A convenient synthesis of 4-arylidene-2-phenyl-5(4H)-oxazolones under solvent-assisted grinding

Article abstract of DOI:10.1016/j.tetlet.2016.06.029

A facile and effective approach for the synthesis of 4-arylidene-2-phenyl-5(4H)-oxazolones has been developed. Under solvent-assisted grinding in the presence of 2,4,6-trichloro-1,3,5-triazine, catalytic triphenylphosphine, and sodium carbonate, dehydrati

Full text of DOI:10.1016/j.tetlet.2016.06.029

Accepted Manuscript
A convenient synthesis of 4-arylidene-2-phenyl-5(4H)-oxazolones under sol-
vent-assisted grinding
Mookda Pattarawarapan, Subin Jaita, Wong Phakhodee
PII:
S0040-4039(16)30689-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.06.029
TETL 47756
Reference:
Tetrahedron Letters
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Revised Date:
Accepted Date:
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3 June 2016
7 June 2016
Please cite this article as: Pattarawarapan, M., Jaita, S., Phakhodee, W., A convenient synthesis of 4-arylidene-2-
phenyl-5(4H)-oxazolones under solvent-assisted grinding, Tetrahedron Letters (2016), doi: http://dx.doi.org/
10.1016/j.tetlet.2016.06.029
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A convenient synthesis of 4-arylidene-2-phenyl-5(4H)-oxazolones under solvent-assisted
grinding
Mookda Pattarawarapan,* Subin Jaita, and Wong Phakhodee
Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of
Science, Chiang Mai University, Chiang Mai 50200, Thailand
To whom correspondence should be addressed.
Department of Chemistry,
Faculty of Science,
Chiang Mai University,
Chiang Mai
50200
Thailand
Tel. +66 5394 3341
Fax. +66 5389 2277
e-mail: mookdap55@gmail.com

A convenient synthesis of 4-arylidene-2-phenyl-5(4H)-oxazolones under solvent-assisted
grinding
Mookda Pattarawarapan,* Subin Jaita, and Wong Phakhodee
Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of
Science, Chiang Mai University, Chiang Mai 50200, Thailand
Abstract
A facile and effective approach for the synthesis of 4-arylidene-2-phenyl-5(4H)-oxazolones has
been developed. Under solvent-assisted grinding in the presence of 2,4,6-trichloro-1,3,5-triazine,
catalytic triphenylphosphine, and sodium carbonate, dehydration-condensation of hippuric acid
with aromatic aldehydes proceeded rapidly within minutes at room temperature to afford the
products in good to excellent yields.
Keywords hippuric acid; cyanuric chloride; triphenylphosphine; azlactones; mechanosynthesis
Introduction
4-Arylidene-2-phenyl-5(4H)-oxazolones or so-called Erlenmeyer azlactones are versatile
precursors in the synthesis of various important compounds such as heterocycles,1 non-natural
amino acids,2 and peptides.3 Several oxazolone-containing molecules have been shown to exhibit
a range of pharmacological and biological activities including anti-inflammatory, antidepressant,
antimicrobial, antidiabetic, antitumor, antihypertensive, and immunomodulatory activities.4
Moreover, their optical properties could also lead to potential applications in microfabrication,
data storage, photodynamic therapy, optical imaging, and sensing.5 These benefits have led to an
increasing number of synthetic methodologies toward oxazolones.
Since the first synthesis of 4-benzylidene-2-phenyl-5(4H)-oxazolone via condensation of N-
acetylglycine (hippuric acid) and benzaldehyde in the presence of acetic anhydride and sodium
acetate,6 a number of modified methods have been described for the synthesis of oxazoline

