Checked by Tadahiro Takemoto and Larry E. Overman.
1. Procedure
B.
2-Hexyl-5-phenyl-1-penten-3-ol. A dry,
500-mL, four-necked, round-bottomed flask is equipped with a
mechanical stirring bar, nitrogen inlet, rubber septum, and a 100-mL, graduated, pressure-equalizing addition funnel that is sealed with a rubber septum. In the flask are placed anhydrous
chromium(II) chloride (CrCl2) (10 g, 80 mmol, (Note 6)) and anhydrous
nickel(II) chloride (NiCl2) (52 mg, 0.40 mmol, (Note 7)) under an
argon atmosphere. The flask is cooled to 0°C and dry,
oxygen-free N,N-dimethylformamide (DMF, 250 mL, (Note 8)) is added to the flask with stirring. The salts are dissolved in a slightly exothermic process. The mixture is stirred at 0°C for 10 min. To the
CrCl2-NiCl2 reagent at 25°C is added a solution of
3-phenylpropanal (2.7 g, 20 mmol, (Note 9)) in DMF (20 mL) by syringe. A solution of
1-hexylethenyl triflate (10 g, 40 mmol, (Note 5)) in DMF (60 mL) is added at 25°C through the addition funnel over a period of 5 min. The entire mixture is stirred at 25°C for 30 min. The reaction mixture is diluted with
ether (200 mL), poured into ice-cooled water (400 mL), and extracted with
ether (3 × 200 mL) repeatedly. The combined extracts are washed with aqueous
sodium chloride solution (150 mL), dried over anhydrous
sodium sulfate, and concentrated with a rotary evaporator (25°C,
water bath). The crude product is distilled using a short-path still to give
4.0–4.6 g (
82–94%) of
2-hexyl-5-phenyl-1-penten-3-ol, bp
109–111°C at 0.11 mm (Note
10) and (Note
11).
2. Notes
1. This procedure was reported by Stang and Summerville.
3
2.
1-Octyne was distilled, bp
125–126°C.
5. The distilled triflate contained 3–9% of isomers, that were confirmed by capillary GLPC (Silicone OV-17, 50 m, 105°C,
1-hexylethenyl triflate: t
R = 11.1 min; isomers: t
R = 11.4 and 12.4 min) and
1H NMR analysis. Because the isomers did not interfere with the second reaction, the triflate was employed without further purification. Spectral data of the distilled triflate was as follows: IR (neat) cm
−1: 2954, 2930, 2858, 1671, 1419, 1250, 1213, 1141, 943, 899, 703, 610;
1H NMR (CDCl
3) δ: 0.89 (t, 3 H, J = 6.9), 1.2–1.4 (m, 6 H), 1.5–1.6 (m, 2 H), 2.34 (t, 2 H, J = 7.5), 4.93 (dt, 1 H, J = 3.5, 1.0), 5.08 (d, 1 H, J = 3.5),
1H NMR peaks of the impurities appeared at δ 2.05–2.20 and 5.18–5.55;
13C NMR (CDCl
3) δ: 13.9, 22.4, 25.9, 28.3, 31.3, 33.8, 103.9, 118.5 (q, J = 320, CF
3), 157.1.
6.
Chromium(II) chloride (95% purity) was purchased from Aldrich Chemical Company, Inc., and used without further purification. The salt is easily oxidized and should be handled under an inert atmosphere.
7. Anhydrous
nickel(II) chloride was purchased from Nacalai Tesque Co. and used without further purification. The salt is hygroscopic and should be handled under an inert atmosphere.
10. The pot residue can be bulb-to-bulb distilled to give an additional
0.5–1 g of product to bring the combined yields to
94–95%.
2-Hexyl-5-phenyl-1-penten-3-ol has the following properties: R
f = 0.29 (
ethyl acetate/hexane = 1/10); IR (neat) cm
−1: 3340, 3024, 2924, 2854, 1647, 1600, 1497, 1456, 1017, 900, 741, 697;
1H NMR (CDCl
3) δ: 0.88 (t, 3 H, J = 6.8), 1.2–1.4 (m, 8 H), 1.7–2.2 (m, 5 H), 2.62 (ddd, 1 H, J = 6.6, 9.6, 13.9), 2.74 (ddd, 1 H, J = 6.1, 9.6, 13.9), 4.10 (dd, 1 H, J = 5.1, 7.5), 4.87 (d, 1 H, J = 1.5), 5.04 (s 1 H), 7.1–7.4 (m, 5 H).
13C NMR (CDCl
3) δ: 14.1, 22.6, 27.9, 29.2, 31.4, 31.7, 31.9, 37.0, 74.7, 109.3, 125.7, 128.3, 128.4, 142.0, 152.0.
11. The following ratio of reactants, aldehyde/alkenyl triflate/CrCl
2/NiCl
2 = 1/2/4/0.02 gave the best results. When the ratio of reagents was reduced to aldehyde/alkenyl triflate/CrCl
2/NiCl
2 = 1/1/2/0.01, the reaction proceeded slowly. When the reaction was carried out at 25°C for 2 hr,
65% of the
2-hexyl-5-phenyl-1-penten-3-ol was isolated and
14% (GLPC analysis) of the 3-phenylpropanal remained.
Compounds of chromium and nickel are toxic. The aqueous layers from Step B and any other waste materials should be disposed of properly (see "Prudent Practices in the Laboratory"; National Academy Press; Washington, DC, 1995).
3. Discussion
In the synthesis of a complex molecule, it is sometimes necessary to prepare an organometallic reagent under mild conditions. Because of the strong basicity and nucleophilicity of alkenyllithium and alkenylmagnesium compounds, only a few electrophilic functional groups are stable under the reaction conditions.
4 In contrast, the alkenylchromium reagents described here react with aldehydes to give adducts in good to excellent yields in the presence of ketones, esters, amides, acetals, ethers, silyl ethers, and nitriles.
5,6,7 The method is especially effective for highly oxygenated molecules.
6 Intramolecular cyclization of iodo aldehydes leading to 13-membered lactones has also been reported.
8
Addition of a catalytic amount of
NiCl2 to
CrCl2 is essential for the formation of alkenylchromium reagents.
5,6,7 However, a substantial amount of 1,3-diene, the coupling product of the alkenyl iodide, is produced if a higher content of NiCl
2 is employed.
9,10
Reduction of alkenyl iodides and bromides to alkenylchromium reagents with CrCl
2 proceeds smoothly under the same conditions.
5,6,7 Several examples of the Grignard-type addition of alkenyl halides and triflates to aldehydes with the combination of
CrCl2 and
NiCl2 are shown in the Table. Iodoalkenes are more reactive than bromoalkenes (compare run 1 and 2). In the case of an α,β-unsaturated aldehyde, the 1,2-addition product is the main product (run 4). The alkenylchromium reagent adds to an aldehyde group selectively (runs 5–7), as do allyl-
11 and alkynylchromium reagents.
12 Steric interaction of substituents at a position cis to halogen causes cis-trans isomerization in some cases.
10 For example, while the reaction of
(E)- and (Z)-2-bromostyrene and
benzaldehyde proceeded stereospecifically (runs 8 and 9), both
(E)- and (Z)-2-iodo-1-phenyl-1-propene reacted with
benzaldehyde to give
(E)-1,3-diphenyl-2-methyl-2-propen-1-ol as the sole product (runs 10 and 11). The regiochemistry of double bonds is maintained during the coupling reaction. The CrCl
2-NiCl
2 system is also effective for the addition of
iodobenzene to an aldehyde (run 12).
7
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