Silica sulfuric acid as a highly efficient catalyst for the synthesis of diarylacetic acids

Article abstract of DOI:10.1080/00397911.2016.1158269

ABSTRACT: An efficient heterogeneous method for the synthesis of diarylacetic acids was developed utilizing silica sulfuric acid as a catalyst. The reaction is highly efficient with a small amount of catalyst for the combination of a variety of electron-n

Full text of DOI:10.1080/00397911.2016.1158269

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Silica Sulfuric Acid as a Highly Efficient Catalyst for
the Synthesis of Diarylacetic Acids
Desiree L. Moore, Allison E. Denton, Rose M. Kohinke, Brandon R. Craig &
William E. Brenzovich Jr
To cite this article: Desiree L. Moore, Allison E. Denton, Rose M. Kohinke, Brandon R. Craig &
William E. Brenzovich Jr (2016): Silica Sulfuric Acid as a Highly Efficient Catalyst for the Synthesis
of Diarylacetic Acids, Synthetic Communications
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Date: 14 March 2016, At: 21:16

Silica Sulfuric Acid as a Highly Efficient Catalyst for the Synthesis of Diarylacetic
Acids
Desiree L. Moore1, Allison E. Denton1, Rose M. Kohinke1, Brandon R. Craig1, William
E. Brenzovich Jr1
1Department of Chemistry, Roanoke College, Salem, Virginia, USA
Abstract
An efficient heterogeneous method for the synthesis of diarylacetic acids was developed
utilizing silica sulfuric acid as a catalyst. The reaction is highly efficient with a small
amount of catalyst for the combination of a variety of electron-neutral to electron-rich
arenes with glyoxylic acid. The reaction can also be utilized to synthesize unsymmetric
derivatives from activated mandelic acids in good to excellent yield.
INTRODUCTION
Much of the recent interest in the reaction design has been in the area of increasing
efficiency and reducing waste, problems frequently solved through the use of
heterogeneous catalysts. Heterogeneous solid catalysts, which offer simple separation
from reaction mixtures, the potential for reusability, and often increased catalytic activity,
afford many ideal properties for advancing synthetic chemistry.1 While there are many
different methods for the creation of these systems, a common strategy is the
development of a solid-supported catalyst where the reactive species is covalently
1

attached or chemically adsorbed onto the surface of an inert material.2 As the reaction
takes place on the surface of the solid, maximizing the surface area of the support is
crucial to maintaining sufficient reactivity.3 In addition, the solid support can provide a
unique environment for a reaction to occur outside of the bulk solvent and even alter a
reaction’s outcome based on the specific properties of the surface.4 Silica gel, with its
porous nature and polar properties, is one of the most commonly used solid supports,
leading to development of a variety of new and interesting solid-phase acid catalysts.5
Silica sulfuric acid, formed from the adsorption of sulfuric acid onto the surface
of dry silica gel, has received increased attention in recent years due to the convenient
nature of the catalyst and the potential for reusability.6 The catalyst is non-corrosive, has
low toxicity, and is not sensitive to moisture in the air.6a Upon completion of a reaction,
silica sulfuric acid can be isolated by a simple filtration, dried, and be reused effectively
up to five times.7 In addition to serving as a proton source, the large and polar surface has
been found to increase overall catalytic activity, allowing for much milder reaction
conditions.6 This robust catalyst has been demonstrated to be an advantageous substitute
for concentrated sulfuric acid for a variety of reactions, including additions,8
condensations,9 and heterocycle synthesis.10
α,α-Diarylacetic acids are a diverse class of molecules that are important starting
materials for a variety of biological compounds. Derivatives differing in the substituents
on the aromatic rings have been shown to have a variety of interesting biological effects,
exhibiting anti-inflammatory, analgesic, and antipyretic properties.11 In addition,
2

