Enantioselective Synthesis of 3,3-Disubstituted Indolines via Asymmetric Intramolecular Carbolithiation in the Presence of (-)-Sparteine [1]

Abstract

The functionalized N-benzyl-protected bromoanilines underwent an asymmetric intramolecular carbolithiation in the presence of t-BuLi and (-)-sparteine yielding 3,3-disubstituted indolines.

Key words

asymmetric synthesis - indolines - lithiations - natural products - sparteine

1

Asymmetric Carbolithiations, Part II; for part I, see reference 10b.

References and Notes

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1

Asymmetric Carbolithiations, Part II; for part I, see reference 10b.

16

General Procedure for the Carbolithiation: All experiments were carried out under an argon atmosphere using Schlenk techniques. A solution of substrate 5 (0.83 mmol) and (-)-sparteine (1.5 equiv) in toluene (10 mL) was cooled to -78 °C and t-BuLi (2.2 equiv, 1.5 M in pentane) was added. The reaction mixture was stirred for 16 h at this temperature. MeOH (5 mL) was added to quench the lithium intermediate. After addition of sat. NH₄Cl solution (10 mL) and H₂O (10 mL) the aqueous layer was extracted using EtOAc (3 × 30 mL). The combined organic phases were dried (MgSO₄), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography to give the desired indoline 6.

17

All products have been fully characterized by ¹H NMR and ¹³C NMR. The analyses of known compounds are in agreement with the published data. The characteristics of selected compounds are as follows:
Compound 6b: [α]_D ²⁰ +32.4° (c = 1.15, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 1.34 (s, 3 H, CMe), 3.01, 3.39 [2 × d, J = 8.2 Hz, 2 × 1 H, N(Bn)CH₂], 3.33 (s, 3 H, OMe), 3.35, 3.59 (2 d, J _AB = 10 Hz, 2 H, CH ₂OMe), 4.24, 4.31 (2 × d, J = 15.0 Hz, 2 × 1 H, NCH₂Ph), 6.49 (d, J = 7.8 Hz, 1 H, ArH), 6.68 (t, J = 7.4 Hz, 1 H, ArH), 7.03-7.10 (m, 2 H, ArH), 7.24-7.35 (m, 5 H, ArH). ¹³C NMR (100.6 MHz, CDCl₃): δ = 22.8 (CMe), 44.9 (CMe), 52.7 (CH₂Ph), 59.3 (OMe), 63.1 [N(Bn)CH₂], 79.0 (CH₂O), 106.9, 117.5, 122.9, 127.0, 127.7, 128.0, 128.4 (7 × CH_Ar), 135.0 (CMeC_Ar), 138.4 (C_q,Ph), 151.5 (NC_Ar). MS (EI, 70 eV): m/z = 267 [M⁺], 222 [M⁺ - CH₂ - OMe], 91 [C₇H₇ ⁺]. IR (film): 3026, 2922, 2869, 2823, 1605, 1494, 1453, 1118 cm^-1. Anal. Calcd for C₁₈H₂₁NO: C, 80.86; H, 7.92; N, 5.24. Found: C, 80.60; H, 7.82; N, 5.20.
Compound 6e: [α]_D ²⁰ +19.6° (c = 0.52, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 1.28 (s, 3 H, CMe), 1.42-1.78 (m,
2 × 2 H, CH ₂CH ₂CH₂OMe), 3.00, 3.18 (2 × d, J = 8.6 Hz, 2 × 1 H, NCH ₂CMe), 3.27 (s, 3 H, OMe), 3.30 (t, J = 7.8 Hz, 2 H, CH ₂OMe), 4.17, 4.29 (2 × d, J = 15.2 Hz, 2 × 1 H, NCH₂Ph), 6.47 (d, J = 7.8 Hz, 1 H, ArH), 6.64-6.69 (m, 2 H, ArH), 6.98-7.34 (m, 6 H, ArH). ¹³C NMR (100.6 MHz, CDCl₃): δ = 25.1, 25.9, 37.2, 43.3, 53.1, 58.5, 65.7, 73.2, 106.9, 117.6, 122.5, 127.1, 127.6, 127.8, 128.5, 137.4, 138.6, 151.5. MS (EI, 70 eV): m/z = 295 [M⁺], 222 [M + CH₂CH₂CH₂OMe], 91 [C₇H₇ ⁺].
Compound 6g: [α]_D ²⁰ +21.3° (c = 0.92, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 1.37 (s, 3 H, CMe), 2.02 (s, 3 H, SMe), 2.73, 2.78 (2 × d, J = 12.8 Hz, 2 × 1 H, CH₂SMe), 3.02, 3.38 [2 × d, J = 9.0 Hz, 2 × 1 H, N(Bn)CH₂], 4.18, 4.33 (2 × d, J = 14.8 Hz, 2 × 1 H, NCH₂Ph), 6.50 (d, J = 7.8 Hz, 1 H, ArH), 6.70 (t, J = 7.4 Hz, 1 H, ArH), 7.06-7.09 (m, 2 H, ArH), 7.24-7.37 (m, 5 H, ArH). ¹³C NMR (100.6 MHz, CDCl₃): δ = 17.9 (CMe), 24.3 (SMe), 45.0 (CMe), 45.7 (CH₂SMe), 52.9 (CH₂Ph), 64.9 [N(Bn)CH₂], 107.2, 117.7, 122.6, 127.1, 127.8, 128.1, 128.5 (7 × CH_ArH), 136.3 (C_q,_ArH), 138.3, 151.2 (C_qN). GC-MS (EI, 70 eV): m/z = 283 [M⁺], 222 [M⁺ - CH₂ - SMe], 91 [C₇H₇ ⁺]. Anal. Calcd for C₁₈H₂₁NS: C, 76.28; H, 7.47; N, 4.94. Found: C, 76.20; H, 7.47; N, 5.29.

20

Enantiomeric excess was determined using a HP 6890 Series GC System with a chiral column CycloSil-B (J&W Scientific).