(1; X = Br)

[37865-96-6]  · C6H11BrO2  · 2-(2-Bromoethyl)-2-methyl-1,3-dioxolane  · (MW 195.06) (2; X = I)

[53750-51-9]  · C6H11IO2  · 2-(2-Iodoethyl)-2-methyl-1,3-dioxolane  · (MW 242.06) (3; X = Cl)

[57398-28-4]  · C6H11ClO2  · 2-(2-Chloroethyl)-2-methyl-1,3-dioxolane  · (MW 150.60)

(methyl vinyl ketone equivalent; alkylating agents for attaching a 3-ketobutyl group to various nucleophiles; the derived organometallic reagents attach this group to electrophilic centers such as carbonyl groups; major use in the synthesis of monoprotected 1,4-, 1,5-, and 1,6-diketones and related 1,n-difunctional compounds)

Physical Data: X = Cl: bp 40-43 °C/1 mmHg; 73-74 °C/14 mmHg. X = Br: bp 42-46 °C/0.4 mmHg; 64-68 °C/9 mmHg; 84-88 °C/12 mmHg, 88-94 °C/27 mmHg. X = I: decomposes on distillation.

Preparative Methods: X = Br or I: addition of methyl vinyl ketone to a two-phase mixture of benzene and conc aq HX, followed by drying of the benzene phase, addition of ethylene glycol, and removal of water with a Dean-Stark trap.1b,2 X = Cl: acetalization of 4-chloro-2-butanone with ethylene glycol;3 the chloro ketone was made by acylation of ethylene4 but, presumably, can also be made as above. Other preparations of these and related 4-halo-2-butanone acetals have been reported.5

Purification: X = Cl or Br: vacuum distillation from a trace of sodium bicarbonate; X = I: filter through a small plug of alumina; the acetal should not be distilled.

Handling, Storage, and Precautions: even purified samples contain some b-halo ketone which slowly loses HX, catalyzing further decomposition. Store at <=0 °C.

Electrophilic 3-Ketobutyl Reagent.

Attachment of a 3-ketoalkyl chain to the a-position of a preexisting ketone gives a 1,5-diketone which, upon treatment with base, undergoes aldol condensation to give a 2-cyclohexen-1-one.6 In the case of relatively acidic ketones (such as b-dicarbonyl compounds), chain attachment can be effected by Michael addition of their enolates (generated with a catalytic amount of base) to an alkyl vinyl ketone, generally in a protic solvent. With simple ketones, however, the high basicity of the enolate causes polymerization of the alkyl vinyl ketone. Furthermore, enolate equilibration often occurs, resulting in attachment of the chain to both the a- and a-carbons. Compounds (1) and (2) have found some use in solving these problems in the case of a,b-unsaturated ketones (eq 1).7

Reagents (1) and (2) have found little use in alkylation of unsymmetrical saturated ketones, presumably because they are insufficiently electrophilic to trap regiospecifically generated enolates. The high nucleophilicity of metallated enamines8 and hydrazones,9 along with the possibility for controlling the site of anion formation,10 may extend the utility of b-haloacetals as annulating agents.11 Reagents for bis-annulation have been prepared by alkylating acyclic carbonyl compounds with (1).12 The variation in eq 2 exploits the synthetic equivalence of 2-alkylpyridines and 2-cyclohexen-1-ones.13

Alkylation of the anions of a-arylnitriles with (1) and (2), followed by Diisobutylaluminum Hydride reduction leads to 5,5-ethylenedioxy aldehydes which have been cyclized to (spiro) 4,4-disubstituted 2-cyclohexen-1-ones.14 A related approach to spiro compounds involves alkylation of a lactone with (2).15

1,4-Diketones, useful as precursors of 2-cyclopenten-1-ones, furans, and other heterocycles, have been prepared by alkylation of terminal acetylides with (1) followed by regioselective hydration.16 Alternatively, 1,4-diketones can be made by alkylation of a-tosyl isocyanide carbanions with (1) followed by hydrolysis;17 both strategies have been used to make cis-jasmone. Presumably the pairing of (1) with other acyl anion equivalents18 represents a general approach to differentially protected 1,4-diketones.

