Methyl 5-Methoxy-3-oxopentanoate

[62462-05-9]  · C7H12O4  · Methyl 5-Methoxy-3-oxopentanoate  · (MW 160.19)

(precursor to the annulating agent, Nazarov's reagent;1 can function as an annulating agent under acidic reaction conditions2)

Physical Data: bp 75-76 °C/0.5 mmHg.

Analysis of Reagent Purity: IR, NMR.3

Preparative Methods: see below.

General Discussion.

Methyl 5-methoxy-3-oxopentanoate was first synthesized by Nazarov1 and co-workers in 1953 utilizing the Hunsdiecker cleavage. Several modern methods have been reported for preparation of this compound. Heathcock2 and co-workers based their synthesis of the ethyl 5-ethoxy analog on a reaction developed by Ireland.4 The magnesium enolate of ethyl hydrogen malonate is reacted with b-ethoxypropionyl chloride followed by decarboxylation (eq 1). The title compound was also prepared in this manner.5

Trost6 prepared methyl 5-phenylthio-3-oxopentanoate by alkylation of the dianion of methyl acetoacetate (eq 2). In this case, iodomethyl phenyl sulfide must be prepared from thioanisole and sulfuryl chloride. The resulting Chloromethyl Phenyl Sulfide is then treated with Sodium Iodide in acetone.

Methyl 5-methoxy-3-oxopentanoate has also been prepared using Chloromethyl Methyl Ether (R2 = H) as the alkylating agent (eq 3).7 Compounds with R1 = R2 = alkyl groups were reported also.

An alternative preparation of methyl 5-methoxy-3-oxopentanoate involves a Friedel-Crafts reaction,3 as shown in eqs 4 and 5.

A novel Wittig-type reaction8 has also been used to prepare 5-alkoxy-3-oxopentanoate esters (eq 6). The advantage here is the flexibility of the alkoxy and ester groups.

Methyl 5-methoxy-3-oxopentanoate has been used in two principal areas. The first is to prepare and isolate Methyl 3-Oxo-4-pentenoate (Nazarov's reagent),2 a now well-known annulating agent. Methanol is eliminated under acidic conditions to give the Michael acceptor (eq 7). The methanol elimination is sometimes difficult and isolation of Nazarov's reagent can be problematic due to rapid polymerization.

In the 5-thiophenoxy compound (eq 2), elimination and isolation are reported to be facile processes (eq 8).6

Heathcock2 circumvented the isolation difficulties of Nazarov's reagent by reaction of ethyl 5-ethoxy-3-oxopentanoate under acid catalysis in the presence of the nucleophile. Nazarov's reagent is generated in situ and the annulation occurs smoothly (eq 9). Several groups have utilized this method in synthesis.5

Related Reagents.

t-Butyl (E)-3-Oxo-4-hexenoate; Chloromethyl Phenyl Sulfide; 1,3-Cyclohexanedione; Ethyl Acetoacetate; Methyl 6-Oxo-1-cyclohexenecarboxylate; Methyl 3-Oxo-4-pentenoate; Methyl Vinyl Ketone.

1. Nazarov, I. N.; Zav'yalov, S. I. ZOB 1953, 23, 1703. Akhrem, A. A.; Chernov, Yu. G. ZOR 1987, 23, 288.
2. Ellis, J. E.; Dutcher, J. S.; Heathcock, C. H. SC 1974, 4, 71.
3. Wakselman, C.; Molines, H. S 1979, 622.
4. Ireland, R. E.; Marshall, J. A. JACS 1959, 81, 2907.
5. Welch, S. C.; Hagan, C. P.; Kim, J. H.; Chu, P. S. JOC 1977, 42, 2879.
6. Trost, B. M.; Kunz, R. A. JOC 1974, 39, 2648.
7. Sum, P.-E.; Weiler, L. CC 1977, 91.
8. Sanchez, I. H.; Larraza, M. I.; Breña, F. K.; Crúz, A.; Sotelo, O.; Flores, H. J. SC 1986, 16, 299.

Regina Zibuck

Wayne State University, Detroit, MI, USA

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