[815-60-1]  · C5H8Br2O  · 2,4-Dibromo-3-pentanone  · (MW 243.93)

(a good source of the dimethyloxyallyl cation; especially useful for [4 + 3] and [3 + 2] cycloadditions1)

Physical Data: bp 194-5 °C/732 mmHg; d 1.771 g cm-3 (18 °C).

Solubility: quantitative data unavailable. Sol moderately polar to polar organic solvents.

Form Supplied in: not generally commercially available and should be prepared as needed.2,3

Analysis of Reagent Purity: obtained as a mixture of (+)-, (-)-, and meso isomers which can be assayed by NMR.

Handling, Storage, and Precautions: is a powerful lachrymator and a skin irritant. If contact with the skin occurs the affected area should be thoroughly washed with soap followed by a solution of sodium bicarbonate.2

[4 + 3] Cycloadditions.

The chemistry of 2,4-dibromo-3-pentanone (1) is dominated by its ability to form oxyallylic cations (2) and (3) under a variety of conditions (eq 1). Though other reaction pathways are possible, these intermediates, particularly (2), have been used in most cases as dienophiles in a [4 + 3] cycloaddition with dienes.1 2,4-Dibromo-3-pentanone serves as a prototype for other polyhalogenated ketones which exhibit similar chemistry (see 1,1,3,3-Tetrabromoacetone).

The reactivity of (2) is determined to a considerable extent by the reaction conditions under which it is generated. Of particular importance is the nature of the reagent used in the reductive debromination of (1). Reagents which have found application in this process include Diethylzinc,4 Zinc/Copper Couple,5 Sodium Iodide-Copper,2,5b Nonacarbonyldiiron,1c,3 Cerium(III) Chloride-Tin(II) Chloride,6 and Zinc/Silver Couple.7 These reagents preclude the formation of (2) as such and require inclusion of a counterion(s) which, in combination with solvent and other effects, modifies the reactivity of (2) with respect to scope, yield, and stereoselectivity in its [4 + 3] cycloaddition reaction with various dienes.

For the reaction of (2) with furan, expected products include isomers of 2,4-dimethyl-8-oxabicyclo[3.2.1]oct-6-en-3-one (4) (eq 2). Table 1 summarizes the results obtained with several different reagents. Yields are generally high and stereoselectivity good in most cases. The need for excess furan in many of these processes limits the generality of the reaction. The high stereoselection in the Zn/Ag reaction is noteworthy.7 All of the methods are convenient, though concerns about the toxicity and expense of nonacarbonyldiiron make its use less attractive.

A variety of other furans have successfully undergone [4 + 3] cycloaddition with (2). However, it appears that an exhaustive study of substituent effects on the cycloaddition process has not been made. The reaction of pinofuran (5) with (2) gave (6) as a mixture of isomers, resulting from a sterically controlled approach of the oxyallyl anti to the gem-dimethyl group of (5), but through both extended and compact transition states (eq 3).8

The cycloadducts derived from (2) and various furans have found considerable application in synthesis. They have been used in the synthesis of the Prelog-Djerassi lactone,9 nonactic acid,10 and fragments of rifamycin S11 and ionomycin12 and hold considerable promise as templates for the stereoselective synthesis of polyfunctional acyclic systems.13

Other dienes have been used to trap (2). Cyclopentadienes,3b,5c fulvenes,5c,14 anthracenes,15 and acyclic butadienes3b have been successfully employed, especially with (2) generated using the reaction of (1) with Fe2(CO)9 (eq 4). Iron tricarbonyl complexes of the dienes may also be used to both generate (2) and subsequently trap it. Cycloadducts from the reaction of (2) with acyclic butadienes have been converted in a general fashion to tropones and tropolones.16

Pyrroles can also be effective traps for (2), leading to [4 + 3] cycloadducts. N-Methylpyrrole gave a [4 + 3] cycloadduct upon reaction with (2) generated from NaI/Cu but only Friedel-Crafts substitution products with the oxyallyl generated from Zn/Cu or Fe2(CO)9 (eq 5).3b,17 Better results were obtained in the latter case using N-methoxycarbonyl- or N-acetylpyrroles (eq 6).18

Generally, thiophenes give only Friedel-Crafts substitution products upon attempted [4 + 3] cycloaddition with oxyallyls.1 However, 2,5-dimethylthiophene gave [4 + 3] cycloadducts with (2) generated from Fe2(CO)9 (eq 7).19 This result strongly suggests that the use of substituted thiophenes in [4 + 3] cycloaddition processes may be generally feasible.