diarylmoieties are commonly found in many commercial pharmaceutical agents, many of
which utilize diarylacetic acid derivatives as starting materials in synthetic endeavors.12
Due to the increased interest in diarylacetic acids and their derivatives, a cost-effective
and facile synthesis of this class of molecules is essential.
A variety of methods have been explored for the synthesis of diarylacetic acids.
Methods include the reduction of benzilic acids,13 carboxylation with carbon monoxide,14
and condensations of nucleophilic arenes.12b,15 The most efficient synthesis involves the
condensation of two equivalents of a nucleophilic arene into a glyoxylic acid derivative
with the use of a large excess of sulfuric acid.15a Recent groups have improved on this
procedure, reducing the amount of acid required by utilizing alternate acid sources.15e,f
Recently, Prakash and coworkers explored the use of triflic acid on a poly(4-
vinylpyridine) solid support for the condensation of arenes with glyoxylic acid.15e The
reaction proceeded with excellent yields under mild conditions for a variety of alkyl and
halogen substituted aromatic systems; however, no reports of more electron-rich oxygen
bearing substrates were reported.
In line with our group’s interest in the development of cleaner and more efficient
reactions, we sought to develop an alternate and greener approach for the synthesis of
diarylacetic acids utilizing a solid-supported catalyst system. Silica sulfuric acid emerged
as an ideal candidate due to its high activity, low cost, and convenient removal. Silica
sulfuric acid has proven useful in the synthesis of triarylmethanes from a related
condensation of aldehydes with nucleophilic arenes in a related reaction,9d but has yet to
3

be applied to the more electron-deficient carbonyl substrates required for diarylacetic
acid derivatives. In this work, we report the use of silica sulfuric acid as a catalyst for the
direct synthesis of diarylacetic acids by condensation of nucleophilic arenes with
glyoxylic acid monohydrate.
DISCUSSION
Initial exploration of the use of silica sulfuric acid as the catalyst for the condensation of
anisole with glyoxylic acid under neat conditions provided the desired product (2a) in
moderate yield (Table 1). It was quickly determined that the lower yields were likely due
to the insolubility of glyoxylic acid in anisole, which led to polymerization of the
reagents and reduced activity of the catalysts. The addition of a small amount of a polar
solvent significantly increases the yields by solubilizing the substrate intermediates,
allowing for effective mixing during the reaction. Unfortunately, the use of water as a
solvent proved unsuccessful, leading to the formation of a third phase in the already
heterogeneous mixture and complicating the isolation of the products by filtration. Acetic
acid was chosen as the ideal solvent due to convenience and cost. The reaction produces
the highest yields with only a small amount of solvent, and increasing the solvent amount
further does not significantly improve the yields.
The most commonly cited method for the synthesis of silica sulfuric acid involves the
addition of chlorosulfonic acid to dry silica gel with removal of the resulting hydrogen
chloride.9b A more convenient method involves the addition of sulfuric acid to a
suspension of silica gel followed by drying.10e Both procedures produce a functional
4

catalyst for the condensation of arenes with glyoxylic acid, returning no significant
difference in yields (Table 2). Even more surprising, silica sulfuric acid can be created in
situ by the addition of silica gel and a small amount of concentrated sulfuric acid directly
to the reaction mixture. The small amount of water present is readily adsorbed into the
silica gel and does not have a significant effect on the reaction yield. This method
remains a viable alternative to preforming the catalyst. The reaction was unsuccessful
with just silica gel or sulfuric acid in similar concentrations to the solid-supported system,
reinforcing the cooperative effect of the heterogeneous catalyst that has widely reported
in other studies.2,3,6
The reaction is general to a variety of electron-rich arenes, as shown in Table 3.
Reaction yields are good to excellent, and most products are analytically pure following a
simple acid/base extraction and precipitation. Only three equivalents of the reacting
arene are required for the formation of the products, which is significantly lower than the
large excesses often used in the homogeneous reaction.15 The reaction with active
nucleophiles, such as substituted anisoles, are complete after four hours at 60 °C. More
electron-poor arenes, such as xylene and toluene, require elevated temperatures (120 °C)
to promote high yields, while the highly nucleophilic 1,3-dimethoxybenzene must be
added at 0 °C and then warmed to room temperature to prevent unwanted side reactions.
The products are generally formed a single regioisomer with addition occurring at the
most nucleophilic position of the aromatic ring; however, substrates with equally
activated positions, such as o-xylene and 3-methylanisole, produce the expected mixture
of regioisomers with the double para addition preferred. The ratio of the regioisomers
5

