Synthesis of arylglyoxylic acids and their collision-induced dissociation

Article abstract of DOI:10.1080/00397910802369554

A variety of substituted arylglyoxylic acids (2a-g) were synthesized via oxidation of the corresponding aryl-methylketones (1a-e) using selenium dioxide or Friedel-Crafts acylation of phenol (3) with ethyl chlorooxoacetate and further transformations. It was found that the arylglyoxylic acids (2) undergo facile unimolecular dissociation with loss of carbon monoxide to give the corresponding arylcarboxylic acids (7) under collisionally induced mass spectrometric conditions. Copyright Taylor & Francis Group, LLC.

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Synthesis of Arylglyoxylic Acids
and Their Collision-Induced
Dissociation
Kuldeep Wadhwa a , Chengxi Yang a , Paul R. West
a , Kris C. Deming a , Sanjay R. Chemburkar a &
Rajarathnam E. Reddy a
a API Products, Manufacturing Science and
Technology, Global Pharmaceutical Operations,
Abbott Laboratories, North Chicago, Illinois, USA
Version of record first published: 07 Nov 2008.
To cite this article: Kuldeep Wadhwa, Chengxi Yang, Paul R. West, Kris C. Deming,
Sanjay R. Chemburkar & Rajarathnam E. Reddy (2008): Synthesis of Arylglyoxylic Acids
and Their Collision-Induced Dissociation, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 38:24, 4434-4444
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Synthetic Communications1, 38: 4434–4444, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802369554
Synthesis of Arylglyoxylic Acids and Their
Collision-Induced Dissociation
Kuldeep Wadhwa, Chengxi Yang, Paul R. West, Kris C. Deming,
Sanjay R. Chemburkar, and Rajarathnam E. Reddy
API Products, Manufacturing Science and Technology, Global
Pharmaceutical Operations, Abbott Laboratories, North Chicago,
Illinois, USA
Abstract: A variety of substituted arylglyoxylic acids (2aꢀg) were synthesized via
oxidation of the corresponding aryl-methylketones (1a–e) using selenium dioxide
or Friedel–Crafts acylation of phenol (3) with ethyl chlorooxoacetate and further
transformations. It was found that the arylglyoxylic acids (2) undergo facile unim-
olecular dissociation with loss of carbon monoxide to give the corresponding aryl-
carboxylic acids (7) under collisionally induced mass spectrometric conditions.
Keywords: Arylcarboxylic acids, arylglyoxylic acids, dissociation, synthesis
INTRODUCTION
Arylglyoxylic acids (2) are important structural units for a variety of
applications (e.g., the preparation of oxygenated heterocycles,[1] key
intermediates for generation of combinatorial libraries,[2] and substrates
for asymmetric synthesis of biologically active natural products.[3,4] In
addition, several natural products containing the glyoxylic acid group
have been identified with potential medical applications.[5] As a result
of the unique structural features of this functional unit, which is also
commonly known as a-keto acid or 2-oxoacetic acid, numerous studies
Received March 26, 2008.
Address correspondence to Paul R. West, API Products (Dept 04Ar, Bldg.
13), Manufacturing Science and Technology, Global Pharmaceutical
R
Operations, Abbott Laboratories, 1401 Sheridan Road, North Chicago, IL
60064-6291, USA. E-mail: rajarathnam.reddy@abbott.com
4434

