Synthesis of Spiropyrrolidines and Spiropyrrolizidines by Azomethine Ylide Cycloaddition of Baylis-Hillman Adducts Derived from N-Methyl Maleimide

Abstract

The stereoselective synthesis of a series of novel spiropyrrolidines and spiropyrrolizidines has been accomplished through an intermolecular 1,3-dipolar cycloaddition of an azomethine ylides with dipolarophiles derived from the Baylis-Hillman reaction of ­isatins with N-methyl maleimide.

Baylis-Hillman reaction - azomethine ylide cycloadditon - spiropyrrolidines - spiropyrrolizidines

References and Notes

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<A NAME="RG23610ST-19">19</A>

Experimental Procedure for the Synthesis of Baylis-Hillman Adducts 3a-g A mixture of isatin 1a-g (1.62 mmol), N-methyl maleimide (2, 1.35 mmol), and DABCO (30 mol%) was stirred at 80 ˚C under neat conditions. Completion of the reaction was evidenced by TLC analysis. The residue was dissolved in EtOAc (20 mL) and H₂O washed (2 × 20 mL). The EtOAc layer was dried over anhyd Na₂SO₄, and the solvent was removed under reduced pressure to obtain a crude product, which was purified by column chromatography with EtOAc-PE (2:8) as an eluent to obtain Baylis-Hillman adducts 3a-g.
Baylis-Hillman Adduct 3a Colorless solid; mp 148-150 ˚C. IR: 3368, 3115, 1722, 1610, 1488, 1380, 1162 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 2.88 (s, 3 H), 3.25 (s, 3 H), 4.73 (br s, 1 H), 6.77 (s, 1 H), 6.91 (d, 1 H, J = 7.7 Hz), 7.09 (t, 1 H, J = 7.7 Hz), 7.28 (d, 1 H, J = 6.9 Hz), 7.38 (t, 1 H, J = 7.6 Hz). ^¹³C NMR (125 MHz, CDCl₃): δ = 23.8, 26.8, 74.6, 109.4, 123.8, 124.8, 127.5, 128.8, 131.2, 143.9, 147.4, 168.9, 169.5, 174.5. MS: m/z = 273 [M + H]⁺. Anal. Calcd for C₁₄H₁₂N₂O₄ (272.08): C, 61.76; H, 4.44; N, 10.29. Found: C, 61.84; H, 4.47; N, 10.16.

<A NAME="RG23610ST-20">20</A>

Crystallographic data of compound 3f in this letter have been deposited with the Cambridge Crystallographic Data Centre as supplemental publication No. CCDC-787472. Copies of the data can be obtained, free of charge on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: [phone] or email: [e-mail]].

<A NAME="RG23610ST-21">21</A>

Experimental Procedure for the Synthesis of Spiropyrrolidines 5a-e A mixture of isatin 1 (1 mmol), sarcosine (4, 1.5 mmol), and Baylis-Hillman adducts 3 (1 mmol) was refluxed in MeOH (10 mL). Completion of the reaction was evidenced by TLC analysis. The solvent was removed under vacuo, and the crude product was subjected to column chromatography using EtOAc-PE (2:8) as an eluent to afford pure spiropyrrolidines 5a-e.
3a′-(3-Hydroxy-1-methyl-2-oxoindolin-3-yl)-1,2′,5′-trimethyl-3′,3a′-dihydro-2′ H -spiro{indoline-3,1′-pyrrolo[3,4- c ]pyrrole}-2,4′,6′(5′ H ,6a′ H )-trione (5a)
Colorless solid; mp 258-260 ˚C. IR: 3361, 2963, 1699, 1612, 1471, 1373, 1124 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 1.99 (s, 3 H), 2.65 (s, 3 H), 3.21 (s, 3 H), 3.24 (s, 3 H), 3.62 (d, 1 H, J = 11.5 Hz), 3.92 (s, 1 H), 4.32 (d, 1 H, J = 11.5 Hz), 5.81 (br s, 1 H), 6.77 (d, 1 H, J = 7.7 Hz), 6.82 (d, 1 H, J = 7.7 Hz), 6.89-6.93 (m, 2 H), 7.08-7.10 (m, 2 H), 7.26 (t, 1 H, J = 6.9 Hz), 7.38 (t, 1 H, J = 7.6 Hz). ^¹³C NMR (125 MHz, CDCl₃): δ = 25.1, 26.2, 26.4, 34.6, 53.2, 55.0, 63.4, 72.3, 74.3, 108.8, 108.9, 121.8, 123.3, 123.4, 123.9, 126.4, 126.9, 130.4, 130.7, 143.9, 144.1, 174.0, 175.4, 177.1, 177.6. MS: m/z = 461 [M + H]⁺. Anal. Calcd for C₂₅H₂₄N₄O₅ (460.17): C, 65.21; H, 5.25; N, 12.17. Found: C, 65.29; H, 5.23; N, 12.24.

