Synthesis of chiral diamine ligands for nickel-catalyzed asymmetric cross-couplings of alkylchloroboronate esters with alkylzincs: (1R,2R)-N,N’-dimethyl-1,2-bis(2-methylphenyl)-1,2-diaminoethane

Graphical Abstract

Procedure

A. (1R,2R)-N,N’-bis(2-hydroxyphenylmethylene)-1,2-bis(2-methylphenyl)-1,2-diaminoethane (1).

An oven-dried, 100-mL, two-necked, round-bottomed flask equipped with a magnetic stir bar (13 × 9 mm, octagon-type), a rubber septum, and a nitrogen line is evacuated under high vacuum (1.0 mmHg) and filled with nitrogen (three cycles). (1S,2S)-1,2-bis(2-hydroxyphenyl)-1,2-diaminoethane (1.0 g, 4.1 mmol, 1.0 equiv) (Note 1) is added through the open neck under a positive pressure of nitrogen. The open neck is capped with a rubber septum, and then anhydrous DMSO (20 mL) (Note 2) and 2-methylbenzaldehyde (1.3 g, 11 mmol, 2.5 equiv) (Note 3) are added into the flask by syringe through the rubber septum. After the yellow solution is stirred for 14 h at room temperature, the reaction is quenched by the addition of distilled water (100 mL), and the mixture is extracted with Et₂O (20 mL × 3). The combined organic layer is washed with water (30 mL) and a saturated aqueous solution of NaCl (30 mL), dried over anhydrous Na₂SO₄ (5 g), filtered through filter paper, and concentrated by rotary evaporation (30 mmHg, 30 °C) and under vacuum (1.0 mmHg). The product, obtained as a yellow oil as a mixture with unreacted 2-methylbenzaldehyde, is used in the next step without further purification (1.7 g, ~80% yield) (Note 4).

B. (1R,2R)-1,2-bis(2-methylphenyl)-1,2-diaminoethane (2).

An oven-dried, 100-mL, two-necked, round-bottomed flask equipped with a magnetic stir bar (13 × 9 mm, octagon-type), a rubber septum, and a nitrogen line is evacuated under high vacuum (1.0 mmHg) and filled with nitrogen (three cycles). The solution of crude (1R,2R)-N,N’-bis(2-hydroxyphenylmethylene)-1,2-bis(2-methylphenyl)-1,2-diaminoethane (1) (1.7 g, ~3.3 mmol) in THF (50 mL) (Note 5) is added into the flask by syringe through the rubber septum, and then a 12 M HCl solution (1.5 mL) (Note 6) is added into the stirred reaction mixture by syringe over 1 min at room temperature. After the solution is stirred for 4 h, Et₂O (50 mL) is added to the reaction mixture, and then the diamine product is extracted with a 1 M HCl solution (10 mL × 3). The combined aqueous phase is washed with Et₂O (10 mL), and then it is basified with a 2 M NaOH solution (40 mL). The resulting yellow suspension is extracted with Et₂O (20 mL × 3). The combined organic layer is washed with water (30 mL) and a saturated aqueous solution of NaCl (30 mL), dried over anhydrous Na₂SO₄ (3 g), and filtered through filter paper. The volatiles are removed by rotary evaporation (30 mmHg, 30 °C) and under vacuum (1.0 mmHg) to give (1R,2R)-1,2-bis(2-methylphenyl)-1,2-diaminoethane (740 mg, 3.1 mmol, 75% (2 steps)) as yellow oil (Note 7).

