GLYOXYLIC ACID

1

Glyoxylic Acid

CHO

CO

2

H

[298-12-4]

C

2

H

2

O

3

(MW 74.04)

InChI = 1/C2H2O3/c3-1-2(4)5/h1H,(H,4,5)/f/h4H
InChIKey = HHLFWLYXYJOTON-JLSKMEETCL

(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); pK

a

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 Precaution:

corrosive and hygroscopic.

Mannich and Related Condensations.

Glyoxylic acid (1)

has been extensively used in the Pictet–Spengler reaction to
synthesize various β-carboline derivatives from the corresponding
tryptamines (eq 1).

2

Reaction of glyoxylic acid and Hydroxyl-

amine

in water at pH 5 with excess LiBH

3

CN at rt affords

α

-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

CHO

CO

2

H

BnO

N
H

CO

2

Et

NH

2

BnO

N
H

CO

2

Et

N

(1)

1.

(1)

toluene, reflux
2. xylenes, Pd/C, reflux

CHO

CO

2

H

LiBH

3

CN (excess)

HO

H
N

CO

2

H

(1)

NH

2

OH, H

2

O

(2)

CHO

CO

2

H

OH

OMe

HO

OMe

CO

2

H

OH

(1)

NaOH (aq)

(3)

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 ke-

tones and aldehydes with (1) in acetic acid and hydrochloric acid
at rt results in transthioacetalization and liberates the carbonyl
compounds (eq 6).

8

CHO

CO

2

H

(4)

S

(1)

S

HO

2

C

H
N

CO

2

Et

2.

1. H

2

NCO

2

Et

CHO

CO

2

H

(5)

RNH

2

, Fe(CO)

5

R

H
N

CO

2

H

(1)

R = Me, Bu, Ph, PhCH

2

1N KOH, EtOH, CO, rt

CHO

CO

2

H

S

S

R

1

R

2

O

R

2

R

1

(1)

AcOH, HCl, rt

(6)

R

1

, R

2

= –(CH

2

)

5

–, Ph, H

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

Reac-

tion 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

CHO

CO

2

H

(7)

O

O

NO

2

O

O

NO

2

HO

CO

2

H

(1)

2N NaOH, EtOH, 20 °C

CHO

CO

2

Bu

N

O

CO

2

Bu

O

(2)

1.

cyclohexane, reflux

(8)

2. 50% HCl, rt

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

CHO

CO

2

Me

N

O

CO

2

Me

CO

2

Me

(3)

DMSO, 90 °C

(9)

proline

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 diene

13a

or Cohen diene,

13b

to furnish the

corresponding tetrahydropyridines.

12

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2

GLYOXYLIC ACID

CHO

CO

2

R

1

R

N

PPh

3

O

N

O

CO

2

R

1

R

(3) R

1

= Me

(4) R

1

= Et

C

6

H

6

,

∆

(10)

R = Me, t-BuO, BnO

Methyl glyoxylate (3) itself undergoes a hetero–Diels–Alder

reaction with the Danishefsky diene in refluxing benzene. Hydro-
lysis of the resultant adduct furnishes a 1:1 mixture of stereoiso-
mers of 2-methoxy-6-methoxycarbonyl-5,6-dihydro-γ-pyrone
(eq 11).

12

Similarly, reaction of methyl glyoxylate with 1,1-

dimethoxy-3-trimethylsiloxy-1,3-butadiene,

catalyzed

by

Eu(fod)

3

in CH

2

Cl

2

at rt, regioselectively produces 2-methoxy-

6-methoxycarbonyl-5,6-dihydro-γ-pyrone which, on subsequent
hydrolysis with dilute aq HCl in refluxing benzene, produces
6-methoxycarbonyl-3-oxo-δ-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

CHO

CO

2

Me

MeO

OTMS

O

O

OMe

CO

2

Me

(3)

1.

(11)

C

6

H

6

, reflux

2. 0.1N HCl, THF

CHO

CO

2

Me

OMe

MeO

OTMS

O

O

OMe

CO

2

Me

O

O

O

CO

2

Me

(3)

Eu(fod)

3

CH

2

Cl

2

, rt

(12)

dil HCl

benzene

reflux

CHO

CO

2

Bu

OEt

O

EtO

CO

2

Bu

(2)

60 °C

(13)

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 com-
plex (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 α-hydroxy-γ-methyl-
4-pentenoate in high optical purity (eq 15).

17

Under similar reac-

tion conditions, methyl glyoxylate (3) reacts with the symmetrical
bis-allyl silyl ether shown in eq 16 to produce the correspond-
ing α-hydroxy ester (>99% ee) through an asymmetric catalytic
desymmetrization (eq 16).

18

CHO

CO

2

Bu

(14)

(2)

cyclohexene, SnCl

4

CO

2

Bu

OH

CHO

CO

2

Me

CO

2

Me

OH

(i-PrO)

2

TiCl

2

(R)-BINOL

molecular sieves (4 Å)

CH

2

Cl

2

95% ee

(3)

(15)

CHO

CO

2

Me

O

Si(Me

2

)

O

CO

2

Me

OH

Si(Me

2

)

(i-PrO)

2

TiCl

2

(R)-BINOL

molecular sieves (4 Å)

CH

2

Cl

2

, 0 °C

99% ee

(3)

(16)

Reaction of methyl or ethyl glyoxylate with (S)-4-benzyl-

oxypent-(2E)-2-enyl(tributyl)stannane in the presence of SnCl

4

at

−78

◦

C produces (1R,5S,3Z)-5-benzyloxy-1-methoxycarbonyl-

hex-3-en-1-ol with excellent diastereoselectivity (eq 17).

