Hydroxyalkyl Thiazolines, a New Class of Highly Efficient Ligands for Carbonyl Additions

Abstract

Hydroxyalkyl thiazoline ligands can easily be obtained in an isonitrile-based multicomponent reaction. These ligands are significantly more stable than the comparable oxazoline ligands, and give excellent enantiomeric excess in carbonyl additions of alkyl- and arylzinc compounds.

carbonyl additions - ligands - multicomponent reactions - nonlinear effect - thiazolines

References and Notes

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16

Synthesis of Thioamide 1 Pivalaldehyde (7.82 mL, 72.0 mmol) and (S)-2-isocyano-3-methyl-1-butanol (5.46 g, 48.2 mmol) were added to a solution of Na₂S₂O₃ (11.4 g, 72.0 mmol) and PPTS (18.1 g, 72.0 mmol) in H₂O (40 mL) at 0 ˚C. The mixture was allowed to stir at 0 ˚C for further 30 min, before the ice bath was removed and the solution warmed to r.t. Then, H₂O was added, and the product was extracted three times with CH₂Cl₂. The combined organic layers were extracted with aq NaHCO₃, KHSO₄, and H₂O and dried over Na₂SO₄. After evaporation of the solvent, the crude product was purified by flash chromatography (silica gel, hexanes-EtOAc, 7:3) giving rise to a colorless solid. The diastereomeric thioamides could be separated by crystallization from benzene, providing (R,S)-1 (1.59 g, 6.9 mmol, 36%) as colorless crystals; mp 129-130 ˚C. The S,S-isomer was obtained (1.78 g, 7.7 mmol, 41%) by a second flash chromatography (silica gel, hexanes-EtOAc, 8:2) as a colorless oil, which solidified to a wax. R _f  = 0.47 [(S,S)-1] and 0.53 [(R,S)-1] (Et₂O).
Compound (R,S)-1: [α]_D ^²0 -57 (c 1.3, CHCl₃). ^¹H NMR (500 MHz, DMSO-d ₆): δ = 0.89, 0.92 (2 d, J = 6.8 Hz, 6 H), 0.94 (s, 9 H), 2.07 (m, 1 H), 3.49 (ddd, J = 9.9, 4.8, 4.6 Hz, 1 H), 3.58 (ddd, J = 9.9, 5.0, 4.8 Hz, 1 H), 4.03 (d, J = 6.0 Hz,
1 H), 4.35 (dddd, J = 9.0, 7.0, 4.8, 4.6 Hz, 1 H), 4.69 (dd, J = 5.0, 4.8 Hz, 1 H), 5.41 (d, J = 6.0 Hz, 1 H), 9.07 (d, J = 9.0 Hz, 1 H). ^¹³C NMR (125 MHz, DMSO-d ₆): δ = 18.8, 19.1, 26.6, 27.8, 34.8, 59.5, 60.9, 84.1, 202.5. HRMS (CI): m/z calcd for C₁₁H₂₄NO₂S [M + H]⁺: 234.1528; found: 234.1530. Anal. Calcd for C₁₁H₂₃NO₂S (233.37): C, 56.61; H, 9.93; N, 6.00. Found: C, 56.60; H, 9.70; N, 5.96.
Compound (S,S)-1: [α]_D ^²0 -92 (c 1.7, CHCl₃). ^¹H NMR (500 MHz, DMSO-d ₆): δ = 0.89, 0.91 (2 d, J = 6.9 Hz, 6 H), 0.95 (s, 9 H), 2.07 (m, 1 H), 3.50 (ddd, J = 11.0, 4.9, 4.7 Hz, 1 H), 3.60 (ddd, J = 11.0, 5.0, 4.8 Hz, 1 H), 4.05 (d, J = 5.9 Hz,
1 H), 4.34 (dddd, J = 8.8, 6.9, 4.8, 4.7 Hz, 1 H), 4.68 (dd, J = 5.0, 4.9 Hz, 1 H), 5.42 (d, J = 5.9 Hz, 1 H), 9.13 (d, J = 8.8 Hz, 1 H). ^¹³C NMR (125 MHz, DMSO-d ₆): δ = 19.0, 26.7, 28.0, 34.9, 59.3, 61.0, 84.2, 202.7. HRMS (CI): m/z calcd for C₁₁H₂₄NO₂S [M + H]⁺: 234.1528; found: 234.1547. Anal. Calcd for C₁₁H₂₃NO₂S (233.37): C, 56.61; H, 9.93; N, 6.00. Found: C, 56.61; H, 9.70; N, 5.62.

