One-pot synthesis of 3-alkoxy-2,3-dihydro-1H-isoindol-1-ones by the reactions of 2-(Azidomethyl)benzoates with NaH

Article abstract of DOI:10.1002/hlca.201500051

Abstract A new and facile method for the general preparation of 3-alkoxy-2,3-dihydro-1H-isoindol-1-ones has been developed. Thus, the reaction of 2-(azidomethyl)benzoates with NaH affords, after workup with H₂O, 3-alkoxy-2,3-dihydro-1H-isoindol

Full text of DOI:10.1002/hlca.201500051

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Helvetica Chimica Acta – Vol. 98 (2015)
One-Pot Synthesis of 3-Alkoxy-2,3-dihydro-1H-isoindol-1-ones by the
Reactions of 2-(Azidomethyl)benzoates with NaH
by Kazuhiro Kobayashi*, Yuuki Chikazawa, and Kosuke Ezaki
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 new and facile method for the general preparation of 3-alkoxy-2,3-dihydro-1H-isoindol-1-ones
has been developed. Thus, the reaction of 2-(azidomethyl)benzoates with NaH affords, after workup
with H2O, 3-alkoxy-2,3-dihydro-1H-isoindol-1-ones 2. 2-Substituted 3-alkoxy-2,3-dihydro-1H-isoindol-1-
ones 4 can be obtained by adding alkyl halides prior to workup with H2O.
Introduction. – Recently, 3-alkoxy-2,3-dihydro-1H-isoindol-1-ones are attracting
much attention, because this structure is present in a large number of molecules of
pharmaceutical and biological interest [1]. Utilization of a 3-alkoxy-2,3-dihydro-1H-
isoindol-1-one derivative as a precursor for the synthesis of an isoindoloisoquinoline
derivative has also been demonstrated [2]. Accordingly, some new methods for the
preparation of these derivatives have recently been developed [3], though the method
by the reaction of 2-cyanobenzaldehyde with alcohols was reported by Sato et al. [4].
For example, a synthesis of 3-alkoxy-2-alkyl-2,3-dihydro-1H-isoindol-1-ones by the
reaction of 2-alkylphthalimides with Grignard reagents followed by the addition of
alkyl halides has been reported by Jayawardena et al. [3a], and Dennis et al. have
reported a synthesis of 3-alkoxy-2-aryl-2,3-dihydro-1H-isoindol-1-ones by the reaction
of 2-arylphthalimides with Et2Zn followed by the treatment with an alcohol under
acidic conditions [3b]. We therefore embarked on the research on developing a novel
and facile methodology for the preparation of 3-alkoxy-2,3-dihydro-1H-isoindol-1-
ones 2. In this article, we describe a one-pot synthesis of 2 and 3-alkoxy-2-alkyl-2,3-
dihydro-1H-isoindol-1-ones 4 from 2-(azidomethyl)benzoates 1.
Results and Discussion. – Scheme 1 illustrates the initial attempts at preparing 3-
alkoxy-2,3-dihydro-1H-isoindol-1-ones 2a and 2b from 2-(azidomethyl)benzoates 1a
and 1b, respectively. Treatment of methyl 2-(azidomethyl)benzoate (1a) with NaH in
DMF at 08 resulted in immediate consumption of the starting material to give the
desired 3-methoxy-2,3-dihydro-1H-isoindol-1-one (2a) in 24% yield along with 3’-
methoxy-1H-1,2’-biisoindole-1’,3(2H,3’H)-dione (3a; 26%). The reaction of ethyl 2-
(azidomethyl)benzoate (1b) under the same conditions also led to the isolation of 19%
of 3-ethoxy-2,3-dihydro-1H-isoindol-1-one (2b) along with 3’-ethoxy-1H-1,2’-biisoin-
dole-1’,3(2H,3’H)-dione (3b; 21%), as anticipated.
We then conducted the treatment of 1a and 1b in THF in place of DMF.