19

Ethyl

glyoxylate (4)u undergoes a [3 + 2] cycloaddition with 5-
ethoxy-2-phenyloxazole in the presence of a Lewis acid cat-
alyst (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 SnCl

4

reverses the selectivity and yields the same mixture in a

15:85 ratio (eq 18).

20

CHO

CO

2

Me

SnBu

3

OCH

2

Ph

PhCH

2

O

CO

2

Me

OH

SnCl

4

, –78 °C

(3)

(17)

CHO

CO

2

Et

N

O

Ph

OEt

N

O

Ph

CO

2

Et

CO

2

Et

N

O

Ph

CO

2

Et

CO

2

Et

acetonitrile

Lewis acid (cat)

(4)

(18)

+

TiCl

4

, Ti(OR)

4

(1:1)

SnCl

4

84:16
15:85

The imine derived from methyl glyoxylate and di-p-anisyl-

methylamine (DAM-NH

2

)

21

reacts with ketene (generated in situ

from the reaction of the corresponding alkanoyl chloride and tri-
ethylamine in refluxing hexane, benzene or methylene chloride)
to afford the corresponding cis-4-methoxycarbonyl-β-lactams as
single isomers (eq 19).

22

HC

CO

2

R

(19)

N DAM

R

1

O

Cl

N

O

DAM

CO

2

R

R

1

Et

3

N,

∆

CH

2

Cl

2

or hexane or PhH

R

1

= Me, Et, i-Pr, Bn, Ph

Related Reagents.

Formaldehyde.

1.

Jung, M. E.; Shishido, K.; Davis, L. H., J. Org. Chem. 1982, 47, 891,
and references cited therein.

2.

Hollinshead, S. P.; Trudell, M. L.; Skolnick, P.; Cook, J. M., J. Med.
Chem. 1990

, 33, 1062. For a review on the Pictet–Spengler reaction, see

Whaley, W. M.; Govindachari, T. R., Org. React. 1951, 6, 151.

A list of General Abbreviations appears on the front Endpapers

GLYOXYLIC ACID

3

3.

Ahmad, A., Bull. Chem. Soc. Jpn. 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., Yakugaku Zasshi 1987, 107, 268 (Chem. Abstr. 1988,
108

, 21 459v).

6.

Gardner, J. P.; Jackson, B. G., Org. Prep. Proced. Int. 1987, 19, 439.

7.

Watanabe, Y.; Shim, S. C.; Mitsudo, T.; Yamashita, M.; Takegami, Y.,
Chem. Lett. 1975

, 699.

8.

Muxfeldt, H.; Unterweger, W. D.; Helmchen, G., Synthesis 1976, 694.

9.

Williams, T. M.; Crumbie, R.; Mosher, H. S., J. Org. Chem. 1985, 50,
91.

10.

Barco, A.; Benetti, S., Synthesis 1981, 199.

11.

Forte, M.; Orsini, F.; Pelizzoni, F., Gazz. Chim. Ital. 1985, 115, 569.

12.

Jung, M. E.; Shishido, K.; Light, L.; Davis, L., Tetrahedron Lett. 1981,
22

, 4607.

13.

(a) Danishefsky, S.; Kitahara, T., J. Am. Chem. Soc. 1974, 96, 7807.
(b) Cohen, T.; Ruffner, R. J.; Shull, D. W.; Fogel, E. R.; Falck, J. R., Org.
Synth. 1979

, 59, 202; Org. Synth., Coll. Vol. 1988, 6, 737.

14.

Castellino, S.; Sims, J. J., Tetrahedron Lett. 1984, 25, 2307.

15.

Huang, J.; Chen, X., Zhongshan Daxue Xuebao, Ziran Kexueban 1991,
30

, 74 (Chem. Abstr. 1992, 117, 90 083r).

16.

Klimova, E. I.; Antonova, N. D.; Arbuzov, Y. A., Zh. Org. Khim. 1969,
5

, 1345 (Chem. Abstr. 1969, 71, 112 473d).

17.

Mikami, K.; Terada, M.; Nakai, T., J. Am. Chem. Soc. 1989, 111,
1940.

18.

Mikami, K.; Narisawa, S.; Shimizu, M.; Terada, M., J. Am. Chem. Soc.
1992

, 114, 6566.

19.

McNeill, A. H.; Thomas, E. J., Tetrahedron Lett. 1990, 31, 6239.

20.

Suga, H.; Shi, X.; Fujieda, H.; Ibata, T., Tetrahedron Lett. 1991, 32, 6911.

21.

Kobayashi, Y.; Ito, Y.; Terashima, S., Bull. Chem. Soc. Jpn. 1989, 62,
3041.

22.

Palomo, C.; Aizpurua, J. M.; Ontoria, J. M.; Iturburu, M., Tetrahedron
Lett. 1992

, 33, 4823.

M. Sreenivasa Reddy & James M. Cook

University of Wisconsin–Milwaukee, Milwaukee, WI, USA

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