formed is similar to previously published methods.15 Sterically-hindered mesitylene
proved to be a reasonable substrate for the reaction, providing the product 2m in 82%
yield. Benzene proved to be an unsuitable substrate, providing only a trace amount of the
desired product (2n), though large amounts of polymerized products were observed.
Increasing temperature or equivalents of benzene did not significantly improve the
observed yield of diphenylacetic acid.
In an attempt to expand the scope of the reaction, we sought to explore a method to create
differentially substituted diarylacetic acids. Mechanistically, α-aryl-α-hydroxyacetic
acids (3) are a likely intermediate in the formation of diarylacetic acids from glyoxylic
acid following the initial addition (Scheme 1). Therefore, 3 could be used as substrates
for arylation under similar conditions to provide access to unsymmetric diarylacetic
acids. The direct arylation of α-aryl-α-hydroxyacetic acids to diarylacetic acids has been
reported, but typically utilizes stoichiometric amounts of strong Lewis acids, such as
AlCl3 or SnCl4.16 Silica sulfuric acid has the potential to greatly expand the scope of this
transformation, removing the requirement for anhydrous conditions. Gratifyingly,
treatment of 2-(4-methoxyphenyl)acetic acid (3a) in the presence of anisole and silica
sulfuric acid produced the desired diarylacetic acid 2a in an excellent 87% yield as a
single regioisomer. As shown in Table 4, a variety of diaryl products can be formed from
hydroxyacids in good to excellent yield utilizing silica sulfuric acid as a catalyst.
Unsubstituted, electron-poor, or highly sterically hindered hydroxyacids, such as 2-(2-
methylphenyl)acetic acid (3c), do not undergo arylation, but instead cleanly produce
acetate esters (6c) through reaction with the solvent. Stabilization of the developing
6

charge at the α-position is crucial for the reaction to occur. Without substantial
stabilization through conjugation, either due to the lack of an appropriately strong
activating substituents or the sterically induced twisting of the aromatic ring, the reaction
cannot reasonably occur at the α-position. In this case, the previously reported Fisher
esterification of alcohols occurs instead.17
In summary, we have expanded the utility of silica sulfuric acid catalysis of
electrophilic aromatic substitution to include less electrophilic carbonyl substrates
through the synthesis of diarylacetic acids from glyoxylic acid. This method serves as a
compliment to recently reported green syntheses of these substrates, able to include
increase regioselectivity and utilize electron-rich arenes. While the reuse of the catalyst
in the current reaction has been explored, the activity of the recovered catalyst has been
found to be significantly reduced. We are currently exploring alternative reaction and
isolation conditions to improve reusability. Given the interesting properties of silica
sulfuric acid, we hope to further explore its use in related acid-catalyzed reactions.
EXPERIMENTAL
All reagents and solvents are commercially available and were used directly with no
further purification. The 1H and 13C NMR spectra were recorded on 400- (100-) MHz
Varian spectrometer and calibrated using residual undeuterated solvent (CDCl3, δH =
7.26 ppm, δC = 77.16 ppm) as an internal reference. CDCl3 was purchased from
Cambridge Isotopes and used with no further purification. The following abbreviations
were used to designate multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m =
7

multiplet, br = broad. Infrared (IR) spectra were recorded on a Perkin−Elmer 100 FT-IR
spectrometer. Elemental analysis was performed by Galbraith Laboratories (Knoxville,
TN, USA) using a CE-440 Elemental Analyzer. E. Merck silica gel (60, partical size
0.040–0.063 mm) was used for flash column chromatography. Silica sulfuric acid was
prepared by the method of Zolfigol through the addition of chlorosulfonic acid to dry
silica gel.9b
General Procedure For The Reaction Of Glyoxylic Acid
Glyoxylic acid monohydrate (0.200 g, 2.2 mmol) and silica sulfuric acid (0.200 g, 1 mass
equivalent) were suspended in acetic acid (1.0 mL) in a vial. The arene was then added
dropwise at room temperature with vigorous stirring, and then the reaction mixture was
heated to the appropriate temperature for the indicated time. Following cooling to room
temperature, the mixture was diluted with ethyl acetate (20 mL), filtered, and the filtrate
was concentrated in vacuo. The residue was purified to analytical purity either by acid-
base extraction or column chromatography.
General Procedure For The Reaction Of Hydroxyacetic Acids
Substituted mandelic acid (0.200 g) and silica sulfuric acid (0.200 g, 1 mass equivalent)
were suspended in acetic acid (1.0 mL) in a vial. The arene (3 mole equivalents) was
then added dropwise at room temperature with vigorous stirring, and then the reaction
mixture was heated to the appropriate temperature for the indicated time. Following
cooling to room temperature, the mixture was diluted with ethyl acetate (20 mL), filtered,
8

