30.25 © 2005 American Chemical Society
Published on Web 01/27/2005
1432
J. Org. Chem. 2005, 70, 1432-1437

Synthesis of Isoindolin-1-ones via Electrophilic Cyclization
SCHEME 2
TABLE 1. Iodocyclization of o-(1-Alkynyl)benzamide 1
tion of phthalaldehyde15 also afford isoindolinones. Besides
the classical methods, metal-catalyzed syntheses of isoin-
dolinones have also been reported. Cobalt and rhodium
carbonyl complexes can be used as the catalysts to
synthesis isoindolinones.16 Several examples of palladium
catalysis have appeared.17 Recently, the intramolecular
cyclization of alkynamides has been reported to produce
isoindolinones.18
(eq 1)a
time % yield % yield
entry electrophile
base
solvent (h)
of 2
of 3
1b
2
ICl
I2
CH2Cl2 0.5
54
60
75
86
85
40
20
14
10
8
CH2Cl2
CH3CN
1
1
1
1
3
I2
4
5
I2
I2
NaHCO3 CH3CN
NaHCO3 MeOH
We and others have developed methods for the syn-
thesis of benzo[b]thiophenes,19 isoquinolines and naph-
thyridines,20 isocoumarins and R-pyrones,21 benzofurans,22
furans,23 indoles,24 furopyridines,25 cyclic carbonates,26
2,3-dihydropyrroles and pyrroles,27 pyrilium salts,28 and
bicyclic â-lactams29 via electrophilic cyclization of func-
tionally substituted alkynes. In a continuation of our
studies, we have investigated the possibility of using
electrophilic cyclization for the synthesis of isoindolinones
and isoquinolinones. Herein, we report the successful
electrophilic cyclization of o-(1-alkynyl)benzamides for
a All reactions were run under the following conditions, unless
otherwise indicated: 0.30 mmol of 1, 0.90 mmol of electrophile,
and 0.90 mmol of base in 3 mL of solvent were stirred at room
temperature under Ar for the specified period of time. b 0.36 mmol
of electrophile was employed.
the synthesis of isoindolinones. This chemistry generally
produces good to excellent yields of the five-membered
ring lactams with good regioselectivity.
Results and Discussion
A two-step approach to isoindolinones has been exam-
ined involving (i) preparation of o-(1-alkynyl)benzamides
by a Sonagashira coupling reaction,30 and (ii) electrophilic
cyclization (Scheme 2).
The o-(1-alkynyl)benzamides required for our approach
are readily prepared by Sonogashira coupling30 of the
corresponding iodobenzamides with terminal alkynes
using 2% PdCl2(PPh3)2 and 1% CuI in Et3N solvent at
55 °C. The yields of this process range from 74 to 99%,
and this procedure should readily accommodate consider-
able functionality.
(15) (a) Yamamoto, I.; Tabo, Y.; Gotoh, H. Tetrahedron Lett. 1971,
2295. (b) Dominh, T.; Johnson, A. L.; Jones, J. E.; Senise, P. P., Jr. J.
Org. Chem. 1977, 42, 4217. (c) Grigg, R.; Gunaratne, H. Q. N.;
Sridharan, V. J. Chem. Soc., Chem. Commun. 1985, 1183. (d) Taka-
hashi, I.; Kawakami, T.; Hirano, E.; Yokota, H.; Kitajima, H. Synlett
1996, 353. (e) Takahashi, I.; Hatanaka, M. Heterocycles 1997, 45, 2475.
(16) Wilkinson, G.; Stone, F. G. A.; Abel, E. W. Comprehensive
Organometallic Chemistry, 1st ed.,; Pergamon: Oxford, 1982; Vol. 1.
(17) (a) Mori, M.; Chiba, K.; Ban, Y. J. Org. Chem. 1978, 43, 1684.
(b) Larock, R. C.; Liu, C.-L.; Lau, H. H.; Varaprath, S. Tetrahedron
Lett. 1984, 25, 4459. (c) Burns, B.; Grigg, R.; Santhakumar, V.;
Sridharan, V.; Stevenson, P.; Worakun, T. Tetrahedron 1992, 48, 7297.
