Methyl Glyoxylate

(1; R = Me)

[922-68-9]  · C3H4O3  · Methyl Glyoxylate  · (MW 88.07) (2; R = Et)

[924-44-7]  · C4H6O3  · Ethyl Glyoxylate  · (MW 102.10) (3; R = n-Bu)

[6295-06-3]  · C6H10O3  · Butyl Glyoxylate  · (MW 130.16) (4; R = PhCH2)

[52709-42-9]  · C9H8O3  · Benzyl Glyoxylate  · (MW 164.17) (5; R = i-Pr)

[924-53-8]  · C5H8O3  · Isopropyl Glyoxylate  · (MW 116.13) (6; R = phenylmenthyl)

[129444-92-4]  · C18H24O3  · 8-Phenylmenthyl Glyoxylate  · (MW 288.42)

(two-carbon synthon utilized in electrocyclic processes (Diels-Alder reaction1, ene reactions2), various condensations (Mannich,3 aldol,4 Wittig,5 Prins,6 acyloin7), carbinolamine formation,8 and Friedel-Crafts reactions9)

Alternate Name: methyl oxoacetate.

Physical Data: (1) bp 45-50 °C/29 mmHg. (2) bp 49 °C/35 mmHg. (3) mp 46-48 °C; bp 55 °C/14 mmHg. (4) bp 130-132 °C/25 mmHg. (5) bp 34-36 °C/18 mmHg. (6) bp 135-140 °C/0.3 mmHg.

Solubility: sol most organic solvents, e.g. ether, CH2Cl2, THF, acetone, etc. (1) sol H2O (as monohydrate).

Form Supplied in: prepare fresh before use for optimum results. Drying: distill from P2O5.10b

Preparative Methods: efficient methods include oxidative cleavage of tartrate diesters, ozonolysis of maleate/fumarate derivatives, exchange reaction between appropriate dialkoxyacetate and glyoxylic acid, and NaOAc-catalyzed elimination of nitrite ion from nitrate esters.10

Purification: distillation of methyl glyoxylate monohydrate through a 10-cm Vigreux column.

Handling, Storage, and Precautions: store under N2 in a refrigerator due to their tendency to form a monohydrate and/or polymerize.

Ene Reactions.

Thermal ene reactions of glyoxylate esters with alkenes (cyclohexene, 1-alkenes, b-pinene and isobutene) occur at 150 °C, whereas the Lewis acid (AlCl3, SnCl4, FeCl3) catalyzed ene reactions proceed at a lower temperature (25-45 °C).11 The endo/exo selectivity of the thermal and Iron(III) Chloride-catalyzed ene reactions of methyl glyoxylate with cis- and trans-2-butene, cyclohexene, 2-methyl-2-butene and 1-methylcyclohexene has been well studied. With cis-2-butene at 200 °C, a 7.4:1 mixture of endo/exo adducts is obtained. Similar reaction with trans-2-butene produced a 1:0.57 mixture of endo/exo adducts (eq 1). With cyclohexene and FeCl3 catalyst, a 4.4:1 mixture of endo/exo adduct is obtained.12 Extensive cis-trans isomerization of the double bond in the substrate under the reaction conditions, as well as contamination of halogen adducts in the products, point to a stepwise cationic mechanism for the Lewis acid-catalyzed glyoxylate-ene reactions.13

The reaction course of vinylsilane with glyoxylate, on the other hand, depends on the geometry of the vinylsilane and the Lewis acid employed.14 Tin(IV) Chloride-catalyzed reaction of trans-vinylsilane produces the ene adduct; that of the cis-vinylsilane produces both the ene adduct and a silicon substitution product. When Titanium(IV) Chloride was substituted for SnCl4, the cis isomer underwent substitution to the exclusion of ene reaction (eq 2).

When the alkene bears a silyl substituent, the glyoxylate-ene reaction produces only a single regioisomer, the vinylsilane (eq 3).15 Allylic ethers with a wide range of protecting groups also produce single regioisomers via glyoxylate-ene reactions (eq 4).16 Excellent stereo- and regiocontrol are obtained with a 1,2-unsymmetrically disubstituted allylic component, producing exclusively the anti ester, which serves as a synthetic precursor for oxetanocin A (eq 5).17

By appropriate choice of the Lewis acid, the glyoxylate-ene reactions have been shown to proceed with a high level of either syn or anti diastereoselection, irrespective of the ene geometry (eq 6).18b The regio- and stereoselective glyoxylate-ene reactions have been exploited in the syntheses of brassinosteroids,18b avenaciolide,18 tetrahydrofuranyl units of polyether antibiotics (eq 7),19 and highly functionalized unsaturated amino acids (eq 8).20