17

Synthesis of the Thiazoline Ligand ( S , S )-2 Thioamide (S,S)-1 (8.40 g, 36.0 mmol) and Et₃N (11.1 mL, 79.2 mmol) were dissolved in abs. THF (180 mL). This solution was cooled to 0 ˚C before MsCl (3.09 mL, 39.6 mmol) in THF (35 mL) was added dropwise. After the addition was complete, the ice bath was removed and the mixture allowed to warm to r.t. The mixture was diluted with Et₂O and washed with H₂O. After drying of the organic layer (Na₂SO₄) and evaporation of the solvent a colorless solid (7.44 g, 34.4 mmol, 96% yield) was obtained. The crude product was crystallized twice (hexane) giving colorless crystals (3.02 g, 14.0 mmol, 39% yield); mp 88-90 ˚C. R _f  = 0.19 (hexane-Et₂O, 8:2). [α]_D ^²0 -57 (c 1.4, CHCl₃). ^¹H NMR (500 MHz, CDCl₃): δ = 0.96 (d, J = 6.8 Hz, 3 H), 0.99 (s, 9 H), 1.03 (d, J = 6.8 Hz, 3 H), 1.97 (m, 1 H), 3.04 (dd, J = 10.5, 10.1 Hz, 1 H), 3.29 (dd, J = 10.5, 8.7 Hz, 1 H), 3.61 (br s, 1 H), 4.05 (d, J = 4.0 Hz, 1 H), 4.17 (dddd, J = 10.1, 8.7, 6.5, 1.1 Hz, 1 H). ^¹³C NMR (125 MHz, CDCl₃): δ = 18.9, 19.6, 25.9, 32.8, 35.2, 35.8, 79.5, 81.6, 172.8. HPLC: column: LiChrosorb Si 60, hexane-Et₂O (90:10), flow: 2.0 mL/min; t _R = 11.80 min. HRMS (CI): m/z calcd for C₁₁H₂₂NOS [M + H]⁺: 216.1422. Found: 216.1447. Anal. Calcd for C₁₁H₂₁NOS (215.35): C, 61.35; H, 9.83; N, 6.50. Found: C, 61.17; H, 9.50; N, 6.36.
Synthesis of the Thiazoline Ligand ( R , S )-2 Ligand (R,S)-2 was prepared according to the same procedure from (R,S)-1 (466 mg, 2.00 mmol). The crude product was purified by flash chromatography giving rise to colorless crystals (363 mg, 1.69 mmol, 85% yield); mp 69 ˚C. R _f  = 0.38 (hexane-Et₂O, 8:2). [α]_D ^²0 -71 (c 1.5, CHCl₃). ^¹H NMR (500 MHz, CDCl₃): δ = 0.97 (d, J = 6.8 Hz, 3 H), 1.005 (s, 9 H), 1.006 (d, J = 6.8 Hz, 3 H), 1.98 (m, 1 H, 5-H), 3.07 (dd, J = 10.9, 9.1 Hz, 1 H), 3.33 (dd, J = 10.9, 9.0 Hz, 1 H), 3.59 (d, J = 4.5 Hz, 1 H), 3.99 (m,
1 H), 4.23 (dddd, J = 9.1, 9.0, 6.4, 1.7 Hz, 1 H). ^¹³C NMR (125 MHz, CDCl₃): δ = 19.1, 19.4, 26.0, 32.6, 35.4, 35.7, 79.5, 81.5, 171.8. HPLC: column: LiChrosorb Si 60, hexanes-Et₂O (90:10), flow: 2.0 mL/min; t _R = 5.65 min. HRMS (CI): m/z calcd for C₁₁H₂₂NOS [M + H]⁺: 216.1422; found: 216.1445. Anal. Calcd for C₁₁H₂₁NOS (215.35): C, 61.35; H, 9.83; N, 6.50. Found: C, 60.93; H, 9.65; N, 6.45.

18 General Procedure for ZnEt ₂ Additions towards Aldehydes A solution of ZnEt₂ in hexane (15%, 2 mL, 1.76 mmol) was added to the ligand (S,S)-2 (4.3 mg, 0.02 mmol, 2 mol%) in toluene (2 mL) in a Schlenk tube under argon. The mixture was stirred at r.t. for 30 min before the aldehyde (1 mmol) in toluene (1 mL) was added. After 22 h, 1 N HCl was added. After stirring for 10 min the product was extracted with Et₂O (twice) and the enantiomeric ratio of the crude product was determined by GC using a chiral cyclodextrin column. Afterwards the crude product was purified by flash chromatography

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28

General Procedure for Arylations of Aldehydes
The pinacol ester of phenylboronic acid (306 mg, 1.5 mmol) was dissolved in toluene (4 mL) in a Schlenk tube. A 1 M solution of ZnEt₂ in hexane (1.5 mL, 1.5 mmol) was added, and the mixture was heated to 60 ˚C for 12 h. After cooling to r.t., this solution was added to the ligand (S,S)-2 (5.4 mg, 0.025 mmol, 5 mol%) in another Schlenk tube. After stirring for 10 min at r.t., the aldehyde was added in hexane (1 mL). The reaction was monitored by TLC. After complete conversion, sat. NH₄Cl solution was added to quench the reaction and the aqueous layer was extracted with CH₂Cl₂ (2 ×). The combined organic layers were dried and evaporated. The product was purified by flash chromatography, and the enantiomeric ratio was determined by HPLC (Chiracel OD-H).

29

The ee was determined by HPLC using the chiral column Chiracel OD-H.

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