(e) Cho, C. S.; Jiang, L. H.; Shim, S. C. Synth. Commun. 1998, 28,
849. (f) Kundu, N. G.; Khan, M. W. Tetrahedron 2000, 56, 4777. (g)
Kondo, Y.; Shiga, F.; Murata, N.; Sakamoto, T.; Yamanaka, H.
Tetrahedron 1994, 50, 11803.
The reaction of o-(1-alkynyl)benzamide 1 with electro-
philes was chosen as a model system for optimization of
this electrophilic cyclization process (eq 1). The results
are summarized in Table 1.
(18) (a) Koseki, Y.; Kusano, S.; Sakata, H.; Nagasaka, T. Tetrahedron
Lett. 1999, 40, 2169. (b) Kundu, N. G.; Khan, M. W.; Mukhopadhyay,
R. Tetrahedron 1999, 55, 12361.
(19) (a) Larock, R. C.; Yue, D. Tetrahedron Lett. 2001, 42, 6011. (b)
Yue, D.; Larock, R. C. J. Org. Chem. 2002, 67, 1905. (c) Flynn, B. L.;
Verdier-Pinard, P.; Hamel, E. Org. Lett. 2001, 3, 651.
(20) (a) Huang, Q.; Hunter, J. A.; Larock, R. C. Org. Lett. 2001, 3,
2973. (b) Huang, Q.; Hunter, J. A.; Larock, R. C. J. Org. Chem. 2002,
67, 3437.
(21) (a) Yao, T.; Larock, R. C. Tetrahedron Lett. 2002, 43, 7401. (b)
Yao, T.; Larock, R. C. J. Org. Chem. 2003, 68, 5936. (c) Oliver, M. A.;
Gandour, R. D. J. Org. Chem. 1984, 49, 558. (d) Biagetti, M.; Bellina,
F.; Carpita, A.; Stabile, P.; Rossi, R. Tetrahedron 2002, 58, 5023. (e)
Rossi, R.; Carpita, A.; Bellina, F.; Stabile, P.; Mannina, L. Tetrahedron
2003, 59, 2067.
Benzamide 1 reacts at room temperature in CH2Cl2 to
afforded a mixture of lactams 2 and 3 (Table 1, entry 1).
Compared with the stronger electophile ICl, the weaker
electrophile I2 shows better regioselectivity (compare
entries 1 and 2). The regioselectivity of this process also
depends on the solvent employed in the reaction. Using
CH3CN as the solvent afforded better regioselectivity and
(22) Arcadi, A.; Cacchi, S.; Fabrizi, G.; Marinelli, F.; Moro, L. Synlett
1999, 1432.
(23) (a) Bew, S. P.; Knight, D. W. J. Chem. Soc., Chem. Commun.
1996, 1007. (b) Djuardi, E.; McNelis, E. Tetrahedron Lett. 1999, 40,
7193.
(24) Barluenga, J.; Trincado, M.; Rublio, E.; Gonzalez, J. M. Angew.
Chem., Int. Ed. 2003, 42, 2406.
(25) Arcadi, A.; Cacchi, S.; Di Giuseppe, S.; Fabrizi, G.; Marinelli,
F. Org. Lett. 2002, 4, 2409.
(26) Marshall, J. A.; Yanik, M. M. J. Org. Chem. 1999, 64, 3798.
(27) Knight, D. W.; Redfern, A. L.; Gilmore, J. J. Chem. Soc., Chem.
Commun. 1998, 2207.
(30) For reviews, see: (a) Campbell, I. B. The Sonogashira Cu-Pd-
Catalyzed Alkyne Coupling Reaction. Organocopper Reagents; Taylor,
R. J. K., Ed.; IRL Press: Oxford, UK, 1994; pp 217-235. (b) Sono-
gashira, K.; Takahashi, S. Yuki Gosei Kagaku Kyokaishi 1993, 51,
1053. (c) Sonogashira, K. In Comprehensive Organic Synthesis; Trost,
B. M., Ed.; Pergamon: Oxford, 1991; Vol. 3, pp 521-549.
(28) Barluenga, J.; Vazque-Villa, H.; Ballesteros, A.; Gonzalez, J.