Fortunately, exclusive formation of 2a and 2b was achieved in satisfactory yields as
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Scheme 1
illustrated in Scheme 2. The starting materials were consumed gradually at room
temperature, and the desired products were obtained after workup with H2O followed
by purification using column chromatography on SiO2. Methyl 2-(azidomethyl)-4-
chlorobenzoate (1c) was similarly treated with NaH. Unfortunately, however, the
corresponding desired product 5-chloro-2,3-dihydro-3-methoxy-1H-isoindol-1-one
(2c) could be isolated from a rather complex reaction mixture of products only in
lower yield than those of 2a and 2b, though the reason for this is unclear yet.
Thereafter, we tried to introduce a substituent to the 2-position of the products.
Thus, after treatment of 1 with NaH in THF as described above, alkyl halides were
added prior to workup with H2O to afford 3-alkoxy-2-alkyl-2,3-dihydro-1H-isoindol-1-
ones 4, as shown in Scheme 3. The yields of the products were compiled in the Table.
These results indicate that the N-alkylation of the intermediate from 1a (Entries 1 – 5)
took place cleanlier than that from 1b (Entries 6 – 10). This is probably due to the
difference of the steric bulkiness between MeO and EtO substituents. We found that a
non-activated haloalkane, such as BuBr, could work well to give the corresponding
product 4b, but in somewhat diminished yield (Entry 2). Entries 11 and 12 indicate a
considerable decrease in the yields of the products from 1c. This is predictable from the
low yield of 2c.
The formation of 4 from 1 is thought to proceed as shown in Scheme 4. Treatment
of 1 with NaH generates the corresponding benzyl anion intermediates 5, which upon
Scheme 2
Scheme 3

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Table. Preparation of 2-Substituted 3-Alkoxy-2,3-dihydro-1H-isoindol-1-ones 4
Entry
1
R3X
4
Yield [%]a)
1
2
3
4
5
6
7
8
9
1a (R1 ¼ H, R2 ¼ Me)
MeI
BuBr
BnBr
t-BuOCOCH2Br
NCCH2Br
MeI
4a
4b
4c
4d
4e
4f
4g
4h
4i
60
53
60
67
62
43
43
37
48
39
33
32
1a
1a
1a
1a
1b (R1 ¼ H, R2 ¼ Et)
1b
1b
1b
1b
BnBr
BnOCH2Cl
t-BuOCOCH2Br
NCCH2Br
MeI
10
11
12
4j
4k
4l
1c (R1 ¼ Cl, R2 ¼ Me)
1c
t-BuOCOCH2Br
a) Yield of isolated product.
Scheme 4
continuous denitrogenation provides the benzylidenaminide anion intermediate 6.
Intramolecular nucleophilic addition/elimination reaction of 6 gives 1H-isoindol-1-one
intermediate 7. An alkoxide, eliminated from 6, attacks at the 3-position of 7 to give
1-oxo-1H-isoindol-2-yl anion intermediate 8, of which alkylation with alkyl halides
leads to 4.
In conclusion, we have demonstrated that the one-pot sequence from 2-
(azidomethyl)benzoates provides a new and efficient approach to 3-alkoxy-2,3-
dihydro-1H-isoindol-1-ones. Although the yields of products are not so high, the
present synthesis may be valuable in organic synthesis because of the good availability
of the starting materials, and mild and operationally simple reaction conditions.
Experimental Part
General. All chemicals used in this study were commercially available. All org. solvents used in this
work were dried over appropriate drying agents and distilled prior to use. TLC: Merck silica gel 60 PF254
.