A variety of very basic carbanions have been alkylated with (1) and (2), including sulfoxide and sulfone anions,19 dianions from b-dicarbonyl compounds5d,i,12,20 and b-keto sulfoxides,21 and carboxylic acid dianions.22 Alkylation of allylic carbanions23 with (1) or (2) has been used in syntheses of bridged dioxabicyclo[3.2.1]octanes5d,i,23b,c including (1S,5R)-frontalin (14) (eq 3).23c

Nucleophilic 3-Ketobutyl Reagent.

Addition, at 25 °C, of a THF solution of (1) (containing 1,2-Dibromoethane as an entraining agent) to excess Magnesium gives the Grignard reagent (15);24a ultrasonication is beneficial.25 Reagent (15) reacts with electrophiles very slowly, presumably due to internal coordination of magnesium by the dioxolane ring. Its reaction with cyclohexanones or even aldehydes (used in syntheses of several natural products)26 typically requires several hours at 25 °C. The lithium reagent from (1), made using t-Butyllithium in THF-Et2O-pentane at -95 °C, is more reactive than (15), and gives 1,2-addition to a hindered a,b-unsaturated ketone within 1 h at 25 °C.27 For use with cyclopentanones or aromatic ketones, (15) is prepared in benzene-THF (2:1); even in this solvent, complete consumption of 6-methoxy-1-tetralone required 4 h. An a-oxo group was then introduced, giving (17),24a,24d a precursor of (18), previously prepared28 by Robinson annulation of the relatively inaccessible 6-methoxy-2-tetralone (eq 4). A more direct procedure was devised where the a-oxygen function is present before attachment of the ketobutyl group. Thus, for example, treatment of 2-benzoyloxycyclohexanone with (15) gave (21) directly,24b presumably via hydride shift24c in (20) (cf. the Serini reaction).29 These reactions are examples of annulations in which a 3-ketobutyl unit is attached to a ketone at the carbonyl carbon, rather than next to it (eq 5).

Several approaches to terpenes employ acid-catalyzed rearrangements in adducts between (15) and bicyclic alkoxyketones (eq 6).25a,30

Ketones result from the reaction of (15) with acid chlorides at low temperatures;24a this idea is used in several syntheses of cis-jasmone (eq 7).5e,31

In the presence of copper(I) salts, (15) adds in conjugate fashion to a,b-unsaturated ketones32a and a,b-unsaturated lactones,32b leading to monoprotected 1,6-dicarbonyl compounds. This reaction has been used for annulation of a five-membered ring onto a preexisting ring (eq 8).32a

The Grignard reagent, in the presence of copper salts, has been used for nucleophilic substitution reactions with halides and sulfonate esters,33 epoxides,34 and b-lactones (alkyl-oxygen fission).35

Wittig reaction using the triphenylphosphonium salt from (1) (best prepared at 15 kbar pressure)36 is employed in two syntheses of optically active brevicomins from carbohydrate-derived aldehydes.37 The analogous diphenylphosphinyl carbanion also has synthetic utility for Wittig-Horner reactions.38

Related Reagents.

1-Bromo-2-iodo-2-butene; 1,3-Dichloro-2-butene; Methyl Vinyl Ketone; 3-Trimethylsilyl-3-buten-2-one.

