1 7 8
A stirred solution of the labelled bromohydrin 3.30d (66.9 mg, 0.317 mmol) in 2.0 mL of dry CH2Cl2 was cooled to 0˚C. Pyridine (27.7 µL, 0.342 mmol) was added, followed by trifluoroacetic anhydride (48.2 µL, 0.341 mmol) and the solution was allowed to warm to room temperature. After 10 min, 5 mL of pentane was added and the mixture was washed with 10 mL of water. The aqueous phase was extracted with 2 × 10 mL of pentane, and the combined organic phase was dried (MgSO4) and evaporated, to yield an oil (0.10 g). Flash chromatography (pentane) over 3 g of silica provided pure
3.31d as a colourless oil (61.8 mg, 0.201 mmol, 64%).
Crossover experiment
A mixture of 5.88 mg (1.91 × 10-5 mol) of 18O-labelled (91.9% enriched) β- bromoester 3.31b and 5.93 mg (1.93 × 10-5 mol) of d2-labelled (99.2 atom% D) β- bromoester 3.31d was placedin a 3 mL Reactivial, fitted with a stirrer vane and capped with a Mininert valve. To this mixture was added 1.00 mL of dry, purified benzene and the resulting solution was stirred while a stream of dry nitrogen was bubbled through for 3 min to remove oxygen. The Mininert valve was closed and the vial was placed in an 80±1˚C bath for 15 min before tris(trimethylsilyl)silane (16.0 µL, 5.19 × 10-5 mol) was rapidly injected, followed by 10.0 µL of an 0.118 M AIBN solution in benzene (1.18 ×
10-6 mol, 3.1 mol% relative to silane). The progress of the reaction was monitored by GC, the reaction requiring two more 10.0 µL injections of the initiator solution to ensure that it went to completion. The molar ratio of the rearranged to non-rearranged ester was
determined from the GC peak integration to be 9.47:1.
After cooling to room temperature, 50 µL of the solution was dissolved in 2 mL of pentane, to provide a solution of appropriate concentration for GCMS analysis. Relevant mass-spectral data for the rearranged (table 3.13) and unrearranged (table 3.14) esters are provided.
Table 3.13. Partial mass-spectral data for the rearranged product ester 3.35 from the crossover experiment m/z 3.35 (pure d2) (%) 3.35b ( 18O ) (%) 3.35 From crossover experiment (%) 3 . 3 5 Calculated for zero crossover (%) 155 0 2.32±0.29 1.96±0.34 1.16±0.15 156 0 4.13±0.53 1.61±0.33 2.06±0.27 157 10.43±0.47 22.90±1.85 17.88±1.43 16.64±1.16 158 2.25±0.50 6.15±0.89 3.78±0.37 4.19±0.70 159 100 100 100 100 160 10.23±0.32 9.05±0.49 9.75±0.85 9.64±0.41 161 0.40±0.09 0.26±0.07 0.45±0.31 0.33±0.08 162 0.03±0.07
Table 3.14. Partial mass-spectral data for the unrearranged product ester 3.34 from the crossover experiment
m/z 3.34 (pure d2) (%) 3.34b ( 18O ) (%) 3.34 From crossover experiment (%) 3 . 3 4 Calculated for zero crossover (%) 155 0 8.59±0.27 5.85±0.44 4.27±0.14 156 0 14.41±0.44 12.33±0.31 7.18±0.22 157 100 100 100 100 158 5.51±0.33 5.51±0.14 5.56±0.26 5.51±0.24 159 0.38±0.14 0.12±0.04 0.21±0.09 0.25±0.09
Attempt to trap the 2-methyl-1-heptene radical cation
A reaction of the 18O-oxy-labelled β-bromoester 3.31b (91.9±0.7% enriched) with tris(trimethylsilyl)silane in acetonitrile solution, in the presence of unlabelled trifluoroacetate ion was conducted to test whether any exchange of unlabelled for labelled trifluoroacetate occurs during the rearrangement of the incipient radical 3.32b. Successful trapping of the radical-cation fragment of the postulated intermediate may be detected by a decrease in the 18O enrichment of the ester products 3.34b and 3.35b
relative to the bromoester. Difficulties encountered in the GCMS analysis necessitated a control experiment as a basis for comparison.
