Stereoselective Synthesis of syn- and anti-1,2-Aminoalcohols Using Iridium-Catalyzed Allylic Amination Reactions

Abstract

A methodology for the stereoselective synthesis of syn- and anti-1,2-aminoalcohols, employing iridium-catalyzed amination reactions of allylic carbonates, was developed.

Key words

allylic amination - amino alcohol - catalysis - iridium - transition metals

References and Notes

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10

Hartwig reported that solvent influences the reactivity and enantioselectivity of enantioselective allylic amination. Although reactions in the polar solvents, such as DMF and EtOH were fast (100% conversion after 2 h), low ee’s were observed (80-77% ee). As a result, THF was recommended as the most suitable balance of rate (100% conversion after 8-10 h) and enantioselectivity (95% ee). See reference 6.

14

Representative Experimental Procedure: A Schlenk flask under argon was charged with [Ir(cod)Cl]₂ (21 mg, 0.032 mmol) and L1 (32 mg, 0.060 mmol). THF (3.0 mL) and n-propylamine (3.0 mL) were added, and the reaction mixture was stirred at 50 ˚C for 30 min. Evaporation of the volatile materials gave the activated catalyst as a crude yellow solid, which was dissolved in DMF (2.0 mL) and used as catalyst for the next reaction. Under an argon atmosphere, allylic carbonate 6 (205 mg, 0.75 mmol) and 2,4-dimethoxyaniline (175 mg, 1.10 mmol) were added to the solution quickly, and the flask was sealed under argon. After standing at room temperature for 1 d, the reaction mixture was diluted with H₂O and Et₂O. The organic layer was separated and the aqueous layer was extracted with Et₂O. The combined organic extracts were washed with H₂O and brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (Et₂O-hexane, 1:10) gave an inseparable mixture of branched allylamines 10b and 11b (250 mg, 95%) and linear allylamine 12b (10 mg, 4%). The resulting branched allylamines were analyzed by HPLC to determine the ratio to be 92:8. Branched allylamine 10b: ^¹H NMR (C₆D₆, 400 MHz): δ = 0.06 (s, 3 H), 0.13 (s, 3 H), 1.01 (s, 9 H), 1.12 (d, J = 6.5 Hz, 3 H), 3.31 (s, 3 H), 3.46 (s, 3 H), 3.63 (m, 1 H), 4.00 (dq, J = 6.5, 3.5 Hz, 1 H), 4.73 (d, J = 8.0 Hz, 1H, NH), 5.13 (ddd, J = 10.5, 2.0, 1.0 Hz, 1 H), 5.19 (ddd, J = 17.5, 2.0, 1.0 Hz, 1 H), 5.85 (ddd, J = 17.5, 10.5, 7.0 Hz, 1 H), 6.47 (dd, J = 8.5, 2.5 Hz, 1 H), 6.51 (d, J = 2.5 Hz, 1 H), 6.64 (d, J = 8.5 Hz, 1 H); ^¹³C NMR (CDCl₃, 100 MHz): δ = -5.08, -4.16, 18.0, 20.6, 25.7, 55.3, 55.7, 62.5, 70.6, 99.1, 103.6, 111.8, 117.4, 131.5, 136.3, 148.3, 151.7.

15

The allylic amination of 6 with an achiral iridium complex decorated with triphenylphosphite was briefly investigated. In this case, a 53:47 mixture of products 10b and 11b, together with recovered starting material 6 (17%) was isolated (77% yield based on the consumed starting material; Scheme  [7] ).

16

Our initial attempts to promote N-dearylation of 11a with CAN were complicated by formation of varying amounts of p-quinone ii (Scheme  [8] ). See also the reference 18b.

17

A competitive experiment using a 1:1 mixture of p-anisidine and 2,4-dimethoxyaniline was carried out in order to compare reactivity. In this reaction, a 7:3 mixture of products 10b and 10a was obtained in 86% combined yield (Scheme  [9] ). This indicates that 2,4-dimethoxyaniline is approximately two times more nucleophilic than p-anisi-dine.

19

Oxidative N-Dearylation: To a solution of branched allylamine 11b (220 mg, 0.61 mmol) in a mixture of MeCN (10 mL) and pH 7 phosphate buffer (10 mL) at 0 ˚C, was added CAN (1.10 g, 2.46 mmol). After stirring at 0 ˚C for 15 min, the reaction mixture was diluted with saturated aqueous NaHCO₃ (10 mL) and then treated with methyl chloroformate (0.10 mL, 1.3 mmol) at 0 ˚C. After stirring at r.t. for 50 min, the reaction mixture was diluted with H₂O and Et₂O. The separated aqueous layer was extracted with Et₂O, and the combined organic extracts were washed with aqueous 1M KHSO₄, H₂O, saturated aqueous NaHCO₃ and brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (EtOAc-hexane, 1:5) gave methyl carbamate 13 (138 mg, 82% from 11b). ^¹H NMR (CDCl₃, 400 MHz): δ = 0.03 (s, 3 H), 0.05 (s, 3 H), 0.87 (s, 9 H), 1.16 (d, J = 6.0 Hz, 3 H), 3.69 (s, 3 H), 3.92 (m, 1 H), 4.05 (m, 1H), 5.02 (br, 1 H, NH), 5.14 (dt, J = 10.5, 1.5 Hz, 1 H), 5.19 (dt, J = 17.0, 1.5 Hz, 1 H), 5.81 (ddd, J = 17.0, 10.5, 5.5 Hz, 1 H); ^¹³C NMR (CDCl₃, 100 MHz): δ = -4.90, -4.48, 17.9, 20.7, 25.7, 52.0, 58.6, 70.0, 115.2, 137.2, 156.8.

20

In initial attempts to synthesize the intermediate in the polyoxamic acid synthesis, allylic carbonate i was synthesized from an intermediate prepared in our previous synthesis of polyoxamic acid (ref. 4a). Iridium-catalyzed allylic amination of i resulted in predominant formation of the linear product ii, and none of desired branched products was recognized (Scheme  [¹0] ). It appears that the acetonide group is responsible for the erosion in regioselectivity through steric interactions and/or chelation effects. Further studies to reveal the effects of protecting groups on the iridium-catalyzed allylic amination reaction are underway.