M. J. Am. Chem. Soc. 2003, 125, 9028.
(29) Ren, X.-F.; Konaklieva, M. I.; Shi, H.; Dickey, S.; Lim, D. V.;
Gonzalez, J.; Turos, E. J. Org. Chem. 1998, 63, 8898.
J. Org. Chem, Vol. 70, No. 4, 2005 1433

Yao and Larock
a higher yield than CH2Cl2 (compare entries 2 and 3).
The yield and selectivity can be further improved by
adding NaHCO3 to neutralize the acid generated in the
reaction (compare entries 3 and 4). A similar yield and
regioselectivity were also obtained when using MeOH as
the solvent (entry 5). Thus, we have chosen the following
reaction conditions A for the synthesis of isoindolin-1-
ones: 0.30 mmol of the o-(1-alkynyl)benzamide, 3 equiv
of I2, and 3 equiv of NaHCO3 in 3 mL of CH3CN stirred
at room temperature for 1 h. We have also employed
reaction conditions B on occasion: 0.30 mmol of the o-(1-
alkynyl)benzamide and 1.2 equiv of ICl in 3 mL of
CH2Cl2 stirred at room temperature for 0.5 h. The
reaction of amide 1 with bis(collidine)iodonium hexafluoro-
phosphate in CH2Cl2 afforded only very slow reactions
and a mixture of five- and six-membered ring lactams
with the former predominating.
To explore the scope of this electrophilic cyclization
strategy, the reactions of alkynyl amide 1 with different
electrophiles (ICl, I2, NBS, p-O2NC6H4SCl, and PhSeCl)
at room temperature have been studied (Table 2, entries
1-5). When using ICl, I2, and NBS as the electrophilic
reagents, a mixture of five- and six-membered ring
products has been obtained. In all cases, the five-
membered ring product predominates. However, ICl
generally affords larger amounts of the six-membered
ring lactam. When using p-O2NC6H4SCl and PhSeCl, the
reaction proceeds smoothly. Unfortunately, the five-
membered ring products could not be isolated because
they appear to decompose easily. Only small amounts of
the six-membered ring products could be isolated.
The effect of ICl and I2 on the regiochemistry of ring
closure of several different amide moieties has been
examined (compare entries 1 and 2, 7 and 8, and 9 and
10). Although the results vary somewhat with the nature
of the substituent on the nitrogen, I2 exhibits much better
regioselectivity than ICl in all cases examined. A small
amount of the six-membered ring product is always
observed. However, when using I2 and nonsubstituted or
disubstituted amides, none of the desired cyclization
products could be obtained (entries 11 and 12).
A wide variety of alkynylarenecarboxamides have been
examined in this cyclization process. First of all, using
N-phenylcarboxamides, we have examined the effect of
various substituents on the remote end of the alkyne
moiety (entries 13-16). Aryl- (entries 1 and 2) and a long-
chain alkyl-substituted alkyne 22 (entry 13) afford
similar results. Even the TMS-substituted alkyne 25
underwent smooth iodocyclization with I2 (entry 14). The
isoindolinone 26 was obtained in 77% yield, along with
a small amount of the corresponding diiodoisoquinolinone
27. Obviously, the silyl group in the isoquinolinone has
undergone iododesilylation either prior to or soon after
cyclization. Surprisingly, the presence of an olefin (entries
15 and 16) affords the six-membered ring isoquinolinone
30 as the major product, no matter whether ICl or I2 is
used. The six-membered ring lactam is formed fairly
cleanly when using ICl (entry 16).
group has been replaced by a hydrogen failed to give any
recognizable products (entry 18).
This electrophilic cyclization is not limited to simple
benzene-containing aromatics. The pyridine-containing
substrates 37, 40, and 43 have also been observed to give
good yields of cyclization products (entries 19-25). A
comparison of entry 19 with entry 20 indicates that a
higher yield of the five-membered ring product 38 can
actually be obtained using a shorter reaction time. It
appears that this isoindolinone is somewhat unstable
under the reaction conditions. Interestingly, using ICl
produces the six-membered ring product 39 as the major
product, while I2 affords the five-membered ring product
as the major isomer (compare entries 20 and 21). The
alkyl-substituted alkyne 40 reacts in a similar fashion
affording the five-membered ring lactam 41 as the major
product when using I2 and generating the six-membered
ring product 42 as the major product when ICl is used
as the electrophile (entries 22 and 23). Introduction of a
vinylic moiety directly on the alkyne leads to exclusive
six-membered ring formation no matter whether I2 or ICl
is employed (entries 24 and 25).
