TETRAHEDRON LETTERS Tetrahedron Letters 43 (2002) 9163–9165
Pergamon
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 City807, 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 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
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;7and 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.
Scheme 1.
* Corresponding author. Fax: 886-7-3125339; e-mail:[email protected]
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved. PII: S 0 0 4 0 - 4 0 3 9 ( 0 2 ) 0 2 2 7 3 - 6
E.-C. Wang et al./Tetrahedron Letters43 (2002) 9163–9165
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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).
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 (NaCNBH3in 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)
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 reacreac-tion is presented in Scheme 2.
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
E.-C. Wang et al./Tetrahedron Letters43 (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.
Selected spectral data for 2d: Colorless crystal; mp 190–191°C;1H NMR (400 MHz, CDCl 3):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 (CO). Anal calcd for C12H15NO2: C, 70.22; H, 7.37; N, 6.82. Found: C, 69.93; H, 7.56; N, 6.69%.
General procedure for the preparation of 3-alkyl-2,3-dihydroisoindol-1-ones (3a–e)
Procedure for 3a–c: Under nitrogen, 3-alkyl-2,3-dihy-droisoindol-1-ones (3a–c) (12 mmol) dissolved in MeOH (30 mL) were stirred at room temperature, and then added portionwise to NaCNBH3 (0.84 g, 13.4 mmol), followed by concd HCl (5–6 drops). The reac-tion mixture was allowed to stir at ambient temperature for 2 h, and then concentrated in vacuo. The residue was in partition with ethyl acetate (50 mL) and water (50 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3×25 mL). The organic layers were combined, washed with brine (2×25 mL), dried with anhydrous K2CO3, and then filtered. The filtration was concentrated in vacuo, and the resulting residue was purified with silica gel chromatographic column (ethyl acetate/n-hexane=1/1) to give pure 3a (94%),8 3b (92%),8 and 3c (93%), respectively.
Procedure for3d–e: The procedure was the same as for
3a–c, but the solvent (THF) and the acidic medium (TFA) were used instead to give 3d (83%),8 and 3e (85%),8 respectively.
Selected spectral data for 3b (2.12 g, 77%): Colorless crystals; mp 88–89°C (ethyl acetate/n-hexane); 1H NMR (400 MHz, CDCl3): l 0.87 (t, J=7.1 Hz, 3H, Me), 1.29–1.37 (m, 3H), 1.43–1.47 (m, 1H), 1.64–1.66 (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, 1H), 8.17 (br s, 1H, NH); 13C NMR (100 MHz, CDCl3):l 13.80 (Me), 22.55, 27.49, 34.18 (CH2), 57.06 (NCH), 122.33, 123.59, 127.88, 131.59, 132.05, 147.80 (Ar-C), 171.39 (CO); MS (EI, 70 eV), m/z 189 (M+, 11.34), 132 (100), 104 (14). Anal calcd for C12H15NO: C, 76.16; H, 7.99; N, 7.40. Found: C, 76.18; H, 8.01; N, 7.43%.
Procedure for 2d–e: Using a similar procedure as for the
preparation of 3a–c, methanol in the presence of concd HCl (as solvent) gave 4d–e.
Selected spectral data for4e (60%):14Colorless crystals; mp 136°C (ethyl acetate);1H NMR (400 MHz, CDCl 3): l 3.12 (s, 3H, OMe), 7.26–7.34 (m, 4H), 7.43–7.56 (m, 5H), 7.82 (d, J=7.8 Hz, 1H); 13C NMR (100 MHz, 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 (CO). 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.
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