New Odorless Protocols for the Synthesis of Aldehydes and Ketones from Thiol Esters

Abstract

Dodecanethiol esters derived from odorless dodecanethiol proved to be suitable substrates for Pd-catalyzed reduction with triethylsilane, coupling with organozinc reagents, and coupling with terminal acetylenes.

odorless dodecanethiol - thiol esters - palladium-catalyzed reaction - aldehyde - ketone

References

For representative examples, see:

1a Mosettig E. Org. React.  1954,  8:  218 

1b Cha JS. Kim JE. Yoon MS. Kim YS. Tetrahedron Lett.  1987,  28:  6231 

1c Corriu RJP. Lanneau GF. Perrot M. Tetrahedron Lett.  1987,  28:  3941 

1d Brown HC. Cha JS. Nazer B. Yoon NM. J. Am. Chem. Soc.  1984,  106:  8001 

For reviews, see:

2a O’Neill BT. Nucleophilic Addition to Carboxylic Acid Derivatives, In Comprehensive Organic Synthesis   Vol. 1:  Trost BM. Fleming I. Pergamon; Oxford: 1991.  Chap. 1.13. p.397 

2b Jorgenson MJ. Org. React.  1970,  18:  1 

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5b Wittenberg R. Srogl J. Egi M. Liebeskind LS. Org. Lett.  2003,  5:  3033 

6a Fukuyama T. Lin S.-C. Li L. J. Am. Chem. Soc.  1990,  112:  7050 

6b Tokuyama H. Yokoshima S. Lin S.-C. Li L. Fukuyama T. Synthesis  2002,  1121 

6c Tokuyama H. Yokoshima S. Yamashita T. Lin S.-C. Fukuyama T. J. Braz. Chem. Soc.  1998,  9:  381 

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8 Tokuyama H. Miyazaki T. Yokoshima S. Fukuyama T. Synlett  2003,  1512 

9a Kanda Y. Fukuyama T. J. Am. Chem. Soc.  1993,  115:  8451 

9b Fujiwara A. Kan T. Fukuyama T. Synlett  2000,  1667 

9c Evans DA. Black WC. J. Am. Chem. Soc.  1993,  115:  4497 

9d Evans DA. Ng HP. Rieger DL. J. Am. Chem. Soc.  1993,  115:  11446 

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11c

1-Dodecanethiol is available from Aldrich at $22.90 (500 mL).

12

3-(4-Methoxyphenyl)-thiopropionic Acid ( S )-dodecyl Ester ( 3). (a) Via mixed anhydride: To a solution of 3-(4-methoxyphenyl)propionic acid (1; 1.02 g, 5.66 mmol) in CH₂Cl₂ (23 mL) was added isobutyl chloroformate (0.880 mL, 6.79 mmol) and Et₃N (0.780 mL, 5.66 mmol). After stirring for 30 min at r.t., 1-dodecanethiol (1.60 mL, 6.79 mmol), Et₃N (0.780 mL, 5.66 mmol), and DMAP (35.0 mg, 0.283 mmol) were added successively and the resulting mixture was stirred for 70 min at r.t. The reaction was quenched by addition of H₂O (50 mL). The mixture was partitioned, and the aqueous layer was extracted with EtOAc twice. The combined organic extracts were washed with brine, dried over MgSO₄, and concentrated. Purification by flash column chromatography on silica gel (66 g, 0-2% EtOAc/hexanes) gave the thiol ester 3 (1.82 g, 4.99 mmol, 88%) as a white crystalline solid: mp: 31-32 °C. IR(film): 2925, 2853, 1693, 1612, 1514, 1465, 1248, 1178, 1040, 823 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 7.10 (d, J = 8.8 Hz, 2 H), 6.82 (d, J = 8.8 Hz, 2 H), 3.78 (s, 3 H), 2.94-2.79 (m, 6 H), 1.58-1.51 (m, 2 H), 1.25 (br, 18 H), 0.88 (t, J = 6.8 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 198.8, 158.2, 132.3, 132.3, 129.3, 129.3, 113.9, 55.2, 45.8, 31.9, 30.7, 29.6, 29.6, 29.5, 29.5, 29.3, 29.1, 28.9, 28.8, 22.7, 14.1. Anal. Calcd for C₂₂H₃₆O₂S: C, 72.48; H, 9.95. Found: C, 72.38; H, 9.67. (b) With water-soluble carbodiimide (WSCD): To a solution of acid (1; 1.05 g, 5.83 mmol), WSCD (1.34 g, 6.99 mmol), and DMAP (36.0 mg, 0.292 mmol) in CH₂Cl₂ (23 mL) was added 1-dodecanethiol (1.67 mL, 6.99 mmol). The solution was stirred for 40 min at r.t., and the reaction was quenched by addition of H₂O (50 mL). A similar purification procedure as above afforded the thiol ester 3 (2.01 g, 5.51 mmol, 95%). (c) Via acid chloride: To a solution of acid (1; 104 mg, 0.577 mmol) in CH₂Cl₂ (2.0 mL) was added oxalyl chloride (0.050 mL, 0.58 mmol) and DMF (2.3 µL, 0.029 mmol). The solution was stirred for 30 min at r.t., and concentrated. The residue was dissolved in CH₂Cl₂ (2.0 mL) and to this solution was added 1-dodecanethiol (0.160 mL, 0.692 mmol), followed by Et₃N (0.160 mL, 1.15 mmol). After stirring for 20 min at r.t., the reaction was quenched by addition of water (2 mL). A similar purification procedure as above gave the thiol ester 3 (183 mg, 0.502 mmol, 87%).

