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DOI:10.15227/orgsyn.070.0231

Organic Syntheses, Coll. Vol. 9, p.548 (1998); Vol. 70, p.231 (1992).

(E,Z)-1-METHOXY-2-METHYL-3-(TRIMETHYLSILOXY)-1,3PENTADIENE[Silane, [[1-(2-methoxy-1-methylethenyl)-1-propenyl]oxy]trimethyl-, (Z,E)-]

Submitted by David C. Myles and Mathew H. Bigham1,2.
Checked by David I. Magee and Robert K. Boeckman, Jr..

1. Procedure
CAUTION! Benzene has been identified as a carcinogen; OSHA has issued emergency standards on
its use. All procedures involving benzene should be carried out in a well-ventilated hood, and glove
protection is required.
A. A 5-L, three-necked, round-bottomed flask equipped with a mechanical stirrer, calcium sulfate
drying tube, and 500-mL pressure equalizing addition funnel is charged with 2.4 L of dry benzene (Note1), 81.7 g (2.04 mol) of 60% sodium hydride dispersion in benzene (Note 2), and 1.9 mL (0.05 mol) ofmethyl alcohol (Note 3). The flask is immersed in an ice bath and the addition funnel is charged with amixture (Note 4) of 222 mL (172 g, 2 mol) of 95% 3-pentanone and 163 mL (148 g, 2 mol) of 99%ethyl formate (Note 5). This mixture is added dropwise to the cooled, stirred suspension over 1.5 hr.
During the addition, there is a visible evolution of gas, the mixture darkens, and a paste-like precipitateforms. At the completion of the addition, the ice bath is removed and the mixture is stirred an additional
1.5 hr, until gas evolution has ceased. The stirred reaction mixture is then diluted with 1.5 L ofanhydrous ether (Note 6). The suspension is filtered through an 18.5-cm Büchner funnel fitted with two
Whatman 1 filter papers and the solid is washed with two 500-mL portions of anhydrous ethyl ether.
The solid is transferred to a 19 × 10-cm evaporating dish and dried under reduced pressure in a vacuum
desiccator to afford crude sodium salt of 1 (270–280 g) as a colorless or slightly tan hygroscopic solid.
The material is carried on directly in the continuation of this procedure.
A 4-L Erlenmeyer flask equipped with a 2-in Teflon-coated magnetic stirbar is charged with 1.5 Lof deionized water and placed in an ice bath. To the stirring water is added in small portions( CAUTION, (Note 7)) the crude sodium salt of 1. When all of the salt has dissolved, the cooled, darkbrown solution is acidified to pH 5 (Hydrion paper) by dropwise addition of concd hydrochloric acid.
The resultant two-phase mixture is poured into a 3-L separatory funnel and the Erlenmeyer flask iswashed with two 100-mL portions of ethyl ether which are added to the separatory funnel. An additional
800 mL of ether is added to the mixture. The upper (organic) and lower (aqueous) phases are separated.