Column chromatography (CC): Wako Gel C-200E. M.p.: Laboratory Devices MEL-TEMP II melting-
point apparatus; uncorrected. IR Spectra: PerkinElmer Spectrum65 FT-IR spectrophotometer; n˜ in

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cmÀ1. 1H-NMR Spectra: Bruker Biospin AVANCE II 600 FT-NMR spectrometer or JEOL ECP500 FT-
NMR spectrometer (at 600 or 500 MHz, resp.); d in ppm rel. to Me4Si as internal standard in CDCl3, J in
Hz. 13C-NMR Spectra: Bruker Biospin AVANCE II 600 FT-NMR spectrometer or JEOL ECP500 FT-
NMR spectrometer (at 150 or 125 MHz, resp.); d in ppm rel. to Me4Si as internal standard in CDCl3. HR-
MS (DART, pos.): Thermo Scientific Exactive spectrometer; in m/z.
Methyl 2-(azidomethyl)benzoate (1a) [5], ethyl 2-(azidomethyl)benzoate (1b) [6], and methyl 2-
(bromomethyl)-4-chlorobenzoate [7] were prepared according to the appropriate reported procedures.
Methyl 2-(Azidomethyl)-4-chlorobenzoate (1c) was prepared from methyl 2-(bromomethyl)-4-
chlorobenzoate [7] and NaN3 as described previously for the preparation of 1a [5]. Yield: 86%. White
1
solid. M.p. 42 – 438 (pentane). IR (KBr): 2118, 1730. H-NMR (500 MHz): 3.92 (s, 3 H); 4.84 (s, 2 H);
7.37 (dd, J ¼ 8.6, 2.3, 1 H); 7.53 (d, J ¼ 2.3, 1 H); 7.97 (d, J ¼ 8.6, 1 H). Anal. calc. for C9H8ClN3O2
(225.63): C 47.91, H 3.57, N 18.62; found: C 47.87, H 3.64, N 18.59.
Reaction Procedure of Methyl 2-(Azidomethyl)benzoate (1a) with NaH in DMF. To a stirred
suspension of NaH (60% in mineral oil; 31 mg, 0.78 mmol) in DMF (2 ml) at 08 was added dropwise a
soln. of 1a (0.15 g, 0.78 mmol) in DMF (2 ml). After 2 h, a sat. aq. NH4Cl (20 ml) soln. was added, and
the mixture was extracted with AcOEt (3 Â 10 ml). The combined extracts were washed with H2O (2 Â
15 ml) and brine (10 ml), dried (Na2SO4), and concentrated by evaporation. The residue was separated
by CC (SiO2; AcOEt/hexane 1:1) to afford 2a (31 mg, 24%) and 3a (30 mg, 26%).
2,3-Dihydro-3-methoxy-1H-isoindol-1-one (2a) [4][8]. Pale-yellow solid. M.p. 99 – 1018 (hexane/
1
CH2Cl2) ([4]: 1008). IR (KBr): 3226, 1708, 1681. H-NMR (500 MHz): 3.22 (s, 3 H); 5.99 (s, 1 H); 7.54
(br., 1 H); 7.55 (t, J ¼ 7.6, 1 H); 7.57 (d, J ¼ 7.6, 1 H); 7.63 (t, J ¼ 7.6, 1 H); 7.85 (d, J ¼ 7.6, 1 H). 13C-NMR
(125 MHz): 51.6; 84.4; 123.6; 123.7; 129.9; 132.1; 132.6; 142.7; 170.5.
3’-Methoxy-1H-1,2’-biisoindole-1’,3(2H,3’H)-dione (3a). White solid. M.p. 150 – 1518 (hexane/
1
CHCl3). IR (KBr): 3275, 1706, 1615. H-NMR (500 MHz): 3.20 (s, 3 H); 6.01 (s, 1 H); 6.95 (s, 1 H);
7.40 (br., 1 H); 7.42 (d, J ¼ 7.6, 1 H); 7.52 – 7.56 (m, 2 H); 7.59 – 7.62 (m, 3 H); 7.86 (d, J ¼ 7.6, 1 H); 7.87 (d,
J ¼ 7.6, 1 H). 13C-NMR (125 MHz): 50.3; 61.9; 84.6; 123.6; 123.6; 123.8; 123.9; 129.4; 129.9; 130.1; 131.4;
132.1; 133.0; 141.0; 143.6; 168.8; 170.6. HR-MS: 295.1081 ([M þ H]þ, C17H15N2O3þ ; calc. 295.1082). Anal.
calc. for C17H14N2O3 (294.30): C 69.38, H 4.79, N 9.52; found: C 69.31, H 5.01, N 9.32.