13

The enantiomeric excess of the dodecanethiol ester 4 was determined by HPLC (DAICEL Chiral-OD, 4.6 mm I.D. × 250 mm, 10% 2-propanol/n-hexane, 0.3 mL/min, 25 °C).

14

It is essential to carry out the reaction using 0.5 M or higher concentration of the substrate in order to complete the reaction.
A Typical Procedure for Reduction of ( S )-Dodecyl Thioester: To a mixture of the thioester 4 (521 mg, 1.08 mmol) and 10% Pd/C (57.5 mg, 0.0540 mmol) in acetone (2.2 mL) was added triethylsilane (0.518 mL, 3.24 mmol). After being stirred for 40 min at r.t., the mixture was diluted with Et₂O (11 mL) and filtered through a pad of Celite. The filtrate was concentrated and the residue was treated with hexane (5 mL). The precipitate was collected by filtration and washed twice with hexane. Additional amount of the product was recovered from the filtrate by the same manner to give the desired aldehyde [6b] as a white crystalline solid (217 mg, 0.766 mmol, 71%).

15

The enantiomeric excess of dodecanethiol ester prepared from proline was determined by HPLC (DAICEL Chiral-OD, 4.6 mm I.D. × 250 mm, 10% 2-propanol/n-hexane, 0.5 mL/min, 25 °C).

16

The enantiomeric excesses of the aldehydes prepared in entries 3 and 4 were determined by HPLC analysis after conversion of these aldehydes as described below (DAICEL Chiral-OD, 4.6 mm I.D. × 250 mm, 10% 2-propanol/n-hexane, 0.3 mL/min, 25 °C, Scheme [3] ).

17

A Typical Procedure for Coupling with Ethylzinc Iodide: To a solution of the thiol ester 4 (509 mg, 1.05 mmol) and PdCl₂(PPh₃)₂ (73.8 mg, 0.105 mmol) in toluene (3.5 mL) was added ethylzinc iodide (3.95 mL, 3.15 mmol, 0.80 M solution in THF). The reaction mixture was stirred for 25 min at r.t., then quenched with 1 M HCl (10 mL). The mixture was partitioned and the aqueous layer was extracted twice with EtOAc. The combined organic extracts were washed with sat. NaHCO₃ and brine, dried over MgSO₄, and concentrated. Purification by flash chromatography (Florisil on 20 g of silica gel, 20-40% EtOAc/hexanes) gave the desired ethyl ketone [7] [6c] (307 mg, 0.986 mmol, 94%) as a yellow oil.

18

A Typical Procedure for Coupling with 1-Hexyne: To a solution of the thiol ester (3; 202 mg, 0.554 mmol), PdCl₂(dppf) (45.2 mg, 0.0554 mmol), CuI (211 g, 1.11 mmol) and tri-2-furylphosphine (32.2 mg, 0.139 mmol) in DMF (1.0 mL) and Et₃N (0.2 mL) was added 1-hexyne (126 µL, 1.11 mmol). The reaction mixture was stirred for 3 h at 50 °C, diluted with Et₂O (5 mL), and quenched with 5 × H₂O (5 mL). The mixture was filtered through a pad of Celite and the filtrate was partitioned. The aqueous layer was extracted twice with Et₂O. The combined organic extracts were washed with brine, dried over MgSO₄, and concentrated. Purification by flash column chromatography on silica gel (5 g, 5-10% Et₂O/hexanes) gave the alkynyl ketone (134 mg, 0.548 mmol, 99%) as a brown oil. IR (film): 2958, 2871, 2214, 1671, 1513, 1247, 1178, 1036, 825 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 7.11 (d, J = 8.3 Hz, 2 H), 6.82 (d, J = 8.5 Hz, 2 H), 3.78 (s, 3 H), 2.92 (t, J = 6.8 Hz, 2 H), 2.83 (t, J = 7.1 Hz, 2 H), 2.37 (t, J = 6.8 Hz, 2 H), 1.58-1.52 (m, 2 H), 1.46-1.40 (m, 2 H), 0.93 (t, J = 7.3 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 187.1, 158.0, 132.4, 129.2, 113.9, 94.8, 80.8, 55.2, 47.3, 29.7, 29.1, 21.9, 18.6, 13.5. HR-MS (FAB): m/z calcd for C₁₆H₂₀O₂: 244.1463. Found: 244.1458.

19 Gage JR. Evans DA. Org. Synth., Coll. Vol. VIII   Wiley and Sons; New York: 1993.  p.339 

For removal of the auxiliary with benzyl mercaptan, see:

20a Damon RE. Coppola GM. Tetrahedron Lett.  1990,  31:  2849 

20b With 1-octanethiol, see: Narasaka K. Saitou M. Iwasawa N. Tetrahedron: Asymmetrie  1991,  2:  1305