and the filtrate was concentrated in vacuo. The residue was purified to analytical purity
either by acid-base extraction or column chromatography.
2,2-Bis(4-methoxyphenyl)acetic acid (2a): Using the standard procedures, glyoxylic
acid monohydrate (0.200 g, 2.2 mmol) was reacted with anisole (0.70 mL, 6.5 mmol) at
60 °C for 4 hours. Following filtration to remove the catalyst and an acid-base
extraction, 2a (0.556 g, 94%) was isolated as an off-white solid. Spectral data is
consistent with previously published reports.12b 1H NMR (400 MHz, CDCl3) δ = 7.22 (d,
J = 9.1 Hz, 2H), 6.85 (d, J = 9.1 Hz, 2H), 4.93 (s, 1H), 3.77 (s, 6H) ppm; 13C NMR (100
MHz, CDCl3) δ = 178.1, 158.8, 130.4, 129.6, 114.0, 55.2, 55.2 ppm; IR (ATR) υ = 2971,
1699, 1610, 1584, 1457, 1440, 1305, 1218, 1174, 1113, 1027, 924, 812, 737 cm–1; Anal.
Calcd. for C16H16O4: C, 70.58; H, 5.92. Found: C, 70.26; H, 6.20.
FUNDING
Acknowledgement is made to the donors of the American Chemical Society Petroleum
Research fund for partial support of this research. We also thank Roanoke College
Faculty Development Grant for support.
SUPPORTING INFORMATION
Full experimental details and 1H and 13C NMR spectra for all synthesized compounds can
be found via the Supplementary Content section of this article’s Web page.
9

REFERENCES
1.
Ono, Y.; Hattori, H. Solid base catalysis; Springer series in chemical physics;
Springer: Heidelberg, 2011.
2.
Ma, Z.; Zaera, F. In Encyclopedia of Inorganic Chemistry; King, R. B., Crabtree,
R. H., Lukehart, C. M., Atwood, D. A., Scott, R. A., Eds.; John Wiley & Sons, Ltd:
Chichester, UK, 2006.
3.
Clark, J. H.; Rhodes, C. N. Clean synthesis using porous inorganic solid catalysts
and supported reagents; RSC clean technology monographs; Royal Society of
Chemistry: Cambridge, 2000.
4.
J. E.; Raleigh, J. S. J. Org. Chem. 1995, 60 (13), 4146–4152.
5. (a) Sartori, G.; Maggi, R. Chem. Rev. 2006, 106 (3), 1077–1104; (b) Devi, L.;
Kropp, P. J.; Breton, G. W.; Craig, S. L.; Crawford, S. D.; Durland, W. F.; Jones,
Singh, O. In Heterogeneous Catalysis; CRC Press, 2014; pp 163–190; (c) Gawande, M.;
Hosseinpour, R.; Luque, R. Curr. Org. Synth. 2014, 11 (4), 526–544; (d) Vekariya, R. H.;
Patel, H. D. Synth. Commun. 2015, 45 (9), 1031–1054.
6.
For recent reviews on the use of silica sulfuric acid, see: (a) Chávez, F.; Suárez,
S.; Díaz, M. A. Synth. Commun. 1994, 24 (16), 2325–2339; (b) Baghernejad, B. Mini-
Reviews in Organic Chemistry 2011, 8 (1), 91–102; (c) Gawande, M.; Hosseinpour, R.;
Luque, R. Curr. Org. Synth. 2014, 11 (4), 526–544.
7.
Zhang, Y.; Chen, X.; Liang, J.; Shang, Z. Synth. Commun. 2011, 41 (16), 2446–
2454.
8.
Additions using silica sulfuric acid: (a) Wang, Y.; Yuan, Y.-Q.; Guo, S.-R.
Molecules 2009, 14 (11), 4779–4789; Zolfigol, M. A.; Veisi, H.; Mohanazadeh, F.;
10