C. (1R,2R)-N,N’-diethoxycarbonyl-1,2-bis(2-methylphenyl)-1,2-diaminoethane (3).

An oven-dried, 100-mL, two-necked, round-bottomed flask equipped with a magnetic stir bar (13 × 9 mm, octagon-type), a rubber septum, and a nitrogen line is evacuated under high vacuum (1.0 mmHg) and filled with nitrogen (three cycles). Potassium carbonate (2.0 g, 15 mmol, 6.0 equiv) (Note 8) is added through the open neck under a positive pressure of nitrogen. The open neck is capped by a rubber septum, and then a solution of (1R,2R)-1,2-bis(2-methylphenyl)-1,2-diaminoethane (2) (600 mg, 2.5 mmol, 1.0 equiv) in THF (20 mL) (Note 5) and distilled water (3 mL) are sequentially added into the flask by syringe through the rubber septum. After the resulting suspension is stirred for 10 min at room temperature, ethyl chloroformate (2.5 mL, 2.9 g, 25 mmol, 10 equiv) (Note 9) is added dropwise into the flask by syringe over 5 min. The resulting mixture is stirred for 16 h at room temperature, and then it is diluted with distilled water (50 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layer is washed with water (30 mL) and a saturated aqueous solution of NaCl (30 mL), dried over anhydrous Na₂SO₄ (5 g), filtered through filter paper, and concentrated by rotary evaporation (20 mmHg, 40 °C). The resulting yellow solid is purified by column chromatography on SiO₂ (wet packed in 30% EtOAc/hexanes; 3 cm diameter × 12 cm height; 50 g; eluting with 500 mL of 30% EtOAc/hexanes, 15-mL fractions) (Note 10). The desired product 3 has an R_f = 0.3 (TLC analysis on SiO₂; 30% EtOAc/hexanes, visualization with a 254 nm UV lamp) (Note 11). The desired product is obtained as a white solid (900 mg, 2.3 mmol, 94% yield) (Note 12).

D. (1R,2R)-N,N’-dimethyl-1,2-bis(2-methylphenyl)-1,2-diaminoethane (4).

An oven-dried, 100-mL, two-necked, round-bottomed flask equipped with a condenser fitted with a nitrogen line, a magnetic stir bar (13 × 9 mm, octagon-type), and a rubber septum is evacuated under high vacuum (1.0 mmHg) and filled with nitrogen (three cycles). Lithium aluminum hydride (460 mg, 12 mmol, 5.0 equiv) (Note 13) is added through the open neck under a positive pressure of nitrogen. The open neck is capped by a rubber septum, and the flask is cooled by an ice/water bath. Anhydrous THF (10 mL) (Note 5) is added by syringe through the rubber septum, and the gray suspension is stirred at 0 °C for 5 min. Next, a solution of (1R,2R)-N,N’-diethoxycarbonyl-1,2-bis(2-methylphenyl)-1,2-diaminoethane (3) (900 mg, 2.3 mmol, 1.0 equiv) in THF (10 mL) is added dropwise by syringe through the rubber septum over 5 min. The ice/water bath is replaced by an oil bath, and the reaction mixture is heated at reflux for 18 h. Next, the mixture is cooled to 0 °C in an ice bath. Water (1 mL) is added dropwise by syringe through the septum over 10 min (Note 14), and then an aqueous solution of NaOH (3 M; 1 mL) is added in one portion. The resulting mixture is heated at reflux for 1 h until the color of the precipitate changes from gray to white. The warm solution is filtered through a Büchner funnel that contains a bed of celite (1.0 cm height), and the precipitate is washed with Et₂O (50 mL). The filtrate is concentrated by rotary evaporation (20 mmHg, 40 °C) and under vacuum (1 mmHg). The residue is dissolved in hexanes (50 mL), and the solution is filtered through a Büchner funnel with filter paper. The filtrate is concentrated by rotary evaporation (20 mmHg, 30 °C) and then under vacuum (1 mmHg), which yields the desired diamine ligand 4 as an off-white solid (550 mg, 88% yield, >99% ee) (Note 15 and 16).

Notes

1. (1S,2S)-1,2-bis(2-hydroxyphenyl)-1,2-diaminoethane (min. 97%) was purchased from Strem and used as received.

2. Anhydrous DMSO (99.8+%) was purchased from Alfa-Aesar and used as received.

3. 2-Methylbenzaldehyde (97%) was purchased from Combi-Blocks and distilled (15 mmHg, 100 °C) before use to remove carboxylic acid.