A high level of asymmetric induction (>99%) can be obtained in the glyoxylate-ene reaction with chiral glyoxylate esters derived from cyclohexyl-based chiral auxiliaries (eq 9).21

A chiral titanium complex prepared in situ from (i-PrO)2TiX2 (X = Cl or Br) and (R)- or (S)-binaphthol in the presence of molecular sieves (MS 4Å) has been shown to be a catalyst for an efficient asymmetric glyoxylate-ene reaction (eq 10).22 The catalytic glyoxylate-ene reaction has been extended to vinyl sulfides, providing a high level of enantioface selection (>99% ee) along with high anti diastereoselectivity (eq 11).23

The catalytic ene technology has been utilized in the asymmetric synthesis of functionalized carbocyclic building blocks,24 a 1a,25-(OH)2-vitamin D3 synthon,25 as well as in asymmetric desymmetrization of prochiral bis-allylic silyl ethers (eq 12).26

In asymmetric ene reactions of racemic allylic as well as homoallylic ethers, the chiral BINOL-titanium catalyst discriminates between the two enantiomeric substrates sufficiently to provide efficient kinetic resolution.16a,2c Also, the chiral titanium complex derived from partially resolved BINOL is found to exhibit a remarkable level of asymmetric amplification, wherein the enantiomeric excess of the product significantly exceeds that of the chiral mediator employed.27

Cycloaddition Reactions.

[4 + 2] Cycloadditions of various alkoxy-1,3-butadiene derivatives with alkyl glyoxylates, under thermal as well as Lewis acid-catalyzed conditions, afford the corresponding dihydropyran derivatives, which are important intermediates in the total synthesis of monosaccharides and d-lactones (eq 13).28 These cycloadditions are facilitated by high pressure and microwave radiation.29

The chiral BINOL-titanium complex (eq 10) is also an effective catalyst for the hetero Diels-Alder reaction between methyl glyoxylate and 1-methoxy-1,3-butadiene, providing the cis adduct in 96% ee (eq 14). Similar cycloaddition of methyl glyoxylate and 1-methoxy-1,3-pentadiene simultaneously produces three stereogenic centers with high selectivity (eq 15).30

Organometallic Addition.

The reaction of 2-butenylstannanes with glyoxylate esters is syn selective, whereas the anti isomer is preferentially produced via the corresponding 9-BBN derivative. The selectivity increases with increasing steric bulk of the ester group (eq 16).31

Asymmetric addition of various organometallic reagents (M = Mg, Zn, Sn) to chiral 8-phenylmenthyl glyoxylate produces the corresponding a-hydroxy esters in high (>99%) enantiomeric excesses.32

Aromatic Substitution.

Ortho-hydroxyalkylation of phenols (via complexes of metal phenolates) with chiral glyoxylates produces the corresponding ortho-hydroxymandelic ester in high diastereomeric purity (eq 17).33

Glyoxylate as Nucleophile.

The two-carbon acyl anion equivalent derived from a glyoxylate ester acetal has been utilized for the preparation of novel heterocyclic a-oxoacetic acid esters (eq 18).34

Cross Coupling.

Reductive cross-coupling reactions of glyoxylate esters with carbonyl compounds in the presence of low-valent titanium compounds produce the corresponding a,b-dihydroxy carboxylates (eq 19).35

The glyoxylate esters have been utilized as valuable synthetic intermediates in the syntheses of actinolbin,36 oxacyclic carbocyclic esters,37 tetrahydro-4H-furoazepines,38 and (±)-naphthyridinomycin.39 A chiral synthesis of Pravastatin®, an important HMG-CoA reductase inhibitor, utilizes desymmetrization of 1-methyl-4-methylenecyclohexane by a catalytic asymmetric ene reaction, which provides the initial asymmetric framework (eq 20).26b

a-Imino esters derived from glyoxylate esters are valuable synthetic intermediates and act as enophiles40 and/or dienophiles41 to produce nonproteinogenic a-amino acids,42 b-lactams,43 an anti-Bredt lactam,44 b,g-alkynylglycine derivatives,45 and proline analogs.46

Related Reagents.

Glyoxal Diethyl Acetal; Ethyl Diethoxyacetate; Glyoxal; Glyoxylic Acid; Glyoxylic Acid Diethyl Dithioacetal; 8-Phenylmenthyl Glyoxylate; Tin(IV) Chloride; Titanium(IV) Chloride.

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Apurba Bhattacharya

Hoechst Celanese Corporation, Corpus Christi, TX, USA

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