Reaction of Ethyl 2-(Azidomethyl)benzoate (1b) with NaH in DMF. Compound 1b (0.20 g,
0.97 mmol) was treated with an equiv. of NaH, worked up, and purified as described above for the
reaction of 1a with NaH to afford 2b (33 mg, 19%) and 3b (35 mg, 21%).
3-Ethoxy-2,3-dihydro-1H-isoindol-1-one (2b) [4][9]. Pale-yellow solid. M.p. 103 – 1048 (hexane/
1
CH2Cl2) ([4]: 1058). IR (KBr): 3190, 1715, 1702. H-NMR (500 MHz): 1.22 (t, J ¼ 7.6, 3 H); 3.35 – 3.41
(m, 1 H); 3.54 – 3.60 (m, 1 H); 5.98 (s, 1 H); 7.44 (br., 1 H); 7.54 (t, J ¼ 7.6, 1 H); 7.58 (d, J ¼ 7.6, 1 H); 7.62
(t, J ¼ 7.6, 1 H); 7.84 (d, J ¼ 7.6, 1 H). 13C-NMR (125 MHz): 15.3; 60.7; 83.9; 123.6; 123.7; 129.8; 131.9;
132.5; 143.3; 170.3.
3’-Ethoxy-1H-1,2’-biisoindole-1’,3(2H,3’H)-dione (3b). Pale-yellow solid. M.p. 183 – 1848 (hexane/
1
CH2Cl2). IR (KBr): 3195, 1709, 1615. H-NMR (500 MHz): 0.47 (t, J ¼ 6.9, 3 H); 2.69 – 2.75 (m, 1 H);
2.89 – 2.95 (m, 1 H); 6.02 (s, 1 H); 6.96 (s, 1 H); 7.42 (d, J ¼ 7.6, 1 H); 7.49 – 7.54 (m, 2 H); 7.56 – 7.61 (m,
4 H); 7.83 (d, J ¼ 8.4, 1 H); 7.50 (d, J ¼ 8.4, 1 H). 13C-NMR (125 MHz): 14.1; 59.5; 61.8; 84.4; 123.5; 123.6;
123.7; 123.8; 129.3; 129.9; 131.1; 131.5; 132.2; 132.8; 141.7; 144.1; 168.4; 170.7. HR-MS: 309.1233 ([M þ
H]þ, C18H17N2O3þ ; calc. 309.1239). Anal. calc. for C18H16N2O3 (308.33): C 70.12, H 5.23, N 9.09; found: C
70.01, H 5.29, N 9.06.
Reaction Procedure of 2-(Azidomethyl)benzoates 1 with NaH in THF. To a stirred suspension of
NaH (60% in mineral oil; 31 mg, 0.78 mmol) in THF (1.5 ml) at 08 was added dropwise a soln. of 1
(0.78 mmol) in THF (1.5 ml). The temp. was raised to r.t., and stirring was continued until complete
consumption of the starting materials was confirmed by TLC analyses on SiO2 (AcOEt/hexane 1:2) (ca.
5 h for 1a, 8 h for 1b, and 1 h for 1c). A sat. aq. NH4Cl (20 ml) soln. was added, and the mixture was
extracted with AcOEt (3 Â 10 ml). The combined extracts were washed with brine (10 ml), dried
(Na2SO4), and concentrated by evaporation. The residual solid was purified by recrystallization to
afford 2.
