Checked by Shridhar Hegde and Robert M. Coates.
1. Procedure
A.
Geranial. A
2-L, three-necked, round-bottomed flask is dried in an
oven and equipped with a
mechanical stirrer, a
thermometer, a
Claisen adapter, and
two pressure-equalizing dropping funnels. The flask is charged with
500 mL of dichloromethane (Note
1) and
20 mL (29.2 g, 0.23 mol) of oxalyl chloride (Note
2). The solution is stirred and cooled at −50 to −60°C as
34 mL (37.5 g, 0.48 mol) of dimethyl sulfoxide (Note 3) in 100 mL of dichloromethane is added dropwise at a rapid rate. After 5 min
30.8 g (0.2 mol) of geraniol (Note
4) is added dropwise over 10 min maintaining the temperature at −50 to −60°C. After another 15 min,
140 mL of triethylamine is added dropwise while keeping the temperature at or below −50°C. Stirring is continued for 5 min, after which time the mixture if allowed to warm to room temperature and 700 mL of water is added. The aqueous layer is separated and extracted with two
300-mL portions of dichloromethane. The organic layers are combined, washed with two
100-mL portions of saturated sodium chloride, and dried over anhydrous
magnesium sulfate. The filtered solution is concentrated to 500 mL by rotary evaporation and washed successively with
1% hydrochloric acid until it is no longer basic. The
dichloromethane solution is washed with water,
5% sodium carbonate, water, and saturated
sodium chloride before drying over anhydrous
magnesium sulfate. Rotary evaporation of the solvent gives ca.
30 g of crude product. Distillation in a Kugelrohr apparatus (Note
5) with an oven temperature of 80–85°C (1 mm) affords
27.3–28.5 g (
90–94%) of
geranial, n
D24 1.4870 (Note
6).
B.
(E)-4,8-Dimethyl-1,3,7-nonatriene. A
1-L, three-necked, round-bottomed flask equipped with a pressure-equalizing dropping funnel, thermometer,
magnetic stirring bar, and
serum caps (Note
7) is charged with
50 g (0.12 mol) of methyltriphenylphosphonium iodide (Note
8) and
320 mL of tetrahydrofuran (Note
9) and is flushed with
argon. The flask is cooled in an
ice bath and the suspension is stirred under a positive pressure of
argon, while about
0.2–0.6 mL of 2.05 M phenyllithium in 30 : 70 ether: cyclohexane (Note
10) and (Note
11) is added dropwise until the suspension develops a permanent yellow color (Note
12). Then
56 mL (0.115 mol) of 2.05 M phenyllithium is added dropwise over 10 min. The ice bath is removed, and the orange suspension containing excess phosphonium salt is stirred at room temperature for 30 min. The reaction mixture is stirred and cooled at 0–5°C, and
17.2 g (0.11 mol) of geranial in 50 mL of tetrahydrofuran is added dropwise over 10 min. The dropping funnel is rinsed with a small amount of
tetrahydrofuran. The mixture is stirred at room temperature for 2 hr. The light-orange mixture is hydrolyzed by adding
2 mL of methanol, and most of the solvent is removed on a
rotary evaporator until a slurry results (Note
13). The slurry is diluted with
200 mL of petroleum ether (bp
60–68°C), and the supernatant solution is decanted and filtered through
150 g of Celite on a Büchner funnel. The solids remaining in the flask are heated with three
100-mL portions of hot petroleum ether, and the supernatant solutions are also filtered through Celite. The filtrate is concentrated by rotary evaporation to a yellowish liquid that is filtered through
150 g of Florisil on a Büchner funnel, and the Florisil is washed with
300 mL of petroleum ether. Rotary evaporation of the eluate provides ca.
15 g of clear liquid, which on distillation in a
Kugelrohr apparatus with an oven temperature of 60–70°C (2 mm) gives
13.1–13.5 g (
77–80%) of the triene, n
D22 1.4871 (Note
14) and (Note
15).
C.
