Radicals from Aldehydes: A Convergent Access to Dienes and δ-Lactones

Abstract

A convenient method for the generation of O,S-acetal xanthates from aldehydes has been developed. The corresponding nucleophilic radicals undergo facile addition to unactivated olefins and the resulting adducts can be further elaborated to generate dienes and unsaturated δ-lactones.

aldehydes - xanthates - radical reactions - lactones - dienes

References and Notes

For an example of the use of protected cyanohydrins, see:

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6

The reaction yields reported are for preliminary studies and hence are unoptimised.

7

Yields based upon recovered starting material are given in parentheses.

8 Langlois DP. Wolff H. J. Am. Chem. Soc.  1948,  70:  2624 

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15

General Procedure for Preparation of Xanthates 4a-e.
To a flask containing freshly fused catalytic ZnCl₂ (ca. 5 mg) under argon was added acetyl chloride (2.4 mmol) and the mixture cooled to -5 °C to -10 °C. The aldehyde (1 mmol) was then added dropwise and the resulting reaction mixture stirred at r.t. for 1 h. The mixture was then concentrated under reduced pressure to afford crude chloride 3. To a solution of crude chloride 3 in EtOH or acetone (1 M) at 0 °C under argon was added portionwise potassium O-ethyl xanthate (1.5 mmol) and the resulting mixture stirred at r.t. for 18 h overnight. The mixture was then concentrated under reduced pressure and diluted with H₂O and Et₂O. The aqueous layer was extracted with Et₂O and the organic layers were combined, washed with H₂O, brine, dried (Na₂SO₄), filtered and concentrated in vacuo. Purification by flash chromatography (silica gel) gave xanthates 4 as yellow oils. Note that in some cases, using 0.5 equiv of acetyl chloride gave higher product yields.
Data for (±)-Xanthate 4e.
R _f = 0.2 [PE (40-60)-Et₂O, 97:3]. IR (film): ν_max = 2929 (s), 2855 (s), 1753 (s), 1368 (s), 1221 (s), 1111 (s), 1051 (s) cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 0.93-1.30 (5 H, m), 1.40 (3 H, t, J = 7.0 Hz), 1.61-1.90 (6 H, m), 2.07 (3 H, s), 4.55-4.70 (2 H, m), 6.57 (1 H, d, J = 5.5 Hz). ¹³C NMR (100.6 MHz, CDCl₃): δ = 13.7 (CH₃), 20.9 (CH₃), 25.8 (2 CH₂), 26.0 (CH₂), 28.5 (CH₂), 28.9 (CH₂), 42.0 (CH), 70.1 (CH₂), 84.7 (CH), 169.3 (C), 210.7 (C). MS (CI): m/z (%) = 294 (10) [MNH₄ ⁺], 277 (10) [MH⁺], 217 (100). HRMS: m/z calcd for C₁₂H₂₀O₃S₂: 276.0854. Found: 276.0845 [M⁺].

16

General Procedure for Radical Addition. A solution of xanthate (1 mmol) and the desired olefin (2 mmol) in 1,2-dichloroethane (DCE, 2 mL) was refluxed for 15 min under nitrogen. Lauroyl peroxide (DLP, 5% mol) was then added to the refluxing solution, followed by additional portions (5% mol) every 1.5 h until the xanthate was completely consumed. The mixture was then cooled to r.t., concentrated under reduced pressure and purified by flash chromatography (silica gel). A small layer of basic alumina was placed on top of the silica to remove any lauric acid present. Data for (±)-Xanthate Adduct 5eD.
R _f = 0.2 [PE (40-60)-Et₂O, 4:1]. IR (film): ν_max = 2929 (s), 2855 (s), 2251 (w), 1735 (s), 1446 (s), 1234 (s), 1051 (s), 733 (s) cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 0.93-1.28 (10 H, m), 1.36-1.45 (6 H, m), 1.45-1.59 (2 H, m), 1.59-1.80 (10 H, m), 1.97-2.08 (4 H, m), 2.05 (3 H, s), 2.09 (3 H, s), 2.80-3.05 (4 H, m), 3.78-3.87 (1 H, m), 3.88-3.97 (1 H, m), 4.59-4.68 (4 H, m), 4.78-4.86 (1 H, m), 4.88-4.97 (1 H, m). ¹³C NMR (100.6MHz, CDCl₃): δ = 13.8 (2 CH₃), 21.1 (2 CH₃), 22.6 (CH₂), 24.4 (CH₂), 25.9 (2 CH₂), 26.0 (2 CH₂), 26.2 (CH₂), 26.3 (CH₂), 27.9 (CH₂), 28.2 (CH₂), 28.5 (CH₂), 28.9 (CH₂), 33.8 (CH₂), 34.3 (CH₂), 41.5 (CH), 41.9 (CH), 43.1 (CH), 43.9 (CH), 70.5 (CH₂), 70.6 (CH₂), 74.4 (2 CH), 116.9 (C), 117.1 (C), 170.5 (C), 171.0 (C), 212.0 (C), 212.3 (C). MS (EI): m/z (%) = 343 (40) [M⁺], 283 (100). HRMS: m/z calcd for C₁₆H₂₅O₃NS₂: 343.1276. Found: 343.1287 [M⁺].