Synthesis of Arylglyoxylic Acids
4435
have been carried out to understand its physico-chemical properties.[6]
Generally, the glyoxylic acids exhibit a tendency to decarboxylate and=or
or polymerize, and therefore it is recommended that they are to be stored
as metal salts or neutral solution at low temperature.[4a] Therefore, it is cri-
tical to understand the dissociation behavior of arylglyoxylic acids (2) to
utilize this class of compounds more effectively for medical and pharma-
ceutical applications. In this context, sekiguch; and coworkers have
recently described the dissociation of protonated glyoxylic acid (HCO-
CO2H) and reported that the only observed ionic product was H3Oþ, thus
indicating the loss of two carbon monoxide molecules.[7] In addition, they
have postulated the pattern and dynamics of glyoxylic acid dissociation
process. We became interested in studying the unimolecular dissociation
of arylglyoxylic acids (2) as well as understanding the effect of various sub-
stituents on the phenyl ring during the dissociation process. In this article,
we describe the synthesis of a variety of substituted arylglyoxylic acids
(2a–g) and evaluation of their collision-induced dissociation.
RESULTS AND DISCUSSION
The substituted arylglyoxylic acids (2a–e) were synthesized based on oxi-
dation of the corresponding aryl-methylketones (1a–e) using a selenium
dioxide (Scheme 1) reagent.[8] The oxidation reaction was carried out in
pyridine at an elevated temperature, and the desired products (2a–e) were
isolated by silica-gel column chromatography in excellent yield (78–99%).
Purity was also excellent as determined by analytical reverse-phase high
performance liquid chromatography (HPLC). We have devised a differ-
ent approach (Scheme 2) for the synthesis of 2-(4-hydroxy-3,5-diiodophe-
nyl)-2-oxoacetic acid (2g) because the selenium dioxide oxidation method
gave a complex mixture of products during the preparation of a similar
acid-containing chlorines at the 3- and 5-positions of the aryl ring.
Thus, arylglyoxylic acids (2f–g) were synthesized from phenol (3)
based on Friedel–Crafts acylation using ethyl chlorooxoacetate[9] and
Scheme 1. Synthesis of arylglyoxylic acids (2a–e). a) X ¼ H, Y: Cl; b) X ¼ H,
Y ¼ NO2; c) X¼Y¼OMe; d) X ¼ H, Y ¼ OPh; and e) X ¼ H, Y ¼ OPh-p-OMe.

4436
K. Wadhwa et al.
Scheme 2. Synthesis of arylglyoxylic acids (2f–g).
subsequent transformations (Scheme 2). Accordingly, the phenol (3) was
treated with anhydrous aluminum chloride and ethyl chlorooxoacetatein
nitromethane to afford the key intermediate, ethyl (4-hydroxyphenyl)-2-
oxoacetate (4), in low yields. In this acylation reaction, the corresponding
O-substituted regioisomer was also formed, as determined by HPLC and
liquid chromatography-mass spectrometry (LC-MS), which was sepa-
rated easily during the silica-gel column chromatography purification
process. The ester 4 was then hydrolyzed using lithium hydroxide in
THF–water mixture at room temperature followed by crystallization to
afford 2-(4-hydroxyphenyl)-2-oxoacetic acid (2f) in 94% yield.[10] Reac-
tion of ethyl 2-(4-hydroxyphenyl)-2-oxoacetate (4) with 3.7 equivalents
of iodine monochloride in a mixture of acetic acid and water afforded
the corresponding 3,4-diiodo ester (5) in an excellent yield (>98%).
Finally, hydrolysis of the ethyl ester (5) was achieved using potassium
hydroxide in THF–water to give 2-(4-hydroxy-3,5-diiodophenyl)-2-oxoa-
cetic acid (2g) in 74% yield.
The arylglyoxylic acids (2a–g) were analyzed on a ThermoFinnigan
LCQ DECA XP system using negative-ion atmospheric pressure
chemical ionization [APCI(-)]. The MS=MS (tandem mass spectro-
metry) analysis of the parent ion was carried out at 35% collision
energy levels. The resulting MS=MS spectra from the collision-induced
dissociation of the deprotonated molecular ion of arylglyoxylic
acids (2a and 2c–g) showed the loss of carbon monoxide (M–H–
CO)– (Table 1) and resulted in formation of corresponding arylcar-
boxylic acids (7). Although, the oxidative decarboxylation of
arylglyoxylic acids (2) using singlet oxygen has been reported,[11] the

