[53356-78-8]  · C4H7LiO  · 1-Methoxyallyllithium  · (MW 78.05)

(reagent used for three-carbon homologation as a homoenolate anion equivalent)

Preparative Methods: the lithio anions of alkyl allyl ethers can generally be prepared by deprotonation with s-Butyllithium in THF at -65 °C or in ether or pentane with added N,N,N,N-Tetramethylethylenediamine in less than 30 min. n-Butyllithium can also be used as the base in THF with added TMEDA at -78 °C for 7 h.1

Handling, Storage, and Precautions: this and similar 1-alkoxyallyllithium reagents are stable for at least 1 day at -75 °C. At -50 °C there is at least 40% conversion to Wittig rearrangement products after 4 h and >81% conversion after 24 h. After 2 h at -25 °C, there is >89% rearrangement.2

General Considerations.

The impetus in the development of the title compound (1) was the desire for a convenient homoenolate anion equivalent. The first studies of the generation and reactivity of (1) brought out the major problem associated with its use: ambiguity in the site of its reactivity with electrophiles. Studies began almost immediately to find alternative reagents which exhibited predictable, controlled a vs. g reactivity with electrophiles. This section will be concerned not only with (1), but with allied nucleophilic 3-alkoxy-1-propenyl reagents. Reagents of this genre have been covered in small sections of several larger reviews.3


The parent substance (1) was reported in 19744 along with brief studies of the reactivity of other alkyl allyl ethers. Mixtures of a and g adducts were obtained in all reactions of the lithio anion regardless of the identity of R1 (eq 1). The only reasonable (and often repeated) generalities arising from this study are that reaction with alkyl halides takes place predominantly at the g-position while reaction with aldehydes and ketones occurs at the a-position. Even so, there are many exceptions, and perhaps the most accurate statement one may make regarding the reactivity of 1-alkoxyallyllithiums is that the site of reaction is dependent in a complex way on the identities of the cation, electrophile, solvent system, temperature, and the presence of additives.5 In the case of reaction at the g-site, cis isomers (4g and 5g) are formed exclusively. This observation has prompted many workers to assume the structure of (1) to be the internally chelated species (6), whether or not a s-bonded structure is called for in this and related cases. Attempts at rationalizing the observed selectivities have been few and are inadvisable in any case when dealing with mixtures where either the transition state energy differences in a kinetic process or the product energy differences in a thermodynamic process are, for the most part, less than 1 kcal mol-1. Regioselectivity control with the lithio anions and simple alkyl groups for R1 appears to be problematic at this point. It was found by Evans in the original study that treatment of the anion (3) (R1 = Me) with 1 equiv of Zinc Chloride or Cadmium Chloride6 favors a-alkylation (5a) with carbonyl compounds. Yamamoto also realized good regiochemical control in the reaction of 1-isopropoxyallyllithium and 1-(methoxymethoxy)allyllithium with carbonyl compounds by forming aluminum ate complexes with Triethylaluminum prior to addition of the electrophile resulting in exclusively a-adducts (5a).7 A noteworthy aspect of the reactivity of these reagents is the aldehyde vs. ketone selectivity shown in eq 2.

A report by Still8 describes the generation and reactivity of the silyloxy anions (9), which also show the trend of predominant, but not exclusive, reaction at the g-position with alkyl halides (4g). A subsequent report by Still describes the trend of predominant, but not exclusive, reaction at the a-position with carbonyl compounds (5a).9 However, when R1 = trimethylsilyl and 5% Hexamethylphosphoric Triamide is included in the reaction mixture, exclusive a-addition to aldehydes and ketones is observed (eq 3).

Generation of 1-Silyloxyallyllithiums via Brook Rearrangement.

1-Silyloxyallyllithiums as a class can also be formed in situ via Brook rearrangement (eq 4). The intermediate lithioalkoxide (11) is generated either by addition of vinyllithiums (see Vinyllithium) to silyl ketones (10)10 or by deprotonation of silyl carbinols (13) by n-BuLi.11 Carbon to oxygen silyl group migration allows entry to the 1-silyloxyallyllithium reagents which can be trapped in situ with alkyl halides, resulting in the g-alkylation products (14) in good yield. However, this technology has not been applied to the parent allyl systems (10 or 13) (R = H).

Lithiated Allyloxybenzimidazoles.

