A convenient synthesis of 2,3-dihydro-3-methylidene-1H-isoindol-1-ones by reaction of 2-formylbenzonitriles with dimethyloxosulfonium methylide

Article abstract of DOI:10.1002/hlca.201000035

A facile method for the synthesis of 2,3-dihydro-3-methylidene-1H-isoindol- 1-one and its derivatives carrying substituent(s) at C(5) and/or C(6) has been developed. The reaction of 2-formylbenzonitrile (1a) with dimethyloxosulfonium methylide, generated by the treatment of trimethylsulfoxonium iodide with NaH in DMSO/THF at 0°, resulted in the formation of 2,3-dihydro-3-methylidene- 1Hisoindol-1-one (2a) in 77% yield. Similarly, six 2-formylbenzonitriles carrying substituent(s) at C(4) and/ or C(5), i.e., 1b - 1g, also gave the corresponding expected products 2b - 2g in comparable yields.

Full text of DOI:10.1002/hlca.201000035

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Helvetica Chimica Acta – Vol. 93 (2010)
A Convenient Synthesis of 2,3-Dihydro-3-methylidene-1H-isoindol-1-ones by
Reaction of 2-Formylbenzonitriles with Dimethyloxosulfonium Methylide
by Kazuhiro Kobayashi*, Kota Matsumoto, Daizo Nakamura, Shuhei Fukamachi, and Hisatoshi Konishi
Division of Applied Chemistry, Department of Chemistry and Biotechnology, Graduate School of
Engineering, Tottori University, 4-101 Koyama-minami, Tottori 680-8552, Japan
(phone/fax: þ 81-857-315263; e-mail: kkoba@chem.tottori-u.ac.jp)
A facile method for the synthesis of 2,3-dihydro-3-methylidene-1H-isoindol-1-one and its deriva-
tives carrying substituent(s) at C(5) and/or C(6) has been developed. The reaction of 2-formylbenzoni-
trile (1a) with dimethyloxosulfonium methylide, generated by the treatment of trimethylsulfoxonium
iodide with NaH in DMSO/THF at 08, resulted in the formation of 2,3-dihydro-3-methylidene-1H-
isoindol-1-one (2a) in 77% yield. Similarly, six 2-formylbenzonitriles carrying substituent(s) at C(4) and/
or C(5), i.e., 1b – 1g, also gave the corresponding expected products 2b – 2g in comparable yields.
Introduction. – The use of dimethyloxosulfonium methylide, generated from
trimethylsulfoxonium iodide and an appropriate base, for the preparation of epoxides
from carbonyl compounds has already been described in the literature [1]. In this
article, we describe the results of our study on the reaction of 2-formylbenzonitriles
with this sulfur ylide. We have found that the reaction provides a convenient method to
prepare 2,3-dihydro-3-methylidene-1H-isoindol-1-ones. Some molecules including 3-
alkyl- or 3-arylmethylideneisoindol-1-one moiety have been shown to possess consid-
erable medicinal versatility [2]1). The development of synthetic protocols for the
preparation of this class of heterocycles from readily available starting materials has,
consequently, attracted the attention of several groups recently [3]. However, there are
a few reports on the methods applicable to the preparation of 2,3-dihydro-3-
methylidene-1H-isoindol-1-ones [3a][3f][3g][4]. For example, the construction of
this skeleton by treating 1-(2-bromophenyl)ethanones with titanium – isocyanate
complex prepared from TiCl4 under atmospheric pressure of molecular N2 and CO in
the presence of a Pd catalyst has been achieved by Uozumi, Mori, and Shibasaki [3a].
Meyer and Cossy have synthesized 2-(2-bromophenyl)- and 2-allyl-2,3-dihydro-3-
methylidene-1H-isoindol-1-ones by a Pd-catalyzed cyclization of the corresponding N-
ethynyl-2-iodobenzamides [3f].
Results and Discussion. – We initiated our investigation by reacting 2-formylben-
zonitrile (1a) with dimethyloxosulfonium methylide. Thus, trimethylsulfoxonium
iodide was treated with NaH in DMSO/THF 1:1 (v/v) at 08 to generate the
corresponding sulfur ylide. To this solution was added 1a, which was consumed within
5 min. After usual workup and subsequent purification of the crude product by column
1
)
See also pertinent references cited in [3d] and [3f].
ꢀ 2010 Verlag Helvetica Chimica Acta AG, Zꢁrich

