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DOI:10.15227/orgsyn.069.0072

Organic Syntheses, Coll. Vol. 8, p.512 (1993); Vol. 69, p.72 (1990).

ENOL ETHERS BY METHYLENATION OF ESTERS: 1-PHENOXY-1PHENYLETHENE AND 3,4-DIHYDRO-2-METHYLENE-2H-1BENZOPYRAN[Ether, phenyl 1-phenylvinyl and 2H-1-benzopyran, 3,4-dihydro-2-methylene-]

Submitted by Stanley H. Pine1 , Gia Kim2 , and Virgil Lee.
Checked by Roger B. Ruggeri and Clayton H. Heathcock.

1. Procedure
Caution! Dialkylzinc compounds, especially in undiluted form, are pyrophoric and must not beallowed to come into contact with air or moisture. These compounds should only be handled byindividuals trained in their proper and safe use. [Note added January 2011]
A. 1-Phenoxy-1-phenylethene. To a 250-mL round-bottomed flask (Note 1) equipped with a magnetic
stirring bar is added 5.0 g (20.0 mmol) of titanocene dichloride [bis(cyclopentadienyl)titanium dichloride](Note 2). The flask is fitted with a rubber septum through which a large-gauge needle is passed to flush
the system with dry nitrogen. After the vessel has been thoroughly purged, the nitrogen line flowing to
the needle is opened to a mineral oil bubbler and 20 mL of a trimethylaluminum solution (2.0 M intoluene, 40 mmol) is added by a nitrogen-purged syringe (Note 3). Methane gas evolved by the reactionis allowed to vent as the resulting red solution is stirred at room temperature for 3 days. The Tebbereagent 3 thus formed is used in situ by cooling the mixture in an ice-water bath (Note 4), then adding 4.0
g (20 mmol) of phenyl benzoate (Note 5) dissolved in 20 mL of dry tetrahydrofuran (Note 6) by syringeor cannula to the cooled stirring solution over 5–10 min. After the addition, the reaction mixture isallowed to warm to room temperature and is stirred for about 30 min. The septum is removed and 50 mLof anhydrous diethyl ether is added. To the stirring reaction mixture is gradually added 50 drops of anaqueous solution of 1 M sodium hydroxide over 10–20 min (Note 7). Stirring is continued until gas
evolution essentially ceases; then to the resulting orange slurry are added a few grams of anhydrous
sodium sulfate to remove excess water. The mixture is filtered through a Celite pad on a large coarse fritusing suction and liberal amounts of diethyl ether to transfer the product and rinse the filter pad.

using suction and liberal amounts of diethyl ether to transfer the product and rinse the filter pad.
Concentration of the filtrate with a rotary evaporator (Note 8) to 5–8 mL provides crude product, which
is purified by column chromatography on basic alumina (150 g) eluting with 10% diethyl ether in pentane(Note 9). Fractions that contain product (Note 10) are combined and evaporated to give 2.69–2.79 g (68–70%) of the desired enol ether (Note 11) as a pale-yellow oil.
B. 3,4-Dihydro-2-methylene-2H-1-benzopyran. Formation of the exo-methylene enol ether withdihydrocoumarin is carried out as in the foregoing procedure except that the reaction solution is cooledwith a dry ice–acetone bath before addition of the lactone. From 3.0 g (20 mmol) of dihydrocoumarin(Note 5) is obtained 1.85–1.97 g (63–67%) of the product (Note 12) as a pale-yellow oil, after column
chromatography on basic alumina (150 g) eluting with 5% diethyl ether in pentane.