5-Chloro-2,3-dihydro-3-methoxy-1H-isoindol-1-one (2c). Pale-yellow solid. M.p. 168 – 1698 (hexane/
CH2Cl2). IR (KBr): 3218, 1740, 1616. 1H-NMR (500 MHz): 3.20 (s, 3 H); 5.95 (s, 1 H); 6.75 (br., 1 H);

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Helvetica Chimica Acta – Vol. 98 (2015)
7.52 (dd, J ¼ 8.0, 1.7, 1 H); 7.55 (d, J ¼ 1.7, 1 H); 7.77 (d, J ¼ 8.0, 1 H). 13C-NMR (125 MHz): 52.0; 83.9;
124.3; 124.9; 130.5; 130.5; 139.2; 144.5; 169.3. HR-MS: 198.0317 ([M þ H]þ, C9H9ClNO2þ ;
calc. 198.0322). Anal. calc. for C9H8ClNO2 (197.62): C 54.70, H 4.08, N 7.09; found: C 54.41, H 4.17,
N 7.08.
2,3-Dihydro-3-methoxy-2-methyl-1H-isoindol-1-one (4a) [10] (Representative Procedure). Com-
pound 1a (0.15 g, 0.78 mmol) was treated with NaH (60% in mineral oil; 31 mg, 0.78 mmol) in THF
(3 ml) as described above. After complete consumption of 1a had been confirmed by TLC analyses on
SiO2 (AcOEt/hexane 1:2), MeI (0.11 g, 0.78 mmol) was added, and stirring was continued overnight.
The resulting mixture was worked up, and the crude product was purified as described above for the
reactions in DMF to afford 4a (83 mg, 60%). Yellow oil. Rf (AcOEt/hexane 1:1) 0.39. IR (neat): 1708,
1617. 1H-NMR (500 MHz): 2.90 (s, 3 H); 3.10 (s, 3 H); 5.78 (s, 1 H); 7.53 (t, J ¼ 7.6, 1 H); 7.54 (d, J ¼ 7.6,
1 H); 7.59 (td, J ¼ 7.6, 1.5, 1 H); 7.84 (d, J ¼ 7.6, 1 H). 13C-NMR (125 MHz): 26.4; 49.1; 87.9; 123.3; 123.4;
129.9; 131.9; 133.1; 140.1; 167.5.
2-Butyl-2,3-dihydro-3-methoxy-1H-isoindol-1-one (4b) [11]. Pale-yellow oil. Rf (AcOEt/hexane 1:4)
0.22. IR (neat): 1708, 1617. 1H-NMR (600 MHz): 0.96 (t, J ¼ 7.4, 3 H); 1.36 – 1.42 (m, 2 H); 1.62 – 1.68 (m,
2 H); 2.88 (s, 3 H); 3.20 – 3.25 (m, 1 H); 3.79 – 3.83 (m, 1 H); 5.89 (s, 1 H); 7.51 – 7.54 (m, 2 H); 7.58 (td,
J ¼ 7.4, 1.1, 1 H); 7.83 (dd, J ¼ 7.4, 1.1, 1 H). 13C-NMR (150 MHz): 13.8; 20.3; 30.2; 39.2; 49.1; 86.2; 123.4;
123.4; 129.9; 131.9; 133.3; 140.3; 167.7.
2,3-Dihydro-3-methoxy-2-(phenylmethyl)-1H-isoindol-1-one (4c) [11]. Colorless oil. Rf (AcOEt/
hexane 1:3) 0.33. IR (neat): 1707, 1617. 1H-NMR (500 MHz): 2.89 (s, 3 H); 4.21 (d, J ¼ 14.5, 1 H); 5.20 (d,
J ¼ 14.5, 1 H); 5.72 (s, 1 H); 7.28 (d, J ¼ 7.6, 1 H); 7.33 (t, J ¼ 7.6, 2 H); 7.37 (d, J ¼ 7.6, 2 H); 7.49 (d, J ¼ 6.9,
1 H); 7.53 (dd, J ¼ 7.6, 6.9, 1 H); 7.58 (t, J ¼ 6.9, 1 H); 7.88 (d, J ¼ 6.9, 1 H). 13C-NMR (125 MHz): 43.0;
49.3; 85.5; 123.5; 123.7; 127.6; 128.6; 128.7; 129.9; 131.1; 132.8; 136.7; 140.3; 167.5.