The aqueous phase is extracted six additional times (Note 8) with 400 mL of ether each time. The
combined organic phases are dried over anhydrous magnesium sulfate, filtered, and concentrated under
reduced pressure at 10°C to afford approximately 250 mL of crude 1 as a clear amber oil. This isdistilled (Note 9) under reduced pressure (bp 58.5°C, 20 mm) to afford 125–137 g (55–60% yield) of 1
as a slightly yellow oil which solidifies on standing. An analytical sample of 1 was prepared byrecrystallization from pentane (mp 42–43°C) (Note 10).
B. A 3-L, three-necked, round-bottomed flask is equipped (see Figure 1) with a 2-in Teflon-coatedmagnetic stirring bar, a 150-mm Vigreux column topped by a 500-mL pressure-equalizing addition
funnel and calcium sulfate drying tube, a short path distillation apparatus, and a ground glass stopper.
The flask is charged with 1 L of benzene and 0.5 L of a 60:40 mixture of benzene/methanol (Note 11).
To this solution is added 114 g (1.0 mol) of 1-hydroxy-2-methylpent-1-en-3-one (1) in a small amountof benzene and 0.95 g (0.005 mol) of p-toluenesulfonic acid monohydrate. The addition funnel ischarged with 500 mL of the 60:40 benzene/methanol mixture. The magnetically stirred solution iswarmed to a gentle reflux at which time the solution begins to darken to a light brown color. The
distillation temperature rises to 59°C (the boiling point of the benzene/methanol azeotrope) andstabilizes. The distillate volume is monitored throughout the course of the reaction. When 250 mL of
distillate has collected, the reaction vessel is replenished with 250 mL of fresh benzene/methanol
mixture. This cycle is repeated 6 times until starting material is consumed (Note 12). At this time any
residual benzene/methanol mixture in the addition funnel is discarded and the funnel is charged with
500 mL of benzene. The reaction volume is maintained by the addition of benzene as the boiling pointof the distillate rises to 79°C. In this way, a total of 750 mL of benzene is distilled out of the reaction
mixture as the reaction is driven to completion. The reaction mixture is allowed to cool to room
temperature and is quenched by the addition of 500 mL of 1.0 M aqueous sodium bicarbonate solution.
The two phase mixture is stirred for 5 min and then transferred to a 2-L separatory funnel. The phasesare separated and the aqueous (lower) phase is extracted two times with 500 mL of ether each time. The
combined organic phases are dried over anhydrous magnesium sulfate, filtered, and concentrated under
reduced pressure to give crude 2 as a brown oil. The oil is fractionally distilled under reduced pressure(bp 94–96°C, 22 mm) to afford 90–96 g (70–75%) of 2. Assay of this material by GLC shows it to beca. 95% pure (Note 13).
Figure 1

C. A 2-L, round-bottomed flask equipped with a 2-in Teflon-coated magnetic stirring bar is charged
with 750 mL of anhydrous ether, 102 g (1.0 mol) of 99% triethylamine (Note 14) and 96 g (0.75 mol) of
1-methoxy-2-methylpent-1-en-3-one (2). The flask is capped with a rubber septum equipped with a 16gauge needle connected to a dry nitrogen source. The magnetically stirred solution is cooled in an ice
bath and 167 g (0.75 mol) of trimethylsilyl trifluoromethanesulfonate (Note 15) is added via an 18gauge cannula over 10 min. The cooled mixture is stirred for 30 min, during which time a red-brownoily precipitate forms. The reaction mixture is transferred to a 2-L separatory funnel and the red-brown(lower) phase is separated and discarded. The remaining ethereal phase is washed with 500 mL of 1.0 M
aqueous sodium bicarbonate solution and separated. The aqueous (lower) phase is extracted with 500
mL of ether, separated and discarded. The combined organic phases are dried over anhydrous sodium
sulfate, filtered, and concentrated under reduced pressure to yield crude diene 3 as a yellow oil. This isfractionally distilled through a 150-mm Vigreux column at reduced pressure (bp 83–85°C, 22 mm) toafford 121–131 g (81–87%) of 3 as a colorless or slightly yellow liquid. Assay of this material by GLC
shows it to be ca. 95% pure (Note 16).

2. Notes
1. Unless otherwise indicated, the solvents are reagent grade and are used without further purification.
2. Commercially available (Aldrich Chemical Company, Inc.) 60% sodium hydride dispersed in mineral
oil is dispersed in benzene in the following manner: 81.7 g of 60% sodium hydride mineral oil
dispersion is suspended in 100 mL of benzene in a 500-mL Erlenmeyer flask equipped with a Tefloncoated magnetic stirbar. The suspension is vigorously stirred for 1 hr until all of the lumps are gone. Thesuspension is then transferred to the reaction vessel with a small amount of benzene.
3. Methyl alcohol functions as a catalytic base in this reaction.
4. The efficiency of the procedure is enhanced by complete premixing of the 3-pentanone and ethyl