We have also briefly examined the cyclization of a ring-
containing alkenynamide 46. The five-membered ring
substrate 46 reacts with I2 to afford a mixture of lactams
47 and 48 in which the six-membered ring product 48
predominates presumably due to ring strain (entry 26).
The isoindolinones have been distinguished from the
isoquinolinones on the basis of their IR spectra. The five-
membered ring products generally exhibit a carbonyl
absorption band at 1710-1680 cm-1, while in the six-
membered ring products the carbonyl absorption is
observed at 1640-1650 cm-1. The (E)-stereochemistry of
isoindolinone 32 has been assigned using a NOESY
experiment. This compound exhibits a cross-peak be-
tween the CH2 of the benzyl group and the CH3 of the
TMS group. The stereochemistry of the other isoindoli-
nones is assigned by analogy to lactam 32.
We propose the following mechanism for this electro-
philic cyclization (Scheme 3). Nucleophilic attack by the
nitrogen of the amide group on the carbon-carbon triple
bond activated by coordination to I+ is followed by
deprotonation to afford the cyclized products.
An interesting feature of this process is the fact that
the isoindolinones and isoquinolinones produced by iodo-
cyclization can be further elaborated using various pal-
ladium-catalyzed processes. For example, the Sonagash-
ira reaction30 of lactam 2 affords the coupling product
49 in an excellent yield (eq 2).
To further demonstrate the versatility of this electro-
philic cyclization chemistry, we have applied this meth-
odology to the synthesis of the biologically interesting
alkaloid cepharanone B. Cepharanone B displays many
pharmacological activities, including fertility-regulat-
The effect of substitution on the aromatic ring has also
been examined. Isoindolinone 32 bearing two electron-
donating methoxy substituents on the aromatic ring and
a silyl moiety has been obtained in a good yield (entry
17). However, the corresponding alkyne in which the silyl
1434 J. Org. Chem., Vol. 70, No. 4, 2005

Synthesis of Isoindolin-1-ones via Electrophilic Cyclization
TABLE 2. Electrophilic Cyclization of Alkynyl Carboxamidesa
a All reactions were run under the following conditions, unless otherwise specified: 0.3 mmol of the alkynamide, 3 equiv of the electrophile,
and 3 equiv of NaHCO3 in 3 mL of CH3CN at room temperature for 1 h. b 0.3 mmol of the alkynamide and 1.2 equiv of the electrophile
in 3 mL of CH2Cl2 at room temperature for 0.5 h.
J. Org. Chem, Vol. 70, No. 4, 2005 1435

Yao and Larock
SCHEME 3
mild reaction conditions has been developed. A wide
variety of alkynyl amides bearing various functional
groups readily undergo cyclization using I2 and ICl. The
resulting iodine-containing products are readily elabo-
rated to more complex products using known organopal-
ladium chemistry. This methodology should prove quite
useful for the synthesis of biologically interesting isoin-
dolin-1-ones such as the aristolactams.
Experimental Section
General Procedure for Preparation of the Alkynyl-
amides. To a solution of the corresponding organic iodide (1.0
mmol) and the terminal alkyne (1.2 mmol, 1.2 equiv) in Et3N
(4 mL) were added PdCl2(PPh3)2 (1.4 mg, 2 mol %) and CuI
(2.0 mg, 1 mol %). The resulting mixture was then heated
under an N2 atm at 55 °C. The reaction was monitored by TLC
to establish completion. When the reaction was complete, the
mixture was allowed to cool to room temperature, and the
ammonium salt was removed by filtration. The solvent was
removed under reduced pressure, and the residue was purified
by column chromatography on silica gel to afford the corre-
sponding alkynylamide.
