Propargylmagnesium Bromide

[13254-27-8]  · C3H3BrMg  · Propargylmagnesium Bromide  · (MW 143.27)

(propargylation and propadienylation of electrophilic centers)

Physical Data: prepared and used in situ.

Solubility: sol ether, THF.

Preparative Methods: prepared from propargyl bromide (see Propargyl Chloride) and amalgamated magnesium, generated in situ from Magnesium and Mercury(II) Chloride. Without HgCl2, only a mixture of acetylenic and allenic hydrocarbons is obtained. Reaction at reflux temperature in ether using a recycling reactor1 results in a greater than 90% yield of Grignard reagent consisting of a 4:1 ratio of allenic and acetylenic forms.2 Low temperature and slow addition of a dilute solution of a mixture of propargylic bromide and substrate to a reacting mixture, initiated with a small amount of the bromide, is a technique that reduces equilibration of the Grignard reagent before its reaction with the substrate.3,4 The same slow addition of a dilute ether solution of propargyl bromide to an initiated reaction is said to lead to the pure allenic Grignard reagent.5 The Grignard reagent prepared from propargyl bromide has been converted into a solid powder by complexation with tris(3,6-dioxaheptyl)amine.6

Handling, Storage, and Precautions: the reagent should be prepared and used when needed. Solutions undergo disproportionation to propyne, allene, the acetylenic Grignard reagent, and di-Grignard reagent over days. The reagent is easily hydrolyzed to gaseous hydrocarbons and must be handled and used in a dry and inert atmosphere. Pure propargyl bromide, the compound required for preparing the Grignard reagent, is shock sensitive.7 Propargyl bromide is also supplied as an 80% by wt solution in toluene, which does not show this hazardous property.8

Propargylation by Addition to Carbonyl Compounds.

Propargylmagnesium bromide adds to ketones,9 aldehydes,10 esters,11 and Carbon Dioxide12 to give a mixture of propargylic and allenic adducts. Additions to ketones and aldehydes (which can be present in the reaction mixture as the Grignard reagent is produced)3,4 lead to mixtures of homopropargylic and allenic alcohols. Low reaction temperatures, ranging from 25 to -100 °C have been employed to favor formation of the acetylenic alcohol. Addition of propargylmagnesium bromide to benzaldehyde at 0 °C is highly regioselective for the acetylenic isomer (eq 1).10c The selectivity of this reaction is better than the 93:7 obtained by the addition of propargylzinc bromide to phenacyltrimethylsilane. The propargylzinc halide/acyltrimethylsilane route gives consistently higher selectivity for the acetylenic alcohol than the aldehyde/Grignard route with higher propargyl homologs (eq 2).10c

The 1,2-addition to a,b-unsaturated ketones gives consistently high yields and is a highly regioselective process that does not show competition from conjugate additions (eq 3).9 A protocol is available, however, for conjugate propargylation of a,b-unsaturated ketones using stannylallenes generated from propargylmagnesium bromide.13 The addition of propargyl Grignard reagents to esters is usually a low yield reaction.11 Low temperature and reverse addition techniques ensure that the reaction gives the ketone as the product. Predominance of the acetylenic or allenic ketone depends on the ester. For example, ethyl acetate is converted in 18% yield to a mixture of ketones consisting of 70% of 1,2-pentadien-4-one and 30% of 1-pentyn-4-one. Ethyl propionate gives a 30% yield of a 63:37 mixture of 1-hexyn-4-one and 1,2-hexadien-4-one, respectively.11b,c Carboxylation of propargylmagnesium bromide with CO2 is also a low yield reaction that gives a mixture of acetylenic and allenic carboxylic acids.12 The yield of carboxylic acids is better with the higher homologs of the propargyl Grignard reagent.

Propargylation by Addition to C=N Bonds.

A Grignard reagent prepared from propargyl bromide, described as allenylmagnesium bromide, adds efficiently to the C=N bonds of benzoxazoles, benzothiazoles,14 quinoxalines,15 and pyrimidines.16 Benzoxazoles and unsubstituted benzothiazole add two propargyl groups at the 2-position to give ring-opened compounds (eqs 4 and 5). 2-Substituted benzothiazoles, on the other hand, add only one propargyl group, no matter how much Grignard reagent is present (eq 6). Quinoxaline adds a propargyl group to each of the C=N bonds (eq 7), whereas 2,3-dimethylquinoxaline affords a monoadduct regardless of how much excess Grignard reagent is present. 2-Chloro-3-methylquinoxaline gives 2-propargyl-3-methylquinoxaline, the product of nucleophilic aromatic substitution, when treated with a 50% excess of allenylmagnesium bromide (eq 8). Chloropyrimidines, however, only undergo addition to the C=N bond with allenylmagnesium bromide, uncomplicated by nucleophilic aromatic substitution (eq 9).