Synthesis of Arylglyoxylic Acids
4437
Table 1. Collision-induced dissociation of arylglyoxylic acids (2a–g)
Arylglyoxylic
acid (2)
Nominal Molecular ion
(M–H)–
Entry
Formula
mass
(M–H–CO)–
1
2
3
4
5
6
7
2a
2b
2c
2d
2e
2f
C8H5ClO3
C8H5NO5
C10H10O5
C14H10O4
C15H12O5
C8H6O4
184
195
210
242
272
166
417
183 C8H4ClO3 155 C7H4ClO2
194 C8H4NO5 Not observed
209 C10H9O5
241 C14H9O4
181 C9H9O4
213 C13H9O3
271 C15H11O5 243 C14H11O4
165 C8H5O4 137 C7H5O3
416 C8H3I2O4 389 C7H3I2O3
2g
C8H4I2O4
loss of carbon monoxide under the mass spectrometric collision-
induced conditions is unique for this class of compounds. The facile
nature of this unimolecular dissociation process is general which is
shown with a variety of substitution on the aryl ring (e.g., hydroxy,
methoxy, chloride, phenoxy, and iodine groups). The arylglyoxylic
acid (2b), which contains a nitro group (–NO2), did not show the loss
of carbon monoxide (M–H–CO)–, presumably because of the meta-
directing effect of the nitro group rather than electron-withdrawing
effect, because the 2a, which contains chlorine (–Cl) at para-position,
underwent dissociation with loss of carbonmoxide. MSMS spectra ana-
lysis of 2a and 2c–g further indicated that decarbonylation peak (M–
H–CO)– for carboxylate ion (7) is major. In addition, the parent ion
(M–H)– and a peak corresponding to the further dissociation of 7
with loss of carbon dioxide (M–H–CO–CO2)– were also present. We
believe that the dissociation process involved (Scheme 3) an initial
deprotonation of arylglyoxylic acid (2) followed by 1,2-rearrangement
Scheme 3. Collision-induced dissociation of arylglyoxylic acids (2).

4438
K. Wadhwa et al.
with migration of aryl group from the carbonyl carbon to carboxylic
acid carbon, and thus loosing carbon monoxide and leading to the
formation of the corresponding arylcarboxylic acids (7). An analogous
migration of the aryl group has been proposed with the loss of carbon
monoxide from the deprotonated benzyl benzoate esters under acti-
vated mass spectrometric conditions.[12]
In summary, we have synthesized a variety of substituted aryl-
glyoxylic acids (2a–g) and analyzed their unimolecular dissociation by
mass spectrometry. The loss of carbon monoxide is facile under these
collisionally induced mass spectrometric conditions, and the dissociation
process is general with a variety of substituents. The arylglyoxylic acid
(2) containing highly electron-withdrawing groups, such as –NO2,
proved to be stable under these conditions and did not undergo
dissociation.
EXPERIMENTAL
General Methods and Materials
1H and 13C NMR spectra were recorded on a Varian Gemini spectro-
meter (400 MHz), and the chemical shifts (d) were reported. Mass spec-
trometry was performed on a ThermoFinnigan LCQ DECA XP
quadrupole ion trap mass spectrometer utilizing negative-ion APCI(-).
Sample introduction was accomplished by flow injection with a flow sol-
vent consisting of 1:1 acetonitrile=0.1 M NH4OH at a flow rate of
0.3 mL=min. High-resolution exact mass determinations were carried
out on an Agilent LC=MSDTOF instrument using negative-ion electro-
spray [ESI(-)] using internal mass references. Helium is used as the colli-
sion gas for acquisition of LCQ DECA data. Sample introduction was
accomplished by flow injection with a flow solvent consisting of 1:1 acet-
onitrile=0.1% HCOOH at a flow rate of 0.3 mL=min. Thin-layer chroma-
tography (TLC) was performed on precoated Whatman MK6F silica gel
˚
60-A plates (layer thickness: 250 mm) and visualized with UV light,
KMnO4 reagent [KMnO4 (1.0 g) and NaOH (8.0 g) in water (200 mL)],
and phosphomolybdic acid reagent (20 wt% solution in ethanol). Column
chromatography was performed on silica gel, Merck grade 60
(230–400 mesh). All reagents were purchased from Aldrich Chemical
Co. (Milwaukee, Wisc.) and used without purification, except where
noted. All of the solvents employed were of HPLC grade purchased from
EM Science (Gibbstown, N.J.) and used as received. Analytical reverse-
phase (RP) HPLC was performed using an Agilent Zorbax Eclipse
XDB-C18 8 ꢁ 100-mm, 5-mm column (solvents ratio v=v reported) unless
otherwise stated.