Sedrpoushan, A. J. of Heterocyc. Chem. 2011, 48 (4), 977–986; (c) Sultan, A.; Raza, A.;
Abbas, M.; Khan, K.; Tahir, M.; Saari, N. Molecules 2013, 18 (8), 10081–10094.
9.
Condensations using silica sulfuric acid: (a) Riego, J. M.; Sedin, Z.; Zaldívar, J.;
Marziano, N. C.; Tortato, C. Tetrahedron Lett. 1996, 37 (4), 513–516; (b) Zolfigol, M. A.
Tetrahedron 2001, 57 (46), 9509–9511; (c) Niknam, K.; Mirzaee, S. Synth. Commun.
2011, 41 (16), 2403–2413; (d) Mohammadpoor-Baltork, I.; Moghadam, M.;
Tangestaninejad, S.; Mirkhani, V.; Mohammadiannejad-Abbasabadi, K.; Zolfigol, M. A.
Comptes Rendus Chimie 2011, 14 (10), 934–943; (e) Zhang, J.; Zhang, B.; Zhou, J.; Li,
J.; Shi, C.; Huang, T.; Wang, Z.; Tang, J. J. Carbohydr. Chem. 2011, 30 (3), 165–177; (f)
Zhang, F.; Wang, Y.-X.; Yang, F.-L.; Zhang, H.-Y.; Zhao, Y.-F. Synth. Commun. 2011,
41 (3), 347–356; (g) Zhang, Y.; Chen, X.; Liang, J.; Shang, Z. Synth. Commun. 2011, 41
(16), 2446–2454.
10.
Heterocycle synthesis using silica sulfuric acid: (a) Shaterian, H. R.; Ghashang,
M.; Feyzi, M. Applied Catalysis A: General 2008, 345 (2), 128–133; (b) Pathak, S.;
Debnath, K.; Pramanik, A. Beilstein J. Org. Chem. 2013, 9, 2344–2353; (c) Dabiri, M.;
Salehi, P.; Baghbanzadeh, M.; Zolfigol, M. A.; Agheb, M.; Heydari, S. Catal. Commun.
2008, 9 (5), 785–788; (d) Datta, B.; Pasha, M. A. Chin. J. Catal. 2011, 32 (6-8), 1180–
1184; (e) Maleki, B.; Keshvari Shirvan, H.; Taimazi, F.; Akbarzadeh, E. Int. J. Org.
Chem. 2012, 2 (1), 93–99; (f) Basyouni, W. M.; El-Bayouki, K. A. M.; Tohamy, W. M.;
Abbas, S. Y. Synth. Commun. 2015, 45 (9), 1073–1081.
11.
(a) Maryanoff, B. E.; Nortey, S. O.; Gardocki, J. F. J. Med. Chem. 1984, 27 (8),
1067–1071; (b) Roufos, I.; Hays, S. J.; Dooley, D. J.; Schwarz, R. D.; Campbell, G. W.;
b. Kaiser, C.; Spangnuolo, C. J.; Adams, Jr., T. C.; Audia, V. H.; Dupont, A. C.; Hatoum,
11

H.; Lowe, V. C.; Prosser, J. C.; Sturm, B. L.; Noronha-Blob, L. J. Med. Chem. 1992, 35
(23), 4415–4424; (c) Probert, A. W. J. Med. Chem. 1994, 37 (2), 268–274; (d) Roufos, I.;
Hays, S.; Schwarz, R. D. J. Med. Chem. 1996, 39 (7), 1514–1520; (e) Martelli, C.;
Coronnello, M.; Dei, S.; Manetti, D.; Orlandi, F.; Scapecchi, S.; Novella Romanelli, M.;
Salerno, M.; Mini, E.; Teodori, E. J. Med. Chem. 2010, 53 (4), 1755–1762; (f) Autore,
G.; Caruso, A.; Marzocco, S.; Nicolaus, B.; Palladino, C.; Pinto, A.; Popolo, A.;
Sinicropi, M. S.; Tommonaro, G.; Saturnino, C. Molecules 2010, 15 (3), 2028–2038; (g)
Teodori, E.; Dei, S.; Floriddia, E.; Perrone, M. G.; Manetti, D.; Romanelli, M. N.;
Contino, M.; Colabufo, N. A. ChemMedChem 2015, 10 (8), 1339–1343.
12.
(a) Bogeso, K. P.; Christensen, A. V.; Hyttel, J.; Liljefors, T. J. Med. Chem. 1985,
28 (12), 1817–1828; (b) Baarschers, W. H.; Vukmanich, J. P. Canadian J. Chem. 1986,
64 (5), 932–935; (c) Lowe, J. A.; Hageman, D. L.; Drozda, S. E.; McLean, S.; Bryce, D.
K.; Crawford, R. T.; Zorn, S.; Morrone, J.; Bordner, J. J. Med. Chem. 1994, 37 (22),
3789–3811; (d) De Risi, C.; Ferraro, L.; Pollini, G. P.; Tanganelli, S.; Valente, F.;
Veronese, A. C. Bioorg. Med. Chem. 2008, 16 (23), 9904–9910.
13.
Strazzolini, P.; Giumanini, A. G.; Verardo, G. Synth. Commun. 1987, 17 (16),
1919–1928.
14.
Takahashi, K.; Shibasaki, K.; Ogura, K.; Iida, H. J. Org. Chem. 1983, 48 (20),
3566–3569.
15.
(a) Fuson, R. C.; Ward, M. L. J. Am. Chem. Soc. 1946, 68 (3), 521–522; (b)
Giuseppe Werber; Buccheri, F. Gazz. Chim. Ital. 1966, 96 (4), 465–474; (c) Baarschers,
W. H.; Vukmanich, J. P. Canadian J. Chem. 1986, 64 (5), 932–935; (d) Klumpp, D. A.;
Lau, S.; Garza, M.; Schick, B.; Kantardjieff, K. J. Org. Chem. 1999, 64 (20), 7635–7637;
12