These derivatives have been found by Mukaiyama to be easily deprotonated and to undergo reaction with alkyl halides and aldehydes to give products of predominantly a-alkylation (15 -> 16 or 17) (eq 5).12 Because the 2-benzimidazolyl group can act as a good leaving group, this process can be exploited as a method to produce cis- and trans-vinyloxiranes (eqs 6 and 7).13 When the addition is mediated by Et3Al, the syn-products (21) are predominant and these lead to the cis-isomers (22).14

Lithiated Allylic Carbamates.

A significant advance in developing regiocontrolled g-reactivity of 1-alkoxyallylcarbanions has been made by Hoppe.15 The lithio derivatives of (23) and (24) undergo predominantly g-alkylation when treated with alkyl halides16 or aldehydes,17 respectively, realizing a long sought goal of developing a homoenolate equivalent in the 1-alkoxyallyllithium system. Hydrolysis of the aldol adducts (25) leads to d-hydroxy carbonyl compounds as lactols (26) or lactol ethers (eq 8). More importantly, deprotonation of substituted derivatives of (23) and (24) also proceeds well, opening up a family of homoenolate equivalents. Using this methodology, a synthesis of protected 4-oxoalkanoates has been developed (27 -> 29) which proceeds in moderate yield and with excellent g-selectivity (eq 9).18

Diastereoselectivity in Additions to Aldehydes with g-Alkoxyallylboronates.

1-Methoxyallyllithium may be converted to an intermediate g-alkoxyallylboronate (30) by treatment with (RO)2B-X (eq 10). This species undergoes highly regio- and diastereoselective additions to aldehydes to generate syn- and anti-1,2-diols.19 A family of reagents (31 and 32) were prepared20 and examined for their diastereoselectivity in reactions with aldehydes. The cis-isomers (31) give rise to predominantly the syn-products (33) (eq 11) while the trans-isomers (32) produce predominantly anti-products (34) (eq 12). A related study agrees with these results in the case of cis-g-alkoxyallylboronates21 and these reagents have seen use in target molecule synthesis.22

Brown later extended this methodology, developing an enantioselective method for constructing syn-1,2-diols.23 The boranes (36) and (39) are prepared from 1-methoxyallyllithium as exemplified in (1) -> (36) (eq 13). These enantiocomplementary reagents regio- and enantioselectively transfer a three-carbon unit to aldehydes, giving the enantiomeric diol precursors (38) (eq 13) and (40) (eq 14) in good yield with excellent enantioselectivity.

The stannane (41), also prepared from (1) shows diastereoselectivity similar to (31) in its Lewis acid-promoted reactions with aldehydes (eq 15).24 Transformations analogous to the (1) to (38) conversion can be performed on systems having considerable complexity (42).25

Arene Ring Annulation.

The zinc ate complex of 1-methoxyallyllithium has been used in a method for the annulation of catechol rings onto cyclic ketones.26 Reaction of the a-hydroxymethylene ketone (43) with the zinc reagent gives the enal (44). Without purification, this is oxidized to the methyl ketone (45) which is cyclized and aromatized with base to the catechol monomethyl ether (46) in good overall yield (eq 16).

g-Keto Aldehyde Synthesis.

Trialkylsilyloxyallyllithiums can be generated and treated with trialkylchlorosilanes to trap the Brook rearrangement product (49) as the bis-silanes (50) in good yield. These substances can be treated with acyl chlorides in the presence of Titanium(IV) Chloride to provide g-keto aldehydes (51) after a hydrolytic workup (eq 17).27

Related Reagents.

Allyllithium; t-Butoxymethyllithium; (E)-1-(N,N-Diisopropylcarbamoyloxy)crotyllithium.

