Synlett 2018; 29(20): 2648-2654
DOI: 10.1055/s-0037-1611294
letter
© Georg Thieme Verlag Stuttgart · New York

Unprecedented Alkene Transposition in Phthalate–Amino Acid Adducts

Ishika Saha
a  Department of Chemistry, Durham University, South Road, DH1 3LE, Durham, UK
,
a  Department of Chemistry, Durham University, South Road, DH1 3LE, Durham, UK
,
b  School of Chemistry, University College Dublin, Science Centre South, Belfield, Dublin 4, Ireland   Email: marcus.baumann@ucd.ie
› Author Affiliations
The authors acknowledge generous support by the Royal Society (to IRB) and the School of Chemistry at University College Dublin (to MB).
Further Information

Publication History

Received: 08 September 2018

Accepted after revision: 04 October 2018

Publication Date:
07 November 2018 (online)


Abstract

A detailed account on the outcome of the thermal reaction between benzylidene phthalides and various amino acid derivatives is reported. It was discovered that the tricyclic pyrroles as previously described are not the products formed in these reactions. Instead under high-temperature conditions decarboxylated phthalamide adducts are formed within 5-10 minutes. Additionally, an unprecedented alkene transposition mechanism has been identified leading to the final products of these reactions.

Supporting Information

 
  • References and Notes

    • 2a Taylor AP, Robinson RP, Fobian YM, Blakemore DC, Jones LH, Fadeyi O. Org. Biomol. Chem. 2016; 14: 6611
    • 2b Mendez-Lucio O, Medina-Franco JL. Drug Discovery Today 2017; 22: 120
    • 2c Jorgensen WL. Acc. Chem. Res. 2009; 42: 724

