Glyoxylic Acid

[298-12-4]  · C2H2O3  · Glyoxylic Acid  · (MW 74.04)

(formaldehyde equivalent in Mannich reaction; reagent and its esters undergo a variety of additions, condensations, and Diels-Alder reactions)

Alternate Name: glyoxalic acid; oxoacetic acid.

Physical Data: deliquescent prisms; mp 98 °C (anhydrous), 50-52 °C (monohydrate); pKa 2.32.

Solubility: sparingly sol ether, alcohol, benzene; v sol water.

Form Supplied in: crystalline solid as monohydrate [563-96-2] and in 50% aqueous solution.

Preparative Methods: glyoxylic acid is widely available, but the methyl, ethyl, and benzyl esters can be made easily from the ozonolysis of the corresponding maleate and fumarate esters.1

Purification: crystallized from water as the monohydrate.

Handling, Storage, and Precautions: corrosive and hygroscopic.

Mannich and Related Condensations.

Glyoxylic acid (1) has been extensively used in the Pictet-Spengler reaction to synthesize various b-carboline derivatives from the corresponding tryptamines (eq 1).2 Reaction of glyoxylic acid and Hydroxylamine in water at pH 5 with excess LiBH3CN at rt affords a-hydroxyaminoacetic acid (eq 2).3 The reagent reacts with an alkaline solution of o-methoxyphenol to form (R,S)-4-hydroxy-3-methoxymandelic acid (eq 3).4 On the other hand, condensation of (1) with acetophenone gives 3-benzoylacrylic acid.5

Treatment of glyoxylic acid with ethyl aminoformate followed by benzothiophene gives N-ethoxycarbonylbenzothienylglycine (eq 4) via the Mannich reaction.6 Reaction of (1) with an alkyl- or arylamine in the presence of Pentacarbonyliron in alcoholic 1N KOH, under an atmosphere of carbon monoxide followed by HCl acidification affords the corresponding N-alkyl- or arylglycines (eq 5).7 Treatment of the thioacetals of various ketones and aldehydes with (1) in acetic acid and hydrochloric acid at rt results in transthioacetalization and liberates the carbonyl compounds (eq 6).8

Glyoxylic acid, in the presence of 2N NaOH in ethanol, adds to 3-nitropropanal ethylene acetal to give 2-hydroxy-3-nitro-5-ethylenedioxypentanoic acid in quantitative yield (eq 7).9 Reaction of n-butyl glyoxylate (2) with 1-morpholinocyclopentene in refluxing cyclohexane (Dean-Stark trap), followed by cooling and hydrolysis affords butyl 2-oxocyclopentylideneacetate (eq 8).10

Treatment of methyl glyoxylate (3) with (S)-Proline in a 2:1 ratio in DMSO at 90 °C gives a diastereomeric mixture of oxapyrrolizidines (eq 9).11

Diels-Alder Reactions.

Methyl or ethyl glyoxylates react with acylaza-Wittig reagents in refluxing benzene to produce the diacylimines, as shown in eq 10.12 These are moderately reactive dienophiles for Diels-Alder reactions with various dienes, such as the Danishefsky diene13a or Cohen diene,13b to furnish the corresponding tetrahydropyridines.12

Methyl glyoxylate (3) itself undergoes a hetero-Diels-Alder reaction with the Danishefsky diene in refluxing benzene. Hydrolysis of the resultant adduct furnishes a 1:1 mixture of stereoisomers of 2-methoxy-6-methoxycarbonyl-5,6-dihydro-g-pyrone (eq 11).12 Similarly, reaction of methyl glyoxylate with 1,1-dimethoxy-3-trimethylsiloxy-1,3-butadiene, catalyzed by Eu(fod)3 in CH2Cl2 at rt, regioselectively produces 2-methoxy-6-methoxycarbonyl-5,6-dihydro-g-pyrone which, on subsequent hydrolysis with dilute aq HCl in refluxing benzene, produces 6-methoxycarbonyl-3-oxo-d-lactone (eq 12).14 Hetero-Diels-Alder reaction of n-butyl glyoxylate with 2-ethoxy-1,3-butadiene at 60 °C affords 4-ethoxy-6-butoxycarbonyl-5,6-dihydro-2H-pyran as the main adduct (eq 13).15