Propargylation by Substitution.

The Grignard reagent from propargyl bromide reacts poorly with saturated alkyl halides, but very well with allylic,17 benzylic,17 and some propargylic18 halides. For example, trans-1,4-dibromo-2,3-dimethyl-2-butene is converted to an enediyne in 51% yield using allenylmagnesium bromide (eq 10), whereas use of 3-lithio-1-trimethylsilylpropyne gives less than a 5% yield. Allyl Bromide, however, gives a mixture in which the allenic product predominates (eq 11).19 With benzylic halides, bromides react better than chlorides. The palladium(0)-catalyzed cross coupling with benzyl halides is more efficient (eq 12).20 The reaction of propargylmagnesium bromide with trimethylsilylpropargyl bromide is reported to be a high yield route to the 1,5-diyne (eq 13).18 Propargylmagnesium bromide can open epoxides with regioselectivity that depends on the steric effect of substituents on the epoxide (eq 14).21 Alkoxymethyldialkylamines are converted in high yields to b-acetylenic tertiary amines.22 Regioselectivity is usually high and is also affected by steric factors at the carbon bearing the alkoxy leaving group (eq 15). b-Acetylenic amines are accessible from the addition of propargylmagnesium bromide to N-trimethylsilyl imines followed by hydrolysis.23 Propargyl Grignard reagents also displace the acetoxy group from dialkoxymethyl acetates to give homopropargylic acetals.24

1. Wotiz, J. H. JACS 1950, 72, 1639.
2. Wotiz, J. H. In Chemistry of Acetylenes; Viehe, H. G., Ed.; Dekker: New York, 1969; p 365.
3. Sondheimer, F.; Amiel, Y.; Gaoni, Y. JACS 1962, 84, 270.
4. Viola, A.; MacMillan, J. H. JACS 1968, 90, 6141.
5. Prevost, C.; Gaudemar, M.; Honigberg, J. CR(C) 1950, 230, 1186.
6. Boudin, A.; Cerveau, G.; Chuit, C.; Corriu, R. J. P.; Reye, C. TL 1989, 45, 171.
7. Fire Technol. 1969, 5, 100.
8. Aldrich Handbook of Fine Chemicals; Aldrich: Milwaukee, 1992-1993; p 1061.
9. (a) Hirama, M.; Gomibuchi, T.; Fujiwara, K.; Sugiura, Y.; Uesugi, M. JACS 1991, 113, 9851. (b) Wehlage, T.; Krebs, A.; Link, T. TL 1990, 31, 6625. (c) Wender, P. A.; Tebbe, M. J. TL 1991, 32, 4863.
10. (a) Baldwin, J. E.; Reddy, V. P. JACS 1987, 109, 8051. (b) Fryhle, C. B.; Williard, P. G.; Rybak, C. M. TL 1992, 33, 2327. (c) Yanagisawa, A.; Habaue, S.; Yamamoto, H. T 1992, 48, 1969.
11. (a) Missiaen, P.; De Clercq, P. J. BSB 1987, 96, 105. (b) Couffignal, R.; Gaudemar, M. BSF(2) 1969, 3218. (c) Couffignal, R.; Gaudemar, M. CR(C) 1967, 265, 42.
12. Wotiz, J. H.; Matthews, J. S.; Lieb, J. A., JACS 1951, 73, 5503.
13. Haruta, J.; Nishi, K.; Matsuda, S.; Akai, S.; Tamura, Y.; Kita, Y. JOC 1990, 55, 4853.
14. Babudri, F.; Florio, S. S 1986, 638.
15. Epifani, E.; Florio, S.; Ingrosso, G.; Sgarra, R.; Stasi, F. T 1987, 43, 2769.
16. Epifani, E.; Florio, S.; Ingrosso, G.; Babudri, F. T 1989, 45, 2075.
17. Ireland, R. E.; Dawson, M. I.; Lipinski, C. A. TL 1970, 26, 2247.
18. Zhang, Y.; Wu, G.; Agnel, G.; Negishi, E. JACS 1990, 112, 8590.
19. Groizeleau-Miginiac, L. BSF(2) 1963, 1449.
20. Wang, R.-T.; Chou, F.-L.; Luo, F.-T. JOC 1990, 55, 4846.
21. Moreau, J.-L. In The Chemistry of Ketenes, Allenes and Related Compounds; Patai, S., Ed.; Wiley: New York, 1980; p 363.
22. Courtois, G.; Harama, M.; Miginiac, L. JOM 1980, 198, 1.
23. Leboutet, L.; Courtois, G.; Miginiac, L. JOM 1991, 420, 155.
24. Beaudet, I.; Duchene, A.; Parrain, J. L.; Quintard, J. P. JOM 1992, 427, 201.

Godson C. Nwokogu

Hampton University, VA, USA

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