[52815-00-6]  · C7H15ISi  · 1-Iodo-3-trimethylsilyl-2-butene  · (MW 254.21) (E)


(annulation reagent; alkylative equivalent of 3-buten-2-one; 3-ketobutyl synthon)

Alternate Name: (3-iodo-1-methyl-1-propenyl)trimethylsilane.

Physical Data: bp 60 °C/20 mmHg.

Solubility: freely sol organic solvents.

Form Supplied in: not commercially available.

Preparative Methods: the first reported preparation2 of this reagent lacked full experimental details. The preparation given (eq 1) is a compilation of the work of several groups; the various steps have been selected to give optimum yields. 2-Propyn-1-ol is converted3 into its 3-(trimethylsilyl) derivative (1), which is then reduced4 using Sodium Bis(2-methoxyethoxy)aluminum Hydride (Red-Al). The intermediate vinylaluminum is reacted with Iodine to produce the (Z)-iodoalkene (2). Treatment of this with Lithium Dimethylcuprate gives the allylic alcohol (3);5 transformation into (E)-(3-Chloro-1-methyl-1-propenyl)trimethylsilane (4) followed by halogen exchange6 with Sodium Iodide then gives reagent (5).

An alternative, high-yielding synthesis of (3) (eq 2) involves the use of HMPA, but is otherwise straightforward.7

Enolate Alkylation.

One of the most useful applications of the Michael reaction8 is Robinson annulation, using 3-buten-2-one as electrophilic acceptor. However, the Michael reaction, being reversible, is prone to side reactions, and Robinson annulation itself is of only significant utility in relatively simple cases. Hence there has been considerable effort9 devoted to devising alkylative equivalents of 3-buten-2-one, with the goal of achieving regiospecific enolate alkylation under nonequilibrating conditions. Allylic halides possess sufficiently high reactivity for such alkylation. Useful reagents which have been devised include 1,3-Dichloro-2-butene (Wichterle's reagent),10 Stork's halomethylisoxazoles,11 and Stotter's g-iodotiglate.12 However, these alternatives can all present problems either before or during further transformation to liberate the 3-ketoalkyl chain prior to final cyclization. For example, the Wichterle sequence requires the use of concentrated sulfuric acid to hydrolyze the vinyl chloride moiety.

The use of halomethyl vinylsilanes would appear to offer significant promise. As allylic halides, they should be sufficiently reactive to permit regiospecific alkylation; as vinylsilanes, they can be converted, via a,b-epoxysilanes, into carbonyl compounds.13 The conditions for this last transformation, with simple a,b-epoxysilanes, are rather vigorous, requiring hot methanol/sulfuric acid.

Examples of Use.

Iodide (5) reacts with lithium enolates,9,14 generated in a variety of ways, including kinetic generation from enol acetates (eq 3), regiospecific production by lithium-ammonia reduction of enones, and similar regiospecific production by lithium dimethylcuprate addition to enones (eq 4). Enamines can also be used in a sequence which demonstrates the possibility of reducing enones without affecting the vinylsilane (eq 5); the reagent used in this case was chloride (4) in the presence of Potassium Iodide, i.e. via the in situ generated iodide (5).

Release of the latent carbonyl function in these vinylsilanes can be achieved9,14 under much milder conditions than for simple epoxysilanes, which require hot methanol/sulfuric acid. Here, treatment of the epoxide, formed using m-Chloroperbenzoic Acid, with formic acid for 30 s led cleanly to the dione (eq 6); alternatively, use of a slight excess of m-CPBA and a reaction time of 4 h achieved the same conversion. The extreme and contrasting ease of this transformation has been ascribed to nucleophilic participation of the carbonyl group in epoxide opening (eq 7).

The diones so formed can be cyclized under basic conditions to the corresponding enones (eqs 8 and 9).

Iodide (5) has also been used15 in a regiocontrolled route (eq 10) to 4,5-disubstituted 2-(and 3-)cyclohexenones. Alkylation of the anion of sulfone (6) with (5) gave (7), subsequent transformations leading sequentially to enones (8) and (9). No further manipulation of these enones has been reported.

A different application16 of reagent (5) can be seen in the total synthesis of artemisinin (10). Alkylation of the kinetic enolate of (11), derived from (-)-isopulegol, with (5) gave an 6:1 mixture of epimeric products from which the major isomer (12) was isolated in 62% yield. Further transformations led to vinylsilane (13). Liberation of the latent carbonyl group to provide ketone (14) was again achieved under very mild conditions, although here the possibility of carbonyl participation would seem less likely. Further steps then led to artemisinin (10).

1. FF 1975, 5, 355.
2. Stork, G.; Jung, M. E.; Colvin, E; Noel, Y. JACS 1974, 96, 3684.
3. Denmark, S. E.; Jones, T. OS 1986, 64, 182.
4. Denmark, S. E.; Habermas, K. L.; Hite, G. A. HCA 1988, 71, 168.
5. For alternative preparations of this alcohol, see (a) Altnau, G.; Rösch, L.; Bohlmann, F.; Lonitz, M. TL 1980, 21, 4069. (b) Sato, F; Watanabe, H.; Tanaka, Y.; Sato, M. CC 1982, 1126; see also Ref. 7.
6. Jung, M. E., cited in Gawley, R. E. S 1976, 777.
7. Audia, J. E.; Marshall, J. A. SC 1983, 13, 531.
8. Bergmann, E. D.; Ginsburg, D.; Pappo, R. OR 1959, 10, 179.
9. Jung, M. E. T 1976, 32, 3.
10. (a) Wichterle, O.; Prochazka, J.; Hofmann, J. CCC 1948, 13, 300. (b) Review: House, H. O. Modern Synthetic Reactions, 2nd ed; Benjamin: Menlo Park, CA, 1972; p 611.
11. (a) Stork, G.; Danishefsky, S.; Ohashi, M. JACS 1967, 89, 5459. (b) Stork, G.; McMurry, J. E. JACS 1967, 89, 5463.
12. Stotter, P. L.; Hill, K. A. JACS 1974, 96, 6524.
13. (a) Stork, G.; Colvin, E. JACS 1971, 93, 2080. (b) See also Gröbel, B.-Th.; Seebach, D. AG(E) 1974, 13, 83.
14. Stork, G.; Jung, M. E. JACS 1974, 96, 3682.
15. (a) Paquette, L. A.; Kinney, W. A. TL 1982, 23, 5127. (b) Kinney, W. A.; Crouse, G. D.; Paquette, L. A. JOC 1983, 48, 4986.
16. Schmid, G.; Hofheinz, W. JACS 1983, 105, 624.

Ernest W. Colvin

University of Glasgow, UK

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