1. For short reviews of the preparation and uses of b-haloacetals, see (a) Stowell, J. C.; Keith, D. R.; King, B. T. OS 1984, 62, 140. (b) Hsung, R. P. SC 1990, 20, 1175.
2. Stowell, J. C.; King, B. T.; Hauck, H. F., Jr. JOC 1983, 48, 5381.
3. Zebovitz, T. C.; Heck, R. F. JOC 1977, 42, 3907.
4. (a) Sondheimer, F.; Woodward, R. B. JACS 1953, 75, 5438. (b) Hajos, Z. G.; Micheli, R. A.; Parrish, D. R.; Oliveto, E. P. JOC 1967, 32, 3008.
5. (a) see ref 1a. (b) Willimann, L.; Schinz, H. HCA 1949, 32, 2151. (c) Borch, R. Ph. D. Dissertation, Columbia University, New York, 1965, p. 17. (d) Gerlach, H.; Künzler, P. HCA 1977, 60, 638. (e) Sato, T.; Kawara, T.; Sakata, K.; Fujisawa, T. BCJ 1981, 54, 505. (f) Kametani, T.; Suzuki, Y.; Furuyama, H.; Honda, T. JOC 1983, 48, 31. (g) Larson, G. L.; Klesse, R. JOC 1985, 50, 3627. (h) Rigby, J. H.; Wilson, J. Z. JOC 1987, 52, 34. (i) Ohta, H.; Ozaki, K.; Tsuchihashi, G. CL 1987, 225.
6. For reviews of annulation reactions, see (a) Jung, M. E. T 1976, 32, 3. (b) Gawley, R. E. S 1976, 777.
7. (a) Green, M. J.; Abraham, N. A.; Fleischer, E. B.; Case, J.; Fried, J. CC 1970, 234. (b) Rosen, P. Ph. D. Dissertation, Columbia University, New York, 1962. (c) Zomer, G.; Wynberg, H.; Drayer, N. M. Steroids 1984, 44, 283. (d) Sucrow, W.; Brinkkötter, G. CB 1985, 118, 4330 and previous papers. (e) See Ref. 4b. for analogous use of 2-(2-bromoethyl)-2-ethyl-1,3-dioxolane.
8. (a) The bromomagnesium salt of cyclohexanone N-cyclohexylimine reacts with (1) to give, ultimately, D1,9-octalone in 66% overall yield: Stork, G.; Dowd, S. R. JACS 1963, 85, 2178. (b) The lithium salt of crotonaldehyde N-cyclohexylimine reacts with a similar b-haloacetal in 45% yield: see Ref. 5f.
9. The lithium salt of acetone dimethylhydrazone reacts with (1) or (2) to give 2,6-heptanedione 2-acetal 6-dimethylhydrazone in high yield: (a) Petersen, J. S.; Töteberg-Kanlan, S.; Rapoport, H. JOC 1984, 49, 2948. (b) Mitra, R. B.; Reddy, G. B. S 1989, 694.
10. (a) Whitesell, J. K.; Whitesell, M. A. S 1983, 517. (b) Gawley, R. E.; Termine, E. J.; Aube, J. TL 1980, 21, 3115. (c) Wender, P. A.; Eissenstat, M. A. JACS 1978, 100, 292.
11. It should be pointed out that cuprate reagents derived from lithiated dimethylhydrazones undergo conjugate addition to methyl vinyl ketone: Corey, E. J.; Enders, D. TL 1976, 3.
12. (a) Poirier, J.-M.; Hennequin, L. T 1989, 45, 4191. (b) Zoretic, P. A.; Yu, B.-C.; Biggers, M. S.; Caspar, M. L. JOC 1990, 55, 3954.
13. Stevens, R. V.; Canary, J. W. JOC 1990, 55, 2237.
14. (a) Crombie, L.; Tuchinda, P.; Powell, M. J. JCS(P1) 1982, 1477. (b) Sánchez, H.; Lemini, C.; Hernández, C.; Larraza, M. I.; Flores, H. J.; Garcia, R.; Machin, G. SC 1983, 13, 43. (c) A 2-cyano-6-oxazolopyrrolidine has also been alkylated with (1): Arseniyadis, S.; Huang, P. Q.; Husson, H.-P. TL 1988, 29, 1391.
15. Solas, D.; Wolinsky, J. JOC 1983, 48, 670.
16. (a) Stork, G.; Borch, R. F. JACS 1964, 86, 936. (b) See also: Mulholland, R. L., Jr.; Chamberlin, A. R. JOC 1988, 53, 1082.
17. Rama Rao, A. V.; Deshpande, V. H.; Pulla Reddy, S. SC 1984, 14, 469.
18. (a) Hase, T. A.; Koskimies, J. K. Aldrichim. Acta 1981, 14, 73. (b) Hase, T. A. Umpoled Synthons; Wiley: New York, 1987.