4. The purity of crude compound 1 (87%) was determined by quantitative ¹H NMR analysis (C₂H₂Cl₄ as internal standard). Compound 1 can be purified by column chromatography on SiO₂, eluting with 10% EtOAc/hexanes: R_f = 0.4 (10% EtOAc/hexanes, visualization with a 254 nm UV lamp). Compound 1 is obtained as a yellow solid, which has the following properties: Mp 161–162 °C; [α]²³_D +21.6 (c 1.0, CHCl₃); IR (film) 3063, 3021, 2975, 2879, 2737, 1628, 1493, 1461, 1278, 1212, 1152, 1054, 755 cm⁻¹; ¹H NMR (CDCl₃, 300 MHz) δ: 2.07 (s, 6H), 5.12 (s, 2H), 6.79 (td, J = 7.5, 0.9 Hz, 2H), 6.92 (dd, J = 8.1, 0.9 Hz, 2H), 6.96–6.99 (m, 2 H), 7.08 (td, J = 7.5, 1.5 Hz, 2H), 7.13–7.20 (m, 4H), 7.22–7.28 (m, 2H), 7.62 (dd, J = 7.8, 1.5 Hz, 2H), 8.33 (s, 2H), 13.36 (s, 2H); ¹³C NMR (CDCl₃, 100 MHz) δ: 19.6, 74.8, 116.8, 118.6, 118.7, 126.1, 127.4, 128.7, 130.5, 131.7, 132.5, 135.3, 137.6, 160.9, 165.9; GC-MS (EI) m/z calcd. for C₃₀H₂₈N₂O₂ ([M]⁺) 448; found 448. The purity of compound 1 (98%) was determined by quantitative ¹H NMR analysis (C₂H₂Cl₄ as an internal standard).

5. Anhydrous THF (99+%) was purchased from J.T. Baker (water content: 24 ppm) and purified by passage through activated alumina under argon.

6. A solution of 12 M HCl was purchased from Fisher Scientific and used as received.

7. Compound 2 has the following properties: [α]²²_D +22.0 (c 1.0, CHCl₃); IR (neat) 3372, 3300, 3062, 3021, 2929, 1583, 1493, 1463, 1380, 1279, 1049, 860, 757, 729 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz) δ: 1.68 (bs, 4H), 2.12 (s, 6H), 4.34 (s, 2H), 7.02 (d, J = 7.5 Hz, 2H), 7.10 (td, J = 7.5, 1.5 Hz, 2H), 7.20 (td, J = 7.5, 1.5 Hz, 2H), 7.58 (dd, J = 7.5, 1.5 Hz, 2H); ¹³C NMR (CDCl₃, 100 MHz) δ: 19.6, 55.7, 125.9, 126.68, 126.74, 130.3, 135.2, 141.7; GC-MS (EI) m/z calcd. for C₁₆H₂₀N₂ ([M]⁺) 240; found 240. The purity of compound 2 (97%) was determined by quantitative ¹H NMR analysis (C₂H₂Cl₄ as an internal standard).

8. Potassium carbonate (anhydrous, 99%) was purchased from Alfa-Aesar and used as received.

9. Ethyl chloroformate (97%) was purchased from Aldrich and used as received.

10. Column chromatography was performed on Silicycle 60 Å silica gel.

11. Analytical thin-layer chromatography was performed using EMD 0.25 mm silica gel 60-F₂₅₄ plates.

12. Compound 3 has the following properties: Mp (dec.) 90–103 °C; [α]²³_D −37.3 (c 1.0, CHCl₃); IR (film) 3317, 3054, 3022, 2981, 2934, 1694, 1538, 1346, 1258, 1051, 770, 732 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz) δ: 1.24 (t, J = 7.5 Hz, 6H), 1.95 (s, 6H), 4.06–4.20 (m, 4H), 5.29–5.31 (m, 2H), 5.57 (s, 2H), 6.93 (d, J = 7.5 Hz, 2H), 7.07 (td, J = 7.5, 1.5 Hz, 2H), 7.17 (td, J = 7.5, 1.5 Hz, 2H), 7.40 (d, J = 7.5 Hz, 2H); ¹³C NMR (CDCl₃, 100 MHz) δ: 14.6, 19.2, 56.3, 61.1, 126.2, 126.6, 127.6, 130.4, 136.1, 137.6, 157.3; GC-MS (EI) m/z calcd. for C₂₂H₂₈N₂O₄ ([M]⁺) 384; found 384. The purity of compound 3 (98%) was determined by quantitative ¹H NMR analysis (C₂H₂Cl₄ as an internal standard).

13. Lithium aluminum hydride (powder, 95%) was purchased from Strem and used as received.

14. Quenching excess lithium aluminum hydride with water is a highly exothermic process that produces H₂. Dropwise addition of water is recommended, and care should be taken to efficiently cool and stir the reaction mixture.

