Checked by Carmen M. Simone and Albert I. Meyers.
1. Procedure
2. Notes
2.
Diethyl chlorophosphate was purchased from Aldrich Chemical Company, Inc., and distilled before use; bp
60°C (2 mm). This reagent is a highly toxic acetylcholinesterase inhibitor and should be handled with care.
5.
2-Phenylcyclohexanone was purchased from Aldrich Chemical Company, Inc., and used without further purification.
6. Alternatively, the orange-brown oil can be crystallized twice from
ethanol (200 mL, 150 mL) (seed crystal) to provide
16.6 g (
50%) of off-white crystals of
1, mp
75–78°C. The checkers observed mp
68–70°C for this material.
7. Spectral and elemental analysis data for
1 are the following:
1H NMR (300 MHz, CDCl
3) δ: 1.3–2.1 (m, 6 H), 2.46 (d, 1 H, J = 14.3), 3.61 (dd, 1 H, J = 3.5, 14.2), 4.22 (s, 1 H), 7.0–8.1 (m, 10 H);
13C NMR (75 MHz, CDCl
3) δ: 20.76, 23.34, 27.17 (d,
3J
F,CH2 = 2.2), 29.42, 38.45 (d,
3J
F,CH = 7.5), 126.35, 127.11, 127.96, 128.65, 129.34, 134.07, 134.96 (d,
2J
F,C = 6.7), 139.46, 139.67, 147.80 (d,
1J
F,C = 280.1);
19F NMR (282 MHz, CDCl
3) δ: −123.4 (s); MS (CI/CH
4) m/z 331 (MH
+). Anal. Calcd for C
19H
19FO
2S: C, 69.06; H, 5.80. Found: C, 68.88; H, 5.86. The structure for
1 was confirmed by X-ray crystallography.
3
9.
Benzene is a known carcinogen. Follow manufacturer's recommended procedures for handling, storage, and disposal.
Cyclohexane was found to be a suitable alternate solvent for other examples of this reaction.
10. Progress of the reaction is followed by either gas chromatography or thin layer chromatography (
silica gel,
hexane) since the time required for completion of the reaction can vary up to 16 hr. An additional
500 mg of AIBN is added to the reaction mixture after 3 hr if starting material is still present.
11. An adapter tube containing a fritted disc prevents loss of silica gel into the condenser of the rotary evaporator. These tubes are available from Aldrich Chemical Company, Inc. Alternatively, the checkers found that the
silica gel can be added to the crude mixture after removal of
benzene.
12. Fractions containing
2 of ca. ≥90% purity by gas chromatography (flame ionization detector) were combined.
13. In some runs, material (≤5%) with the retention time of
tributyltin hydride is present in product
2. This impurity does not interfere in the last step of the reaction sequence. Spectral and elemental analysis data for
2 are the following:
1H NMR (300 MHz, CDCl
3) δ: 0.91 (t, 9 H, J = 7.0), 1.0–1.1 (m, 6 H), 1.2–2.0 (m, 19 H), 2.41 (d, 1 H, J = 13.9), 4.4 (m, 1 H), 7.2 (m, 1 H), 7.3–7.4 (m, 4 H);
13C NMR (75 MHz, CDCl
3) δ: 10.44, 13.74, 21.68, 26.75 (d,
3J
F,CH2 = 11.8), 27.23, 28.37 (d,
4J
F,CH2 = 2.7), 29.06, 29.52, 36.31 (d,
3J
F,CH = 15.0), 125.42, 127.60, 128.21, 135.37, 142.02 (d,
2J
F,C = 5.2), 163.34 (d,
1J
F,C = 306.2);
19F NMR (282 MHz, CDCl
3) δ: −110.52 (84%, m) (16%, dm, J = 282); MS (CI/CH
4) m/z 461 (MH
+ -HR). Anal. Calcd for C
25H
41FSn: C, 62.65; H, 8.62. Found: C, 62.43; H, 8.61. Proton-fluorine NOE difference spectroscopy (CDCl
3) showed an enhancement in the fluorine signal (δ − 110.5) when the benzylic proton (δ 4.4) was irradiated and showed no enhancement when the allylic protons (δ 2.41, equatorial proton and δ 1.77, axial proton) were irradiated. See reference
4 for a discussion of this technique.
14. Progress of the reaction is followed by either gas chromatography or thin layer chromatography (
silica gel,
hexane).
15. Spectral and elemental analysis data for
3 are as follows:
1H NMR (300 MHz, CDCl
3) δ: 1.2–2.0 (m, 7 H), 2.37 (d, 1 H, J = 13.2), 4.2 (m, 1 H), 6.6 (dm, 1 H, J = 87.1), 7.2 (m, 1 H), 7.25–7.35 (m, 4 H);
13C NMR (75 MHz, CDCl
3) δ: 21.72, 25.06 (d,
3J
F,CH2 = 6.9), 27.71 (d,
4J
F,CH2 = 2.8), 29.74, 36.13 (d,
3J
F,CH = 5.2), 123.18 (d,
2J
F,C = 3.8), 125.73, 127.54, 128.31, 141.55, 142.19 (d,
1J
F,C = 252.6);
19F NMR (282 MHz, CDCl
3) δ: − 139.64 (dd, J = 3.4, 86.8); MS (CI/CH
4) m/z 191 (MH
+). Anal. Calcd for C
13H
15F: C, 82.07; H, 7.95. Found: C, 82.13; H, 8.15.
All toxic materials were disposed of in accordance with "Prudent Practices in the Laboratory"; National Academy Press; Washington, DC, 1995.
3. Discussion
The procedure described here provides a stereospecific synthesis of (E)- and (Z)-fluoroalkenes from the corresponding (E)- and (Z)-fluorovinyl sulfones. Fluorovinyl sulfones obtained from ketones are, in most cases, readily separable into (E) and (Z) isomers either by crystallization or by chromatography.
5 In the example described, only the (E)-fluorovinyl sulfone
1 is formed (which is converted into the (Z)-fluoroalkene
3 with complete retention of configuration). The reaction sequence has been used for the stereospecific synthesis of fluoroalkene nucleosides
6 as well as for 1-deutero-1-fluoroalkenes. In the case of fluoroalkenes obtained from aldehydes, conversion of the intermediate monosubstituted fluorovinyl sulfones to (fluorovinyl)stannanes does not proceed with retention of configuration.
7 However, subsequent cleavage of the vinyltributyltin group with either
sodium methoxide,
cesium fluoride or methanolic
ammonia does proceed with retention of configuration. Since (E)- and (Z)-vinylstannanes are usually separable, this method also provides a route to stereochemically-pure, terminal, mono-substituted fluoroalkenes.
4 A significant property of the intermediate (fluorovinyl)stannanes is their ability to act as fluorovinyl carbanion equivalents. Thus, treatment of (fluorovinyl)stannanes with acid chlorides in the presence of a
palladium(0) catalyst provides α-fluoro-α,β-unsaturated ketones with complete retention of configuration.
4 Iodine reacts with (fluorovinyl)stannanes to give 1-iodo-1-fluoroalkenes with complete retention of configuration.
7,4
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