4-Methoxy-3-buten-2-one1

[51731-17-0]  · C5H8O2  · 4-Methoxy-3-buten-2-one  · (MW 100.13)

(versatile four-carbon synthon; precursor to the Danishefsky diene;2 Diels-Alder dienophile;3 dipolarophile;4 electrophilic four-carbon synthon subject to conjugate addition at C-4 followed by elimination of the methoxide anion;5 its enolate is a nucleophilic four-carbon building block6)

Physical Data: bp 200 °C/760 mmHg, bp 61-63 °C/12 mmHg; d420 0.997 g cm-3; nD20 1.469.

Solubility: sol THF, ether, acetonitrile, benzene

Form Supplied in: liquid, over 97% (GC) pure; commercially available in 10 or 50 mL units.

Analysis of Reagent Purity: GC analysis appears best; also IR;7a UV (cyclohexane) lmax 237 nm (ε 13450);7b 1H NMR (CDCl3): d 2.20 (s, 3H), 3.70 (s, 3H), 5.55 (d, 1H, J = 13.0 Hz), and 7.53 (d, 1H, J = 13.0 Hz);6a,7c,d 13C NMR (CDCl3) d 27.5, 57.6, 107.0. 163.6, 196.6.7e,f

Handling, Storage, and Precautions: may be harmful by inhalation, ingestion, or skin absorption; may cause skin and eye irritation; in addition to standard safety practice, mechanical exhaust is required.8 Do not breathe vapor. Store in refrigerator under nitrogen or argon.

Introduction.

4-Methoxy-3-buten-2-one may be regarded as a vinylogous homolog of methyl acetate and has three functional groups and one acidic site. Each of these shows characteristic reactivity.

Danishefsky Diene and Analogs.

4-Methoxy-3-buten-2-one is a valuable starting compound for the preparation of 1-methoxy-3-trimethylsilyloxy-1,3-butadiene, the Danishefsky diene (eq 1), and its equivalent.2 These dienes undergo Diels-Alder cycloaddition or cyclocondensation reactions with a variety of dienophiles (see 1-Methoxy-3-trimethylsilyloxy-1,3-butadiene).2,9 A couple of slightly modified procedures for the preparation of the Danishefsky diene have also been reported.10

Diels-Alder Dienophile and Dipolarophile.

Only a handful of examples of cycloaddition reactions involving the C=C bond of this reagent have been reported. While no reaction can be observed in the absence of a catalyst, this C=C bond undergoes a Diels-Alder reaction with cyclopentadiene in the presence of the Lewis acid Tin(IV) Chloride, providing the adduct with an endo/exo ratio of 15:1 (eq 2).3 In general, the cycloadducts are unstable due to their propensity for the elimination of methanol.

The [2 + 3] cycloaddition reaction involving the C=C bond is also reported. Thus treatment of this reagent with 2-[(trimethylsilyl)methyl]-3-(trimethylsilyl)-2-propenyl carboxylates in the presence of a catalytic amount of Tetrakis(triphenylphosphine)palladium(0) provides the cyclopentane product in a highly regioselective manner (eq 3).11 This captodative enone also undergoes an efficient, highly regioselective [2 + 3] dipolar cycloaddition reaction with acetonitrile oxide to give (after the elimination of methanol) 4-acetyl-3-methylisoxazole (eq 4).4 Interestingly, a reversal in regioselectivity is observed for the corresponding reaction with 3-buten-1-one whereby the major product upon subsequent oxidation is 5-acetyl-3-methylisoxazole.4 The 1-diazo derivative of 4-methoxy-3-buten-2-one is a versatile four-carbon building unit used for the efficient annulation of highly substituted aromatic rings (eq 5).12 The diazo ketone first undergoes photochemical Wolff rearrangement to the vinylketene, which subsequently reacts with alkoxy alkynes in a [2 + 2] cycloaddition mode; the resulting cyclobutenones proceed through a sequence of electrocyclic ring cleavage and closure, and finally aromatization through tautomerization. The product shown in eq 5 has been converted to the host defense stimulant maesanin in 67% yield by oxidation with O2 and Tetra-n-butylammonium Fluoride.12

Synthesis of b-Substituted Enones through a Conjugate Addition/Elimination Sequence.