15. Compound 4 has the following properties: Mp 100–102 °C; [α]²³_D +0.8 (c 1.0, CHCl₃); IR (film) 3299, 3237, 2924, 2862, 2842, 2784, 1488, 1424, 1338, 1176, 1140, 1106, 902, 864, 768, 731 cm⁻¹; ¹H NMR (CDCl₃, 300 MHz) δ: 1.92 (s, 6H), 2.06 (bs, 2H), 2.23 (s, 6H), 3.90 (s, 2H), 6.86 (dd, J = 7.5, 1.5 Hz, 2H), 7.01 (td, J = 7.5, 1.5 Hz, 2H), 7.14 (td, J = 7.5, 1.5 Hz, 2H), 7.48 (dd, J = 8.0, 1.5 Hz, 2H); ¹³C NMR (CDCl₃, 100 MHz) δ: 19.5, 34.3, 65.3, 125.7, 126.5, 126.7, 129.8, 136.9, 139.7; GC-MS (EI) m/z calcd. for C₁₈H₂₄N₂ ([M]⁺) 268; found 268. The purity of compound 4 (97%) was determined by quantitative ¹H NMR analysis (C₂H₂Cl₄ as an internal standard).

16. Compound 4 is converted to the acetylated amide for ee determination as follows: An oven-dried 8-mL vial equipped with a magnetic stir bar is charged with compound 4 (54 mg, 0.20 mmol, 1.0 equiv), and then it is capped with a PTFE-lined pierceable cap. The vial is evacuated and backfilled with nitrogen (three cycles). CH₂Cl₂ (2 mL) is added by syringe. The solution is stirred at room temperature for 5 min, then acetyl chloride (47 mg, 0.60 mmol, 3.0 equiv) (Note 17) and triethyl amine (61 mg, 0.60 mmol, 3.0 equiv) (Note 18) are sequentially added by syringe. The resulting solution is stirred for 16 h. The reaction is quenched by water (5 mL), and the reaction mixture is extracted with ethyl acetate (10 mL × 3). The combined organic layer is washed with water (10 mL) and a saturated aqueous solution of NaCl (10 mL), dried over anhydrous Na₂SO₄ (1 g), filtered through filter paper, and concentrated by rotary evaporation (20 mmHg, 40 °C) and under vacuum (1 mmHg). The resulting yellow oil is purified by preparative thin-layer chromatography with EtOAc as the eluent (R_f = 0.2, Merck 0.25 mm silica gel 60-F₂₅₄ plate), which gives (1R,2R)-N,N’-diacetyl-N,N’-dimethyl-1,2-bis(2-methylphenyl)-1,2-diaminoethane as a white solid. It has the following properties: Mp 31–32 °C; [α]²³_D −30.5 (c 1.0, CHCl₃); IR (film) 3022, 2956, 2928, 2856, 1652, 1462, 1398, 1314, 1010, 740, 615 cm⁻¹; ¹H NMR (CDCl₃, 400 MHz) δ: 2.07 (s, 6H), 2.35 (s, 6H), 2.67 (s, 6H), 6.57 (s, 2H), 6.87–6.92 (m, 4H), 7.03–7.07 (m, 2H), 7.15 (d, J = 8.0 Hz, 2H); ¹³C NMR (CDCl₃, 100 MHz) δ: 19.7, 22.4, 32.4, 51.1, 125.2, 127.4, 129.1, 130.8, 134.8, 137.8, 170.6; GC-MS (EI) m/z calcd. for C₂₂H₂₈N₂O₂ ([M]⁺) 352; found 352. The purity of the compound (98%) was determined by quantitative ¹H NMR analysis (C₂H₂Cl₄ as an internal standard). The ee (> 99%) was determined by HPLC analysis with an Agilent 1100 Series HPLC system equipped with a CHIRALPAK OD-H column (length 250 mm, I.D. 4.6 mm) (hexanes/2-propanol 90:10, 1.0 mL/min) with t_r (major) = 7.3 min, t_r (minor) = 9.0 min. The peak areas were measured at λ = 230 nm.