Synthesis of Arylglyoxylic Acids
4439
General Procedure for the Preparation of Arylglyoxylic Acids (2a–e)
In a dry, single-neck, 25-mL, round-bottom flask equipped with a stir bar
and flushed with nitrogen, the substituted aryl-methylketone (1a–e,
1.0 mmol) and selenium dioxide (SeO2, 0.167 g, 1.5 mmol, 1.5 equiv.) were
added followed by anhydrous pyridine (10 mL). The reaction mixture was
heated in an oil bath to 110 ꢂC for 1 h, and then the bath temperature was
reduced to 90 ꢂC. The mixture was stirred at this temperature (90 ꢂC) for
an additional 4 h, and progress of the reaction was monitored by TLC.
After completion of the reaction, as determined by TLC, the solution
containing precipitated selenium was filtered using a Buckner funnel,
and the residue was washed with ethyl acetate (50 mL). The combined fil-
trate was treated with 1 N HCl (20 mL), the organic layer was separated,
and the aqueous layer was extracted with ethyl acetate (3 ꢁ 50 mL). The
organic layers were combined and treated with 1N NaOH (50 mL), and
the aqueous layer was separated. The organic layer was extracted with
water (25 mL) and the combined aqueous layers were acidified using
1N HCl to about pH 1.5. The mixture was extracted with ethyl acetate
(3 ꢁ 50 mL), and the combined organic layers were dried (anhydrous
Na2SO4) and concentrated on a rotary evaporator (Bath temperature:
40–45 ꢂC). The crude arylglyoxylic acid products 2a–e were purified by
silica-gel column chromatography using ethyl acetate=hexane (ratio:
9:1) as solvent system for elution.
Data
2-(4-Chlorophenyl)-2-oxoacetic Acid (2a)[13]
Yield: 0.162 g in 89%. Analytical HPLC: gradient solvent system, 0.1%
aqueous phosphoric acid–MeCN 80:20 to 10:90 in 7 min and then hold
for 3 min, 1.5 mL=min at 230 nm, Rt: 3.84 min, 94.5%; 1H NMR (CDCl3):
d 8.30 (d, 2H, J ¼ 8.7 Hz), 7.54 (d, 2H, J ¼ 8.6 Hz), 6.60 (br s, 1H); 13C
NMR (CDCl3): d 182.9, 161.5, 142.1, 132.2, 131.3, 129.1; HRMS: calcd.
m=z for C8H5ClO3, 182.9854 (M–H)–; observed m=z, 182.9854.
2-(4-Nitrophenyl)-2-oxoacetic Acid (2b)[14]
Yield: 0.172 g in 88%. Analytical HPLC: gradient solvent system, 0.1%
aqueous phosphoric acid–MeCN 80:20 to 10:90 in 7 min and hold for
1
3 min, 1.5 mL=min at 230 nm, Rt: 2.10 min, 98.5%; H NMR (CDCl3) d
8.55 (d, 2H, J ¼ 9.1 Hz), 8.40 (d, 2H, J ¼ 9.1 Hz), 5.36 (br s, 1H); 13C