More unusual heterocycles, including selenophene and tellurophene,19 diphenylisobenzofuran and N-t-butylisoindole,20 and 1-phenyl-1-thio-3,4-dimethylphosphole,21 have been used to trap (2). In the latter case, an unexpected hydrolysis took place in the course of the reaction to give bicycle (7) as the sole [4 + 3] cycloadduct, albeit in low yield (eq 8).

[3 + 2] Cycloadditions.

The trapping of (2) with p-systems in a [3 + 2] sense has been the subject of a number of studies. The reaction of (2) with morpholino enamines has been shown to lead to cyclopentenones in a general fashion (eq 9).3a,22 Iron-Graphite (C24Fe) has been introduced as a reagent for the conversion of (1) to (2) in the context of this annulation process.23 Related cycloadditions also occur with N,N-bis-silyl enamines and N-tosyl enamines (eq 10).24,25

Aromatic alkenes are also capable of trapping (2) to afford cyclopentanones (eq 11).26 Dienes can also exhibit regioselectivity characteristic of [3 + 2] cycloadditions in their reactions with (2).27

A general synthesis of 3(2H)-furanones based on the reaction of (2) with dimethylamides has been developed (eq 12).28 An interesting example is the synthesis of (8), which, while derived from (2), is also a precursor of this species (eq 13).29

The reaction of (2) with 1,1-dimethoxyethylene resulted in the formation of heterocycle (9) in high yield (eq 14). Attempted trapping with alkynes did not produce [3 + 2] cycloadducts but led to low yields of substituted allenes (eq 15).30

[3 + 3] Cycloadditions.

Only one example of this type of reaction with (2) has been reported. Reaction of (2) with h1-allyl(cyclopentadienyl)dicarbonyliron in the presence of Fe2(CO)9 followed by oxidation resulted in the synthesis of 2,6-dimethyl-4-methoxycarbonylcyclohexanone in low yield (eq 16).25

Miscellaneous Reactions.

A number of other synthetically useful transformations of (1) have been developed. Treatment of (1) with isopropylamine gave imino ketone (10) and diimine (11) in 72% yield in a ratio of 98:2 (eq 17).31 All proposed mechanistic possibilities for this transformation involve oxyallylic species, including (2) and (3).

Nucleophilic trapping of (2) with methanol served to support the intermediacy of this oxyallyl in various cycloaddition processes (eq 18).32 This trapping reaction has not been synthetically exploited.

A palladium-mediated reductive dehalogenation of (1) may hold promise as a new means of generating (2).33 An electrochemical reduction of (1) apparently resulted in the formation of a cyclopropanone which was nucleophilically trapped under the reaction conditions (eq 19).34

Finally, treatment of (1) with cuprates resulted in a unique reductive alkylation. Alkylative trapping of the resulting enolate gave reasonable yields of ketones not easily accessible by other routes (eq 20).35

