[870-63-3]  · C5H9Br  · 1-Bromo-3-methyl-2-butene  · (MW 149.03)

(alkylating (prenylating) agent)

Alternate Names: prenyl bromide; isoprene hydrobromide.

Physical Data: bp 59-60 °C/60 mmHg; d 1.293 g cm-3; fp 32 °C.

Form Supplied in: colorless liquid stabilized with silver wool.

Preparative Method: is readily prepared by treatment of Isoprene with Hydrogen Bromide (eq 1).1-3

Handling, Storage, and Precautions: flammable liquid; corrosive; use in a fume hood.

Alkylating Agent.

Enantiomerically pure (2S)-1-phenylsulfonylalkan-2-ols are available from the ketones by asymmetric reduction with Baker's Yeast. Alkylation of the dianion from these sulfonyl alcohols with 1-bromo-3-methyl-2-butene provides the (S,S)-alcohol in 66% yield (eq 2). Phenylseleno cyclization followed by oxidation-elimination afforded enantiomerically pure 2,5-disubstituted tetrahydrofurans.4

The anion derived from a trimethylsilyl (TMS)-capped alkynic Schiff base can be alkylated quite readily with 1-bromo-3-methyl-2-butene (eq 3). The imine can then be converted to an N-acetyl group, followed by introduction of the second nitrogen atom via the Ritter reaction. After deprotection, the gem-dimethyl diamino product was obtained.5

Intramolecular cyclization of allylic propiolates derived from O-alkylation of a carboxylic acid with various allylic halides has been used to study stannyl radical additions. The products resulting from radical addition to the propiolate lead to moderate yields of a-methylene-g-butyrolactones after treatment of the vinyl a-tributylstannyl intermediate with HCl or HI in ether or benzene for several hours (eq 4).6 A competing pathway with the radical cyclization is simple addition of tin hydride across the propiolate.

Treatment of the pyrido[2,3-d]pyrimidine nucleus with 1-bromo-3-methyl-2-butene in DMF afforded the N-8 alkylated system in good yield (eq 5).7-12

Derived Grignard Reagents.

3-Bromo-1-(phenylsulfonyl)-1-propene (a mixture of cis/trans isomers, 1:4), which is available from Allyl Phenyl Sulfone, reacts with prenylmagnesium bromide to give trans-2-substituted cyclopropyl sulfones (eq 6). It is interesting that the Grignard reagent from 1-bromo-3-methyl-2-butene yields only the trans-2-(a,a-dimethylallyl)cyclopropyl phenyl sulfone. Alkyl Grignard reagents failed to yield the cyclopropyl sulfones. This represents an interesting cyclopropane synthesis via addition of unsaturated organometallics to alkenyl sulfones.13

Nickel Coupling.

Treatment of 1-bromo-3-methyl-2-butene with excess Tetracarbonylnickel in benzene yields m-3-methylbut-2-enylnickel bromide (eq 7). This p-allylnickel intermediate undergoes cross-coupling with aryl bromides in polar solvents such as DMF in quite good yield. This methodology was used in the synthesis of various vitamin K analogs,14 as well as in the synthesis of (+)-epicamphorenone and (+)-epi-b-santalene.15

Derived Copper Reagents.

Allyltriphenylstannane compounds have been used to make allyl lithium reagents which are useful for the synthesis of difficult-to-prepare cuprates. Reaction of the cuprate derived from 1-bromo-3-methyl-2-butene with an unstable 3-furan tosylate afforded perillene in modest yield (eq 8).16,17

Derived Phosphorus Reagents.

Alkylation of diphenylmethylphosphine oxide with 1-bromo-3-methyl-2-butene provided an unsaturated phosphine, which upon further deprotonation afforded an anion which added to a cyclohexenyl methyl ketone to yield a mixture of erythro (53%) and threo (4%) products (eq 9). Elimination of Ph2PO2- from the erythro intermediate afforded (Z)-a-bisabolene.18 A related synthesis of disubstituted alkenes relies on a hydride reduction to establish the correct stereochemistry prior to the elimination step.19

Addition of the Wittig reagent derived from Triphenylphosphine and 1-bromo-3-methyl-2-butene (g,g-dimethylallyltriphenylphosphonium bromide) to 2,3-indolinedione (eq 10) afforded an (E)/(Z) mixture of indolinones which are the major components from the rhizomes of Cimicifuga dahurica Maxim.20

Sigmatropic Rearrangements.

