Reduction of N-alkylsubstituted phthalimides to the corresponding isoindolines by means of diborane is herein described.Fil: Strassert, Cristian A.. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Orgánica; ArgentinaFil: Awruch, Josefina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Orgánica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentin

Awruch, Josefina

Strassert, Cristian A.

Monatshefte für Chemie - Chemical Monthly

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Monatshefte f€ur Chemie 137, 1499–1503 (2006)DOI 10.1007/s00706-006-0554-5Conversion of Phthalimides to Isoindolinesby DiboraneCristian A. Strassert and Josefina AwruchDepartamento de Quı́mica Orgánica, Facultad de Farmacia y Bioquı́mica,Universidad de Buenos Aires, Buenos Aires, ArgentinaReceived June 5, 2006; accepted June 11, 2006Published online November 6, 2006 # Springer-Verlag 2006Summary. Reduction of N-alkylsubstituted phthalimides to the corresponding isoindolines by meansof diborane is herein described.Keywords. Reduction; Hydrides; Heterocycles.IntroductionReduction of amides to the corresponding amines has been examined with a varietyof metal hydrides. Most of them are extremely powerful reducing agents capable ofreducing almost all the functional groups in an organic molecule [1].Reduction of phthalimides has been explored with a limited number of metalhydrides showing that the compound obtained depends on the type of reducingagent employed in the reaction. Thus, N-benzylphthalimide has been reduced withlithium aluminum hydride (LAH) to give essentially N-benzylisoindoline and onlytrace amounts of the corresponding isoindole [2]. Replacement of LAH for sodiumbis-(2-methoxyethoxy)aluminum hydride (SDMA) resulted in the formation ofthe substituted N-benzylisoindole in a 60% yield [2]. Also N-4-pentenylisoindolehas been prepared in ca. 70% yield by reduction of N-4-pentenylphthalimide withSDMA [3]. When N-benzyl-3-nitrophthalimide was reduced with a large excess ofsodium borohydride in methanol, the resulting !-carbinol lactam was isolated in a94% yield as a mixture of positional isomers (65=35) after a 20 minutes to 1 hourperiod of the reaction. This ratio and regioselectivity depends on the reactiontemperature [4].Particularly, diborane proved to be a mild and selective agent allowing thepresence of many other substituents less susceptible to the reducing action of thereagent [1, 5–7]. Besides, diborane has been successfully utilized for reduction of Corresponding author. E-mail: jawruch@ffyb.uba.arhalogen-substituted amide derivatives to the corresponding halosubstituted aminesgiving excellent yields [1].We herein report our results involving the reduction of substituted phthalimidesto the corresponding isoindolines by employing diborane.Results and DiscussionThe required substituted phthalimides 4 and 5 were prepared by alkylation of theunsubstituted precursor 6, according to Samejima et al. [8]. Compound 2 wasconveniently synthesized by a base catalyzed alkylation of 4,5-dichlorophthalimide(1) with 1,3-dibromopropane at reflux temperature (70% yield). The treatment ofN-(3-bromopropyl)-4,5-dichlorophtalimide (2) with an excess of N,N-diethylaminein o-xylene led to substituted phthalimide 3 in quantitative yields (Scheme 1).N-(3-Chloropropyl)isoindoline (7) was obtained in a 90% yield by reduction ofN-(3-chloropropyl)phthalimide (4) employing diborane in THF at room tempera-ture for 72 hours. Under the same conditions, N-(3-bromopropyl)phthalimide (5)afforded N-propylisoindoline (8) due to hydrogenolysis of the halide since bromineis more reactive than chlorine in nucleophilic substitution reactions. The substitutedphthalimide 3 was also successfully converted to the corresponding isoindoline 9 ina 90% yield. However, 9 proved to be unstable and to undergo extensive decom-position by atmospheric exposure even at low temperature. When reduction wasachieved on the unsubstituted