<A NAME="RG23610ST-22">22</A>

Crystallographic data of compound 5c in this letter have been deposited with the Cambridge Crystallographic Data Centre as supplemental publication No. CCDC-787473. Copies of the data can be obtained, free of charge on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: [phone] or email: [e-mail]].

<A NAME="RG23610ST-23">23</A>

Experimental Procedure for the Synthesis of Spiropyrrolizidines 7a-e A mixture of isatin 1 (1 mmol), l-proline (6, 1.5 mmol), and Baylis-Hillman adducts 3 (1 mmol) was refluxed in MeOH (10 mL). Completion of the reaction was evidenced by TLC analysis. The solvent was removed under vacuo, and the crude product was subjected to column chromatography using EtOAc-PE (2:8) as an eluent to afford pure spiropyrrolizidines 7a-e. 8b′-(1-Ethyl-3-hydroxy-2-oxoindolin-3-yl)-1,2′-dimethyl-6′,7′,8′,8a′-tetrahydro-1′ H -spiro{indoline-3,4′-pyrrolo[3,4- a ]pyrrolizine}-1′,2,3′(2′ H ,3a′ H ,8b′ H )-trione (7b) Brown solid; mp 230-232 ˚C. IR: 3342, 2935, 1705, 1610, 1468, 1371, 1089 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 1.31 (t, 3 H, J = 6.9 Hz), 1.72-1.79 (m, 1 H), 1.87-1.91 (m, 3 H), 2.14-2.18 (m, 1 H), 2.31-2.36 (m, 1 H), 2.70 (s, 3 H), 3.21 (s, 3 H), 3.63-3.69 (m, 1 H), 3.80-3.86 (m, 1 H), 4.16 (s, 1 H), 4.76 (t, 1 H, J = 6.9 Hz), 5.66 (br s, 1 H), 6.78 (d, 1 H, J = 7.7 Hz), 6.86 (t, 2 H, J = 8.4 Hz), 6.93 (t, 1 H, J = 7.7 Hz), 7.06 (t, 1 H, J = 6.9 Hz), 7.17 (d, 1 H, J = 6.9 Hz), 7.26 (t, 1 H, J = 7.7 Hz), 7.35 (t, 1 H, J = 7.7 Hz). ^¹³C NMR (125 MHz, CDCl₃): δ = 12.4, 24.6, 24.9, 25.8, 26.3, 35.0, 42.3, 58.5, 62.2, 65.0, 66.9, 75.0, 108.7, 108.8, 122.5, 122.9, 124.2, 124.3, 126.4, 127.6, 130.2, 130.5, 143.4, 143.7, 174.3, 175.0, 177.2. MS: m/z = 501 [M + H]⁺. Anal. Calcd for C₂₈H₂₈N₄O₅ (500.21): C, 67.19; H, 5.64; N, 11.19. Found: C, 67.42; H, 5.66; N, 11.40.