F
I. Saha et al.
Letter
Synlett
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-d6): 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°.
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°.
(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 solu-
tion was allowed to reflux for 24 h. After cooling to ambient
temperature, a base wash with sat. NaHCO3 (ca. 5 ml) was con-
ducted to create the free base form of triethylamine, which was
subsequently removed in vacuo. The compounds in the remain-
ing 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 diastereo-
mers was 54%, 0.90 g.
(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 pre-
pared 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.
2-(S)-(3-(R)-Benzyl-3-hydroxy-1-oxoisoindolin-2-yl)-4-
methylpentanoate (5a)
1
White crystalline solid. H NMR (700 MHz, DMSO-d6): 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-d6):
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)°.
(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.
2-(S)-2-[(3S)-3-Benzyl-3-hydroxy-1-oxoisoindolin-2-yl]-4-
methylpentanoate (5b)
(E)-2-Isobutyl-3-(4-methoxybenzylidene)isoindolin-1-one
(10b)
White crystalline solid. IR: ν = 3342 (br), 2955 (w), 1735 (m),
1675 (s), 1420 (m) cm–1. 1H NMR (700 MHz, DMSO-d6): 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-d6): 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.
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 C20H22
NO2: 308.1651; found: 308.1652.
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(11) General Procedure for Product 7
(E)-2-Isopentyl-3-(4-methoxybenzylidene)isoindolin-1-one
(10c)
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 tem-
perature. After refluxing for 15 h the mixture was cooled to
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
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–G