4440
K. Wadhwa et al.
NMR (CDCl3): d 182.5, 159.6, 135.8, 132.1, 123.7; ESI-MS (m=z): 196.1
(M þ H)þ, HRMS: calcd. m=z for C8H5NO5, 194.0095 (M–H)–; observed
m=z, 194.0091.
2-(2,4-Dimethoxyphenyl)-2-oxoacetic Acid (2c)[15]
Yield: 0.173 g in 82%. Analytical HPLC: gradient solvent system, 0.1%
aqueous phosphoric acid–MeCN 80:20 to 10:90 in 7 min and hold for
1
3 min, 1.5 mL=min at 230 nm, Rt: 3.00 min, 99.6%; H NMR (CDCl3):
d 8.01 (d, 1H, J ¼ 8.8 Hz), 6.65 (d, 1H, J ¼ 8.7 Hz), 6.50 (s, 1H), 3.94 (s,
3H), 3.93 (s, 3H); 13C NMR (CDCl3): d 183.0, 167.9, 166.6, 162.3,
133.1, 115.1, 106.7, 98.2, 56.1, 55.9; HRMS: calcd. m=z for C10H10O5,
209.0455 (M–H)–, observed m=z, 209.0453.
2-Oxo-2-(4-phenoxyphenyl)acetic Acid (2d)[16]
Yield: 0.186 g in 77%. Analytical HPLC: gradient solvent system, 0.1%
aqueous phosphoric acid–MeCN 80:20 to 10:90 in 7 min and hold for
1
3 min, 1.5 mL=min at 230 nm, Rt: 4.93 min, 93.5%; H NMR (CDCl3):
d 8.36 (d, 2H, J ¼ 9.1 Hz), 7.48–7.44 (m, 2H), 7.32–7.26 (m, 1H), 7.16–
8.12 (m, 2H), 7.06 (d, 2H, J ¼ 9.1 Hz); 13C NMR (CDCl3): d 182.1,
163.9, 162.1, 154.9, 133.6, 129.9, 125.8, 125.0, 120.4, 116.9; HRMS: calcd.
m=z for C14H10O4, 241.0506 (M–H)–; observed m=z, 241.0509.
2-(4-(4-Methoxyphenoxy)phenyl)-2-oxoacetic Acid (2e)
Yield: 0.269 g in 99%. Analytical HPLC: gradient solvent system, 0.1%
aqueous phosphoric acid–MeCN 80:20 to 10:90 in 7 min and hold for
1
3 min, 1.5 mL=min at 230 nm, Rt: 4.97 min, 93.8%; H NMR (CDCl3):
d 8.40 (d, 2H, J ¼ 8.9 Hz), 7.07 (d, 2H, J ¼ 9.0 Hz), 7.01 (d, 2H,
J ¼ 8.8 Hz), 6.98 (d, 2H, J ¼ 9.1 Hz), 3.88 (s, 3H); 13C NMR (CDCl3): d
181.7, 164.8, 161.0, 156.6, 147.3, 133.9, 125.4, 121.6, 116.3, 114.9, 55.8;
HRMS: calcd. m=z for C15H12O5, 271.0612 (M–H)–, observed m=z,
271.0611.
2-(4-Hydroxyphenyl)-2-oxoacetic Acid (2f)
In a dry, two-neck 1.0-L, round-bottom flask, equipped with a stir bar,
anhydrous aluminum chloride (156.0 g, 1.17 mol, 2.0 equiv.) was sus-
pended in nitromethane (300 mL) and cooled with an ice–salt bath

Synthesis of Arylglyoxylic Acids
4441
to ꢀ5 ꢂC. Separately, in a 250-mL, round-bottom flask, phenol (3, 54.1 g,
0.574 mol, 1.0 equiv.) and ethyl chlorooxoacetate (87.0 g, 0.637 mol,
1.1 equiv.) was dissolved in nitromethane (75 mL), and the mixture was
added slowly to aluminum chloride–nitromethane while maintaining
the internal temperature colder than 0 ꢂC temperature. After the addition
was complete, the mixture was warmed to 40 ꢂC and stirred for an addi-
tional 2 h. The reaction mixture was quenched into ice water (0.5 Kg) and
acidified using 3 N HCl and diluted with isopropyl acetate (450 mL). The
organic layer was separated and washed with 1.0 M aqueous K2CO3 solu-
tion (3 ꢁ 100 mL), dried (MgSO4), and concentrated on a rotary evapora-
tor (bath temperature 40–45 ꢂC). The crude product was purified by
silica-gel column chromatography (20% IPAc in heptane) to afford
10.1 g of ethyl 2-(4-hydroxyphenyl)-2-oxoacetate (4) in 9.1% yield.
In a 25-mL, single, neck, round-bottom flask equipped with a stir
bar, ethyl 2-(4-hydroxyphenyl)-2-oxoacetate (4, 0.291 g, 1.5 mmol,
1.0 equiv.) was dissolved in THF (12 mL) and cooled to 5–10 ꢂC using
an ice-water bath. Separately, lithium hydroxide (0.72 g, 3.0 mmol,
2.0 equiv.) was dissolved in water (4 mL) and added to the reaction mix-
ture. Progress of the reaction was monitored by HPLC, and after 1 h, an
additional amount of lithium hydroxide (0.72 g, 3.0 mmol, 2.0 equiv.) was
added. The mixture was stirred for 30 min and acidified using acetic acid
(2.0 mL), and the mixture was washed with isopropyl acetate (40 mL).
The aqueous layer was diluted with 10% aqueous NaCl solution
(20 mL) and kept at room temperature for 24 h. The solid was separated
by filtration, and the wet cake was dried in a vacuum oven at 50 ꢂC for
21 h to afford 0.235 g of 2-(4-hydroxyphenyl)-2-oxoacetic acid (2f) in
94% yield.[9] Analytical HPLC (Synergi Max-RP column): 20:80 ratio
of MeCN–organic-phosphate buffer blend (0.35% aqueous K2HPO4
solution and MeCN in 45:55 ratio), 0.5 mL=min at 230 nm, Rt:
1
4.39 min, 96.6%; H NMR [D2O and 3-(trimethylsilyl)propionic acid-d4
sodium salt]: d 7.86 (6, 2 H, J ¼ 8.9 Hz), 6.99 (d, 2 H, J ¼ 9.1 Hz); 13C
NMR [D2 O and 3-(trimethylsilyl)propionic acid-d4 sodium salt]: d
197.4, 175.4, 164.3, 134.8, 126.3, 118.3; HRMS: calcd. m=z for C8H6O4,
165.0193 (M ꢀ H)–; observed m=z, 165.0195.
2-(4-Hydroxy-3,5-diiodophenyl)-2-oxoacetic Acid (2g)
To a 500-mL, single-neck, round-bottom flask equipped with a stir bar,
ethyl 2-(4-hydroxyphenyl)-2-oxoacetate (4, 5.0 g, 25.76 mmol, 1.0 equiv.)
and acetic acid (130 mL) were added. To this mixture, iodine monochlor-
ide (16.0 g, 4.94 mL, 98.5 mmol, 3.82 equiv.) was added at room tempera-
ture and then heated to 57 ꢂC. Water (150 mL) was added in three