phthalimide 6, 2,3-dihydro-1H-isoindol-1-one (10)was obtained as the main product (Scheme 2).The 1H NMR spectra of the N-substituted isoindolines 7, 8, and 9 showed twonon-equivalent doublets at ¼ 4.5 and 4.2 ppm with a characteristic gem-couplingScheme 1Scheme 21500 C. A. Strassert and J. Awruchconstant of J¼ 14 Hz which can be assigned to the pyrrolidine ring. On the con-trary, both hydrogens appear as only one singlet at ¼ 4.5 ppm in the spectrum ofisoindolinone 10.The reduction of the phthalimide rings was evidenced in the IR spectra on ac-count of the disappearance of the corresponding NC¼O stretching signals around¼ 1780 and 1715 cm1. In the case of isoindolinone 10, a typical lactam bandwas observed at 1682 cm1. Mass spectra of 7, 8, and 10 are in good agreementwith the structures proposed. However, the instability of 9 did not allow either massspectrum or recrystallization.In conclusion, the reduction of N-substituted phthalimides by means of dibor-ane is an useful method to directly produce N-substituted isoindolines in excellentyields.ExperimentalMelting points were determined on an Electrothermal 9100 capillary melting point apparatus. 1H NMRwas recorded on a Bruker MSL 300 spectrometer. Mass spectra were obtained with a TRIO 2(electronic ionization 70 eV) spectrometer. Infrared spectra were carried out with a Perkin ElmerSpectrum One FT-IR spectrometer. Elemental analyses (C, H, N) were conducted using the ElementalAnalyzer Carlo Erba EA 1108; their results were found to be in good agreement (0.2%) withcalculated values. Chromatography columns were prepared with TLC Kiesegel (Merck). 4,5-Dichlo-rophthalimide (1) was synthesized according to Wöhrle et al. [9]. Reagents were purchased fromSigma-Aldrich.N-(3-Bromopropyl)-4,5-dichlorophthalimide (2, C11H8BrCl2NO2)A mixture of 5.2 g 1 (24 mmol), 25 cm3 1,3-dibromopropane (245 mmol), and 2 g anhydrous K2CO3(14.5 mmol) was stirred and heated at reflux for 3 h, then poured into 150 cm3 H2O, and extracted with370 cm3 CH2Cl2. The combined extracts were then washed with 370 cm3 H2O, dried (Na2SO4),and evaporated in vacuum. The solid residue was dissolved in a small volume of CH2Cl2 and filteredthrough a silica-gel column, packed and pre-washed with the same solvent. After evaporation of thesolvent, the solid residue was recrystallized from EtOH to give 5.6 g (70%) 2. Mp 134–135C; 1HNMR (CDCl3, 300 MHz): ¼ 7.93 (s, 2H-Ar), 3.83 (t, J¼ 6.9 Hz, NCH2), 3.40 (t, J¼ 6.7 Hz, CH2Br),2.25 (m, NCH2CH2CH2Br) ppm; IR (KBr): ¼ 1779, 1716 (NC¼O phthalimide) cm1.N-[3-(N,N-Diethylamino)propyl]-4,5-dichlorophthalimide (3, C15H18Cl2N2O2)A mixture of 0.27 g 2 (0.8 mmol) and 0.4 cm3 N,N-diethylamine (4 mmol) in 0.6 cm3 anhydrouso-xylene was heated at 85C for 10 h. After evaporation to dryness in vacuum, the solid residue wasdissolved in a small volume of CH2Cl2:MeOH (9:1), and filtered through a silica-gel column, packedTable 1. Elemental analysesCompound Calculated FoundC (%) H (%) N (%) C (%) H (%) N (%)2, C11H8BrCl2NO2 39.20 2.39 4.16 39.30 2.20 4.203, C15H18Cl2N2O2 54.72 5.51 8.51 54.60 5.40 8.607, C11H14ClN 67.51 7.21 7.16 67.62 7.11 7.068, C11H15N 81.94 9.38 8.69 81.80 9.40 8.739, C15H22Cl2N2 59.80 7.36 9.30 59.59 7.15 9.15Conversion of Phthalimides to Isoindolines 1501and pre-washed with the same solvent. After evaporation of the solvent, a highly hygroscopic whitesolid was obtained, 0.265 g (quantitative yields) 3. Mp 230C (dec); 1H NMR (CDCl3, 300 MHz):¼ 7.92 (s, 2H-Ar), 3.78 (t, J¼ 6.8 Hz, NCH2(CH2)2N(C2H5)2), 2.97 (m, CH2N(CH2CH3)2), 2.18(m, NCH2CH2CH2N), 1.29 (t, J¼ 7.2 Hz, CH2N(CH2CH3)2) ppm; IR (KBr): ¼ 1779, 1716(NC¼O phthalimide) cm1.N-(3-Chloropropyl)isoindoline (7, C11H14ClN)Diborane from boron trifluoride etherate (5 cm3) – slowly dropped into a suspension of 1.5 g sodiumborohydride in 5 cm3 diglyme – was bubbled into a suspension of 0.5 g 4 (2.3 mmol) in 60 cm3 dryTHF. The mixture was stirred for 72 h at room temperature and the excess diborane was decomposedby addition of 0.1N HCl until pH 2 was reached, and stirred for an additional 2 h period. 