derivatives using other catalysts to replace sodium acetate.7 Several solvent-free conditions under
microwave irradiation have also been reported.8
Due to the misuse of acetic anhydride in narcotic synthesis, this reagent is highly restricted in
some countries. In this case, alternative methods for the Erlenmeyer reaction have been
developed using other dehydrating agents including POCl3,9 carbodiimides,10 polyphosphoric
acid,11 perchloric acid,12 and 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT).13
Although, all of the reported protocols have certain merits, there are still some drawbacks that
limit their practicality including the use of expensive, low availability or hazardous reagents,
prolonged reaction times, high temperatures, and tedious workup and purification procedures.
2,4,6-Trichloro-1,3,5-triazine (TCT) is an effective dehydration reagent which has been
extensively used in a number of functional group transformations.14 Due to its low-cost, ready
availability, and reactivity, TCT could be potentially useful in oxazolone synthesis. Although the
use of TCT in promoting the condensation between hippuric acid and arylaldehydes has already
been reported,13 the reaction in the presence of N-methylmorpholine (NMM) proceeded slowly
in THF at 75 oC giving low product yields.
In a continuation of our on-going research involving TCT,15 herein, we wish to report a simple,
low cost, and low environmental impact protocol for the synthesis of oxazolones mediated by
TCT.
Results and discussion
To optimize the reaction conditions, we were interested in applying a solvent-assisted grinding
technique as a process intensification tool for oxazolone formation.16a This method has proven
effective for improving the reaction rate, product yield, and selectivity in comparison with
classical solution-based methods.16 Additionally, by using minimal solvent during grinding, not
only could a more homogeneous mixing be achieved, but also equipment size can be
dramatically reduced which is highly practical for scale-up.
We first investigated the reaction using hippuric acid and benzaldehyde as model substrates. In
our preliminary study, equimolar amounts of hippuric acid and TCT were ground together in a
mortar in the presence of two equivalents of base and a few drops of THF. After one minute, the

time at which the starting acid completely disappeared, benzaldehyde (1.2 equiv) was added,
followed by grinding for an additional minute.
According to Table 1, the reaction in the presence of organic bases such as NMM or
triethylamine (entries 1 and 2, respectively) gave a complex mixture, possibly due to side-
reactions of the formed quaternary N-triazinylammonium intermediates.17 Using inorganic bases
including cesium carbonate or potassium carbonate also led to the formation of polar by-products
without detectable amounts of 4-benzylidene-2-phenyl-5(4H)-oxazolone (entries 3 and 4).
However, the corresponding product was obtained in moderate yield when using sodium
carbonate (entry 5). It was believed that the carboxylic group of hippuric acid underwent slow
deprotonation with the less soluble base minimizing decomposition of the formed
acyloxytriazine active ester under grinding conditions.
Table 1. Optimization of the reaction conditionsa
Entry
PPh3 (equiv) TCT (equiv) Base
Yield (%)
1
2
3
4
5
6
7
-
1
NMM
Et3N
complex mixture
complex mixture
-
1
-
1
NP
Cs2CO3
K2CO3
Na2CO3
Na2CO3
Na2CO3
-
1
NP
-
1
56
97 (46)b
0.1
0.1
1
0.4
50
aReaction conditions: hippuric acid (0.0970 g, 0.542 mmol), TCT (0.0100 g,
0.542 mmol), base (1.084 mmol), a few drops of THF, 1 min, then
benzaldehyde (0.069 g, 0.650 mmol), 1 min. bYield from the one-pot
procedure where benzaldehyde was added at the beginning of the reaction. NP
= no product
To our delight, by adding a catalytic amount of triphenylphosphine (10 mol%) to the reaction,
the yield was remarkably improved (entry 6), presumably due to the formation of the highly
reactive triazinylphosphonium chloride which rapidly activated hippuric acid toward
cyclization.15f However, a lower yield was obtained when using less than a stoichiometric