17. Acetyl chloride (98%) was purchased from Sigma-Aldrich and used as received.

18. Triethylamine (>99%) was purchased from Sigma-Aldrich and used as received.

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Discussion

Chiral N,N’-dimethyl-1,2-diphenylethylene-1,2-diamine (DMPEDA) and its derivatives are used as chiral ligands for metal-catalyzed asymmetric reactions. Rhodium and iridium/DMPEDA complexes catalyze asymmetric hydrogen transfer reactions with high enantioselectivity.²

We found that a nickel/diamine catalyst is effective for alkyl-alkyl cross-coupling reactions.³ Furthermore, the use of chiral DMPEDA-type ligands enables the enantioconvergent cross-coupling of racemic alkyl halides with various organometallic compounds.⁴ For the Negishi coupling of alkylchloroboronate esters with alkylzincs, (1R,2R)-N,N’-dimethyl-1,2-bis(2-methylphenyl)-1,2-diaminoethane 4 is the best ligand in terms of yield and enantioselectivity.⁵ Herein, we report a procedure for the synthesis of diamine ligand 4.

The procedure for the synthesis of 1,2-bis(2-methylphenyl)-1,2-diaminoethane 2 is based on the method reported by Chin and co-workers.⁶ A series of diphenylethylenediamine derivatives is synthesized from a single diamine (1,2-bis-(2-hydroxyphenyl)-1,2-diaminoethane) with this method. (Eq 1)

(1)

Biographies

Prof. Greg Fu received a B.S. degree in 1985 from MIT, where he worked in the laboratory of Prof. K. Barry Sharpless. After earning a Ph.D. from Harvard in 1991 under the guidance of Prof. David A. Evans, Prof. Fu spent two years as a postdoctoral fellow with Prof. Robert H. Grubbs at Caltech. In 1993, he returned to MIT, where he served as a member of the faculty from 1993–2012. In 2012, he was appointed the Altair Professor of Chemistry at Caltech. Prof. Fu is currently the Norman Chandler Professor of Chemistry at Caltech. Prof. Fu received the Corey Award of the American Chemical Society (ACS) in 2004, the Mukaiyama Award of the Society of Synthetic Organic Chemistry of Japan in 2006, the Award for Creative Work in Synthetic Organic Chemistry of the ACS in 2012, and the H. C. Brown Award of the ACS in 2018. He is a member of the American Academy of Arts and Sciences (2007) and of the National Academy of Sciences (2014). Prof. Fu serves as an associate editor of the Journal of the American Chemical Society.

Yusuke Masuda was born in Osaka, Japan, in 1990. He received a B.S. degree in 2012 from Kyoto University, and he obtained a Ph.D. degree in 2017 from Kyoto University under the direction of Professor Masahiro Murakami. His graduate research focused on transition metal-catalyzed and photo-induced carbon–carbon bond-forming reactions. In 2017, he joined the group of Professor Greg Fu at Caltech as a postdoctoral fellow. His current research involves the development of transition metal-catalyzed enantioselective cross-coupling reactions.

Appendix

Chemical Abstracts Nomenclature (Registry Number)

(1S,2S)-1,2-Bis(2-hydroxyphenyl)-1,2-diaminoethane: Phenol, 2,2’-[(1S,2S)-1,2-diamino-1,2-ethanediyl]bis-; (870991-68-7)

2-Methylbenzaldehyde: Benzaldehyde, 2-methyl-; (529-20-4)

(1R,2R)-N,N’-Bis(2-hydroxyphenylmethylene)-1,2-bis(2-methylphenyl)-1,2-diaminoethane: Phenol, 2,2’-[[(1R,2R)-1,2-bis(2-methylphenyl)-1,2-ethanediyl]bis[(E)-nitrilomethylidyne]]bis-; (1055301-46-6)

(1R,2R)-1,2-Bis(2-methylphenyl)-1,2-diaminoethane: 1,2-Ethanediamine, 1,2-bis(2-methylphenyl)-, (1R,2R)-; (872595-04-5)

Ethyl chloroformate: Carbonochloridic acid, ethyl ester; (541-41-3)

Potassium carbonate: Carbonic acid, potassium salt (1:2); (584-08-7)

Lithium aluminum hydride: Aluminate(1-), tetrahydro-, lithium (1:1), (T-4)-; (16853-85-3)

(1R,2R)-N,N’-Dimethyl-1,2-bis(2-methylphenyl)-1,2-diaminoethane: 1,2-Ethanediamine, N¹,N²-dimethyl-1,2-bis(2-methylphenyl)-, (1R,2R)-; (2055363-47-6)