(1; R1 = R2 = H)

[7119-27-9]  · C4H5ClO  · (E)-4-Chloro-3-buten-2-one  · (MW 104.52) (2; R1 = Me, R2 = H)

[57982-323-8]  · C5H7ClO  · (E)-1-Chloro-1-penten-3-one  · (MW 118.56) (3; R1 = H, R2 = Me)

[105-32-8]  · C5H7ClO  · (E)-4-Chloro-3-penten-2-one  · (MW 118.56)

(ketovinylation reagent which reacts with a variety of nucleophiles; used as a methyl vinyl ketone equivalent under aprotic conditions; precursor to dienol borinates)

Alternate Name: 2-chlorovinyl methyl ketone.

Physical Data: (1) bp 21 °C/21 mmHg; d 1.130 g cm-3;2a (2) bp 38-40 °C/11 mmHg; (3) bp 43-45 °C/14 mmHg; d 1.076 g cm-3.

Solubility: insol water; sol most organic solvents.

Preparative Method: from acetylene and acetyl chloride catalyzed by aluminum chloride.2

Purification: distillation in vacuo.

Handling, Storage, and Precautions: the chloro enone is lachrymatory and corrosive to the skin. Therefore handling with gloves in a fume hood is essential. The compound has limited stability at room temperature and should be stored under nitrogen at 4 °C or lower; it solidifies at ca. 5 °C. Under these conditions, darkening and HCl loss is minimized, enabling the chloro enone to be stored for several weeks.

Ketovinylation of Carbonyl Compounds.

(E)-4-Chloro-3-buten-2-one (1) is a vinylogous acyl chloride and as such is highly reactive towards nucleophiles. Reaction with the enolates of substituted malonic esters, b-keto esters, and 1,3-diketones leads to highly functionalized products which may be utilized in a variety of synthetic schemes.1a For example, the enolates of substituted b-keto esters undergo conjugate addition to the chloro enone followed by loss of chloride ion to give ketovinyl substituted keto esters. Treatment of these products with Hydrochloric Acid in acetic acid with heating affords substituted a-pyrones (eq 1).1a,3

The ketovinylation of enolates derived from cyclic ketones4 provides an alternative to the use of methyl vinyl ketone as an entry to 1,4-diketones required for the Robinson annulation.5 For example, (1) efficiently traps the enolate derived from the conjugate addition of lithiated (E)-butenyl(t-butyl)phenyl phosphine oxide to 2-methylcyclopentenone. Hydrogenation of the double bonds followed by aldol cyclization affords hydrindenone precursors to vitamin D in 56% overall yield and with high diastereoselectivity (eq 2).5b

Substitution with Hetero Nucleophiles.

Chloride may be replaced by SR,1c NR2, OR, C5H5N+Cl-,4 and RNH in a conjugate addition-elimination.6 In particular, (1) has been utilized extensively in synthetic approaches to the indole alkaloids in which the key step is vinylic substitution by tryptamine (eq 3).6 The coupling of substituted homoallylic amines to 4-chlorobutenone followed by intramolecular photocycloaddition affords fused cyclobutanes, which undergo retro-Mannich fragmentation to ketoimines followed by Mannich ring closure to give perhydroindoles in good yields.6b By using this methodology, synthetic routes to mesembrine6b and vindorosine6d have been achieved.

Substitution with Organometallic Reagents.

Lithium dialkylcuprates and organocopper reagents readily undergo conjugate addition to (1) with predominant retention of the double bond geometry.7 For example, the conjugate addition of bis(trimethylsilylmethyl)copperlithium to (E)-4-chloropent-3-en-2-one (2) affords the silylmethyl derivative in 51% yield (E:Z = 74:26). Irradiation at -76 °C isomerizes the product to the (Z) isomer which upon heating at 38 °C undergoes a 1,5-shift of the silyl group to give a trimethylsilyloxy-substituted butadiene, a compound of general use in Diels-Alder chemistry (eq 4).7a Normally alkenylcopper reagents are too unreactive to add to b-chloro enones. However, in the presence of 3% Tetrakis(triphenylphosphine)palladium(0) coupling with (1) proceeds with high stereoselectivity and in high yield. For example, the formation of (E,Z)-dienones is readily achieved (eq 5).7b

4-Chlorobut-3-en-2-one as a Bifunctional Reagent.

The ability to form dienol borinates while retaining the chloro functionality enables the reagent to react as a dipolar synthon. Thus treatment of the b-chloro enone (3) with Di-n-butylboryl Trifluoromethanesulfonate in the presence of Diisopropylethylamine generates the dienol borinate, which undergoes addition to aldehydes with high syn diastereoselectivity to give substituted hydroxy-b-chloro enones. These can then undergo an intramolecular conjugate addition in the presence of Trimethylsilyl Trifluoromethanesulfonate to afford dihydropyrones in good yields (eq 6).8

A route to a,b-unsaturated aldehydes has been reported in which the vinyl chloride moiety is converted into a dimethyl acetal and the carbonyl group can then react with Grignard reagents to form g-hydroxy acetals. These are then hydrolyzed and dehydrated to the unsaturated aldehydes (eq 7).2a

1. (a) Kochetkov, N. K.; Kudryashov, L. J.; Gottich, B. P. T 1961, 63. For a general discussion on vinyl substitution see: (b) Patai, S.; Rappoport, Z. In The Chemistry of Alkenes, Patai, S., Ed.; Interscience: London, 1964; Chapter 8, pp 525-546 and (c) Modena, G. ACR 1971, 4, 73. (d) Smith, A. B.; Kilényi, S. N. TL 1985, 26, 4419 and references cited.
2. (a) Price, C. C.; Pappalardo, J. A. JACS 1950, 72, 2613. (b) Benson, W. R.; Pohland, A. E. JOC 1964, 29, 385.
3. Kochetkov, N. K.; Gottich, B. P. JGU 1959, 29, 1297.
4. Hills, P. R.; McQuillin, F. J. JCS 1953, 4060.
5. (a) Dancer, R. J.; Haynes, R. K.; Loughlin, W. A.; Vonwiller, S. C. AJC 1990, 43, 1375. (b) Haynes, R. K.; Stokes, J. P.; Hambley, T. W. CC 1991, 58.
6. (a) Büchi, G.; Matsumoto, K. E.; Nishimura, H. JACS 1971, 93, 3299. Ando, M.; Büchi, G.; Ohnuma, T. JACS 1975, 97, 6880. (b) Winkler, J. D.; Muller, C. L.; Scott, R. D. JACS 1988, 110, 4831. (c) Blowers, J. W.; Brennan, J. P.; Saxton, J. E. JCS(P1) 1987, 2079. (d) Winkler, J. D.; Scott, R. D.; Williard, P. G. JACS 1990, 112, 8971.
7. (a) Casey, C. P.; Jones, C. R.; Tukada, H. JOC 1981, 46, 2089. (b) Jabri, N.; Alexakis, A.; Normant, J. F. T 1986, 42, 1369.
8. Paterson, I.; Osborne, S. TL 1990, 31, 2213. Paterson, I.; Smith, J. D. JOC 1992, 57, 3261.

Richard K. Haynes

Hong Kong University of Science and Technology, Hong Kong

Simone C. Vonwiller

The University of Sydney, NSW, Australia

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