Adducts derived from the alkylation of phenols with 1-bromo-3-methyl-2-butene have been used as substrates for thermal rearrangements leading to natural products, as well as being used in mechanistic studies (eq 11). Depending on the reaction temperature, several reaction pathways are possible, leading to both normal and abnormal Claisen rearrangement products. Interestingly, in the case cited the abnormal rearrangement product leads to the natural product anisoxide.21

Base-catalyzed rearrangements of quaternary ammonium salts, derived from the reaction of tertiary amines with allylic halides (such as 1-bromo-3-methyl-2-butene), generally proceed via a [3,2]-sigmatropic rearrangement in aprotic solvents (eq 12). There is, however, often a competing 1,2-Stevens rearrangement. Treatment of diallylammonium cations with base in protic solvent led to a series of events (double bond isomerization, [3,3]-sigmatropic rearrangement, hydrolysis) ultimately yielding an aldehyde in excellent yield.22

a-Allokainic and a-kainic acids are neurophysiologically interesting constituents of algae. N-Alkylation of the bis(ethoxycarbonyl) (Z)-enoate with 13C-labeled 1-bromo-3-methyl-2-butene provided mechanistic evidence for a concerted ene reaction (eq 13). The desired N-alkylation could not be achieved using the corresponding tosylate or chloride.23

1. Claisen, L. JPR 1922, 105, 76.
2. Staudinger, H.; Kreis, W.; Schilt, W. HCA 1922, 5, 743.
3. Fieser, L. F. JACS 1927, 49, 857.
4. Tanikaga, R.; Hosoya, K.; Kaji, A. JCS(P1) 1987, 1799.
5. Casara, P.; Danzin, C.; Metcalf, B.; Jung, M. JCS(P1) 1985, 2201.
6. Lee, E.; Sung, B. K.; Jung, K. W. TL 1989, 30, 827.
7. Srinivasan, A.; Fagerness, P. E.; Broom, A. D. JOC 1978, 43, 828.
8. For the metallation of limonene see: Crawford, R. J.; Erman, W. F.; Broaddus, C. D. JACS 1972, 94, 4298.
9. For alkylation of prenyl bromide with a sulfone intermediate leading to the synthesis of sesquifenchene, see: Grieco, P. A.; Masaki, Y. JOC 1975, 40, 150.
10. For another example of alkylation with the dianion of methyl acetoacetate, see: Sum, F. W.; Weiler, L. TL 1979, 707.
11. For examples of prenylations of but-2-enolides and a synthesis of rosefuran and related natural products, see: Gedge, D. R.; Pattenden, G. TL 1977, 4443.
12. For the chemistry of di- and trianion alkylations of bis(methylsulfonyl)methane with 1-bromo-3-methyl-2-butene, see: Castro, A.; Spencer, T. A. JOC 1992, 57, 3496.
13. Eisch, J. J.; Galle, J. E. JOC 1979, 44, 3277.
14. Sato, K.; Inoue, S.; Saito, K. JCS(P1) 1973, 2289.
15. Hodgson, G. L.; MacSweeney, D. F.; Mills, R. W.; Money, T. CC 1973, 235.
16. Wiley, R. A.; Choo, H.-Y.; McClellan, D. JOC 1983, 48, 1106.
17. For the reaction of an organolithium cuprate with prenyl bromide, see: Coates, R. M.; Ley, D. A.; Cavender, P. L. JOC 1978, 43, 4915.
18. Buss, A. D.; Warren, S. TL 1983, 24, 111.
19. Buss, A. D.; Warren, S. JCS(P1) 1985, 2307.
20. Baba, K.; Kozawa, M.; Kiyoshi, H.; Ishida, T.; Inoue, M. CPB 1981, 2182. For additional examples, see: Haag, T.; Luu, B.; Hetru, C. JCS(P1) 1988, 2353 and references therein.
21. Okely, H. M.; Grundon, M. F. JCS(P1) 1981, 897.
22. Laird, T.; Ollis, W. D.; Sutherland, I. O. JCS(P1) 1980, 1477.
23. Oppolzer, W.; Mirza, S. HCA 1984, 67, 730.

Ronald B. Gammill

The Upjohn Company, Kalamazoo, MI, USA

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