[39872-54-3]  · C7H10O  · 5-(Methoxymethyl)-1,3-cyclopentadiene  · (MW 110.17)

(Diels-Alder cycloaddition diene, particularly useful in prostaglandin synthesis)

Solubility: sol most organic solvents.

Preparative Methods: prepared via the alkylation of freshly sublimed Thallium(I) Cyclopentadienide with Chloromethyl Methyl Ether in ether (-20 °C) according to the method of Corey and co-workers.1,2 Thallium(I) cyclopentadienide is prepared via the reaction of cyclopentadiene with thallium(I) sulfate and aqueous potassium hydroxide (eq 1).2-4 Caution: thallium and its salts are known to be highly toxic.5 Other 5-alkyl-substituted 1,3-cyclopentadienes (e.g. 5-(benzyloxymethyl)-1,3-cyclopentadiene2,6) are prepared similarly.

Handling, Storage, and Precautions: 5-alkyl-substituted 1,3-cyclopentadienes undergo facile double bond migration;7,8 as such, 5-(methoxymethyl)-1,3-cyclopentadiene is typically prepared fresh and used without isolation.

General Considerations.

The reactions of 5-(methoxymethyl)-1,3-cyclopentadiene with Diels-Alder cycloaddition ketene equivalents9 have been widely studied due to their pivotal role in the classic Corey approach to the synthesis of prostaglandins. The cycloadducts are converted to the norbornenone which undergoes Baeyer-Villiger oxidation and subsequent rearrangement to the key lactone precursor to prostaglandins (eq 2).10

The reaction of 5-(methoxymethyl)-1,3-cyclopentadiene with 2-Chloroacrylonitrile catalyzed by dry Copper(II) Tetrafluoroborate (0.3 equiv, 0 °C, 18 h) is reported to yield cycloadduct in 80-90% yield.1 Aqueous Cu(BF4)2 apparently leads to facile isomerization of 5-(methoxymethyl)-1,3-cyclopentadiene and the use of aq Cu(BF4)2 catalysis leads to formation of the cycloadduct derived from 1-(methoxymethyl)-1,3-cyclopentadiene.11 The reaction of 5-(methoxymethyl)-1,3-cyclopentadiene with 2-chloroacryloyl chloride in ether (0 °C, 18 h), without added Lewis acid catalyst, affords a mixture of diastereomeric cycloadducts.12 Treatment of the cycloadduct with Sodium Azide (dimethoxyethane, 25 °C (1.5 h), then reflux (2 h)), followed by hydrolysis in 35% aq HOAc (55-60 °C) affords the 7-syn-methoxymethyl-2-norbornen-5-one (eq 3). The yield of norbornenone is 82% based on the amounts of thallium(I) cyclopentadienide and chloromethyl methyl ether used.

Treatment of 5-(methoxymethyl)-1,3-cyclopentadiene with Nitroethylene at -15 °C (or lower) affords a 9:1 mixture of cycloadducts in good yield (eq 4).13,14 The minor cycloadduct arises from apparent isomerization to 1-(methoxymethyl)-1,3-cyclopentadiene. Acrylic acid has also been used as a dienophile in the reaction with 5-(methoxymethyl)-1,3-cyclopentadiene.15

Kanematsu and co-workers16 reported the formation of a novel class of photoresponsive crown ethers via the [4 + 2] cycloaddition of 5-(methoxymethyl)-1,3-cyclopentadiene with a crowned p-benzoquinone followed by photochemical [2 + 2] cycloaddition. 5-(Methoxymethyl)-1,3-cyclopentadiene undergoes regio- and stereoselective cycloaddition with the benzoquinone under Lewis acid catalysis (Boron Trifluoride Etherate, -20 °C, CH2Cl2, 93%). The resulting cage compound undergoes quantitative thermal ring opening (110 °C, 3 h) and clean photochemical reclosure (eq 5).

5-Alkyl-substituted 1,3-cyclopentadienes undergo facile double bond migration.7 For example, thermolysis of 5-(methoxymethyl)-1,3-cyclopentadiene via flash vacuum pyrolysis (FVP; 220 °C) affords a 1:1.5 equilibrium mixture of the 1- and 2-(methoxymethyl)-1,3-cyclopentadienes (eq 6).8

Related Reagents.

5-Bromo-1,3-cyclopentadiene; Cyclopentadiene; 5,5-Dimethoxy-1,2,3,4-tetrachlorocyclopentadiene.

1. Corey, E. J.; Koelliker, U.; Neuffer, J. JACS 1971, 93, 1489.
2. Ranganathan, S.; Ragnanathan, D.; Iyengar, R. T 1976, 32, 961.
3. Cotton, F. A.; Reynolds, L. T. JACS 1958, 80, 269.
4. Meister, H. AG 1957, 69, 533.
5. Taylor, E. C.; McKillop, A. ACR 1970, 3, 338.
6. Corey, E. J.; Ravindranathan, T.; Terashima, S. JACS 1971, 93, 4326.
7. Goering, H. L.; Chang, C. S. JOC 1975, 40, 2565.
8. Mironov, V. A.; Luk'yanov, V. T.; Bernadskii, A. A. ZOR 1984, 20, 69.
9. Ranganathan, S.; Ranganathan, D.; Mehrotra, A. K. S 1977, 289.
10. Corey, E. J.; Albonico, S. M.; Koelliker, U.; Schaaf, T. K.; Varma, R. K. JACS 1971, 93, 1491.
11. Inukai, N.; Iwamoto, H.; Nagano, N.; Yanagisawa, I.; Tamura, T.; Ishii, Y.; Murakami, M. CPB 1976, 24, 2517.
12. Corey, E. J.; Ravindranathan, T.; Terashima, S. JACS 1971, 93, 4326.
13. Ranganathan, D.; Rao, C. B.; Ranganathan, S.; Mehrotra, A. K.; Iyengar, R. JOC 1980, 45, 1185.
14. Ranganathan, S.; Ranganathan, D.; Mehrotra, A. K. JACS 1974, 96, 5261.
15. Trost, B. M.; Tamaru, Y. JACS 1975, 97, 3528.
16. Hayakawa, K.; Naito, R.; Kanematsu, K. H 1988, 27, 2293.

James M. Takacs

University of Nebraska-Lincoln, NE, USA

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