Helvetica Chimica Acta – Vol. 93 (2010)
1049
chromatography on silica gel, 2,3-dihydro-3-methylidene-1H-isoindol-1-one (2a) was
isolated as the sole product in relatively good yield, as shown in Scheme 1. The structure
1
of the product was determined by comparison of its spectral (IR and H-NMR) data
with those reported in [3a]. No trace of 2-(oxiran-2-yl)benzonitrile (4) was isolated.
Scheme 1
To explore the generality of this reaction, six other substituted 2-formylbenzoni-
triles 1b – 1g were prepared from the respective 2-bromobenzaldehydes according to
the procedure developed by Astles et al. [5]. Using these starting materials, the
corresponding substituted 2,3-dihydro-3-methylidene-1H-isoindol-1-ones 2b – 2g could
be obtained under the conditions described above in comparable yields to that of 2a.
These results are also summarized in Scheme 1. All products were easily purified by
column chromatography on silica gel or recrystallization.
A probable pathway leading to the formation of 2,3-dihydro-3-methylidene-1H-
isoindol-1-ones 2 from 2-formylbenzonitriles 1 is illustrated in Scheme 2. Thus,
dimethyloxosulfonium methylide adds to the C¼O C-atom of 1 to give the adduct 3.
Formation of 2-(oxiran-2-yl)benzonitrile 4 by the intramolecular attack of the alkoxide
of 3 at the C-atom adjacent to the oxosulfonium S-atom (Path a) does not occur.
Instead, the alkoxide of 3 attacks intramolecularly the C-atom of the CꢀN group (Path
b) to generate the imino anion intermediate 5. The latter rearranges to the lactam anion
intermediate 6, from which elimination of dimethyl sulfoxide, accompanied by H-atom
transfer, gives rise to 2. Similar rearrangement reactions have been reported previously
[6].
In summary, we have developed a convenient method for preparing 2,3-dihydro-3-
methylidene-1H-isoindol-1-ones, which are difficult to prepare by previous methods, by
the reaction of 2-formylbenzonitriles with dimethyloxosulfonium methylide, generated
from trimethylsulfoxonium iodide with NaH. Since the method employs readily
available starting materials and is operationally very simple, it may be of value in
organic synthesis.