formate.
5. 3-Pentanone and ethyl formate were purchased from Aldrich Chemical Company, Inc. and usedwithout further purification.
6. Efficient mixing is essential during the addition of the ether to ensure the formation of a flocculent
precipitate. Inadequate agitation results in the formation of large clumps of product.
7. CAUTION: Small amounts of sodium hydride from the previous step may remain in the solid. Theaddition should be carried out slowly enough to allow any residual sodium hydride to quench
completely before the next portion of solid is added.
8. TLC analysis (Merck 0.25-mm silica gel plates with 254 nm UV indicator, 1:4 ethyl acetate:hexanes)of the organic phase of each extraction reveals the presence of 1 (Rf = 0.32). Extraction is continued
until 1 is no longer seen in the organic extracts.
9. Crude 1 may solidify in the pot as any remaining solvent evaporates, but can be reliquified by gentle
heating. Stirring is facilitated by a powerful magnetic stirrer and 2-in Teflon-coated magnetic stirbar. To
prevent solidification of the distillate on the condenser, the water temperature through the condenser ismaintained at 25°C. To minimize product loss, all fractions were collected in a receptacle cooled with
an ice bath.
10. The 1H-NMR spectrum of 1 is as follows: (90 MHz, CDCl3, TMS = 0 ppm) δ: 1.13 (t, 3 H, J = 7),
1.79 (s, 3 H), 2.46 (q, 2 H, J = 7), 7.45 (s, 1 H), 7.57 (s, 1 H).
11. The composition of the binary azeotrope of benzene and methanol is 60.5% benzene, 39.5%
methanol.
12. The progress of the reaction is monitored by TLC (Rf of 1 = 0.32, Rf of 2 = 0.25; 1:4 ethyl
acetate:hexanes). A non-UV absorbing spot (Rf = 0.29) is seen to form as an intermediate between 1 and2. This is presumed to be the 1,1-dimethyl acetal of 1. When this spot is nearly gone, the reaction ispresumed to be complete.
13. The 1H-NMR of 2 is as follows: (90 MHz, CDCl3, TMS) δ: 1.10 (t, 3 H, J – 7.4), 1.71 (s, 3 H), 2.52
(q, 2 H, J = 7.4), 3.86 (s, 3 H), 7.23 (bs, 1 H).
14. Triethylamine was purchased from Aldrich Chemical Company, Inc. and was used without furtherpurification.
15. Trimethylsilyl trifluoromethanesulfonate was purchased from Petrarch Systems and was usedwithout further purification.
16. The 1H-NMR of 3 is as follows: (90 MHz, CDCl3, CHCl3, δ 7.27) δ: 0.23 (s, 9 H), 1.63 (d, 3 H, J =7), 1.70 (s, 3 H), 3.66 (s, 3 H), 4.75 (q, 1 H, J = 7), 6.35 (s, 1 H).

Waste Disposal Information
All toxic materials were disposed of in accordance with "Prudent Practices in the Laboratory";
National Academy Press; Washington, DC, 1995.

3. Discussion
Siloxy dienes have been shown to be highly effective in both the Diels-Alder3 4 reaction and thehetero Diels-Alder (diene-aldehyde cyclocondensation)5 reactions. Diene 3 has been used in thesynthesis of several important natural products including zincophorin,6 rifamycin,7 and the PrelogDjerassi lactone.8 Recently, under the aegis of chiral catalysts, 3 has been shown to participate in thediene-aldehyde cyclocondensation reaction with several aldehydes to afford cycloadducts of very highenantiomeric excess.9 10
The procedure described here allows the convenient preparation of large quantities of diene 3 andhas several advantages over previously published sequences. 1-Methoxy-2-methylpenten-3-one (2) canbe prepared in ca. 90-g lots and can be stored for several months at 0°C under argon. The earlier
procedure for the synthesis of 211 relies on dimethyl sulfate as the methylating reagent in the formationof the methyl enol ether moiety. The high toxicity of this reagent renders this strategy unattractive forroutine use. The published procedure for the conversion of 2 to 1-methoxy-2-methyl-3(trimethylsiloxy)-1,3-pentadiene (3)3 uses trimethylsilyl chloride, triethylamine and a catalytic amountof zinc chloride in benzene (40°C, ca. 12 hr) for the silylation. This mixture results in the formation ofcopious quantities of triethylamine hydrochloride, which greatly complicates the work up andpurification. This new procedure, using trimethylsilyl trifluoromethanesulfonate and triethylamine,allows the convenient separation of the amine salt and significantly shortens the reaction time (30min vs 12 hr). The silylation can be carried out on scales ranging from 0.10 mol to 0.75 mol withconsistently good yields. Diene 3 can be stored for several months at 0°C under argon without
significant decomposition.