SCHEME 4
N-Phenyl 2-(phenylethynyl)benzamide (1). Purification
by flash chromatography (5:1 hexane/EtOAc) afforded 218.2
mg (74%) of the product as a white solid with spectral
properties identical to those previously reported: mp 150-
152 °C (lit.15f mp 151-153 °C).
General Procedure for Electrophilic Cyclization of
the Alkynylamides by ICl. The alkynylamide (0.30 mmol)
in 3 mL of CH2Cl2 was placed in a 4 dram vial and flushed
with N2. The ICl (1.2 equiv) in 0.5 mL of CH2Cl2 was added
dropwise to the vial by a syringe. The reaction was stirred at
room temperature for 30 min unless otherwise indicated. The
reaction mixture was then diluted with 50 mL of ether, washed
with 25 mL of satd aq Na2S2O3, dried (MgSO4), and filtered.
The solvent was evaporated under reduced pressure, and the
product was isolated by chromatography on a silica gel column.
(3E)-3-[Iodo(phenyl)methylene]-2-phenylisoindolin-1-
one (2). Purification by flash chromatography (10:1 hexane/
EtOAc) afforded 68.8 mg (54%) of the product as a yellow
ing,31 cyclooxygenase inhibitory,32 and cytotoxic activity.33
Although the synthesis of cepharanone B has been
achieved previously,34 our approach may provide a useful
alternative to existing methodology.
The construction of the isoindolinone unit of lactam 53
has been accomplished by using our iodocyclization
chemistry (Scheme 4). The requisite starting alkyne 52
is easily prepared using straightforward methodology and
the Sonogashira reaction of aryl iodide 51 and trimethyl-
silyl acetylene. The iodocyclization of amide 52 afforded
an 80% yield of vinylic iodide 53. Desilylation and Suzuki
cross-coupling with 2-bromophenylboronic acid afforded
the (Z)-arylmethylene-1H-isoindolin-1-one 54 in good
yield. Initially we tried to obtain the fused aristolactam
directly via organopalladium chemistry. Unfortunately,
none of the desired aristolactam could be obtained.
However, this constitutes a convenient synthesis of the
intermediate 54, which should prove useful for the
synthesis of the desired cepharanone B using previous
reported methodology.34
1
solid: mp 97-99 °C; H NMR (CDCl3) δ 7.09 (t, J ) 6.6 Hz,
1H), 7.22-7.36 (m, 7H), 7.59-7.73 (m, 4H), 8.05 (d, J ) 7.5
Hz, 1H), 8.86 (d, J ) 7.8 Hz, 1H); 13C NMR (CDCl3) δ 124.1,
125.07, 125.1, 125.4, 128.1, 128.7, 130.5, 130.9, 132.0, 132.8,
135.8, 140.6, 145.0, 147.8, 152.0 (one carbon missing due to
overlap); IR (neat, cm-1) 1684; HRMS calcd for C21H14INO
423.0120, found 423.0129.
4-Iodo-2,3-diphenylisoquinolin-1(2H)-one (3). Purifica-
tion by flash chromatography (10:1 hexane/EtOAc) afforded
50.5 mg (40%) of the product as a light yellow solid: mp 131-
132 °C; 1H NMR (CDCl3) δ 7.06 (t, J ) 7.3 Hz, 1H), 7.20-7.33
(m, 4H), 7.39-7.41 (m, 3H), 7.49 (t, J ) 7.5 Hz, 1H), 7.59-
7.67 (m, 3H), 7.76 (d, J ) 7.5 Hz, 1H), 8.40 (d, J ) 7.8 Hz,
1H); 13C NMR (CDCl3) δ 123.1, 124.0, 124.1, 127.7, 128.2,
128.9, 129.4, 130.1, 130.2, 131.5, 133.2, 135.0, 135.6, 146.1,
148.7, 153.4; IR (neat, cm-1) 1645; HRMS calcd for C21H14INO
423.0120, found 423.0129.