1,1-Dimethylethyl 2-(1,3-Dihydro-1-methoxy-3-oxo-2H-isoindole-2-yl)acetate (4d). Yellow oil. Rf
(AcOEt/hexane 1:2) 0.48. IR (neat): 1741, 1716, 1617. 1H-NMR (600 MHz): 1.47 (s, 9 H); 2.92 (s,
3 H); 3.83 (d, J ¼ 17.5, 1 H); 4.56 (d, J ¼ 17.5, 1 H); 6.05 (s, 1 H); 7.54 (t, J ¼ 7.4, 1 H); 7.56 (d, J ¼ 6.9, 1 H);
7.61 (ddd, J ¼ 7.4, 6.9, 1.0, 1 H); 7.87 (d, J ¼ 7.4, 1 H). 13C-NMR (150 MHz): 28.1; 41.3; 49.5; 82.3; 86.7;
123.6; 123.8; 130.0; 132.3; 132.5; 140.7; 167.8; 168.0. HR-MS: 278.1387 ([M þ H]þ, C15H20NO4þ ;
calc. 278.1392). Anal. calc. for C15H19NO4 (277.32): C 64.97, H 6.91, N 5.05; found: C 64.95, H 7.06, N 5.81.
2-(1,3-Dihydro-1-methoxy-3-oxo-2H-isoindol-2-yl)acetonitrile (4e). Pale-yellow oil. Rf (AcOEt/
hexane 1:4) 0.17. IR (neat): 2257, 1718, 1617. 1H-NMR (600 MHz): 3.00 (s, 3 H); 4.32 (d, J ¼ 17.5, 1 H);
4.66 (d, J ¼ 17.5, 1 H); 6.01 (s, 1 H); 7.59 (t, J ¼ 7.5, 1 H); 7.60 (d, J ¼ 7.5, 1 H); 7.68 (td, J ¼ 7.5, 1.0, 1 H);
7.89 (d, J ¼ 7.5, 1 H). 13C-NMR (150 MHz): 27.8; 50.1; 86.6; 114.7; 123.9; 124.2; 130.5; 131.3; 133.2; 140.1;
166.8. HR-MS: 203.0810 ([M þ H]þ, C11H11N2O2þ ; calc. 203.0820). Anal. calc. for C11H10N2O2 (202.21): C
65.34, H 4.98, N 13.85; found: C 65.29, H 5.03, N 13.65.
3-Ethoxy-2,3-dihydro-2-methyl-1H-isoindol-1-one (4f). Colorless oil. Rf (AcOEt/hexane 1:2) 0.30.
IR (neat): 1709, 1617. 1H-NMR (600 MHz): 0.98 (t, J ¼ 6.9, 3 H); 2.82 – 2.88 (m, 1 H); 2.94 (s, 3 H); 2.98 –
3.04 (m, 1 H); 5.60 (s, 1 H); 7.34 (td, J ¼ 7.3, 1.2, 1 H); 7.37 (d, J ¼ 6.8, 1 H); 7.41 (ddd, J ¼ 7.3, 6.8, 1.0,
1 H); 7.66 (d, J ¼ 7.3, 1 H). 13C-NMR (150 MHz): 15.1; 26.5; 57.6; 87.7; 123.2; 123.3; 129.8; 131.9; 132.7;
140.9; 167.7. HR-MS: 192.1018 ([M þ H]þ, C11H14NO2þ ; calc. 192.1024). Anal. calc. for C11H13NO2
(191.23): C 69.09, H 6.85, N 7.32; found: C 69.05, H 6.76, N 7.14.