      For recent examples, please see:
    • 3a Yamamoto Y, Hayashi H. Tetrahedron 2007; 63: 10149
    • 3b Mondal SK, Mandal A, Manna SK, Ali SA, Hossain M, Venugopal V, Jana A, Samanta S. Org. Biomol. Chem. 2017; 15: 2411
    • 3c Zheng Z, Tu H, Zhang L. Chem. Eur. J. 2014; 20: 2445
    • 3d Rihak KJ, Bissember AC, Smith JA. Tetrahedron 2018; 74: 1167
    • 3e Mir NA, Choudharry S, Ramaraju P, Singh D, Kumar I. RSC Adv. 2016; 6: 39741
    • 3f Guirguis DB. Eur. Chem. Bull. 2013; 2: 797
  • 4 Hassan KM, El-Garby Younes M, El-Maghraby MA. Indian J. Chem. 1974; 12: 1031
  • 5 Ibrahim TM. Arch. Pharm. Res. 1991; 14: 342
  • 6 Napolitano E, Fiaschi R, Scartoni V, Marsili A. J. Chem. Soc., Perkin Trans 1 1986; 781
  • 7 We opted to use this 4-methoxyphenyl-substituted phthalide to facilitate 1H NMR analysis of crude reaction mixtures due to the characteristic signal of the methoxy group.
  • 8 A handheld IR thermometer from Extech Instruments was used (type K, model 42515, temperature range –58 to 1472 F).
  • 9 General Procedure for Products 3 Equimolar amounts of benzylidene phthalide 1 and glycine were heated (ca. 180–190 °C) and stirred in a round-bottomed flask for 4 h. After cooling, the reaction mixture was dissolved in DCM, and a base wash was conducted using sat. aq NaHCO3 (3 × 10 ml). Aqueous HCl (1 M, ca. 50 ml) was used to back-extract the acidic species from the aqueous layer into DCM. After drying the organic layer with anhydrous Na2SO4 the solvent was removed in vacuo. The remaining semisolid product was recrystallised from a 1:1 mixture of acetic acid and water furnishing crystals of the E-isomer (30% isolated yield). The mother liquor subsequently yielded single crystals of the Z-isomer (2% isolated yield). (E)-2-(3-Benzylidene-1-oxoisoindolin-2-yl)-acetic Acid ((E)-3) Orange crystalline solid; melting range: 201.8–202.5 °C. 1H NMR (600 MHz, DMSO-d 6): δ = 13.00 (br s, 1 H), 7.78 (d, J = 7.5 Hz, 1 H), 7.51 (app t, J = 7.4 Hz, 1 H), 7.41–7.48 (m, 5 H), 7.36–7.40 (m, 1 H), 7.30 (d, J = 7.8 Hz, 1 H), 6.71 (s, 1 H), 4.62 (s, 2 H) ppm. 13C NMR (150 MHz, DMSO-d 6): δ = 169.9 (C), 165.9 (C), 135.5 (C), 135.2 (C), 135.1 (C), 132.6 (CH), 130.2 (CH), 129.9 (C), 128.3 (CH), 129.7 (2 CH), 129.2 (2 CH), 123.4 (CH), 123.1 (CH), 111.4 (CH), 41.2 (CH2) ppm. IR: ν = 2981 (br), 1752 (m), 1670 (s), 1655 (m), 1643 (m) cm–1. ES+: m/z = 280.1 [M + H]+, ES: m/z = 278.1 [M – H]+. HRMS (ES-TOF+): m/z calcd for C17H14NO3: 280.0968; found: 280.0974. Anal. Calcd for C17H13NO3: C, 73.11; H, 4.69; N, 5.02. Found: C, 72.67; H, 4.66; N, 4.97. Crystal data CCDC 1863430: space group: P21/n; a = 9.4136(8), b = 14.1529(12), c = 10.1118(8) Å; α = 90°, β = 97.034(3)°, γ = 90°. Z-2-(3-Benzylidene-1-oxoisoindolin-2-yl)-acetic Acid ((Z)-3) White crystalline solid; melting range: 174.6–176.1 °C. 1H NMR (600 MHz, DMSO-d 6): δ = 12.73 (br s, 1 H), 8.07 (app dd, J = 7.8, 0.9 Hz, 1 H), 7.81 (app dt, J = 7.1, 1.0 Hz, 1 H), 7.76 (app td, J = 7.6, 1.2 Hz, 1 H), 7.40–7.48 (m, 5 H), 7.33–7.36 (m, 1 H), 7.07 (s, 1 H), 4.17 (s, 2 H) ppm. 13C NMR (150 MHz, DMSO-d 6): δ = 169.7 (C), 168.3 (C), 138.6 (C), 134.6 (C), 134.5 (C), 133.1 (CH), 130.1 (2 CH), 129.9 (2 CH), 129.6 (CH), 128.1 (CH), 127.7 (C), 123.2 (CH), 120.8 (CH), 107.5 (CH), 43.9 (CH2) ppm. IR: ν = 2981 (br), 1710 (m), 1642 (s), 1249 (s), 760 (s) cm–1. Crystal data CCDC 1863431: space group: Pbca; a = 9.4099(5), b = 8.4569(5), c = 33.1462(19) Å; α = 90°, β = 90°, γ = 90°.
  • 10 General Procedure for Products 5 To a pre-stirred mixture of l-leucine methyl ester hydrochloride (4.5 mmol) and triethylamine (4.5 mmol) in acetonitrile (12 ml) was added benzylidene phthalide (1, 4.5 mmol), and the solution was allowed to reflux for 24 h. After cooling to ambient temperature, a base wash with sat. NaHCO3 (ca. 5 ml) was conducted to create the free base form of triethylamine, which was subsequently removed in vacuo. The compounds in the remaining mixture were separated by silica column chromatography using a gradient in the eluent system, Hex/EtOAc (6:4 to 7:3). The isomers were recrystallised from a mixture of EtOAc and hexane. The major isomer 5a was found by single crystal X-ray diffraction to have (2S3R) configuration. A diastereomeric ratio of ca. 5:2 was established by 1H NMR spectroscopy of the unseparated mixture. The combined yield for both diastereomers was 54%, 0.90 g. 2-(S)-(3-(R)-Benzyl-3-hydroxy-1-oxoisoindolin-2-yl)-4-methylpentanoate (5a) White crystalline solid. 1H NMR (700 MHz, DMSO-d 6): δ = 7.58 (app dt, J = 7.5, 1.0 Hz, 1 H), 7.43 (app tt, J = 7.4, 1.2 Hz, 1 H), 7.37 (app td, J = 7.5, 1.2 Hz, 1 H), 7.21–7.25 (m, 3 H), 7.14–7.18 (m, 2 H), 6.62 (s, 1 H), 6.55 (d, J = 7.6 Hz, 1 H), 4.30 (dd, J = 8.3, 5.8 Hz, 1 H), 3.61 (s, 3 H), 3.43 (d, J = 13.8 Hz, 1 H), 2.80 (dd, J = 13.8, 1.6 Hz, 1 H), 2.05–2.10 (m, 1 H), 1.91–1.96 (m, 1 H), 1.72 (dddd, J = 13.2, 12.0, 8.4, 6.5 Hz, 1 H), 0.89 (d, J = 6.6 Hz, 3 H), 0.84 (d, J = 6.6 Hz, 3 H) ppm. 13C NMR (175 MHz, DMSO-d 6): δ = 172.0 (C), 165.7 (C), 147.2 (C), 136.5 (C), 132.1 (CH), 131.4 (2 CH), 131.1 (C), 129.5 (CH), 127.9 (2 CH), 127.0 (CH), 123.5 (CH), 123.4 (CH), 90.5 (C), 52.5 (CH3), 52.0 (CH), 44.4 (CH2), 39.1 (CH2), 24.8 (CH), 23.3 (CH3), 22.4 (CH3) ppm. IR: ν = 3188 (br), 2954 (w), 1749 (m), 1672 (s), 1420 (m) cm–1. ES+: m/z = 368.1 [M + H]+. HRMS (ES-TOF+): m/z calcd for C22H26NO4: 368.1856; found: 368.1875. Crystal data CCDC 1863432: space group: P-1; a = 9.6024(13), b = 11.2692(15), c = 19.438(3) Å; α = 95.240(6)°, β = 98.235(6)°, γ =110.172(6)°. 2-(S)-2-[(3S)-3-Benzyl-3-hydroxy-1-oxoisoindolin-2-yl]-4-methylpentanoate (5b) White crystalline solid. IR: ν = 3342 (br), 2955 (w), 1735 (m), 1675 (s), 1420 (m) cm–1. 