(1; X = Br, R,R = -CH2CH2-)

[24400-75-7]  · C7H13BrO2  · 2-(3-Bromopropyl)-2-methyl-1,3-dioxolane  · (MW 209.08) (2; X = Cl, R,R = -CH2CH2-)

[5978-08-5]  · C7H13ClO2  · 2-(3-Chloropropyl)-2-methyl-1,3-dioxolane  · (MW 164.63) (3; X = I, R,R = -CH2CH2-)

[3695-28-1]  · C7H13IO2  · 2-(3-Iodopropyl)-2-methyl-1,3-dioxolane  · (MW 256.08) (4; X = I, R,R = Me,Me)

[88794-75-6]  · C7H15IO2  · 5-Iodo-2-pentanone Dimethyl Acetal  · (MW 258.10)

(alkylating agents for attaching a 4-ketopentyl group to various nucleophiles; the derived organometallic reagents attach this group to electrophilic centers such as carbonyl groups; the major use has been for synthesis of monoprotected 1,5- and 1,6-diketones and related 1,n difunctional compounds)

Alternate Name: 5-bromo-2-pentanone ethylene acetal.

Physical Data: bp (1), 94-97 °C/10 mmHg; (2), 79-81 °C/8 mmHg; (3), 70-72 °C/2 mmHg; (4) 100 °C/11 mmHg.

Preparative Methods: acetalization of the 5-halo-2-pentanone (made by opening 2-acetylbutyrolactone with HX).1 5-Chloro-2-pentanone is commercially available, and has been converted to 5-iodo-2-pentanone by treatment with sodium iodide/acetone.1g,2 Alternatively, (2) is treated with sodium bromide/ethyl bromide to give (1);3a (1) or (2) may be treated with sodium iodide to give (3).3b-d

Purification: vacuum distillation from a trace of sodium bicarbonate.

Handling, Storage, and Precautions: store at <=0 °C; use in a fume hood.

Electrophilic 4-Ketopentyl Reagent.

Alkylation of ketone enolates with (1) gives 1,6-diketone monoacetals.4 Similarly, enolate equivalents, namely the anions of acetone dimethylhydrazone5a and acetylmethylenetriphenylphosphorane,5b have been alkylated with (1) to give, after partial hydrolysis, 7,7-ethylenedioxy-2-octanone. These substances can be cyclized to acetylcyclopentenes (eq 1).4a

Alkylation of (8) followed by acetalization/deacetalization leads to the tricyclic alkaloid intermediate (11) (eq 2).6

Alkylation of nitriles7 and a-aminonitriles8 with 5-halo-2-pentanone acetals is well established. A nonstereoselective synthesis of (-)-pumiliotoxin-C (15) starts with the alkylation of (12) (eq 3).8c

o-Halo-2-alkanone acetals have been used in the synthesis of n,m-dihydroxy-2-alkanones which, upon internal acetalization, give various bridged dioxabicyclic insect pheromones (see 2-(2-Bromoethyl)-2-methyl-1,3-dioxolane). Stereoselective alkylation of lactone (16)9 (derived from L-lactic acid) with (4) is the basis of an enantioselective synthesis of (-)-frontalin (18) (eq 4).1g A different approach to (18) involves Sharpless epoxidation of (21) derived from alkylation of malonic ester with (1) (eq 5).10a Several examples of alkylation of monoanions of 1,3-dicarbonyl and 2-cyanocarbonyl compounds with 5-halo-2-pentanone acetals are known.10

A short synthesis of (+)-endo-brevicomin (25) involves alkylation of the dianion of (22) (readily available from Baker's Yeast reduction of 2-propionyl-1,3-dithiane), followed by chemoselective monohydrolysis of (23) and stereoselective reduction (eq 6).11a Other 1,3-dithianes have been alkylated with 5-halo-2-pentanone acetals in connection with syntheses of insect substances11b,c and the macrocyclic lactone zearalenone.11d A synthesis of (E)-9-keto-2-decenoic acid (queen substance) relies on alkylation of a 1,3-disulfone with (3).12

5-Halo-2-pentanone acetals have been used to alkylate lithium and sodium acetylides,1b,c,13 allenyllithiums,14 alkenyllithiums15 and -cuprates,16 allylic lithiums,17 3-furyllithiums,18 and an allylic phosphonate anion.19 Several of these applications lead to dioxabicyclic insect pheromones.13a,b,16b,17b,19

Nucleophilic 4-Ketopentyl Reagent.