1N NaOHwas added until pH 10 was reached and the solution was then extracted with 330 cm3 CH2Cl2. Thecombined extracts were washed with 330 cm3 H2O, dried (Na2SO4), and evaporated in vacuum. Thesolid residue was dissolved in a small volume of CH2Cl2 and filtered through a silica-gel column,packed and pre-washed with the same solvent. After evaporation of the solvent, the solid residue wasrecrystallized from CH2Cl2:n-hexane to give 0.394 g (90%) 7. Mp 79–81C; 1H NMR (CDCl3,300 MHz): ¼ 7.28 (m, 2H-Ar), 7.22 (m, 2H-Ar), 4.56 (d, J¼ 14 Hz, Ar(CHH)2N), 4.19 (d, J¼ 14 Hz,Ar(CHH)2N), 3.58 (t, J¼ 6.0 Hz, CH2Cl), 3.16 (t, J¼ 8.0 Hz, NCH2), 2.29 (m, NCH2CH2CH2Cl) ppm;IR (KBr): no phthalimide signal was observed; MS (70 eV): m=z (%)¼ 196 (4.10, Mþ þ 1), 195 (3.05,Mþ), 194 (11.83, Mþ-1), 132 (46.81), 118 (44.54), 105 (100).N-Propylisoindoline (8, C11H15N)Reduction of 0.5 g 5 (1.87 mmol) using the same procedure described for 7 afforded after recrystally-zation from MeOH-H2O 0.2 g (67%) 8. Mp 66–69C; 1H NMR (CDCl3, 300 MHz): ¼ 7.27 (m,2H-Ar), 7.18 (m, 2H-Ar), 4.53 (d, J¼ 14 Hz, Ar(CHH)2N), 4.17 (d, J¼ 14 Hz, Ar(CHH)2N), 2.94(t, J¼ 8.5 Hz, NCH2), 1.72 (m, NCH2CH2CH3), 0.88 (t, J¼ 7.4 Hz, CH3) ppm; IR (KBr): nophthalimide signal was observed; MS (70 eV): m=z (%)¼ 160 (21.06, Mþ), 132 (50.25), 118(12.28), 105 (100).N-[3-(N,N-Diethylamino)propyl]-4,5-dichloroisoindoline (9, C15H22Cl2N2)Reduction of 0.4 g 3 (1.2 mmol) using the same procedure described for 7 afforded after purifica-tion by filtering through a silica-gel column, packed and pre-washed with CH2Cl2:MeOH (99.5:0.5),0.33 g (90%) 9. 1H NMR (CDCl3, 300 MHz): ¼ 7.32 (s, 2H-Ar), 4.45 (d, J¼ 14 Hz, Ar(CHH)2N),4.15 (d, J¼ 14 Hz, Ar(CHH)2N), 2.97 (t, J¼ 8.0 Hz, NCH2(CH2)2N(C2H5)2), 2.84 (q, J¼ 7.4 Hz,CH2N(CH2CH3)2), 2.64 (t, J¼ 8.2 Hz, CH2N(C2H5)2), 2.28 (m, NCH2CH2CH2N), 1.19 (t, J¼ 7.4 Hz,CH2N(CH2CH3)2) ppm.2,3-Dihydro-1H-isoindol-1-one (10, C8H7NO)Reduction of 0.1 g 6 (0.68 mmol) using the same procedure described for 7 afforded after purificationby TLC using CH2Cl2:MeOH (9:1), Rf¼ 0.6, followed by recrystallization from CH2Cl2-n-hexane0.032 g (35%) 10. Mp 149–151C (Ref. [10] 151C); 1H NMR (CDCl3, 300 MHz): ¼ 8.05 (bs, NH),7.87 (m, 1H-Ar), 7.57 (m, 1H-Ar), 7.48 (m, 2H-Ar), 4.47 (s, ArCH2N) ppm; IR (KBr): ¼ 1682(NC¼O amide) cm1; MS (70 eV): m=z (%)¼ 133 (100, Mþ), 104 (52.82), 77 (48.87).AcknowledgementsThis work was supported by grants from the Universidad de Buenos Aires, the Consejo Nacionalde Investigaciones Cientı́ficas y Tecnicas and the Agencia Nacional de Promocion Cientı́fica yTecnologica. We wish to thank Ms. J.A. Valdez for her technical assistance as regards chromatographyas well as Prof. R. Davis for language supervision.1502 C. A. Strassert and J. AwruchReferences[1] Brown HC, Heim P (1973) J Org Chem 38: 912[2] Garmaise DL, Ryan A (1970) J Heterocyclic Chem 7: 413[3] Ciganek E (1980) J Org Chem 45: 1512[4] Chihab-Eddine A, Daich A, Jilale A, Decroix B (2000) J Heterocyclic Chem 37: 1543[5] Paquette LA (ed) (1999) Encyclopedia of Reagents for Organic Synthesis, vol 1. John Wiley andSons, Chichester, England, p 638[6] Awruch J (1990) Tetrahedron 46: 1171[7] Strassert CA, Dicelio LE, Awruch J (2006) Synthesis 799[8] Samejima K, Takeda Y, Kawase M, Okada M, Kyougoku Y (1984) Chem Pharm Bull 32: 3428[9] Wöhrle D, Eskes M, Shigehara K, Yamada A (1993) Synthesis 194[10] Lide DR, Frederikase HPR (eds) (1997–1998) CRC Handbook of Chemistry and Physics 78th ed.CRC Press, Boca Raton, New York, USAConversion of Phthalimides to Isoindolines 1503

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Conversion of Phthalimides to Isoindolines by Diborane

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Conversion of Phthalimides to Isoindolines by Diborane

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