amount of TCT (entry 7). This was unsurprising since the activation process should undoubtedly
proceed at a much slower rate with the less reactive di- and mono-chlorotriazines formed after
the initial TCT activation.
It was noted that an attempt to perform a one-pot procedure where benzaldehyde was
added at the beginning of the reaction led to significantly lower product yield (see entry 6, in
parenthesis). This data suggested a rapid decomposition of the formed reactive intermediates in
the presence of the aldehyde. It is also important to noted that, when the reaction conditions in
entry 6 was applied under conventional stirring, no detectable amount of the product was
observed (data not shown) indicating that the grinding process plays an essential role in
accelerating the reaction through increasing the contact surface area between reactants.16a
Table 2. TCT-mediated synthesis of oxazolone
Entry
1
2
3
4
5
6
7
8
ArCHO (Ar- =)
Ph-
2-BrC6H4-
3-BrC6H4-
4-BrC6H4-
3-NO2C6H4-
4-NO2C6H4-
4-MeC6H4-
4-iPrC6H4-
4-MeOC6H4-
3,4-(MeO)2C6H3-
Oxazolone 1
Isolated yield (%)
95
87
91
90
90
95
94
90
92
89
82
1a
1b
1c
1d
1e
1f
1g
1h
1i
9
10
11
1j
1k
12
13
4-HOC6H4-
4-Me2NC6H4-
75
92
1l
1m
14
15
94
85
1n
1o
16
90
1p
aReaction conditions: hippuric acid (0.0970 g, 0.542 mmol), TCT
(0.0100 g, 0.542 mmol), base (1.084 mmol), a few drops of THF, 1 min,
then aldehyde (0.650 mmol), 1 min.

With the optimized reaction conditions in hand (Table 1, entry 6), we turned our attention to
evaluating the scope and limitation of TCT-assisted oxazolone formation. In this context, the
reaction of hippuric acid with a variety of aromatic aldehydes containing electron-withdrawing
or electron-donating groups was investigated.
According to Table 1, benzaldehydes containing electron-withdrawing groups were shown to
react with hippuric acid with comparable rates as those having electron-donating groups. Among
the electron-deficient aldehyde derivatives (entries 2-6), the highly reactive 4-nitrobenzaldehyde
gave the best yield of the corresponding oxazolone (entry 6). Surprisingly, unlike the Erlenmeyer
reaction using acetic anhydride,18 the reaction with the electron-rich aldehydes proceeded
extremely well to provide the products in high yields within short reaction times (entries 7-13).
Notably, the presence of a free hydroxyl group in the starting aldehyde did not significantly
affect the reaction (entry 12). Similarly, allylic and heteroaromatic aldehydes were found to be
compatible with the reaction conditions (entries 14-16).
While the dehydration-condensation reaction between hippuric acid and aromatic aldehydes were
rapid giving oxazolones in high yields, aliphatic aldehydes such as propanal or hexanal failed to
give the desired products even after prolonged reaction times. These results are consistent with
previously reported procedures where reactions using aliphatic aldehydes were sluggish and
generally required additive catalysts or more forcing conditions.5a, 8d, 19, 20
A possible mechanistic pathway for the TCT-mediated oxazolone formation is shown in Scheme
1. The reaction is initiated through the formation of the triazinylphosphonium salt (I).15f
Substitution of the phosphonium ion of I with hippuric acid then produces intermediate II with
release of PPh3 into the catalytic cycle. Cyclization of II provides 2-phenyl-5-oxazolone (III)
which was confirmed by TLC analysis with authentic sample prepared according to the reported
method.7a Further condensation of the intermediate azlactone anion with the aldehyde carbonyl
group then leads to formation of the oxazolone product.8d

Scheme 1. Proposed mechanism for oxazolone formation mediated by the TCT-PPh3 system.
It is important to note also that, unlike the previously reported acetic anhydride-mediated
reactions which often proceed with side-reactions such as the Dakin–West reaction or
condensation of III with the activated hippuric acid giving by-products IV and V (Fig. 1),
respectively, the TCT-mediated oxazolone formation led to clean conversion without these side-
products. It was hypothesized that due to the low basicity of the reaction media and mild reaction
conditions, the competitive side reaction was minimized leading to higher yields of the desired
oxazolones.
Figure 1. Side-products from the acetic anhydride-mediated reactions