Feugeas and Normant noted in 1963 that the Grignard reagents (26a) and (26b) (from (1) and (2), respectively) could be prepared in THF but not in diethyl ether (where dioxolane ring cleavage occured).20 Despite this caveat, at least three other groups have prepared (26a) in diethyl ether21 and, to further complicate the picture, a fourth group has claimed that, even in THF, the preparation of (26b) is capricious.22 It is likely that the key to success in both solvents is temperature control23 and the use of freshly distilled (1) or (2);21a the use of Rieke Magnesium24 has been recommended,25 as has also the use of 1,2-Dibromoethane as an entraining agent.26a In two reports,1b,22 reaction of (26b) with aldehydes produces, in addition to the expected secondary alcohol, large amounts of ketone, presumably via Oppenauer-like intramolecular hydride transfer. Reaction of (26) with ketones frequently gives low yields of tertiary alcohols;27 in one case this has been traced to production of large amounts of secondary alcohol,27c presumably via b-hydride transfer. Despite these problems, reaction of (26) with aldehydes and ketones has often been used successfully in natural products synthesis;21,27a,b,28 for example, in the synthesis of monomorine I(29) (eq 7).28a

The corresponding lithium reagent (30) has been prepared by reaction of (1) in diethyl ether with Lithium containing 1-2% sodium,29 or with lithium-arene radical anions.30 Reagent (30) reacts more rapidly than (26) with aldehydes and ketones, and reacts selectively with a variety of electrophiles.30a Townsend and co-workers used both (26a)25a and (30)29a with equally good results in syntheses of averrufin (33) (eq 8).

The relatively low reactivity of (26) allows the reaction with acid chlorides31a and anhydrides31b,c to be stopped after monoaddition, enabling preparation of 1,5-diketone monoacetals. Reagent (26a) has been paired successfully with enol lactones21c,31c,32 in the Fujimoto-Belleau reaction (eq 9).

Simple esters, such as ethyl formate, consume 2 mol of the Grignard reagent (producing secondary alcohols),33 but monoaddition to oxalate esters can be effected at -40 °C, leading to a-keto esters; this latter process has been used in syntheses of anatoxin A.25b,c Reactions of (26a) and (26b) with hemi-aminals and immonium salts,34a carbon disulfide,34b triphenyltin chloride,34c and trimethyl borate34d have been reported.

The Grignard reagent (26a) in the presence of copper salts has been used for nucleophilic substitution reactions with saturated alkyl halides and sulfonate esters,26 and with allyl35 and propargyl36 halides and sulfonates (1,3-substitution). The triphenylphosphonium ylide derived from (1)-(3) has been treated with carbonyl compounds to make alkenes.2,3b,37 For example, deprotonation of (36) with Sodium Amide in benzene, filtration (to produce a salt-free ylide), and reaction with acetaldehyde gives, in 35% overall yield, (39c) (contaminated by 5% of (39t), an intermediate in the synthesis of cinerolone.37a The Horner-Wittig variant, employing the diphenylphosphine oxide (37), has the advantage that either cis- or trans-alkenes may be prepared (eq 10). Very high levels of isomer purity may be achieved since the intermediate erythro/threo hydroxy compounds are crystalline and easily separated by chromatography.1a