2. Notes
1. The checkers found that the acid ability of the enol ether products requires rigorous treatment of all
glassware used for the reaction in order to avoid migration of the double bond in susceptible cases (e.g.,
dihydrocoumarin in Preparation B). Satisfactory results were obtained by treating the glassware
sequentially with ethanolic 0.5 M solutions of hydrogen chloride and potassium hydroxide forapproximately 1 hr, thoroughly rinsing with distilled water after each treatment, and finally oven-drying.
This protocol is also effective for removing stubborn deposits on the glassware used for the reaction.
2. Titanocene dichloride was purchased from Aldrich Chemical Company, Inc. and used without further
purification. This compound is normally obtained as bright red crystals. If its purity is in question
Soxhlet extraction using dichloromethane is usually effective; titanocene dichloride is slightly soluble indichloromethane and slowly dissolves from insoluble materials present.
3. Trimethylaluminum was purchased from Aldrich Chemical Company, Inc. and obtained as a 2.0 M
solution in toluene sealed under nitrogen in a Sure/Seal bottle. Trimethylaluminum is pyrophoric andreacts violently with water and air; the syringe and needle used should be rinsed with toluene or hexenes
immediately after addition. Note that the rinse, although dilute, contains pyrophoric material and should
be handled accordingly.
4. Reaction with the ester is relatively exothermic. Sensitivity of the substrate product to heating varies
and should be considered for each particular compound. Phenyl benzoate can be methylenated at room
temperature with no significant decrease in product yield. By contrast, dihydrocoumarin (Preparation B)
gives no product under these conditions and must be methylenated at −78°C to obtain a good yield. For
most substrates it is satisfactory to carry out reactions at 0°C.
5. Substrate esters were purchased from Aldrich Chemical Company, Inc. and used without furtherpurification.
6. Tetrahydrofuran was freshly distilled from the sodium ketyl of benzophenone.
7. Evolution of methane can be quite vigorous so that the reaction vessel must be large enough to prevent
bubbling over. If the aqueous solution is delivered slowly in 10-drop increments over the addition period,a controlled quench of the reaction mixture is possible. Cooling slows gas evolution, but also greatly
prolongs the hydrolysis step.
8. Methylene enol ethers are usually lower-boiling than their ester precursors. Low-molecular-weight
products can be easily lost in evaporation; therefore, the toluene must be removed with care.
9. The checkers used Fisher Scientific basic alumina, Brockman activity I, 80–200 mesh. Neutral alumina
and silica gel have also been used. Basic alumina minimizes the potential hazards of hydrolysis or
proton-catalyzed isomerization of the carbon–carbon double bond in susceptible enol ethers. Gaseous
trimethylamine has also been added to the eluent to minimize these problems during purification.
10. The checkers eluted the columns with a slight positive air pressure on the solvent reservoir to prevent
formation of gas bubbles and cracks in the chromatographic medium. Fractions were collected in 25-mL
test tubes (Note 1), analyzed by TLC on silica gel, eluting with the column solvent, and visualized with aphosphomolybdic acid solution. The checkers observed a nonvolatile hydrocarbon material (not substraterelated) which was eluted in the fractions just prior to the products, which are quite nonpolar themselves
and are eluted in the early fractions, ahead of any unreacted ester. Colored, metal-containing components
usually remain near the top of the column, although some colored material may accompany the product if
much toluene remains in the sample or if the sample is applied to the column in a more polar solvent.
11. The spectral properties for 1-phenoxy-1-phenylethene are as follows: IR (film) cm −1: 1600, 1495,1290, 1230; 1 H NMR (250 MHz, CDCl 3 ) δ: 4.45 (d, 1 H, J = 2.3), 5.05 (d, 1 H, J = 2.3), 7.06–7.11 (m,3 H), 7.29–7.38 (m, 5 H), 7.66–7.70 (m, 2 H).
12. While the submitters observed no complications, the checkers were unable, even after many trials, toobtain the dihydrocoumarin adduct completely free of what appears to be the product of double bondmigration to give the endocyclic enol ether. Initial results were quite erratic. However, use of theglassware treatment described in Note 1, suggested by Professor Pine, has consistently provided thedesired compound contaminated with only a few percent of the unwanted isomer. Spectral properties forthe 3,4-dihydro-2-methylene-2H-1-benzopyran are as follows: IR (film) cm −1: 1665, 1595, 1500, 1470,1250, 990, 770; 1 H NMR (250 MHz, CDCl 3 ) δ: 2.57 (t, 2 H, J = 6.5), 2.80 (t, 2 H, J = 6.5), 4.14 (s, 1H), 4.55 (s, 1 H), 6.85–6.92 (m, 1 H), 7.03–7.07 (m, 1 H), 7.11–7.18 (m, 1 H); impurity (partial) δ: 1.88(bs, 3 H), 3.39 (bs, 2 H), 4.70 (bs, 1 H).
The submitters suggested that the use of CDCl 3 as the NMR solvent may be the cause of the appearanceof unwanted double-bond isomer; they recommend CCl 4 as the solvent of choice.