4442
K. Wadhwa et al.
portions while maintaining the solution temperature between 57 and
60 ꢂC and then stirred for 30 min. The mixture was cooled to room tem-
perature, quenched with sodium sulfite (12 g), and then diluted with iso-
propyl acetate (400 mL). The organic layer was separated and washed
with 4 N NaOH solution (20 mL) followed by 10% aqueous K2CO3 solu-
tion (3 ꢁ 25 mL) and dried (MgSO4). Concentration of the solution on a
rotary evaporator (bath temperature 40–45 ꢂC) afforded 11.41 g of ethyl
2-(4-hydroxy-3,5-diiodophenyl)-2-oxoacetate (5) in >98% yield.
In a 25-mL, single-neck, round-bottom flask equipped with stir bar,
ethyl 2-(4-hydroxy-3,5-diiodophenyl)-2-oxoacetate (5, 0.3 g, 0.673 mmol,
1.0 equiv.) was dissolved in THF (8 mL) and cooled to 5 ꢂC. To this mix-
ture, 25 drops of aqueous potassium hydroxide solution (0.5 g of KOH
dissolved in 3.0 mL of water) was added over a 1 h period and stirred
for an additional 1 h. The reaction mixture was diluted with water and
lyophilized. The crude lyophilized powder was suspended in tert-butyl-
methyl ether (40 mL), and acetic acid (11 drops) was added at room tem-
perature and stirred overnight for 18 h. The solid was separated by
filtration, washed with tert-butylmethyl ether (20 mL), and dried in a
vacuum oven at 22 ꢂC for 24 h to afford 0.210 g of 2-(4-hydroxy-3,5-
diiodophenyl)-2-oxoacetic acid (2g) in 74% yield.[10] Analytical HPLC
(Synergi Max-RP column): 20:80 ratio of MeCN–organic-phosphate buf-
fer blend (0.35% aqueous K2HPO4 solution and MeCN in 45:55 ratio),
1
0.5 mL=min at 230 nm, Rt: 5.23 min, 88.6%; H NMR (D2O and 3-(tri-
methylsilyl) propionic acid-d4 sodium salt): d 8.27 (s, 2 H); 13C NMR
(D2O and 3-(trimethylsilyl)propionic acid-d4 sodium salt): d 194.0,
175.4, 172.9, 143.9, 122.8, 91.2; HRMS: calcd. m=z for C8H4I2O4,
416.8126 (M ꢀ H)–; observed m=z, 416.8119.
ACKNOWLEDGMENTS
We thank Dr. Martin Babcock, director of API Products, for encourage-
ment and support, and Drs. Tom Paulus and Steven Springer-Wilson for
helpful discussions.
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