Homogeraniol. A
250-mL, three-necked, round-bottomed flask is equipped with a magnetic stirring bar, thermometer, pressure-equalizing dropping funnel, and a
gas inlet tube to maintain a positive
argon pressure within the apparatus (Note
7). The flask is charged with
102 mL (94.8 mmol) of 0.93 M diborane in tetrahydrofuran (Note
16), and the contents are cooled to −30°C. The
diborane solution is stirred as
22.1 mL (0.21 mol) of 2-methyl-2-butene (Note
17) is added rapidly. Stirring is continued for 2 hr while maintaining the temperature at 0–2°C. A
500-mL, three-necked, round-bottomed flask equipped with a magnetic stirring bar, thermometer, pressure-equalizing dropping funnel, and a gas inlet tube to keep a positive pressure of
argon (Note
7) is charged with
13.0 g (86.7 mmol) of (E)-4,8-dimethyl-1,3,7-nonatriene and
35 mL of tetrahydrofuran (Note
9). The contents are stirred and cooled at 0°C as the solution of
disiamylborane in the first flask is transferred via a cannula to the pressure-equalizing dropping funnel attached to the second flask. After approximately 20 mL of disiamylborane is transferred to the dropping funnel via a cannula, the dropwise addition of the disiamylborane is started while the transfer continues. The remainder of the
disiamylborane solution in the first flask is kept at 0°C. After the 1-hr addition is completed, stirring is continued for 1 hr at 0°C and overnight at room temperature (15 hr). Excess
disiamylborane is destroyed by adding
2 mL of ethanol, the mixture is cooled to 0°C, and
33 mL of 3 M sodium hydroxide is added rapidly. Stirring and cooling at −10°C are continued as
33 mL of chilled 30% hydrogen peroxide is slowly added (Note
18). The reaction mixture is stirred at room temperature for 3 hr, the layers are separated, and the aqueous layer is extracted with two
75-mL portions of ether (Note
19). The combined organic layers are washed with two
25-mL portions of saturated sodium chloride and dried over anhydrous
magnesium sulfate. Evaporation of the solvent gives ca.
21 g of crude product that is purified by chromatography on 400 g of silica gel packed in a 7.5-cm × 20-cm column. The column is eluted with
dichloromethane and 100-mL fractions are collected, the first two of which are discarded. Elution is continued by collecting the 100-mL fractions in a weighed flask and evaporating the solvent under reduced pressure until a constant weight of product is obtained (nine 100-mL fractions). Distillation of the residue in a Kugelrohr apparatus with an oven temperature of 150°C (0.02 mm) gives
12.6–13.2 g (
88–91%) of
homogeraniol,
nD21 1.4740 (Note
20).
2. Notes
4.
Geraniol was obtained from Aldrich Chemical Company, Inc. (Gold Label) and used without purification.
5. Kugelrohr ovens are available from Rinco Instrument Co., Inc., 5035 Prairie St., P.O. Box 167, Greenville, IL 62246.
6. Thin-layer chromatographic analysis of the product by the submitter on silica gel with
20% ethyl acetate in hexane as developing solvent showed one spot,
Rf 0.5. Gas chromatographic analysis showed the presence of 1.5% of the cis isomer by coinjection with 40 : 60 cis: trans citral mixture available from Aldrich Chemical Company, Inc. The
1H NMR spectral data for the product are as follows δ: 1.61 (s, 3 H, CH
3), 1.69 (s, 3 H, CH
3), 2.17 (s, 3 H, CH
3), 2.19–2.23 (m, 4 H, CH
2CH
2), 5.06 (br s, 1 H, vinyl H at C-6), 5.88 (d, 1 H,
J = 8, vinyl H at C-2), 9.99 (d,
J = 8, CHO).
7. The glassware was dried in an
oven at 150°C, assembled while still hot, and alternately evacuated and flushed with
argon.
10. The
phenyllithium solution was purchased from Aldrich Chemical Company, Inc. The checkers used
64 mL (0.115 mol) of 1.8 M phenyllithium in 75 : 25 benzene : ether, which was purchased from Alfa Products, Morton Thiokol, Inc.
11. The submitter states that the slight excesses of
phenyllithium (5%) and
methyltriphenylphosphonium iodide (10%) specified ensure complete conversion of the aldehyde and simplify the purification of the product since the excess phosphonium salt is readily removed during filtration through Florosil.