Conclusion
In summary, a highly effective mechanochemical synthesis of oxazolone derivatives has been
developed. The TCT/PPh3/Na2CO3 reagent system enables rapid and clean condensation of
hippuric acid with various aromatic aldehydes at room temperature. The method not only
eliminates the use of toxic and limited available acetic anhydride, but also enables effective
synthesis of a series of oxazolones within minutes using inexpensive and easy to handle reagents
with a low volume of solvent minimizing the production of chemical waste.
Acknowledgements
Financial support from the Center of Excellence for Innovation in Chemistry (PERCH-CIC),
Office of the Higher Education Commission, and the graduated school, Chiang Mai University,
Thailand are gratefully acknowledged.
Supplementary data
1H and 13C NMR for representative products are available. Supplementary data related to this
article can be found at http://xxx.
References
1.
2.
Fisk, J. S.; Mosey, R. A.; Tepe, J. J. Chem. Soc. Rev. 2007, 36, 1432.
(a) Mosey, R. A.; Fisk, J. S.; Tepe, J. J. Tetrahedron: Asymm. 2008, 19, 2755. (b)
Esteban, F.; Alfaro, R.; Yuste, F.; Parra, A.; Ruano, J. L. G.; Aleman, J. Eur. J. Org.
Chem. 2014, 2014, 1395.
3.
(a) Cavelier, F.; Verducci, J. Tetrahedron Lett. 1995, 36, 4425. (b) Kobayashi, S.;
Tsukamoto, Y.; Saegusa, T. Macromolecules 1990, 23, 2609.
4.
5.
El-Mekabaty, A. Int. J. Mod. Org. Chem.2013, 2, 40.
(a) Rodrigues, C. A. B.; Mariz, I. F. A.; Macoas, E. M. S.; Afonso, C. A. M.; Martinho, J.
M. G. Dyes Pigm. 2013, 99, 642. (b) Blanco-Lomas, M.; Campos, P. J.; Sampedro, D.
Org. Lett. 2012, 14, 4334.
6.
7.
Erlenmeyer, E. Liebigs Ann. Chem. 1893, 275, 1.
(a) Conway, P. A.; Devine, K.; Paradisi, F. Tetrahedron 2009, 65, 2935. (b) Monk, K. A.;
Sarapa, D.; Mohan, R. S. Synth. Commun. 2000, 30, 3167. (c) Hoseini Jomor, S. J. J.