17

Procedure for Preparation of Xanthate 12. To a flask containing levulinic acid (10, 8 g, 69 mmol, 1 equiv) under nitrogen at 0 °C was added dropwise freshly distilled SOCl₂ (6 mL, 83 mmol, 1.2 equiv) and the resulting mixture stirred for 1 h. The reaction mixture was then allowed to warm to r.t. and concentrated in vacuo to afford crude chloride 11. To a solution of crude chloride 11 in acetone (70 mL) at 0 °C under nitrogen was added portionwise potassium O-ethyl xanthate (13.3 g, 83 mmol, 1.2 equiv) and the resulting mixture stirred at r.t. for 18 h overnight. The mixture was then concentrated under reduced pressure and diluted with H₂O and Et₂O. The aqueous layer was extracted with Et₂O and the organic layers were combined, washed with brine, dried (Na₂SO₄), filtered and concentrated in vacuo. Purification by flash chromatography [PE (40-60)-EtOAc, 9:1] gave xanthate 12 as a yellow oil (13.7 g, 90%, 2 steps).
Data for (±)-Xanthate 12.
R _f = 0.1 [PE (40-60)-EtOAc, 9:1]. IR (film): ν_max = 2981 (s), 2933 (s), 1791 (s), 1241 (s), 1128 (s), 1040 (s), 896 (s) cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 1.50 (3 H, t, J = 7.0 Hz), 1.96 (3 H, s), 2.35-2.42 (1 H, m), 2.63-2.91 (3 H, m), 4.67-4.77 (2 H, m). ¹³C NMR (100.6 MHz, CDCl₃): δ = 13.7 (CH₃), 28.6 (CH₃), 28.8 (CH₂), 35.2 (CH₂), 70.2 (CH₂), 94.4 (C), 175.1 (C), 209.4 (C). MS (CI): m/z (%) = 238 (100) [MNH₄ ⁺], 221 (48) [MH⁺]. HRMS: m/z calcd for C₈H₁₂O₃S₂: 220.0228. Found: 220.0234 [M⁺].

18

Data for (±)-Xanthate Adduct 13H.
R _f = 0.15 [PE (40-60)-Et₂O-CH₂Cl₂, 7.5:1.5:1]. IR (film): ν_max = 2829 (s), 2856 (s), 1774 (s), 1737 (s), 1444 (s), 1364 (s), 1216 (s), 1052 (s), 734 (s) cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 1.23-1.50 (17 H, m), 1.46 (6 H, t, J = 7.0 Hz), 1.47 (3 H, s), 1.53 (3 H, s), 1.57-1.97 (9 H, m), 2.00-2.22 (8 H, m), 2.33 (4 H, t, J = 7.5 Hz), 2.36-2.46 (2 H, m), 2.54-2.75 (4 H, m), 3.69 (6 H, s), 3.78-3.96 (2 H, m), 4.67 (4 H, q, J = 7.0 Hz). ¹³C NMR (100.6 MHz, CDCl₃): δ = 13.8 (2 CH₃), 24.8 (CH₃), 24.9 (2 CH₂), 27.0 (CH₃), 27.0 (CH₂), 28.6 (CH₂), 29.0 (2 CH₂), 29.1 (3 CH₂), 29.2 (4 CH₂), 29.3 (CH₂), 32.5 (CH₂), 34.0 (2 CH₂), 34.7 (2 CH₂), 35.9 (CH₂), 44.3 (CH₂), 45.1 (CH₂), 46.7 (CH), 47.3 (CH), 51.3 (2 CH₃), 69.9 (CH₂), 70.0 (CH₂), 85.9 (C), 86.1 (C), 174.2 (2 C), 176.2 (C), 176.3 (C), 214.0 (C), 214.1 (C). MS (CI): m/z (%) = 436 (100) [MNH₄ ⁺], 419 (44) [MH⁺]. HRMS: m/z calcd for C₂₀H₃₄O₅S₂: 418.1848. Found: 418.1844 [M⁺].