General Procedure for Electrophilic Cyclization of
the Alkynylamides by I2. The alkynylamide (0.30 mmol), I2
(3.0 equiv), NaHCO3 (3.0 equiv), and 3 mL of CH3CN were
placed in a 4 dram vial and flushed with N2. The reaction was
stirred at room temperature for 60 min unless otherwise
indicated. The reaction mixture was then diluted with 50 mL
of ether, washed with 25 mL of satd aq Na2S2O3, dried
(MgSO4), and filtered. The solvent was evaporated under
reduced pressure, and the product was isolated by chroma-
tography on a silica gel column.
Conclusions
An efficient, regio- and stereoselective synthesis of
indolinones from o-(1-alkynyl)benzamides under very
(31) Che, C. T.; Ahmed, M. S.; Kang, S. S.; Waller, D. P.; Bingel, A.
S.; Martin, A.; Rajamahendran, P.; Bunyapraphatsara, N.; Lamkin.
D. C. J. Nat. Prod. 1984, 47, 331.
(32) Proebstle, A.; Bauer, R. Planta Med. 1992, 58, 568.
(33) Sun, N. J.; Antoun, M.; Chang C. J. J. Nat. Prod. 1987, 50,
843.
(34) (a) Couture, A.; Deniau, E.; Grandclaudon, P.; Lebrun, S. Synlett
1997, 1475. (b) Couture, A.; Deniau, E.; Grandclaudon, P.; Hoarau, C.
J. Org. Chem. 1998, 63, 3128.
(3E)-3-[Iodo(phenyl)methylene]-2-methylisoindolin-1-
one (11). Purification by flash chromatography (7:1 hexane/
EtOAc) afforded 86.2 mg (80%) of the product as a yellow
1436 J. Org. Chem., Vol. 70, No. 4, 2005

Synthesis of Isoindolin-1-ones via Electrophilic Cyclization
1
solid: mp 122-125 °C; H NMR (CDCl3) δ 3.16 (s, 3H), 7.28
Hz, 1H), 8.64 (d, J ) 8.1 Hz, 1H); IR (neat, cm-1) 1690; HRMS
(t, J ) 7.2 Hz, 1H), 7.39 (t, J ) 7.5 Hz, 2H), 7.52-7.67 (m,
4H), 7.85 (d, J ) 7.5 Hz, 1H), 8.83 (d, J ) 7.8 Hz, 1H); 13C
NMR (CDCl3) δ 35.2, 73.5, 123.2, 125.2, 128.2, 128.5, 130.4,
calcd for C16H12BrNO 375.0259, found 375.0266.
Acknowledgment. We gratefully acknowledge the
donors of the Petroleum Research Fund, administered
by the American Chemical Society, the National Science
Foundation and the National Institute of General Medi-
cal Sciences (GM070620) for partial support of this
research, and Johnson Matthey, Inc., and Kawaken Fine
Chemicals Co., Ltd. for donations of palladium catalysts.
130.8, 131.4, 132.0, 136.2, 140.9, 147.5, 154.9; IR (neat, cm-1
)
1714; HRMS calcd for C16H12INO 360.9964, found 360.9968.
General Procedure for Electrophilic Cyclization of
the Alkynylamides by NBS. The alkynylamide (0.30 mmol),
NBS (1.5 equiv), and CH2Cl2 (3 mL) were placed in a 4 dram
vial and flushed with N2. The reaction mixture was stirred at
room temperature for 1 h unless otherwise indicated. The
solvent was evaporated under reduced pressure, and the
product was isolated by chromatography on a silica gel column.
(3E)-3-[Bromo(phenyl)methylene]-2-phenylisoindolin-
1-one (4). Purification by flash chromatography (5:1 hexane/
EtOAc) afforded 93.2 mg (82%) of the product as a white
Supporting Information Available: Characterization
data for the compounds listed in Table 2 and experimental
procedures and characterization data for the reactions sum-
marized in eq 2 and Scheme 4. This material is available free
of charge via the Internet at http://pubs.acs.org.
1
solid: mp 90-92 °C; H NMR (CDCl3) δ 7.13 (t, J ) 7.2 Hz,
1H), 7.26-7.41 (m, 7H), 7.60-7.75 (m, 4H), 8.06 (d, J ) 6.6
JO048007C
J. Org. Chem, Vol. 70, No. 4, 2005 1437