Chem. Res., Synop. 2003, 638. (d) Romanelli, G.; Autino, J. C.; Vazquez, P.; Pizzio, L.;
Blanco, M.; Caceres, C. Appl. Catal., A 2009, 352, 208. (e) Yu, C.; Zhou, B.; Su, W.; Xu,
Z. Synth. Commun. 2006, 36, 3447. (f) Rao, P. S.; Venkataratnam, R. V. Indian J. Chem.,
Sect. B Org. Chem. Incl. Med. Chem. 1994, 33B, 984. (g) Ahmadi, S. J.; Sadjadi, S.;
Hosseinpour, M. Ultrason. Sonochem. 2013, 20, 408. (h) Kashyap, J.; Chetry, A. B.; Das,
P. J. Synth. Commun. 1998, 28, 4187.
8.
(a) Mobinikhaledi, A.; Moghanian, H.; Pakdel, S. Chin. Chem. Lett. 2015, 26, 557. (b)
Reddy, M. B. M.; Pasha, M. A. Synth. Commun. 2010, 40, 1895. (c) Hamidian, H.;
Tikdari, A. M. Asian J. Chem. 2007, 19, 970. (d) Chandrasekhar, S.; Karri, P.
Tetrahedron Lett. 2007, 48, 785. (e) Hamidian, H.; Tikdari, A. M. Heterocycl. Commun.
2006, 12, 29. (f) Paul, S.; Nanda, P.; Gupta, R.; Loupy, A. Tetrahedron Lett. 2004, 45,
425. (g) Bautista, F. M.; Campelo, J. M.; Garcia, A.; Luna, D.; Marinas, J. M.; Romero,
A. A. J. Chem. Soc., Perkin Trans. 2 2002, 227. (h) Kidwai, M.; Kumar, R.; Kumar, P.
Indian J. Chem., Sect. B Org. Chem. Incl. Med. Chem 1996, 35B, 1004.
9.
Khosropour, A. R.; Khodaei, M. M.; Jomor, S. J. H. J. Heterocycl. Chem. 2008, 45, 683.
(a) Chen, F. M. F.; Kuroda, K.; Benoiton, N. L. Synthesis 1979, 230. (b) Kidwai, M.;
Kumar, R. Org. Prep. Proced. Int. 1998, 30, 451.
10.
11.
12.
13.
Rao, Y. S. J. Org. Chem. 1976, 41, 722.
Boyd, G. V.; Wright, P. H. J. Chem. Soc., Perkin Trans. 1 1972, 909.
Siddaiah, V.; Basha, G. M.; Sudhakar, D.; Srinuvasarao, R.; Kumar, Y. S. Synth.
Commun. 2013, 43, 2191.
14.
15.
(a) Blotny, G. Tetrahedron 2006, 62, 9507. (b) Kaminski, Z. J. Biopolymers 2000, 55,
140.
(a) Pattarawarapan, M.; Jaita, S.; Wangngae, S.; Phakhodee, W. Tetrahedron Lett. 2016,
57, 1354. (b) Wet-osot, S.; Phakhodee, W.; Pattarawarapan, M. Tetrahedron Lett. 2015,
56, 6998. (c) Wet-osot, S.; Duangkamol, C.; Pattarawarapan, M.; Phakhodee, W.
Monatsh. Chem. 2015, 146, 959. (d) Jaita, S.; Phakhodee, W.; Pattarawarapan, M. Synlett
2015, 26, 2006. (e) Duangkamol, C.; Jaita, S.; Wangngae, S.; Phakhodee, W.;
Pattarawarapan, M. RSC Adv. 2015, 5, 52624. (f) Duangkamol, C.; Jaita, S.; Wangngae,
S.; Phakhodee, W.; Pattarawarapan, M. Tetrahedron Lett. 2015, 56, 4997. (g) Jaita, S.;

Kaewkum, P.; Duangkamol, C.; Phakhodee, W.; Pattarawarapan, M. RSC Adv. 2014, 4,
46947.
16.
(a) James, S. L.; Adams, C. J.; Bolm, C.; Braga, D.; Collier, P.; Friscic, T.; Grepioni, F.;
Harris, K. D. M.; Hyett, G.; Jones, W.; Krebs, A.; Mack, J.; Maini, L.; Orpen, A. G.;
Parkin, I. P.; Shearouse, W. C.; Steed, J. W.; Waddell, D. C. Chem. Soc. Rev. 2012, 41,
413. (b) Hernandez, J. G.; Friscic, T. Tetrahedron Lett. 2015, 56, 4253. (c) Aakeroy, C.
B.; Chopade, P. D. Org. Lett. 2011, 13, 1.
17.
18.
Kolesinska, B.; Kaminski, Z. J. Tetrahedron 2009, 65, 3573.
(a) Chavez, F.; Kennedy, N.; Rawalpally, T.; Williamson, R. T.; Cleary, T. Org. Process
Res. Dev. 2010, 14, 579. (b) Cleary, T.; Rawalpally, T.; Kennedy, N.; Chavez, F.
Tetrahedron Lett. 2010, 51, 1533.
19.
20.
Crawford, M.; Little, W. T. J. Chem. Soc. 1959, 729.
Mukerjee, A. K. Heterocycles 1987, 26, 1077.

Graphical Abstract
Leave this area blank for abstract info.
A convenient synthesis of 4-arylidene-2-phenyl-5(4H)-
oxazolones under solvent-assisted grinding
Mookda Pattarawarapan,* Subin Jaita, and Wong Phakhodee

Highlights
 The TCT-mediated synthesis of Erlenmeyer azlactones is reported.
 Condensation of hippuric acid with aromatic aldehydes proceeded rapidly.
 The products were afforded in high yields without column chromatography.