19

General Procedure for Diene Formation. To a solution of xanthate (1 mmol) in CH₂Cl₂ or MeCN (0.1 M) at r.t. under nitrogen was added DBU (2.2 mmol) dropwise and the resulting mixture stirred for 18 h overnight. The mixture was then concentrated under reduced pressure and diluted with H₂O and Et₂O. The aqueous layer was extracted with Et₂O and the organic layers were combined, washed several times with sat. aq NH₄Cl and then brine, dried (Na₂SO₄), filtered and concentrated in vacuo. Purifi-cation was performed by flash chromatography (silica gel). Data for (±)-(2 E ,4 E )- and (±)-(2 Z ,4 E )-5-Cyclohexyl-penta-2,4-dienenitrile ( 17).
Purification by flash chromatography [PE(40-60)-CH₂Cl₂, 7:3) gave diene 17 as a pale yellow oil (81%) and as a mixture of 2 diastereomers in a 2E,4E/2Z,4E ratio of 1.3:1. Only traces of the 2E,4Z and 2Z,4Z diastereomers could be detected in the NMR spectra.
R _f = 0.5 and 0.35 [PE (40-60)-CH₂Cl₂, 1:1]. IR (film):
ν_max = 3039 (m), 2927 (s), 2856 (s), 2214 (s), 1637 (s), 1595 (s), 994 (s), 742 (s) cm^-1. MS (CI): m/z (%) = 179 (100) [MNH₄ ⁺], 162 (1) [MH⁺]. HRMS: m/z calcd for C₁₁H₁₅N: 161.1205. Found: 161.1207 [M⁺] NMR Data for (±)-(2 E ,4 E )-Isomer.
¹H NMR (400 MHz, CDCl₃): δ = 1.08-1.43 (5 H, m), 1.59-1.86 (5 H, m), 2.07-2.26 (1 H, m), 5.28 (1 H, d, J = 16.0 Hz), 6.11-6.16 (2 H, m), 7.01 (1 H, dd, J = 16.0, 10.0 Hz).
¹³C NMR (100.6 MHz, CDCl₃): δ = 24.3 (CH₂), 24.4
(2 CH₂), 30.6 (2 CH₂), 41.2 (CH), 96.5 (CH), 115.4 (CN, very weak), 125.5 (CH), 151.4 (CH), 151.6 (CH). NMR Data for (±)-(2 Z ,4 E )-Isomer.
¹H NMR (400 MHz, CDCl₃): δ = 1.08-1.43 (5 H, m), 1.59-1.86 (5 H, m), 2.07-2.26 (1 H, m), 5.14 (1 H, d, J = 11.0 Hz), 6.11-6.20 (1 H, m), 6.55 (1 H, dd, J = 15.0, 11.0 Hz), 6.82 (1 H, t, J = 11.0 Hz). ¹³C NMR (100.6 MHz, CDCl₃): δ = 24.3 (CH₂), 24.5 (2 CH₂), 30.7 (2 CH₂), 41.1 (CH), 94.8 (CH), 117.1 (CN, very weak), 124.4 (CH), 150.2 (CH), 151.3 (CH).

20

General Procedure for Lactone Formation. To a solution of 5dD, 5cE or 5cF (100 mg) in EtOH (10 mL) at r.t. under nitrogen was added concd HCl (1 mL) and the resulting mixture refluxed (EtOH) for 72 h. The mixture was then cooled to r.t., concentrated under reduced pressure and diluted with Et₂O (50 mL). The ethereal phase was washed with sat. aq K₂CO₃, dried (MgSO₄), filtered and concen-trated in vacuo. Purification by flash chromatography (silica gel) gave lactones 19, 20, 21 as yellow oils. Data for (±)-6-Isobutyl-3-methyl-5,6-dihydro-pyran-2-one ( 21).
R _f = 0.2 [PE (40-60)-EtOAc, 9:1]. IR (film): ν_max = 2959 (s), 2929 (s), 1726 (s), 1368 (s), 1113 (s), 786 (s) cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 0.88 (6 H, d, J = 6.5 Hz), 1.26-1.37 (1 H, m), 1.65-1.75 (1 H, m), 1.77-1.92 (1 H, m), 1.86 (3 H, s), 2.17-2.28 (2 H, m), 4.34-4.46 (1 H, m), 6.49-6.58 (1 H, m). ¹³C NMR (100.6 MHz, CDCl₃): δ = 17.0 (CH₃), 22.1 (CH), 23.0 (CH₃), 23.9 (CH₃), 30.3 (CH₂), 44.0 (CH₂), 76.4 (CH), 128.4 (C), 139.0 (CH), 166.2 (C). MS (CI): m/z (%) = 186 (100) [MNH₄ ⁺], 169 (100) [MH⁺].