1H NMR (700 MHz, DMSO-d 6): δ = 7.55 (app dt, J = 7.5, 1.0 Hz, 1 H), 7.44 (m, 1 H), 7.39 (app td, J = 7.5, 1.3 Hz, 1 H), 7.18–7.20 (m, 3 H), 7.03–7.06 (m, 2 H), 6.67 (app dt, J = 7.6, 1.0 Hz, 1 H), 6.66 (d, J = 1.0 Hz, 1 H), 4.39 (dd, J = 7.9, 6.5 Hz, 1 H), 3.57 (s, 3 H), 3.47 (d, J = 13.8 Hz, 1 H), 2.83 (dd, J = 13.8, 1.0 Hz, 1 H), 2.18–2.25 (m, 1 H), 1.85–1.91 (m, 1 H), 1.78 (dt, J = 13.4, 6.7 Hz, 1 H), 0.94 (d, J = 6.6 Hz, 3 H), 0.92 (d, J = 6.6 Hz, 3 H) ppm. 13C NMR (175 MHz, DMSO-d 6): δ = 172.1 (C), 166.7 (C), 146.7 (C), 136.1 (C), 131.7 (C), 131.6 (CH), 131.0 (2 CH), 129.6 (CH), 128.0 (2 CH), 127.1 (CH), 124.2 (CH), 122.7 (CH), 91.1 (C), 52.1 (CH), 51.8 (CH3), 44.5 (CH2), 39.3 (CH2), 25.5 (CH), 23.2 (CH3), 22.6 (CH3) ppm.
  • 11 General Procedure for Product 7 To a pre-stirred mixture of 2-aminoacetonitrile hydrochloride (4.5 mmol) and triethylamine (4.5 mmol) in acetonitrile (12 ml) was added benzylidene phthalide (1, 4.5 mmol) at room temperature. After refluxing for 15 h the mixture was cooled to room temperature. A base wash with sat. NaHCO3 (ca. 5 ml) was conducted to create the free base form of triethylamine, which was subsequently removed in vacuo. The remaining mixture was purified by silica column chromatography using an eluent system of Hex/EtOAc (7:3). The title compound was obtained as a pale solid and recrystallised from EtOAc/Hex (2:5); yield 20% (0.253 g). 2-(3-Benzyl-3-hydroxy-1-oxoisonidolin-2-yl)-acetonitrile (7) White crystalline solid; melting range: 144.7–147.9 °C. IR: ν = 3356 (br), 1690 (s), 1616 (w), 1411 (m), 1070 (m) cm–1. 1H NMR (700 MHz, CDCl3): δ = 7.48–7.51 (m, 2 H), 7.39–7.45 (m, 1 H), 7.11–7.21 (m, 4 H), 6.95–7.00 (m, 2 H), 4.31 (dd, J = 17.6, 0.9 Hz, 1 H), 4.17 (br s, 1 H), 4.07 (d, J = 17.6 Hz, 1 H), 3.49 (d, J = 14.1 Hz, 1 H), 3.12 (d, J = 14.1 Hz, 1 H) ppm. 13C NMR (175 MHz, CDCl3): δ = 167.0 (C), 146.3 (C), 133.8 (C), 132.9 (CH), 130.3 (2 CH), 129.9 (2 CH + CH), 129.6 (C), 127.4 (CH), 123.6 (CH), 123.2 (CH), 115.5 (C), 90.8 (C), 43.4 (CH2), 26.1 (CH2) ppm. ES+: m/z = 279.2 [M + H]+. HRMS (ES-TOF+): m/z calcd for C17H15N2O2: 279.1128; found: 279.1134. Crystal data CCDC 1863433: space group: C2/c; a = 23.0705(13), b = 8.1188(4), c = 15.8975(9) Å; α = 90°, β = 108.421(2)°, γ = 90°.
  • 12 General Procedure for Products 10 and 11 A homogeneous mixture of benzylidene phthalide (1, 1 equiv) and an amino acid HCl salt (Phe, Val, Leu; 1–2 equiv) was prepared in a thick-walled glass tube and heated with a heat gun to about 240 °C. After 10 min gas formation ceased, and an amber oil resulted, which solidified upon cooling. The crude residue was dissolved in a minimal amount of EtOH and subjected to silica column chromatography (5–10% EtOAc/hexanes) yielding the individual products 10 and 11 as yellow oils. (E)-3-(4-Methoxybenzylidene)-2-phenethylisoindolin-1-one (10a) Pale yellow oil, 37% yield. 