1. (a) Hoffmann, R. W.; Kemper, B. TL 1981, 22, 5263. (b) Hoffmann, R. W.; Kemper, B.; Metternich, R.; Lehmeier, T. LA 1985, 2246.
2. Schlosser, M.; Strunk, S. T 1989, 45, 2649.
3. (a) Martin, S. F. S 1979, 633. (b) Schlosser, M. AG(E) 1974, 13, 701. (c) Gompper, R.; Wagner, H.-U. AG(E) 1976, 15, 321. (c) Werstiuk, N. H. T 1983, 39, 205. (d) Stowell, J. C. CRV 1984, 84, 409. (e) Biellmann, J.-F.; Ducep, J.-B. OR 1982, 27, 1. (f) Ahlbrecht, H. C 1977, 31, 391.
4. (a) Evans, D. A.; Andrews, G. C.; Buckwalter, B. JACS 1974, 96, 5560. (b) Hartmann, J.; Muthukrishnan, R.; Schlosser, M. HCA 1974, 57, 2261.
5. (a) Coupling of phenoxyallyllithium with allylic electrophiles: Butsugan, Y.; Goto, T.; Araki S. BCJ 1985, 58, 2137. (b) t-BuOK as an additive: Hartmann, J.; Muthukrishnan, R.; Schlosser, M. HCA 1974, 57, 247. (c) Coupling of 1-trialkylsilyloxyallyllithiums with electrophiles, regioselectivity study: Chan, T. H.; Lau, P. W. K. JOM 1979, 179, C24. (d) Regioselectivity study of 1-isopropoxyallyllithium and 1-(methoxymethoxy)allyllithium alkylation mediated by various metals: Yamamoto, Y.; Saito, Y.; Maruyama, K. JOM 1985, 292, 311.
6. Evans, D. A.; Baillargeon, D. J.; Nelson, J. V. JACS 1978, 100, 2242.
7. (a) Yamamoto, Y.; Yatagai, H.; Maruyama, K. JOC 1980, 45, 195. (b) Yamamoto, Y.; Yatagai, H.; Saito, Y.; Maruyama, K. JOC 1984, 49, 1096.
8. Still, W. C.; Macdonald, T. L. JACS 1974, 96, 5561.
9. Still, W. C.; Macdonald, T. L. JOC 1976, 41, 3620.
10. Reich, H. J.; Olson, R. E.; Clark, M. C. JACS 1980, 102, 1423.
11. (a) Kuwajima, I.; Kato, M. CC 1979, 708. (b) Kuwajima, I.; Kato, M.; Mori, A. TL 1980, 21, 2745. (c) Mori, A.; Oshino, H.; Enda, J.; Kobayashi, K.; Kato, M.; Kuwajima, I. JACS 1984, 106, 1773.
12. Mukaiyama, T.; Yamaguchi, M. CL 1979, 657.
13. Yamaguchi, M.; Mukaiyama, T. CL 1979, 1279.
14. Yamaguchi, M.; Mukaiyama, T. CL 1982, 237.
15. (a) Hoppe, D.; Hanko, R.; Bronneke, A.; Lichtenberg, F.; von Hulsen, E. CB 1985, 118, 2822. (b) Hoppe, D. AG(E) 1984, 23, 932.
16. Hanko, R.; Hoppe, D. AG(E) 1981, 20, 127.
17. Hoppe, D.; Hanko, R.; Bronneke, A.; Lichtenberg, F. AG(E) 1981, 20, 1024.
18. Hoppe, D.; Hanko, R.; Bronneke, A. AG(E) 1980, 19, 625.
19. Hoffmann, R. W.; Kemper, B. TL 1981, 22, 5263.
20. Hoffmann, R. W.; Kemper, B.; Metternich, R.; Lehmeier, T. LA 1985, 2246.
21. Wuts, P. G. M.; Bigelow, S. S. JOC 1982, 47, 2498.
22. (a) Roush, W. R.; Michaelides, M. R.; Tai, D. F.; Lesur, B. M.; Chong, W. K. M.; Harris, D. J. JACS 1989, 111, 2984. (b) Roush, W. R.; Michaelides, M. R. TL 1986, 29, 3353.
23. Brown, H. C.; Jadhav, P. K.; Bhat, K. S. JACS 1988, 110, 1535.
24. (a) Koreeda, M.; Tanaka, Y. TL 1987, 28, 143. (b) Koreeda, M.; Tanaka, Y. CC 1982, 845. (c) Keck, G. E.; Abbott, D. E.; Wiley, M. R. TL 1987, 28, 139.
25. Kadota, I.; Matsukawa, Y.; Yamamoto, Y. CC 1993, 1638.
26. Tius, M. A.; Thurkauf, A. JOC 1983, 48, 3839.
27. Hosomi, A.; Hashimoto, H.; Sakurai, H. JOC 1978, 43, 2551.

Kim F. Albizati

University of California, San Diego, CA, USA

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