Butyl glyoxylate (2) undergoes an addition reaction with cyclohexene in the presence of Tin(IV) Chloride at 40-45 °C to produce butyl 2-hydroxy-2-(2-cyclohexenyl)acetate (eq 14).16 Methyl glyoxylate undergoes an asymmetric carbonyl-ene reaction with isobutene catalyzed by a chiral titanium complex (generated in situ from (R)-1,1-Bi-2,2-naphthol (BINOL) and Dichlorotitanium Diisopropoxide over molecular sieves in methylene chloride) to produce (R)-methyl a-hydroxy-g-methyl-4-pentenoate in high optical purity (eq 15).17 Under similar reaction conditions, methyl glyoxylate (3) reacts with the symmetrical bis-allyl silyl ether shown in eq 16 to produce the corresponding a-hydroxy ester (>99% ee) through an asymmetric catalytic desymmetrization (eq 16).18

Reaction of methyl or ethyl glyoxylate with (S)-4-benzyloxypent-(2E)-2-enyl(tributyl)stannane in the presence of SnCl4 at -78 °C produces (1R,5S,3Z)-5-benzyloxy-1-methoxycarbonylhex-3-en-1-ol with excellent diastereoselectivity (eq 17).19 Ethyl glyoxylate (4) undergoes a [3 + 2] cycloaddition with 5-ethoxy-2-phenyloxazole in the presence of a Lewis acid catalyst (a 1:1 mixture of Titanium(IV) Chloride and Titanium Tetraisopropoxide) to produce a mixture of cis- and trans-4,5-bis(ethoxycarbonyl)-2-oxazolines in an 84:16 ratio, whereas use of SnCl4 reverses the selectivity and yields the same mixture in a 15:85 ratio (eq 18).20

The imine derived from methyl glyoxylate and di-p-anisylmethylamine (DAM-NH2)21 reacts with ketene (generated in situ from the reaction of the corresponding alkanoyl chloride and triethylamine in refluxing hexane, benzene or methylene chloride) to afford the corresponding cis-4-methoxycarbonyl-b-lactams as single isomers (eq 19).22

Related Reagents.


1. Jung, M. E.; Shishido, K.; Davis, L. H. JOC 1982, 47, 891, and references cited therein.
2. Hollinshead, S. P.; Trudell, M. L.; Skolnick, P.; Cook, J. M. JMC 1990, 33, 1062. For a review on the Pictet-Spengler reaction, see Whaley, W. M.; Govindachari, T. R. OR 1951, 6, 151.
3. Ahmad, A. BCJ 1974, 47, 1819.
4. Fitiadi, A. J.; Schaffer, R. J. Res. Nat. Bur. Stand., Sect. A 1974, 78, 411.
5. Ozeki, K.; Ishizuka, Y.; Sawada, M.; Shimamura, H.; Ichikawa, T.; Sato, M.; Yaginuma, H. YZ 1987, 107, 268 (CA 1988, 108, 21 459v).
6. Gardner, J. P.; Jackson, B. G. OPP 1987, 19, 439.
7. Watanabe, Y.; Shim, S. C.; Mitsudo, T.; Yamashita, M.; Takegami, Y. CL 1975, 699.
8. Muxfeldt, H.; Unterweger, W. D.; Helmchen, G. S 1976, 694.
9. Williams, T. M.; Crumbie, R.; Mosher, H. S. JOC 1985, 50, 91.
10. Barco, A.; Benetti, S. S 1981, 199.
11. Forte, M.; Orsini, F.; Pelizzoni, F. G 1985, 115, 569.
12. Jung, M. E.; Shishido, K.; Light, L.; Davis, L. TL 1981, 22, 4607.
13. (a) Danishefsky, S.; Kitahara, T. JACS 1974, 96, 7807. (b) Cohen, T.; Ruffner, R. J.; Shull, D. W.; Fogel, E. R.; Falck, J. R. OS 1979, 59, 202; OSC 1988, 6, 737.
14. Castellino, S.; Sims, J. J. TL 1984, 25, 2307.
15. Huang, J.; Chen, X. Zhongshan Daxue Xuebao, Ziran Kexueban 1991, 30, 74 (CA 1992, 117, 90 083r).
16. Klimova, E. I.; Antonova, N. D.; Arbuzov, Y. A. ZOR 1969, 5, 1345 (CA 1969, 71, 112 473d).
17. Mikami, K.; Terada, M.; Nakai, T. JACS 1989, 111, 1940.
18. Mikami, K.; Narisawa, S.; Shimizu, M.; Terada, M. JACS 1992, 114, 6566.
19. McNeill, A. H.; Thomas, E. J. TL 1990, 31, 6239.
20. Suga, H.; Shi, X.; Fujieda, H.; Ibata, T. TL 1991, 32, 6911.
21. Kobayashi, Y.; Ito, Y.; Terashima, S. BCJ 1989, 62, 3041.
22. Palomo, C.; Aizpurua, J. M.; Ontoria, J. M.; Iturburu, M. TL 1992, 33, 4823.

M. Sreenivasa Reddy & James M. Cook

University of Wisconsin-Milwaukee, WI, USA

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