1. (a) Cornish, C. A.; Warren, S. JCS(P1) 1985, 2585. (b) Grob, C. A.; Moesch, R. HCA 1959, 42, 728. Roffey, P.; Sargent, M. V.; Knight, J. A. JCS(C) 1967, 2328. (c) Collonges, F.; Descotes, G. BSF 1973, 3491. (d) Thon, D.; Schneider, W. LA 1976, 2094. (e) Kumadaki, I.; Tamura, M.; Ando, A.; Nagai, T.; Koyama, M.; Miki, T. CPB 1988, 36, 515. (f) Shibagaki, M.; Takahashi, K.; Kuno, H.; Matsushita, H. BCJ 1990, 63, 1258. (g) Naef, R.; Seebach, D. LA 1983, 1930.
2. (a) Findlay, J. A.; MacKay, W. D.; Bowers, W. S. JCS(C) 1970, 2631. (b) Carr, G.; Dean, C.; Whittaker, D. JCS(P2) 1989, 71.
3. (a) Willy, W. E.; McKean, D. R.; Garcia, B. A. BCJ 1976, 49, 1989. (b) Gebhard, R.; Courtin, J. M. L.; Shadid, J. B.; van Haveren, J.; van Haeringen, C. J.; Lugtenburg, J. RTC 1989, 108, 207. (c) Thanei-Wyss, P.; Waser, P. G. HCA 1983, 66, 2198. (d) Rama Rao, A. V.; Deshmukh, M. N.; Sharma, G. V. M. T 1987, 43, 779.
4. (a) Nagata, W.; Terasawa, T.; Aoki, T. TL 1963, 865. (b) Cragoe, E. J., Jr.; Woltersdorf, O. W., Jr.; Gould, N. P.; Pietruszkiewicz, A. M.; Ziegler, C.; Sakurai, Y.; Stokker, G. E.; Anderson, P. S.; Bourke, R. S.; Kimmelberg, H. K.; Nelson, L. R.; Barron, K. D.; Rose, J. R.; Szarowski, D.; Popp, A. J.; Waldman, J. B. JMC 1986, 29, 825.
5. (a) Petersen, J. S.; Töteberg-Kanlen, S.; Rapoport, H. JOC 1984, 49, 2948. (b) Cooke, M. P., Jr. JOC 1973, 38, 4082.
6. Shono, T.; Matsumura, Y.; Tsubata, K.; Sugihara, Y. TL 1982, 23, 1201.
7. (a) Gupta, Y. N.; Doa, M. J.; Houk, K. N. JACS 1982, 104, 7336. (b) Paquette, L. A.; Okazaki, M. E.; Caille, J.-C. JOC 1988, 53, 477.
8. (a) Harris, M.; Grierson, D. S.; Husson, H.-P. TL 1981, 22, 1511. (b) Bonin, M.; Besselièvre, R.; Grierson, D. S.; Husson, H.-P. TL 1983, 24, 1493. (c) Bonin, M.; Royer, J.; Grierson, D. S.; Husson, H.-P. TL 1986, 27, 1569. (d) Takahashi, K.; Asakawa, M.; Ogura, K. CL 1988, 1109.
9. Stereoselective alkylation of a steroid side-chain ester with (1): Wicha, J.; Bal, K. JCS(P1) 1978, 1282.
10. (a) Yadav, J. S.; Joshi, B. U.; Sahasrabudhe, A. B. SC 1985, 15, 797. (b) Joss, U.; Schaltegger, H. HCA 1969, 52, 2465. (c) Bortolussi, M.; Bloch, R.; Conia, J. M. BSF 1975, 2722. (d) Ireland, R. E.; Beslin, P.; Giger, R.; Hengartner, U.; Kirst, H. A.; Maag, H. JOC 1977, 42, 1267. (e) Wani, M. C.; Vishnuvajjala, B. R.; Swain, W. E., Jr.; Rector, D. H.; Cook, C. E.; Petrow, V.; Reel, J. R.; Allen, K. M.; Levine, S. G. JMC 1983, 26, 426. (f) Liu, C.-Y.; Smith, D. A.; Houk, K. N. TL 1986, 27, 4881. (g) Xie, Z.-F.; Suemune, H.; Sakai, K. CC 1988, 612.
11. (a) Noda, Y.; Kikuchi, M. CL 1989, 1755. (b) Bernardi, R.; Ghiringhelli, D. JOC 1987, 52, 5021. (c) Chikashita, H.; Kittaka, E.; Kimura, Y.; Itoh, K. BCJ 1989, 62, 833. (d) Rama Rao, A. V.; Deshmukh, M. N.; Sharma, G. V. M. T 1987, 43, 779.
12. Ferroud, D.; Gaudin, J. M.; Genet, J. P. TL 1986, 27, 845.
13. (a) Bellas, T. E.; Brownlee, R. G.; Silverstein, R. M. T 1969, 25, 5149. (b) Oehlschlager, A. C.; Johnston, B. D. JOC 1987, 52, 940. (c) Collins, P. W.; Dajani, E. Z.; Pappo, R.; Gasiecki, A. F.; Bianchi, R. G.; Woods, E. M. JMC 1983, 26, 786. (d) Ward, J. P.; Van Dorp, D. A. RTC 1969, 88, 1345.
14. (a) Bertrand, M.; Cavallin, B.; Roumestant, M.-L.; Sylvestre-Panthet, P. Isr. J. Chem. 1985, 26, 95. (b) Crandall, J. K.; Mualla, M. TL 1986, 27, 2243.
15. Tokoroyama, T.; Tsukamoto, M.; Iio, H. TL 1984, 25, 5067.