19. (a) Trost, B. M.; Bridges, A. J. JOC 1975, 40, 2014. (b) Kinney, W. A.; Crouse, G. D.; Paquette, L. A. JOC 1983, 48, 4986.
20. (a) Flannery, R. E.; Hampton, K. G. JOC 1972, 37, 2806. (b) Berry, N. M.; Darey, M. C. P.; Harwood, L. M. S 1986, 476.
21. Avery, M. A.; Chong, W. K. M.; Jennings-White, C. JACS 1992, 114, 974.
22. (a) Meyers, A. I.; Hanreich, R.; Wanner, K. T. JACS 1985, 107, 7776. (b) Broka, C. A.; Gerlits, J. F. JOC 1988, 53, 2144.
23. (a) Beslin, P.; Dlubala, A. TL 1986, 27, 1687. (b) Tamao, K.; Nakajo, E.; Ito, Y. JOC 1987, 52, 4412. (c) Chan, T. H.; Chen, L. M.; Wang, D.; Li, L. H. CJC 1993, 71, 60.
24. (a) Ponaras, A. A. TL 1976, 3105. (b) Ponaras, A. A., Ph. D. dissertation, Columbia University, New York, 1972, p 138. (c) Treatment of 2-benzoyloxy-3-methylcyclohexanone with (15) gave 2-(3,3-ethylenedioxy)-6-methylcyclohexanone, establishing that hydride (and not alkyl) migration is involved: Stork, G.; Garcia, G. A., unpublished. (d) The neopentyl glycol acetal variant of (16) condenses with 1,2-bis(trimethylsilyloxy)cyclobutene to give, after acid cyclization, an estrone precursor: Burnell, D. J.; Wu, Y.-J. CJC 1989, 67, 816.
25. (a) Uyehara, T.; Yamada, J.; Furuta, T.; Kato, T.; Yamamoto, Y. T 1987, 43, 5605. (b) Hagiwara, H.; Uda, H. JCS(P1) 1991, 1803.
26. (a) Sibi, M. P.; Altintas, N.; Snieckus, V. T 1984, 40, 4593. (b) Terada, A.; Tanoue, Y.; Hatada, A.; Sakamoto, H. BCJ 1987, 60, 205. (c) Martin, S. F.; Davidsen, S. K.; Puckette, T. A. JOC 1987, 52, 1962 and previous papers. (d) Yadav, J. S.; Reddy, P. S.; Joshi, B. V. T 1988, 44, 7243. (e) Hagiwara, H.; Uda, H. JCS(P1) 1991, 1803.
27. Näf, R.; Velluz, A.; Decorzant, R.; Näf, F. TL 1991, 32, 753.
28. (a) Crowley, G. P.; Robinson, R. JCS 1938, 2001. (b) Nagata, W.; Hirai, S.; Teresawa, T.; Kikkawa, I.; Takeda, K. CPB 1961, 9, 756.
29. For pertinent references, see: Ghera, E. JOC 1970, 35, 660.
30. (a) Monti, S. A.; Chen, S.-C.; Yang, Y.-L.; Yuan, S.-S.; Bourgeois, O. P. JOC 1978, 43, 4062. (b) Kim, S. K.; Pak, C. S. JOC 1991, 56, 6829.
31. (a) Fujisawa, T.; Umezu, K.; Kawashima, M. CL 1984, 1795. (b) Fiandanese, V.; Marchese, G.; Naso, F. TL 1988, 29, 3587.
32. (a) Paquette, L. A.; Galemmo, R. A., Jr.; Caille, J.-C.; Valpey, R. S. JOC 1986, 51, 686. (b) Paquette, L. A.; Kang, H.-J. JACS 1991, 113, 2610.
33. (a) Snider, B. B.; Cartaya-Mario, C. P. JOC 1984, 49, 153. (b) Gras, J.-L.; Bertrand, M. TL 1979, 4549. (c) Nguyen Cong Hao; Mavrov, M. V.; Serebryakov, E. P. IZV 1987, 2080.
34. (a) Hatakeyama, S.; Sakurai, K.; Takano, S. CC 1985, 1759. (b) Gras, J.-L. JOC 1981, 46, 3738. (c) See also: Moon, S.; Stuhmiller, L. M.; Chadha, R. K.; McMorris, T. C. T 1990, 46, 2287.
35. Fujisawa, T.; Sato, T.; Kawara, T.; Noda, A. TL 1982, 23, 3193.
36. (a) Dauben, W. G.; Gerdes, J. M.; Look, G. C. S 1986, 532. (b) Dauben, W. G.; Gerdes, J. M.; Bunce, R. A. JOC 1984, 49, 4293.
37. (a) Yadav, J. S.; Vidyasagar, V.; Reddy, P. S. Carbohydr. Res. 1986, 156, 236. (b) Redlich, H.; Bruns, W.; Francke, W.; Schurig, V.; Payne, T. L.; Vité, J. P. T 1987, 43, 2029.
38. Bell, A.; Davidson, A. H.; Earnshaw, C.; Norrish, H. K.; Torr, R. S.; Trowbridge, D. B.; Warren, S. JCS(P1) 1983, 2879.

Anthony A. Ponaras

The Catholic University of America, Washington, DC, USA

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