A new synthesis of 3-alkyl-1-isoindolinones

Article abstract of DOI:10.1016/S0040-4039(02)02273-6

A new, concise, and efficient method for the synthesis of 3-alkyl-1-isoindolinones was described. 3-Alkyl-3-hydroxy-2,3-dihydro-1-isoindolinones, prepared from the reaction of phthalimide and alkyl lithium, were treated with sodium cyanoborohydride in aci

Full text of DOI:10.1016/S0040-4039(02)02273-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 9163–9165
A new synthesis of 3-alkyl-1-isoindolinones
Eng-Chi Wang,* Hsien-Fan Chen, Pei-Kuan Feng, Yu-Li Lin and Ming-Kuan Hsu
School of Chemistry, Kaohsiung Medical University, Kaohsiung City 807, Taiwan, ROC
Received 2 September 2002; accepted 4 October 2002
Abstract—A new, concise, and efficient method for the synthesis of 3-alkyl-1-isoindolinones was described. 3-Alkyl-3-hydroxy-2,3-
dihydro-1-isoindolinones, prepared from the reaction of phthalimide and alkyl lithium, were treated with sodium cyanoboro-
hydride in acidic medium to concomitantly undergo dehydration and reduction leading to various 3-alkyl-1-isoindolinones in good
yields. © 2002 Elsevier Science Ltd. All rights reserved.
3-Alkyl-1-isoindolinone, a structural unit or key inter-
mediate of naturally occurring alkaloids or synthetic
compounds, attracts both synthetic and natural product
chemists for its various biological activities. Just as
reported include: (i) palladium-catalyzed reaction of
2-iodobenzamide with trimethylsilylacetylene, followed
by cyclization with acid chloride or acetic anhydride,
and finally by catalytic hydrogenation;6 (ii) condensa-
tion of phenylglycinol with the corresponding ketoacid,
followed by ring opening with Lewis acid and triethylsi-
lane;7 and more recently (iii) sequential metalation, and
multi-step C,N-deprotection from 3-benzotriazolyl-2-
dimethylamionophthalimidine, reported by Deniau et
al.8 Even though some drawbacks, such as tedious
reaction conditions, commercially unavailable starting
materials, multiple reaction steps, and low yields, still
exist, the development of a more concise and efficient
method is requisite.
bisquaternary bisphthalimidine derivatives have
a
potential allosteric activity;1 pazinaclone exhibits anxi-
olytic and anticonvulsant activities;2 p-MPPI analogs
display a very high binding affinity for 5-HT1A recep-
tors in vitro;3 indocarbazoles exhibit a protein kinase
activity;4 and (R)-(+)-9b-phenyl-2,3-dihydrothiazolo-
[2,3-a]isoindol-5-(9bH)-one exhibits an activity for anti
HIV-1 reverse transcriptase.5 However, the strategies
for the construction of 3-alkyl-1-isoindolinones are
quite insufficient. Some methods that were recently
Scheme 1.
* Corresponding author. Fax: 886-7-3125339; e-mail: enchwa@kmu.edu.tw
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02273-6