12. The addition of
0.2–0.6 mL of the phenyllithium solution presumably destroys small amounts of moisture or other impurities.
13. The submitter cautions against evaporating all the solvent; the
triphenylphosphine oxide will tenaciously occlude the product, and the yield will be reduced.
14. A gas chromatographic analysis of the product by the submitter on a
15 M capillary column coated with silicone oil SE-54 at 70°C exhibited one peak (98%).
15. An index of refraction of 1.4826 at 20°C is reported
3 for the product. The spectral properties of the product are as follows: IR (neat) cm
−1: 3080, 1645, 1600, 1345, 990, 900;
1H NMR (CDCl
3) δ: 1.61 (3 H, CH
3), 1.68 (s, 3 H, CH
3), 1.76 (s, 3 H, CH
3 at C-4), 1.95–2.12 (broad, 4 H, CH
2CH
2), 4.80–5.15 (broad, 3 H, vinyl H), 5.85 (d, 1 H,
J = 10, vinyl H at C-3), 6.55 (3 d,
J = 10, 10, 17, vinyl H at C-2).
16. The
diborane solution was obtained from Aldrich Chemical Company, Inc. It was titrated
4 before use, although the submitter states that this is not necessary. The solution was transferred from the stock solution to the reaction flask via a cannula. The checkers first transferred the
diborane solution via a cannula into a
graduated cylinder that was capped with a rubber septum and purged with
nitrogen. The specified volume was then transferred into the reaction vessel.
18. The oxidation of organoboranes is exothermic, and efficient cooling and slow addition are necessary to keep the temperature near 0°C.
5.
19. The checkers observed the separation of a heavy, white precipitate presumed to be a borate salt during the addition of
hydrogen peroxide. After the three-phase mixture had been stirred at room temperature for 3 hr, the liquid layers were decanted into a
separatory funnel. The solid remaining in the flask was washed with two
75-mL portions of ether and these washings were used to extract the aqueous layer.
20. Indices of refraction of 1.4722 at 22°C and 1.4718 at 26°C are reported for
homogeraniol.
6,7 The spectral properties of the product are as follows: IR (neat) cm
−1: 3330, 2960 (sh), 2920, 1448, 1435 (sh, m), 1374 (m), 1108 (w), 1045 (s), 875 (w);
1H NMR (CDCl
3) δ: 1.60 (s, 3 H, CH
3 at C-4), 1.64 (s, 3 H, CH
3), 1.68 (s, 3 H, CH
3 at C-4), 1.95–2.15 (s, 4 H, CH
2CH
2), 2.30 (m, 2 H, CH
2CH
2OH), 3.60 (t, 2 H,
J = 7, CH
2OH), 4.95–5.25 (m, 2 H, vinyl H).
3. Discussion
Homogeraniol has been prepared by reduction of
homogeranic acid with
lithium aluminum hydride,
6 by cyclopropylcarbinol rearrangement to
homogeranyl bromide and subsequent displacement of the bromide,
17 by zirconium-catalyzed syn addition of
trimethylaluminum to an
acetylene precursor followed by reaction with
ethylene oxide,
7 and by hydroxymethylation of
geranyl chloride with
diisopropoxymethylsilylmethyl Grignard reagent.
18 Homogeranic acid has been prepared by base-catalyzed hydrolysis of the nitrile,
6,9,19 20 21 copper-catalyzed S
N2-type alkylation of
β-isopropenyl-β-propiolactone with
dimethylallyl Grignard reagent,
22 alkylation of
methoxy(phenylthio)methyllithium with
geranyl chloride and subsequent
chromic acid oxidation,
23 and carboxylation of
geranyl phenyl sulfone followed by reductive desulfonation.
24 Although homogeranic acid prepared by nitrile hydrolysis and by
β-isopropenyl-β-propiolactone alkylation
22 is a 70 : 30 mixture of
E and
Z isomers,
9,25 the
E form may be isolated by crystallization at −10°C
6 or by preparative gas chromatography of their
tert-butyl esters.
26 Homogeraniol prepared by acid-catalyzed
cyclopropylcarbinyl to
homoallyl rearrangement
17 is also a mixture of
E and
Z isomers.
27
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