(e) Prakash, G. K. S.; Paknia, F.; Kulkarni, A.; Narayanan, A.; Wang, F.; Rasul, G.;
Mathew, T.; Olah, G. A. J. Fluorine Chem. 2015, 171, 102–112; (f) Jadhav, S. D.; Singh,
A. J. Org. Chem. 2016, 81 (2), 522–531.
16.
(a) Horák, M.; Staněk, J. Coll. Czech. Chem. Commun. 1949, 14, 551–554; (b)
Hsu, J.-L.; Jen, H.-C.; Lei, H.-H. Yaoxue Xuebao 1960, 8, 105–108; (c) Nadler, E. B.;
Rappoport, Z. J. Org. Chem. 1988, 53 (22), 5361–5363.
17.
Chakraborti, A. K.; Singh, B.; Chankeshwara, S. V.; Patel, A. R. J. Org. Chem.
2009, 74 (16), 5967–5974.
13

Table 1. Optimization of the silica sulfuric acid catalyzed synthesis of diarylacetic acids.
Entry
Solvent
neat
Yieldb
40
1
2
3
4
5
6
7
8
9
H2O (0.5 mL)
AcOH (1.0 mL)
MeCN (1.0 mL)
MeNO2 (1.0 mL)
CHCl3 (1.0 mL)
DMSO (1.0 mL)
AcOH (0.5 mL)
AcOH (2.0 mL)
20
92 (94)c
55
69
trace
43
60
76
a General conditions: glyoxylic acid monohydrate (0.20 g), anisole (3 equiv.), and silica
sulfuric acid (0.20 g) were combined and heated to 60 °C for 4 hours. b Yield determined
by 1H NMR versus 1,3-dinitrobenzene as an internal standard. c Isolated yield.
14

Table 2. The effect of acid source on the synthesis of diarylacetic acids.
Entry Acid Source
Yielda
94
1
2
3
4
5
silica sulfuric acid (Method A)b
silica sulfuric acid (Method B)c
silica gel (0.20 g) + conc. H2SO4 (0.1 mL)
silica gel (0.20 g)
91
89
NR
43
conc. H2SO4 (0.1 mL)
a Yield determined by 1H NMR versus 1,3-dinitrobenzene as an internal standard. b SSA
prepared from chlorosulfonic acid.9b c SSA prepared from concentrated sulfuric acid.10e
15

Table 3. Synthesis of diarylacetic acids from glyoxylic acid.a
a General conditions: glyoxylic acid monohydrate (0.20 g), arene (3 equiv.), and silica
sulfuric acid (0.20 g) were combined in acetic acid (1 mL) and heated to the indicated
temperature for 4 hours. b Isolated as a 4:1 mixture of para/para addition and para/ortho
16

addition c Isolated as a 3:1 mixture of para/para addition and para/ortho addition. d
Isolated as a 3.5:1 mixture of para/para addition and para/ortho addition.
17

Table 4. Synthesis of diarylacetic acids from mandelic acid derivatives.a
a General conditions: mandelic acid (0.20 g), arene (3 equiv.), and silica sulfuric acid
(0.20 g) were combined in acetic acid (1 mL) and heated to 80 °C for four hours. b
Isolated as a 4:1 mixture of para/para addition and para/ortho addition.
18

Scheme 1. Proposed pathway for diarylacetic acid synthesis.
19

Scheme 2. Esterification of unreactive mandelic acid derivatives.
20