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E.-C. Wang et al. / Tetrahedron Letters 43 (2002) 9163–9165
Herein, we disclose a novel, concise, and efficient
method, starting from commercially available and inex-
pensive phthalimide, for the synthesis of various 3-
alkyl-1-isoindolinones in two steps and in high overall
yields (Scheme 1).
to give 4d–e. If an aprotic solvent was present, such as
in THF in TFA, the forming acyliminium ion was
subsequently reduced by NaCNBH3 to furnish the
desired compounds 3d–e, respectively. A proposed reac-
tion mechanism for this reaction is presented in Scheme
2.
When phthalimide (1) was treated with various alkyl
lithiums (2.2 equiv.) in THF/HMPA (4/1), it furnished
3-alkyl-3-hydroxy-2,3-dihydroisoindol-1-ones (2a–e) in
yields of 75–78%, respectively. Subsequently, com-
pounds 2a–c were dehydrated, and reduced concomi-
tantly by sodium cyanoborohydride in the presence of
HCl in methanol, to afford 3-alkyl-1-isoindolinones
(3a–c) in yields of 92–94%, respectively. On the other
hand, when compounds 2d–e were dehydrated and
reduced concomitantly by sodium cyanoborohydride in
the presence of THF in TFA, they afforded 3-alkyl-1-
isoindolinones (3d–e) in yields of 92–94%, respectively.
Under the same conditions as those used for the prepa-
ration of 3a–c, 2d–e gave 3-alkyl-3-methoxy-2,3-dihy-
droisoindol-1-ones (4d–e) instead. From the above
experimental results and previous studies,9 it can be
stated that the primary or secondary alkyl group at the
3-position in compounds 2a–c dehydrated easily into
the N-acyliminium ion, which stabilized and coexisted
with the benzylidene molecule by resonance in an acidic
medium, and was then reduced by the hydride donor
(NaCNBH3 in methanol) to give 3a–b. Under the same
conditions, the tertiary alkyl group at the 3-position of
2d–e underwent dehydration in HCl leading a stable
acyliminium ion, by resonance with benzylic carboca-
tion, and was then attacked by the solvent (methanol)
In conclusion, a new and concise two-step method for
the preparation of various 3-alkyl-1-isoindolinones
from phthalimide through alkylation, dehydration, and
with concomitant reduction by sodium cyanoborohy-
drate in acidic media, was established in good yields.
General procedure for the preparation of 3-alkyl-3-
hydroxy-2,3-dihydroisoindol-1-ones (2a–e)
Under dry N2, phthalimide (2.94 g, 20 mmol) dissolved
in anhydrous THF (24 mL) and HMPA (8 mL) was
stirred at room temperature to give a clear solution.
The solution was cooled to −40°C in an immersion
cooler, then alkyl lithium (14 mL, 21 mmol) was added
dropwise, and the solution was stirred at −40°C for 1 h.
To the cooled solution was added additional alkyl
lithium (14 mL, 21 mmol), and this mixture was then
stirred at −40°C for 9 h. After warming the solution to
room temperature, it was carefully quenched with satu-
rated NH4Cl (5 mL). After removing the THF with a
rotavapor in vacuo, the residue was purified under
vacuum, removing HMPA with a Kugelrohr apparatus,
to give a crude solid. This was purified by a silica gel
Scheme 2.

E.-C. Wang et al. / Tetrahedron Letters 43 (2002) 9163–9165
9165
chromatographic column (ethyl acetate/n-hexane=1/1)
to give pure, colorless crystals of 2a (77%),10 2b
(75%),11 2c (77%),12 2d (76%),13 and 2e (78%),11
respectively.
CDCl3): l 50.25 (OMe), 92.17, 123.05, 123.60, 125.46,
128.42, 128.45, 129.48, 131.06, 132.74, 139.83, 146.48,
170.02 (CꢀO).
Selected spectral data for 2d: Colorless crystal; mp
190–191°C; 1H NMR (400 MHz, CDCl3): l 1.06 (s, 9H,
CMe3), 3.86 (br s, 1H, OH), 7.23 (br s, 1H, NH), 7.33
(td, J=7.6, 1.0 Hz, 1H), 7.46 (d, J=7.6 Hz, 1H), 7.50
(td, J=7.6, 1.0 Hz, 2H), 7.60 (d, J=7.6 Hz, 1H); 13C
NMR (100 MHz, CDCl3): l 25.19, 38.60, 92.46 (COH),
123.35, 123.60, 129.22, 131.27, 132.05, 147.98, 169.60
(CꢀO). Anal calcd for C12H15NO2: C, 70.22; H, 7.37; N,
6.82. Found: C, 69.93; H, 7.56; N, 6.69%.
Acknowledgements
We are indebted to the Emeritus Professor Takao
Yamazaki, Toyama Medical and Pharmaceutical Uni-
versity, Professor Hiroki Takahata, Tohoku Pharma-
ceutical University, and Professor Yoshiro Hirai,
Toyama University, Japan, for encouragement. We are
also grateful to the NSC, Taiwan, for financial support.
General procedure for the preparation of 3-alkyl-2,3-
dihydroisoindol-1-ones (3a–e)
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NMR (400 MHz, CDCl3): l 0.87 (t, J=7.1 Hz, 3H,
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(m, 1H), 1.91–1.96 (m, 1H), 4.62 (dd, J=7.4, 4.7 Hz,
ArCH), 7.42 (d, J=7.3 Hz, 1H), 7.44 (t, J=7.4 Hz,
1H), 7.54 (td, J=7.5, 1.0 Hz, 1H), 7.84 (d, J=7.5 Hz,
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