(R = Me)

[25408-63-3]  · C6H10O  · 3-Methoxyisoprene  · (MW 98.16) (R = Et)

[17466-15-8]  · C7H12O  · 3-Ethoxyisoprene  · (MW 112.19)

(used as an equivalent of isopropenyl methyl ketone in iterative Claisen rearrangements and as a diene in the Diels-Alder reaction)

Alternate Name: 2-methoxy-3-methyl-1,3-butadiene.

Physical Data: R = Me: bp 93-95 °C. R = Et: bp 113-114 °C.

Preparative Method: R = Me: from 2-methyl-3-butyn-2-ol by successive dehydration, addition of methanol, and elimination of methanol.1

Iterative Claisen Rearrangements.

The methoxy group of 3-methoxyisoprene exchanges with secondary allylic alcohols under acid catalysis and the resultant intermediate undergoes Claisen rearrangement.2 This technique has been applied in an iterative synthesis of squalene (1) (eq 1).1a,3 The rearrangement provides cleanly an (E)-alkene and a terminal isopropenyl ketone which, upon reduction, affords an allylic alcohol that is ready for a second rearrangement. Each 3-methoxyisoprene is translated into an isoprene unit in the final product. A similar, alternative, approach to squalene employs isopropenyl methyl ketone dimethyl acetal (2,2-dimethoxy-3-methyl-3-butene) (2), which is readily available from isopropenyl methyl ketone.4

Reagent (2), followed by methyl vinyl ketone diethyl acetal (3,3-diethoxy-1-butene) (3), and, again, reagent (2) have been applied successively in an iterative extension of methallyl alcohol in refluxing toluene with 2,4-dinitrophenol as a catalyst (eq 2).4 Two iterations of methyl 2-hydroxy-3-butenoate with 2-methoxy-3-ethyl-1,3-butadiene1 or 3,3-dimethoxy-2-ethyl-1-butene4 play a critical role in the synthesis of the C18 Cecropia juvenile hormone.

Enolic b-diketones react with 2-methoxy-1,3-butadiene (eq 3)5 and methacrolein diethyl acetal (3,3-diethoxy-2-methyl-1-propene) (eq 4)6 to give products that are believed to arise from exchange of the enol form of the diketone with the alkoxy residue of the reagent followed by sigmatropic rearrangement (see also 2-Methoxy-1,3-butadiene and 3,3-Diethoxy-1-propene). An alternative mechanism holds that the enol adds in an SN2 fashion to the oxonium ion. Hydrolysis of the enol ethers gives carbonyl compounds. The overall process is the equivalent of a neutral Michael addition of the diketone to the unsaturated aldehydes from which the reagents were derived.

Diels-Alder Reaction.

3-Methoxyisoprene reacts regioselectively with methyl coumalate in a thermal Diels-Alder reaction. Hydrolysis of the enol ether affords an a-methylcyclohexanone (eq 5).7

Related Reagents.

1,3-Butadiene; 3,3-Diethoxy-1-propene; 1-Ethoxy-1-propene; Ethyl Vinyl Ether; Isoprene; 2-Methoxy-1,3-butadiene; 2-Methoxypropene; 1-Methoxy-1-(trimethylsilyloxy)propene; Methyl Vinyl Ketone; 2-Trimethylsilyloxy-1,3-butadiene.

1. (a) Faulkner, D. J.; Petersen, M. R. JACS 1973, 95, 553. (b) Favorskaya, I. A.; Kopylov-Shakhmatov, N. N. JGU 1957, 27, 2468.
2. Faulkner, D. J.; Petersen, M. R. TL 1969, 3243.
3. Johnson, W. S.; Werthemann, L.; Bartlett, W. R.; Brocksom, T. J.; Li, T.; Faulkner, D. J.; Petersen, M. R. JACS 1970, 92, 741.
4. Johnson, W. S.; Brocksom, T. J.; Loew, P.; Rich, D. H.; Werthemann, L.; Arnold, R. A.; Li, T.; Faulkner, D. J. JACS 1970, 92, 4463.
5. Dolby, L. J.; Elliger, C. A.; Esfandiari, S.; Marshall, K. S. JOC 1968, 33, 4508.
6. Coates, R. M.; Hobbs, S. J. JOC 1984, 49, 140.
7. Nakahara, Y.; Tatsuno, T. CPB 1980, 28, 1981.

Frederick E. Ziegler & Owen B. Wallace

Yale University, New Haven, CT, USA

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