1) Rearrangement of radical 3.32b in the presence of unlabelled trifluoroacetate ion.
The labelled bromoester 3.31b (5.71 mg, 1.86 × 10-5 mol) was dissolved in a solution of anhydrous tetraethylammonium trifluoroacetate (500 µL of a 0.78 M solution, 3.9 × 10-4 mol, 21 eq.) in dry acetonitrile in a 1 mL Reactivial fitted with a Mininert valve. After deoxygenating with nitrogen, the solution was heated to 80±1˚C and stirred at this temperature for 15 min before rapidly injecting 15.0 µL (4.86 × 10-5 mol) of tris(trimethylsilyl)silane and 5 µL of an 0.24 M solution of AIBN (1.2 × 10-6 mol) in acetonitrile. The reaction was monitored by GC and stopped when no 3.31b remained (several hours). The GC integration ratio for 3.35b:3.34b was 8.5:1. Unrearranged ester 3.34b gave an 18O enrichment of 72.7±0.4% and rearranged ester 3.35b gave ≥
78.1%. See table 3.15 for the relevant mass-spectral data for 3.35b.
2) Control experiment
This was performed in an identical manner to the prior experiment, with the exception that the solvent contained no tetraethylammonium trifluoroacetate. The following quantities were used: 5.81 mg (1.89 × 10-5 mol) of bromoester 3.31b, 500
µL of dry acetonitrile, 15.0 µL (4.86 × 10-5 mol) of tris(trimethylsilyl)silane and 5 µL (1.2 × 10-6 mol) of AIBN solution. Two further 5 µL injections of AIBN were required to ensure the reaction went to completion. The GC integration ratio for 3.35b:3.34b
was 12.3:1. Unrearranged ester 3.34b gave an 18O enrichment of 92.1±0.3% and rearranged ester 3.35b gave ≥ 80.2%. See table 3.15 for the relevant mass-spectral data for 3.35b.
3) Test for exchange in 3.31b prior to rearrangement
To test for exchange prior to rearrangement, 5.0 mg (1.6 × 10-5 mol, 0.032 M) of the labelled β-bromoester 3.31b in 500 µL of a 0.78 M solution of tetraethylammonium trifluoroacetate in dry acetonitrile was heated at 80˚C for 1.5 hours. The 18O isotopic enrichment of the recovered 3.31b was determined by GCMS to be 91.7±0.2%, comparing favourably with the initial enrichment of 91.9±0.7%.
4) Test for exchange in ester products 3.34b and 3.35b after rearrangement
To test for exchange after rearrangement, the reaction solution from the undoped reaction was treated with 500 µL of an 0.78 M solution of anhydrous tetraethylammonium trifluoroacetate in dry acetonitrile, making the overall concentration of the dissolved salt 0.39 M, and heated at 80˚C for a further 1.5 hours. The 18O enrichment of the non-rearranged isomer 3.34b was determined to be 79.4±0.8% and that of the rearranged isomer 3.35b was ≥ 80.5%. See table 3.15 for the relevant mass- spectral data for 3.35b.
Table 3.15. Partial mass spectral data for the rearranged ester 3.35b, from experiments 1,2 and 4 (plotted in figure 3.6)
m/z (1) Test for trappedtrifluoroacetate (%) (2) Control (%)
(4) Control then heated with tetraethylammonium trifluoroacetate (%) 155 1.55±0.07 2.32±0.29 2.51±1.17 156 3.20±0.050 4.13±0.53 3.98±0.84 157 26.61±1.36 22.90±1.85 23.96±0.32 158 7.72±0.66 6.15±0.89 6.67±0.66 159 100 100 100 160 8.95±1.39 9.05±0.49 9.88±0.24 161 0.57±0.41 0.26±0.07 0.54±0.20
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