Synlett 2009(14): 2281-2286  
DOI: 10.1055/s-0029-1217814
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

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

Yoshiyasu Ichikawa*, Shun-Ichi Yamamoto, Hiyoshizo Kotsuki, Keiji Nakano
Faculty of Science, Kochi University, Akebono-cho, Kochi 780-8520, Japan
Fax: +81(88)8448359; e-Mail: ichikawa@kochi-u.ac.jp;
Further Information

Publication History

Received 8 April 2009
Publication Date:
12 August 2009 (online)

Abstract

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

    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.