1H NMR (400 MHz, CDCl3): δ = 7.85 (dt, J = 7.7, 1.0 Hz, 1 H), 7.41 (ddd, J = 7.5, 6.3, 2.0 Hz, 1 H), 7.35–7.22 (m, 9 H), 6.99–6.92 (m, 2 H), 6.38 (s, 1 H), 4.15–4.09 (m, 2 H), 3.88 (s, 3 H), 3.09–3.02 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 166.4 (C), 159.3 (C), 138.8 (C), 135.6 (C), 135.1 (C), 131.4 (CH), 130.8 (2 CH), 130.3 (C), 129.0 (CH), 128.9 (2 CH), 128.6 (2 CH), 127.3 (C), 126.6 (CH), 123.1 (2 CH), 114.1 (2 CH), 110.3 (CH), 55.4 (CH3), 41.2 (CH2), 34.9 (CH2) ppm. IR (neat): ν = 3028 (w), 2957 (w), 1703 (s), 1605 (m), 1509 (s), 1454 (m), 1346 (m), 1250 (s), 1173 (m), 1105 (m), 1031 (m), 832 (w), 756 (m), 697 (m) cm–1. HRMS (AP+): m/z calcd for C24H22NO2: 356.1651; found: 356.1626. (E)-2-Isobutyl-3-(4-methoxybenzylidene)isoindolin-1-one (10b) Pale yellow oil, 33% yield. 1H NMR (600 MHz, CDCl3): δ = 7.82 (dt, J = 7.5, 1.0 Hz, 1 H), 7.39 (td, J = 7.4, 1.1 Hz, 1 H), 7.37–7.33 (m, 3 H), 7.30 (ddd, J = 8.0, 7.2, 1.2 Hz, 1 H), 6.96 (d, J = 8.6 Hz, 2 H), 6.48 (s, 1 H), 3.87 (s, 3 H), 3.71 (d, J = 7.6 Hz, 2 H), 2.22 (sept, J = 6.0 Hz, 1 H), 1.00 (d, J = 6.8 Hz, 6 H) ppm. 13C NMR (150 MHz, CDCl3): δ = 166.8 (C), 159.2 (C), 136.2 (C), 135.0 (C), 131.3 (CH), 130.8 (2 CH), 130.2 (C), 128.9 (CH), 127.4 (C), 123.1 (CH), 123.0 (CH), 114.1 (2 CH), 110.4 (CH), 55.3 (CH3), 46.8 (CH2), 27.8 (CH), 20.3 (2 CH3) ppm. IR (neat): ν = 2959 (m), 1698 (s), 1606 (m), 1510 (s), 1407 (m), 1248 (s), 1175 (m), 1095 (m), 1033 (m), 768 (m), 697 (m), 562 (m) cm–1. HRMS (AP+): m/z calcd for C20H22NO2: 308.1651; found: 308.1652. (E)-2-Isopentyl-3-(4-methoxybenzylidene)isoindolin-1-one (10c) Pale yellow oil, 35% yield. 1H NMR (600 MHz, CDCl3): δ = 7.82 (dt, J = 7.5, 1.0 Hz, 1 H), 7.41–7.34 (m, 4 H), 7.30 (ddd, J = 8.1, 7.2, 1.2 Hz, 1 H), 6.97 (d, J = 8.7 Hz, 2 H), 6.47 (s, 1 H), 3.91–3.88 (m, 2 H), 3.88 (s, 3 H), 1.71 (sept, J = 6.0 Hz, 1 H), 1.66–1.59 (m, 2 H), 1.01 (d, J = 6.0 Hz, 6 H) ppm. 13C NMR (150 MHz, CDCl3): δ = 166.4 (C), 159.3 (C), 135.7 (C), 135.1 (C), 131.2 (CH), 130.8 (2 CH), 130.4 (C), 128.9 (CH), 127.4 (C), 123.0 (2 × CH), 114.1 (2 CH), 110.0 (CH), 55.3 (CH3), 37.9 (CH2), 37.2 (CH2), 26.2 (CH), 22.6 (2 CH3) ppm. IR (neat): ν = 2956 (w), 1698 (s), 1606 (m), 1510 (m), 1407 (m), 1248 (s), 1174 (m), 1096 (m), 1033 (m), 837 (m), 767 (m), 696 (m) cm–1. HRMS (AP+): m/z calcd for C21H24NO2: 322.1807; found: 322.1813. (E)-3-(4-Methoxybenzyl)-2-styrylisoindolin-1-one (11a) Beige solid, 35% yield; melting range 161.3–164.0 °C (hexanes/Et2O). 