A number of nucleophiles have been added to C-4 of 4-methoxy-3-buten-2-one; the resulting adducts rapidly eliminate methanol in the reaction medium, providing a variety of b-substituted enones as shown in eq 6.5b A recent example includes the use of lithiated diethyl prop-2-enylphosphonate as a nucleophile.13

Addition Reactions of the Enolate Derivative.

The addition of the lithium enolate of 4-methoxy-3-buten-2-one to acid chlorides followed by acid treatment of the resulting enol provides g-pyrones in good to excellent yields (eq 7).6a A similar, yet direct formation of g-pyrones has been reported which uses 2.2 equiv of the potassium enolate of 4-methoxy-3-buten-2-one for the reaction with acid chlorides followed by aqueous workup (eq 8).6b In a similar vein, the lithium enolate of this reagent adds to a Boc-protected a-amino aldehyde (eq 9). The formation of the major stereoisomer (indicated in eq 9) of the 88:12 mixture (53% combined yield) is consistent with the prediction on the basis of the Felkin-Anh transition state conformation of the aldehyde.14


1. Franke, W. K.; Kuether, J. Fette, Seifen, Anstrichm. 1980, 82, 82 (CA 1980, 93, 95 102s).
2. (a) Danishefsky, S.; Kitahara, T. JACS 1974, 96, 7807. (b) Danishefsky, S.; Kitahara, T.; Schuda, P. F. OSC 1990, 7, 312.
3. Baldwin, S. W.; Tomesch, J. C. JOC 1974, 39, 2382.
4. Chimichi, S.; Cosimelli, B. SC 1992, 22, 2909.
5. (a) Chu, J. H.; Murty, B. S. R.; Fedor, L. JACS 1976, 98, 3632. (b) Molander, G. A.; Brown, H. C. JOC 1977, 42, 3106. (c) Cho, I.-S.; Gong, L.; Muchowski, J. M. JOC 1991, 56, 7288.
6. (a) Koreeda, M.; Akagi, H. TL 1980, 21, 1197. (b) Morgan, T. A.; Ganem, B. TL 1980, 21, 2773.
7. (a) The Aldrich Library of FT-IR Spectra; Aldrich: Milwaukee, 1989; Vol. 1, p 508B. (b) Dabrowski, J.; Tencer, M. T 1976, 32, 587. (c) The Aldrich Library of NMR Spectra, Aldrich: Milwaukee, 1983; Vol. 2, p 378A. (d) Nuclear Magnetic Resonance Spectra; Sadtler Research Laboratories: Philadelphia, 1974; Vol. 30, p 19611M. (e) Sadtler Standard Carbon-13 NMR Spectra; Sadtler Research Laboratories: Philadelphia, 1983; Vol. 73, p 14430C. (f) Loots, M. J.; Weingarten, L. R.; Levin, R. H. JACS 1976, 98, 4571.
8. The Sigma-Aldrich Library of Chemical Safety Data; Aldrich: Milwaukee, 1987; Vol. 2, p 2245D.
9. (a) Danishefsky, S. ACR 1981, 14, 400. (b) Petrzilka, M.; Grayson, J. I. S 1981, 753.
10. (a) Cazeau, P.; Duboudin, F.; Moulines, F.; Babot, O.; Dunogues, J. T 1987, 43, 2089. (b) Iqbal, J.; Khan, M. A. SC 1989, 19, 515.
11. Trost, B. M.; Mignani, S. M.; Nanninga, T. N. JACS 1988, 110, 1602.
12. Danheiser, R. L.; Cha, D. D. TL 1990, 31, 1527.
13. Phillips, A. M. M. M.; Modro, T. A. JCS(P1) 1991, 1875.
14. Garner, P.; Ramakanth, S. JOC 1986, 51, 2609.

Masato Koreeda

The University of Michigan, Ann Arbor, MI, USA



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