1. (a) Hosomi, A.; Tominaga, Y. COS 1991, 5, 593. (b) Mann, J. T 1986, 42, 4611. (c) Hoffmann, H. M. R. AG(E) 1984, 23, 1. (d) Noyori, R.; Hayakawa, Y. OR 1983, 29, 163. (e) Noyori, R. ACR 1979, 12, 61. (f) Hoffmann, H. M. R. AG(E) 1973, 12, 819.
2. Ashcroft, M. R.; Hoffmann, H. M. R. OSC 1988, 6, 512.
3. (a) Noyori, R.; Yokoyama, K. Kayakawa, Y. OSC 1988, 6, 520. (b) Takaya, H.; Makino, S.; Hayakawa, Y.; Noyori, R. JACS 1978, 100, 1765.
4. Mann, J.; Barbosa, L. C. A. JSC(P1) 1992, 787.
5. (a) Hoffmann, H. M. R.; Clemens, K. E.; Smithers, R. H. JACS 1972, 94, 3940. (b) Rawson, D. I.; Carpenter, B. K.; Hoffmann, H. M. R. JACS 1979, 101, 1786. (c) Joshi, N. N.; Hoffmann, H. M. R. TL 1986, 27, 687.
6. Fukuzawa, S.; Fukushima, M.; Fujinami, T.; Sakai, S. BCJ 1989, 62, 2348.
7. Sato, T.; Noyori, R. BCJ 1978, 51, 2745.
8. Koever, A.; Hoffmann, H. M. R. T 1988, 44, 6831.
9. White, J. D.; Fukuyama, Y. JACS 1979, 101, 226.
10. Arco, M. J.; Trammell, M. H.; White, J. D. JOC 1976, 41, 2075.
11. (a) Rama Rao, A. V.; Yadav, J. S.; Vidyasagar, V. CC 1985, 55. (b) Lautens, M.; Belter, R. K. TL 1992, 33, 2617.
12. Lautens, M.; Chiu, P.; Colucci, J. T. AG(E) 1993, 32, 281.
13. (a) Lautens, M. SL 1993, 177. (b) Lautens, M. PAC 1992, 64, 1873.
14. Kashman, Y.; Rudi, A. T 1979, 30, 109.
15. Hoffmann, H. M. R.; Karama, U. CB 1992, 125, 2803.
16. Takaya, H.; Hayakawa, Y.; Makino, S.; Noyori, R. JACS 1978, 100, 1778.
17. (a) Fierz, G.; Chidgey, R.; Hoffmann, H. M. R. AG(E) 1974, 13, 410. (b) Cowling, A. P.; Mann, J. JSC(P1) 1978, 1564.
18. Noyori, R.; Makino, S.; Baba, Y.; Hayakawa, Y. TL 1974, 1049.
19. Pacheco, D.; Vargas, F.; Rivas, C. PS 1985, 25, 245.
20. El-Khawaga, A. M.; Hoffmann, H. M. R. SL 1990, 519.
21. Kashman, Y.; Awerbouch, O. T 1975, 31, 53.
22. Hayakawa, Y.; Yokoyama, K.; Noyori, R. JACS 1978, 100, 1799.
23. Savoia, D.; Tagliavini, E.; Trombini, C.; Umani-Ronchi, A. JOC 1982, 47, 876.
24. Corriu, R. J. P.; Moreau, J. J. E.; Pataud-Sat, M. JOC 1990, 55, 2878.
25. Hegedus, L. S.; Holden, M. S. JOC 1985, 50, 3920.
26. Hayakawa, Y.; Yokoyama, K.; Noyori, R. JACS 1978, 100, 1791.
27. Hoffmann, H. M. R.; Chidgey, R. TL 1978, 85.
28. (a) Hayakama, Y.; Takaya, H.; Makino, S.; Hayakawa, N.; Noyori, R. BCJ 1977, 50, 1990. (b) Noyori, R.; Hayakawa, Y.; Makino, S.; Hayakawa, N.; Takaya, H. JACS 1973, 95, 4103.
29. (a) Hoffmann, H. M. R.; Clemens, K. E. S.; Schmidt, E. A.; Smithers, R. H. JACS 1972, 94, 3201.
30. Cowling, A. P.; Mann, J. CC 1978, 1006.
31. De Kimpe, N.; D'Hondt, L.; Moens, L. T 1992, 48, 3183.
32. Hoffmann, H. M. R.; Nour, T. A.; Smithers, R. H. CC 1972, 963.
33. Urata, H.; Suzuki, H.; Moro-Oka, Y.; Ikawa, T. JOM 1982, 243, 367.
34. Van Tilborg, W. J. M.; Plomp, R.; De Ruiter, R.; Smit, C. J. RTC 1980, 99, 206.
35. Lion, C.; Dubois, J. E. T 1975, 31, 1223.

Michael Harmata

University of Missouri-Columbia, MO, USA

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