3. Discussion
The formation of carbon–carbon bonds through the condensation of carbonyl compounds withphosphoranes (the Wittig reaction) is a very useful method in organic synthesis.4 5 Allowing theconvergence of a wide variety of substrates enables this reaction to provide considerable flexibility inproduct design. Yet, with limited exceptions,6 7 8 this process has not been effective for the transfer ofmethylene or alkylidenes to the carbonyl group of esters or other carboxylic acid derivatives. However,reaction of the titanium–aluminum complex (the Tebbe reagent) 3 described here does transfer amethylene to the carbonyl group of esters, effecting the conversion of an ester to an enol ether.9 10The Tebbe reagent functions as a nucleophilic carbenoid in its reactions with carbonyl groups. The
carbenoid is activated in the presence of a Lewis base that presumably complexes with the aluminum
atom. Tetrahydrofuran is the Lewis base in the reactions described above. If the reaction is performed in
the absence of added tetrahydrofuran, the carbonyl oxygen atom can function as a weak Lewis base,although the methylenation process is considerably slower.
Vinyl ethers have also been prepared by addition of alkoxides to acetylene,11,12,13 elimination fromhalo ethers and related precursors, 11,13 and vinyl exchange reactions.13 Reaction of an electrophilic
tungsten carbenoid with a methylene phosphorane or diazomethane also produces vinyl ethers.14 Enolethers have resulted from the reaction of some tantalum and niobium carbenoids with esters,15 and thereaction of phosphoranes with electrophilic esters.6,7,8
Methylenation using the titanium–aluminum complex converts a variety of esters to enol ethers ingood yields.9,10 Lactones are converted to synthetically useful exo-methylene enol ethers. Carbon–carbon
double bonds do not interfere with the methylenation reaction, although functional groups containing
acidic hydrogen atoms do consume the reagent and should be protected. The carbonyl group of aldehydes
and ketones reacts in preference to the ester carbonyl group in the methylenation process,10 but thosegroups can also be selectively protected.
Because of the expense of obtaining the Tebbe reagent in its pure form,16 an in situ method for its
preparation and use was developed. 17 The presence of the excess Lewis acidic by-product,
dimethylaluminum chloride, in the in situ preparation may cause reactivity at other sites in the substrateor lower yields of desired products (e.g., 70 vs. 94% for Preparation A, and 65 vs. 85% for Preparation
B).10 However, the overall simplicity of the method can be advantageous with readily obtained substrates.
This preparation is referenced from:
Org. Syn. Coll. Vol. 10, 355

References and Notes

1. Department of Chemistry, California State University, Los Angeles, CA 90032;
2. participant in the NIH-MBRS program.
3. Tebbe, F. N.; Parshall, G. W.; Reddy, G. S. J. Am. Chem. Soc. 1978, 100, 3611.
4. Cadogan, J. I. G.; Ed. "Organophosphorus Reagents in Organic Synthesis"; Academic Press: NewYork, 1979;
5. Maercker, A. Org. Reactions 1965, 14, 270.
6. Uijttewaal, A. P.; Jonkers, F. L.; van der Gen, A. J. Org. Chem. 1979, 44, 3157;
7. LeCorre, M. Bull. Soc. Chim. Fr. 1974, 2005;
8. Bestmann, H. J.; Dornauer, H.; Rostock, K. Chem. Ber. 1970, 103, 2011.
9. Pine, S. H.; Zahler, R.; Evans, D. A.; Grubbs, R. H. J. Am. Chem. Soc. 1980, 102, 3270;
10. Pine, S. H.; Pettit, R. J.; Geib, G. D.; Cruz, S. G.; Gallego, C. H.; Tijerina, T.; Pine, R. D. J. Org.
Chem. 1985, 50, 1212.
11. Shostakovskii, M. F.; Trofimov, B. A.; Atavin, A. S.; Lavrov, V. I. Russ. Chem. Rev. (Engl.)
1968, 37, 907; Chem. Abstr. 1968, 70, 28091z.
12. Rutledge, T. F. in "Acetylenes and Allenes, Addition, Cyclization, and Polymerization Reactions";
Reinhold: New York, 1969, p. 283.
13. Buehler, C. A.; Pearson, D. E. in "Survey of Organic Syntheses"; Wiley: New York, 1977, Vol. 2,p. 335.
14. Casey, C. P.; Brukhardt, T. J. J. Am. Chem. Soc. 1972, 94, 6543.
15. Schrock, R. R. J. Am. Chem. Soc. 1976, 98, 5399.
16. The Tebbe reagent is currently available from Strem and Alpha Chemical Companies.
17. Cannizzo, L. F.; Grubbs, R. H. J. Org. Chem. 1985, 50, 2386.

Appendix
Chemical Abstracts Nomenclature (Collective Index Number);(Registry Number)sodium ketyl of benzophenone
titanocene dichloride [bis(cyclopentadienyl)titanium dichloride
acetylene (74-86-2)hydrogen chloride (7647-01-0)
diethyl ether (60-29-7)
sodium hydroxide (1310-73-2)
sodium sulfate (7757-82-6)
nitrogen (7727-37-9)
aluminum (7429-90-5)
methane (7782-42-5)
potassium hydroxide (1310-58-3)
toluene (108-88-3)
Pentane (109-66-0)
dichloromethane (75-09-2)

Trimethylamine (75-50-3)
Diazomethane (334-88-3)
phenyl benzoate (93-99-2)
Tetrahydrofuran (109-99-9)
phosphomolybdic acid (51429-74-4)
trimethylaluminum (75-24-1)
titanium (7440-32-6)
1-Phenoxy-1-phenylethene,
Ether, phenyl 1-phenylvinyl (19928-57-5)
Titanocene dichloride (1271-19-8)
dihydrocoumarin (119-84-6)
methylene phosphorane (61183-53-7)
dimethylaluminum chloride (1184-58-3)
3,4-Dihydro-2-methylene-2H-1-benzopyran,
2H-1-benzopyran, 3,4-dihydro-2-methylene- (74104-13-5)
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