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Helvetica Chimica Acta – Vol. 93 (2010)
Scheme 2
Experimental Part
General. All of the org. solvents used in this study were dried over appropriate drying agents and
distilled prior to use. 2-Formylbenzonitriles 1d [5], 1e [5], 1f [7], 1g [8], and 2-bromo-4-chlorobenzal-
dehyde [9] were prepared by previously reported methods. TLC: Merck Kieselgel 60 PF254. Column
chromatography (CC): Merck Kieselgel 60 (SiO2; 0.063 – 0.200 mm). M.p.: Laboratory Devices MEL-
TEMP II melting-point apparatus; uncorrected. IR Spectra: Shimadzu FTIR-8300 spectrophotometer;
in KBr disks. 1H-NMR Spectra: JEOL ECP500 FT NMR spectrometer operating at 500 MHz; in CDCl3
with TMS as an internal reference. 13C-NMR Spectra: JEOL ECP500 FT NMR spectrometer operating
at 125 MHz; with TMS as an internal reference. EI-MS (70 eV): JEOL JMS AX505 HA spectrometer.
2-Formylbenzonitriles 1b and 1c. These compounds were prepared from the respective 2-
bromobenzaldehydes according to the procedure reported for the preparation of 1d [5].
5-Chloro-2-formylbenzonitrile (1b). Yield 55%. White solid. M.p. 108 – 1108 (from hexane/CHCl3).
IR: 2228, 1703. 1H-NMR: 7.76 (dd, J ¼ 8.2, 2.3, 1 H); 7.82 (d, J ¼ 2.3, 1 H); 8.01 (d, J ¼ 8.2, 1 H); 10.32 (s,
1 H). Anal. calc. for C8H4ClNO: C 58.03, H 2.43, N 8.46; found: C 58.12, H 2.42, N 8.32.
4-Chloro-2-formylbenzonitrile (1c). Yield 53%. White solid. M.p. 98 – 1008 (from hexane/CHCl3).
IR: 2228, 1705. 1H-NMR: 7.65 (dd, J ¼ 8.2, 2.3, 1 H); 7.72 (d, J ¼ 8.2, 1 H); 7.95 (d, J ¼ 2.3, 1 H); 10.25 (s,
1 H). Anal. calc. for C8H4ClNO: C 58.03, H 2.43, N 8.46; found: C 58.13, H 2.53, N 8.32.
2,3-Dihydro-3-methylidene-1H-isoindol-1-one (2a; Typical Procedure). To a stirred suspension of
Me3Sþ(O)Iꢁ (0.18 g, 0.82 mmol) in DMSO/THF 1:1 (3 ml) at 08 was added NaH (60% in oil; 33 mg,
0.82 mmol) in one portion. After the evolution of H2 gas had ceased, a soln. of 2-formylbenzonitrile (1a)
(0.11 g, 0.68 mmol) in DMSO/THF 1:1 (2 ml) was added dropwise. After 5 min, H2O (10 ml) was added,
and the org. materials were extracted with AcOEt (3 ꢂ 10 ml). The combined extracts were washed with
H2O (3 ꢂ 10 ml) and then brine (10 ml), and dried (Na2SO4). Evaporation of the solvent gave a residual
solid, which was purified by CC (SiO2; THF/hexane 1:3) to afford 2a (91 mg, 76%). Pale-yellow solid.
M.p. 240 – 2438 (from hexane/CH2Cl2). The IR and 1H-NMR data for this product were identical to those
reported in [3a]. 13C-NMR: 90.42; 120.25; 123.34; 129.52; 129.98; 132.25; 137.12; 139.81; 168.77. MS: 145
(100, Mþ).
6-Chloro-2,3-dihydro-3-methylidene-1H-isoindol-1-one (2b). Beige solid. M.p. 1438 (dec.; from
1
hexane/CH2Cl2). IR: 3177, 1717, 1645, 1605. H-NMR: 4.98 (d, J ¼ 2.3, 1 H); 5.19 (d, J ¼ 2.3, 1 H); 7.58