References and Notes1. Department of Chemistry, Yale University, New Haven, CT 06511.
2. The submitters would like to thank Professor Samuel J. Danishefsky and Dr. Sarah E.
Danishefsky for their support and guidance.
3. Danishefsky, S.; Yan, C.-F.; Singh, R. K.; Gammill, R. B.; McCurry, Jr., P.M.; Fritsch, N.;
Clardy, J. J. Am. Chem. Soc. 1979, 101, 7001, and references therein;
4. Danishefsky, S. Acc. Chem. Res. 1981, 14, 400.
5. Danishefsky, S. J. Aldrichimica Acta 1986, 19, 59.
6. Danishefsky, S. J.; Selnick, H. G.; DeNinno, M. P.; Zelle, R. E. J. Am. Chem. Soc. 1987, 109,1572.
7. Danishefsky, S.J.; Myles, D. C.; Harvey, D. F. J. Am. Chem. Soc. 1987, 109, 862.
8. Danishefsky, S. J.; Larson, E.; Askin, D.; Kato, N. J. Am. Chem. Soc. 1985, 107, 1246, andreferences therein.
9. Maruoka, K.; Itoh, T.; Shirasaka, T.; Yamamoto, H. J. Am. Chem. Soc. 1988, 110, 310;
10. Bednarski, M.; Danishefsky, S. J. Am. Chem. Soc. 1986, 108, 7060.
11. Sugasawa, S.; Yamada, S.-i.; Narahashi, M. J. Pharm. Soc. Japan 1951, 71, 1345; Chem. Abstr.
1952, 46, 8034d.

Appendix
Chemical Abstracts Nomenclature (Collective Index Number);(Registry Number)hexanes
1,1-dimethyl acetalhydrochloric acid (7647-01-0)
Benzene (71-43-2)
ethyl acetate (141-78-6)
methyl alcohol,methanol (67-56-1)
ether,ethyl ether (60-29-7)
sodium bicarbonate (144-55-8)
ethyl (2025-56-1)
sodium sulfate (7757-82-6)

nitrogen (7727-37-9)
dimethyl sulfate (77-78-1)
zinc chloride (7646-85-7)
ethyl formate (109-94-4)
Triethylamine hydrochloride (554-68-7)
Pentane (109-66-0)
magnesium sulfate (7487-88-9)
3-pentanone (96-22-0)
sodium hydride (7646-69-7)
triethylamine (121-44-8)
argon (7440-37-1)
trimethylsilyl chloride (75-77-4)
Trimethylsilyl trifluoromethanesulfonate (27607-77-8)
p-toluenesulfonic acid monohydrate (6192-52-5)(E,Z)-1-Methoxy-2-methyl-3-(trimethylsiloxy)-1,3-pentadiene,
Silane, [[1-(2-methoxy-1-methylethenyl)-1-propenyl]oxy]trimethyl-, (Z,E)- (72486-93-2)
1-Hydroxy-2-methylpent-1-en-3-one (50421-81-3)
1-Methoxy-2-methylpent-1-en-3-one,
1-Methoxy-2-methylpenten-3-one
1-methoxy-2-methyl-3-(trimethylsiloxy)-1,3-pentadiene
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