16. (a) Uchida, K.; Utimoto, K.; Nozaki, H. JOC 1976, 41, 2941. (b) Cahiez, G.; Alexakis, A.; Normant, J. F. TL 1980, 21, 1433. (c) Lipshutz, B. H.; Parker, P.; Kozlowski, J. A. JOC 1983, 48, 3334.
17. (a) Akiyama, S.; Hooz, J. TL 1973, 4115. (b) Funk, R. L.; Bolton, G. L. TL 1988, 29, 1111.
18. (a) Chiarello, J.; Joullié, M. M. T 1988, 44, 41. (b) Bock, I.; Bornowski, H.; Ranft, A.; Theis, H. T 1990, 46, 1199.
19. Mori, K. ABC 1976, 40, 2499.
20. (a) Feugeas, C.; Normant, H. BSF 1963, 1441. (b) Feugeas, C. BSF 1963, 2568.
21. (a) Tschesche, R.; Goossens, B.; Piestert, G.; Töpfer, A. T 1977, 33, 735. (b) Sato, F.; Takahashi, O.; Kato, T.; Kobayashi, Y. CC 1985, 1638. (c) Kutney, J. P.; Grice, P.; Pascoe, K. O.; Piotrowska, K.; Rettig, S. J.; Szykula, J.; Trotter, J. HCA 1983, 66, 1806.
22. Anselmi, C.; Berti, G.; Catelani, G.; Coppa, F.; Monti, L. G 1979, 109, 41.
23. (a) Rosenberger, M.; Andrews, D.; DiMaria, F.; Duggan, A. J.; Saucy, G. HCA 1972, 55, 249. See also: (b) Büchi, G.; Wuest, H. JOC 1969, 34, 1122. (c) Ponaras, A. A. TL 1976, 3105. (d) Stowell, J. C.; Keith, D. R.; King, B. T. OS 1984, 62, 140.
24. Riecke, R. D.; Bales, S. E. OSC 1988, 6, 845.
25. (a) Townsend, C. A.; Davis, S. G.; Christensen, S. B.; Link, J. C.; Lewis, C. P. JACS 1981, 103, 6885. (b) Petersen, J. S.; Fels, G.; Rapoport, H. JACS 1984, 106, 4539. (c) Sardina, F. J.; Howard, M. H.; Morningstar, M.; Rapoport, H. JOC 1990, 55, 5025.
26. (a) Ashby, E. C.; De Priest, R. N.; Su, W.-Y. OM 1984, 3, 1718. (b) Hao, N. K.; Mavrov, M. V.; Serebryakov, E. P. IZV 1987, 2080, 2083.
27. (a) Weyerstahl, P.; Zummack, W. CB 1975, 108, 377. (b) Kulkarni, S. N.; Phadke, A. S. IJC(B) 1987, 26B, 685. (c) Thon, D.; Schneider, W. LA 1976, 2094.
28. (a) Stevens, R. V.; Lee, A. W. M. CC 1982, 102. (b) Bernardi, R.; Fuganti, C.; Grasselli, P. TL 1981, 22, 4021. (c) Redlich, H.; Schneider, B.; Hoffmann, R. W.; Geueke, K.-J. LA 1983, 393.
29. (a) Townsend, C. A.; Christensen, S. B.; Davis, S. G. JCS(P1) 1988, 839. (b) Ryckman, D. M.; Stevens, R. V. JACS 1987, 109, 4940.
30. (a) Ramón, D. J.; Yus, M. JOC 1991, 56, 3825. (b) Yus, M.; Ramón, D. J. CC 1991, 398. (c) Verner, E. J.; Cohen, T. JACS 1992, 114, 375.
31. (a) Stetter, H.; Mertens, A. CB 1981, 114, 2479. (b) Joshi, N. N.; Mamdapur, V. R.; Chadha, M. S. JCS(P1) 1983, 2963. (c) Cooper, G. F.; Van Horn, A. R. TL 1981, 22, 1479.
32. (a) Velluz, L.; Nominé, G.; Amiard, G.; Torelli, V.; Cerede, J. CR(C) 1963, 257, 3086. (b) Bucourt, R.; Pietrasanta, Y.; Pucci, B.; Rousselou, J. C.; Vignau, M. T 1975, 31, 3041.
33. Corey, E. J.; Balanson, R. D. JACS 1974, 96, 6516.
34. (a) Courtois, G.; Miginiac, P. BSF(2) 1983, 148. (b) Ireland, R. E.; Brown, F. R., Jr. JOC 1980, 45, 1868. (c) JCS(D) 1974, 1769. (d) Matteson, D. S.; Sadhu, K. M.; Peterson, M. L. JACS 1986, 108, 810.
35. (a) Fujisawa, T.; Sato, T.; Itoh, T. CL 1982, 219. (b) Villiéras, J.; Rambaud, M.; Graff, M. SC 1985, 15, 569. (c) Kal'yan, Yu. B.; Krimer, M. Z.; Smit, V. A.; Moiseenkov, A. M.; Lutsenko, A. I. IZV 1985, 2082.
36. (a) Audin, P.; Doutheau, A.; Goré, J. BSF(2) 1984, 297. (b) Delair, T.; Doutheau, A.; Goré, J. BSF 1988, 125.
37. (a) Crombie, L.; Hemesley, P.; Pattenden, G. JCS(C) 1969, 1016. (b) Salinaro, R. F.; Berson, J. A. JACS 1982, 104, 2228. (c) Kumadaki, I.; Tamura, M.; Ando, A.; Nagai, T.; Koyama, M.; Miki, T. CPB 1988, 36, 515.

Anthony A. Ponaras

The Catholic University of America, Washington, DC, USA

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