Helvetica Chimica Acta – Vol. 93 (2010)
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(dd, J ¼ 8.2, 1.8, 1 H); 7.64 (d, J ¼ 8.2, 1 H); 7.82 (d, J ¼ 1.8, 1 H); 7.95 (br. s, 1 H). 13C-NMR (CDCl3):
91.54; 121.59; 123.48; 131.57; 132.46; 135.27; 135.78; 139.05; 167.56. MS: 179 (100, Mþ). Anal. calc. for
C9H6ClNO: C 60.19, H 3.37, N 7.80; found: C 60.08, H 3.49, N 7.72.
5-Chloro-2,3-dihydro-3-methylidene-1H-isoindol-1-one (2c). Pale-yellow solid. M.p. 1868 (dec.; from
hexane/CH2Cl2). IR: 3177, 1738, 1715, 1660, 1611. 1H-NMR: 4.98 (d, J ¼ 2.3, 1 H); 5.19 (d, J ¼ 2.3, 1 H);
7.50 (dd, J ¼ 8.2, 1.8, 1 H); 7.68 (d, J ¼ 1.8, 1 H); 7.70 (br. s, 1 H); 7.78 (d, J ¼ 8.2, 1 H). 13C-NMR
((D6)DMSO): 92.38; 121.20; 124.48; 128.74; 129.85; 137.36; 138.79; 139.30; 166.86. MS: 179 (100, Mþ).
Anal. calc. for C9H6ClNO: C 60.19, H 3.37, N 7.80; found: C 60.02, H 3.41, N 7.71.
2,3-Dihydro-6-methoxy-3-methylidene-1H-isoindol-1-one (2d). Pale-yellow needles. M.p. 1158 (dec.;
from hexane/CH2Cl2). IR: 3171, 1709, 1697, 1646, 1620. 1H-NMR: 3.89 (s, 3 H); 4.88 (d, J ¼ 1.8, 1 H); 5.08
(d, J ¼ 1.8, 1 H); 7.16 (dd, J ¼ 8.2, 2.3, 1 H); 7.32 (d, J ¼ 2.3, 1 H); 7.60 (d, J ¼ 8.2, 1 H); 8.11 (br. s, 1 H).
13C-NMR (CDCl3): 55.76; 89.49; 105.76; 120.66; 121.53; 129.87; 131.69; 139.64; 161.20; 168.93. MS: 175
(100, Mþ). Anal. calc. for C10H9NO2: C 68.56, H 5.18, N 8.00; found: C 68.54, H 5.14, N 7.96.
2,3-Dihydro-5-methoxy-3-methylidene-1H-isoindol-1-one (2e). Colorless crystals. M.p. 1658 (dec.;
from hexane/CHCl3). IR: 3215, 1697, 1655, 1609. 1H-NMR: 3.94 (s, 3 H); 4.90 (d, J ¼ 1.8, 1 H); 5.14 (d,
J ¼ 1.8, 1 H); 7.05 (dd, J ¼ 8.2, 2.3, 1 H); 7.15 (d, J ¼ 2.3, 1 H); 7.60 (br. s, 1 H); 7.75 (d, J ¼ 8.2, 1 H).
13C-NMR (CDCl3): 55.73; 90.00; 104.45; 116.60; 122.78; 124.78; 139.40; 139.86; 163.47; 168.67. MS: 175
(100, Mþ). Anal. calc. for C10H9NO2: C 68.56, H 5.18, N 8.00; found: C 68.33, H 5.30, N 7.90.
2,3-Dihydro-5,6-dimethoxy-3-methylidene-1H-isoindol-1-one (2f). Beige solid. M.p. 2078 (dec.; from
hexane/CH2Cl2). IR: 3179, 1724, 1686, 1672, 1609. 1H-NMR: 3.96 (s, 3 H); 4.00 (s, 3 H); 4.87 (d, J ¼ 2.3,
1 H); 5.07 (d, J ¼ 2.3, 1 H); 7.12 (s, 1 H); 7.29 (s, 1 H); 7.69 (br. s, 1 H). 13C-NMR (CDCl3): 56.31 (two
overlapped C-atoms); 89.34; 102.12; 104.58; 122.92; 130.99; 139.92; 151.12; 153.24; 168.95. MS: 205 (100,
Mþ). Anal. calc. for C11H11NO3: C 64.38, H 5.40, N 6.83; found: C 64.29, H 5.56, N 6.79.
6,7-Dihydro-7-methylidene-5H-[1,3]dioxolo[4,5-f]isoindol-5-one (2g). Beige solid. M.p. 2388 (dec.;
1
from hexane/THF). IR: 3192, 1701, 1672, 1651, 1614. H-NMR: 4.84 (d, J ¼ 2.3, 1 H); 5.02 (d, J ¼ 2.3,
1 H); 6.09 (s, 2 H); 7.06 (s, 1 H); 7.19 (s, 1 H); 7.52 (br. s, 1 H). 13C-NMR ((D6)DMSO): 89.70; 100.92;
101.79; 102.26; 124.89; 132.68; 140.20; 149.17; 151.40; 167.16. MS: 189 (100, Mþ). Anal. calc. for
C10H7NO3: C 63.49, H 3.73, N 7.40; found: C 63.20, H 3.90, N 7.56.
We acknowledge Mrs. Miyuki Tanmatsu for determining mass spectra and performing combustion
analyses.
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Received January 26, 2010