3-Ethoxy-2,3-dihydro-2-(phenylmethyl)-1H-isoindol-1-one (4g). Pale-yellow needles. M.p. 72 – 758
(hexane). IR (KBr): 1698, 1616. 1H-NMR (600 MHz): 1.09 (t, J ¼ 6.9, 3 H); 2.97 – 3.02 (m, 1 H); 3.12 –
3.17 (m, 1 H); 4.28 (d, J ¼ 16.7, 1 H); 5.15 (d, J ¼ 16.7, 1 H); 5.71 (s, 1 H); 7.27 (tt, J ¼ 7.3, 1.3, 1 H); 7.32 (t,
J ¼ 7.3, 2 H); 7.38 (dd, J ¼ 7.3, 1.3, 2 H); 7.49 (d, J ¼ 7.3, 1 H); 7.51 (td, J ¼ 7.3, 1.1, 1 H); 7.56 (td, J ¼ 7.3, 1.1,
1 H); 7.86 (d, J ¼ 7.3, 1 H). 13C-NMR (150 MHz): 15.1; 43.3; 58.0; 85.5; 123.4; 123.6; 127.6; 128.6; 128.7;
129.8; 132.0; 132.8; 137.0; 141.2; 167.4. HR-MS: 268.1331 ([M þ H]þ, C17H18NO2þ ; calc. 268.1337). Anal.
calc. for C17H17NO2 (267.32): C 76.38, H 6.41, N 5.24; found: C 76.31, H 6.40, N 5.17.
3-Ethoxy-2,3-dihydro-2-[(phenylmethoxy)methyl]-1H-isoindol-1-one (4h).Yellow oil. Rf (AcOEt/
hexane 1:5) 0.23. IR (neat): 1715, 1616. 1H-NMR (500 MHz): 1.14 (t, J ¼ 6.9, 3 H); 3.11 – 3.17 (m, 1 H);
3.25 – 3.29 (m, 1 H); 4.60 (s, 2 H); 4.86 (d, J ¼ 10.9, 1 H); 5.34 (d, J ¼ 10.9, 1 H); 6.04 (s, 1 H); 7.18 – 7.37
(m, 5 H); 7.48 – 7.58 (m, 3 H); 7.86 (d, J ¼ 7.4, 1 H). 13C-NMR (125 MHz): 15.1; 59.0; 69.2; 70.8; 85.3;
123.6; 124.0; 126.9; 127.7; 127.7; 128.3; 129.9; 132.7; 137.8; 141.7; 168.2. HR-MS: 298.1437 ([M þ H]þ,

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C18H20NOþ3 ; calc. 298.1443). Anal. calc. for C18H19NO3 (297.35): C 72.71, H 6.44, N 4.71; found: C 72.73,
H 6.61, N 4.78.
1,1-Dimethylethyl 2-(1-Ethoxy-1,3-dihydro-3-oxo-2H-isoindol-2-yl)acetate (4i). Colorless needles.
M.p. 86 – 878 (hexane/Et2O). IR (KBr): 1741, 1702, 1616. 1H-NMR (600 MHz): 1.14 (t, J ¼ 7.1, 3 H); 1.47
(s, 9 H), 3.03 – 3.08 (m, 1 H); 3.19 – 3.24 (m, 1 H); 3.86 (d, J ¼ 17.6, 1 H); 4.55 (d, J ¼ 17.6, 1 H); 6.04 (s,
1 H); 7.52 (td, J ¼ 7.4, 1.0, 1 H); 7.56 (d, J ¼ 7.4, 1 H); 7.60 (td, J ¼ 7.4, 1.0, 1 H); 7.85 (d, J ¼ 7.4, 1 H).
13C-NMR (150 MHz): 15.2; 28.1; 41.4; 58.1; 82.3; 86.5; 123.5; 123.8; 129.8; 132.2; 132.3; 141.4; 167.7; 168.0.