1H NMR (600 MHz, CDCl3): δ = 7.81 (d, J = 15.2 Hz, 1 H), 7.76 (dd, J = 7.6, 1.0 Hz, 1 H), 7.52 (td, J = 7.5, 1.1 Hz, 1 H), 7.49 (d, J = 7.8 Hz, 2 H), 7.43 (t, J = 7.5 Hz, 1 H), 7.36 (t, J = 7.8 Hz, 2 H), 7.25–7.22 (m, 1 H), 7.21 (dt, J = 7.7, 0.9 Hz, 1 H), 6.82 (d, J = 8.6 Hz, 2 H), 6.69 (d, J = 8.6 Hz, 2 H), 6.30 (d, J = 15.1 Hz, 1 H), 5.15 (dd, J = 7.3, 3.1 Hz, 1 H), 3.73 (s, 3 H), 3.47 (dd, J = 14.2, 3.2 Hz, 1 H), 3.15 (dd, J = 14.1, 7.2 Hz, 1 H) ppm. 13C NMR (150 MHz, CDCl3): δ = 166.4 (C), 158.5 (C), 145.0 (C), 136.5 (C), 132.0 (CH), 131.3 (C), 130.6 (2 CH), 128.8 (2 CH), 128.5 (CH), 126.7 (CH), 126.5 (C), 125.7 (2 CH), 124.1 (CH), 122.9 (CH), 122.7 (CH), 113.6 (2 CH), 112.7 (CH), 59.6 (CH), 55.1 (CH3), 36.6 (CH2) ppm. IR (neat): ν = 3067 (w), 2933 (w), 1700 (s), 1646 (s), 1609 (m), 1508 (s), 1390 (s), 1298 (m), 1242 (s), 1140 (m), 1029 (m), 948 (m), 834 (s), 747 (s), 697 (s), 618 (m) cm–1. HRMS (ES+): m/z calcd for C24H22NO2: 356.1651; found: 356.1675. Crystal data CCDC 1863434: space group: Pbca; a = 9.7463(4), b = 14.9772(7), c = 25.1292(11) Å; α = 90°, β = 90°, γ = 90°. 3-(4-Methoxybenzyl)-2-(2-methylprop-1-en-1-yl)isoindolin-1-one (11b) Colourless oil, 36% yield. 1H NMR (400 MHz, CDCl3) δ/ppm 7.80 (ddd, J = 5.6, 3.0, 0.8 Hz, 1H), 7.41 (dd, J = 5.6, 3.1 Hz, 2H), 6.96 – 6.90 (m, 3H), 6.77 (d, J = 8.6 Hz, 2H), 6.01 – 5.98 (m, 1H), 4.88 (dd, J = 8.5, 4.3 Hz, 1H), 3.77 (s, 3H), 3.35 (dd, J = 13.8, 4.3 Hz, 1H), 2.68 (dd, J = 13.8, 8.5 Hz, 1H), 1.88 (d, J = 1.5 Hz, 3H), 1.74 (d, J = 1.5 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ = 158.5 (C), 145.0 (C), 133.1 (C), 132.0 (C), 131.1 (CH), 130.6 (2 CH), 128.2 (CH), 128.0 (C), 123.8 (CH), 123.0 (CH), 117.7 (CH), 113.8 (2 CH), 62.9 (CH), 55.2 (CH3), 38.0 (CH2), 23.1 (CH3), 19.0 (CH3) (1 C not observed). IR (neat): ν = 2962 (w), 2914 (w), 1698 (s), 1612 (m), 1513 (s), 1402 (m), 1301 (m), 1249 (s), 1178 (m), 1034 (m), 826 (m), 746 (m), 692 (m) cm–1. HRMS (AP+): m/z calcd for C20H22NO2: 308.1651; found: 308.1650. (E)-3-(4-Methoxybenzyl)-2-(3-methylbut-1-en-1-yl)isoindolin-1-one (11c) Yellow oil, 38% yield. 1H NMR (400 MHz, CDCl3): δ = 7.73 (dt, J = 7.4, 1.0 Hz, 1 H), 7.46 (td, J = 7.5, 1.3 Hz, 1 H), 7.38 (ddd, J = 8.0, 7.4, 0.9 Hz, 1 H), 7.12 (dd, J = 7.5, 0.9 Hz, 1 H), 7.04 (ddd, J = 14.8, 1.2, 0.6 Hz, 1 H), 6.81 (d, J = 8.7 Hz, 2 H), 6.69 (d, J = 8.7 Hz, 2 H), 5.32 (dd, J = 14.8, 7.3 Hz, 1 H), 4.97 (dd, J = 7.4, 3.1 Hz, 1 H), 3.74 (s, 3 H), 3.40 (dd, J = 13.9, 3.1 Hz, 1 H), 2.99 (dd, J = 13.9, 7.4 Hz, 1 H), 2.54 (dsext, J = 13.6, 6.8 Hz, 1 H), 1.17 (d, J = 6.8 Hz, 3 H), 1.14 (d, J = 6.8 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 166.2 (C), 158.5 (C), 145.0 (C), 131.8 (C), 131.5 (CH), 130.5 (2 CH), 128.3 (CH), 127.0 (C), 123.9 (CH), 122.8 (CH), 121.2 (CH), 120.5 (CH), 113.6 (2 CH), 59.4 (CH), 55.1 (CH3), 36.3 (CH2), 29.9 (CH), 23.5 (CH3), 23.2 (CH3). IR (neat): ν = 2957 (m), 1698 (s), 1663 (m), 1513 (s), 1467 (m), 1393 (m), 1249 (s), 1178 (m), 1035 (m), 826 (m), 747 (m), 697 (m) cm–1. HRMS (AP+): m/z calcd for C21H24NO2: 322.1807; found: 322.1812.