HR-MS: 292.1535 ([M þ H]þ, C16H22NO4þ ; calc. 292.1549). Anal. calc. for C16H21NO4 (291.34): C 65.96,
H 7.27, N 4.81; found: C 65.88, H 7.25, N 4.77.
(1-Ethoxy-1,3-dihydro-3-oxo-2H-isoindol-2-yl)acetonitrile (4j). Yellow oil. Rf (AcOEt/hexane 1:3)
0.21. IR (neat): 2250, 1716, 1616. 1H-NMR (500 MHz): 1.04 (t, J ¼ 6.9, 3 H); 2.95 – 3.03 (m, 1 H); 3.09 –
3.14 (m, 1 H); 4.17 (d, J ¼ 17.8, 1 H); 4.48 (d, J ¼ 17.8, 1 H); 5.83 (s, 1 H); 7.39 – 7.45 (m, 2 H); 7.50 (t, J ¼
7.4, 1 H); 7.70 (d, J ¼ 7.4, 1 H). 13C-NMR (125 MHz): 14.9; 27.8; 59.0; 86.3; 114.7; 123.7; 124.1; 130.3;
131.0; 133.1; 140.8; 166.7. HR-MS: 217.0969 ([M þ H]þ, C12H13N2O2þ ; calc. 217.0977). Anal. calc. for
C12H12N2O2 (216.24): C 66.65, H 5.59, N 12.96; found: C 66.61, H 5.55, N 12.80.
5-Chloro-2,3-dihydro-3-methoxy-2-methyl-1H-isoindol-1-one (4k). White solid. M.p. 97 – 988 (hex-
ane). IR (KBr): 1710, 1613. 1H-NMR (500 MHz): 2.93 (s, 3 H); 3.08 (s, 3 H); 5.74 (s, 1 H); 7.50 (dd, J ¼
8.0, 1.7, 1 H); 7.53 (d, J ¼ 1.7, 1 H); 7.76 (d, J ¼ 8.0, 1 H). 13C-NMR (125 MHz): 26.5; 49.4; 87.4; 123.8;
124.5; 130.4; 131.5; 138.4; 142.0; 166.6. HR-MS: 212.0473 ([M þ H]þ, C10H11ClNO2þ ; calc. 212.0478).
Anal. calc. for C10H10ClNO2 (211.64): C 56.75, H 4.76, N 6.62; found: C 65.74, H 4.73, N 6.50.
1,1-Dimethylethyl 2-(5-Chloro-1,3-dihydro-3-methoxy-1-oxo-2H-isoindol-2-yl)acetate (4l). Pale-yel-
low solid. M.p. 82 – 838 (hexane/CH2Cl2). IR (KBr): 1750, 1713, 1613. 1H-NMR (500 MHz): 1.47 (s, 9 H);
2.95 (s, 3 H); 3.81 (d, J ¼ 17.2, 1 H); 4.53 (d, J ¼ 17.2, 1 H); 6.02 (s, 1 H); 7.52 (dd, J ¼ 8.0, 1.7, 1 H); 7.55 (d,
J ¼ 1.7, 1 H); 7.79 (d, J ¼ 8.0, 1 H). 13C-NMR (125 MHz): 28.1; 41.3; 49.8; 82.5; 86.2; 124.0; 125.0; 130.5;
130.9; 138.9; 142.4; 166.7; 167.7. HR-MS: 312.0997 ([M þ H]þ, C15H19ClNO4þ ; calc. 312.1002). Anal. calc.
for C15H18ClNO4 (311.76): C 57.79, H 5.82, N 4.49; found: C 57.50, H 5.79, N 4.34.
This work was supported in part by JSPS KAKENHI Grant No. 26410051. We thank Mrs. Miyuki
Tanmatsu at our university for recording mass spectra and performing combustion analyses.
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Received February 26, 2015