Rapid and efficient synthesis of (R)-aryloxypropionic acid esters under microwave irradiation

Article abstract of DOI:10.1080/00397910903395243

A series of (R)-(+)-ethyl aryloxypropionates (4a-4p) have been synthesized by the reaction of substituted phenols with ethyl (S)-(-)-tosyloxy lactate under the conditions of microwave irradiation and without solvents. The reaction conditions have been optimized. A good method for the preparation of (R)-(+)-ethyl aryloxypropionate was developed, with good yields, high enantiomer excess, short reaction times, easy workup, and simple procedure. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910903395243

This article was downloaded by: [New York University]
On: 15 October 2014, At: 03:26
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/lsyc20
Rapid and Efficient Synthesis of (R)-
Aryloxypropionic Acid Esters Under
Microwave Irradiation
Zbigniew Ochal a , Krzysztof Durka a & Łukasz Banach a
a Warsaw University of Technology, Faculty of Chemistry , Warsaw,
Poland
Published online: 04 Oct 2010.
To cite this article: Zbigniew Ochal , Krzysztof Durka & Łukasz Banach (2010) Rapid and Efficient
Synthesis of (R)-Aryloxypropionic Acid Esters Under Microwave Irradiation, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 40:21, 3209-3213,
DOI: 10.1080/00397910903395243
To link to this article: http://dx.doi.org/10.1080/00397910903395243
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the
“Content”) contained in the publications on our platform. However, Taylor & Francis,
our agents, and our licensors make no representations or warranties whatsoever as to
the accuracy, completeness, or suitability for any purpose of the Content. Any opinions
and views expressed in this publication are the opinions and views of the authors,
and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content
should not be relied upon and should be independently verified with primary sources
of information. Taylor and Francis shall not be liable for any losses, actions, claims,
proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or
howsoever caused arising directly or indirectly in connection with, in relation to or arising
out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden. Terms &

Conditions of access and use can be found at http://www.tandfonline.com/page/terms-
and-conditions

Synthetic Communications1, 40: 3209–3213, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903395243
RAPID AND EFFICIENT SYNTHESIS OF
(R)-ARYLOXYPROPIONIC ACID ESTERS UNDER
MICROWAVE IRRADIATION
Zbigniew Ochal, Krzysztof Durka, and Łukasz Banach
Warsaw University of Technology, Faculty of Chemistry, Warsaw, Poland
A series of (R)-(þ)-ethyl aryloxypropionates (4a–4p) have been synthesized by the
reaction of substituted phenols with ethyl (S)-(ꢀ)-tosyloxy lactate under the conditions
of microwave irradiation and without solvents. The reaction conditions have been optimized.
A good method for the preparation of (R)-(þ)-ethyl aryloxypropionate was developed,
with good yields, high enantiomer excess, short reaction times, easy workup, and simple
procedure.
Keywords: (R)-(þ)-Ethyl aryloxypropionates; microwave irradiation; pesticides; solvent-free organic
synthesis
INTRODUCTION
Aryloxypropionic acids are known as systemic hormone-type selective herbi-
cides and plant-growth regulators that control postemergent broad-leaved weeds
in crops. Some are also used at much lower rates to prevent premature drop of
apples. Many aryloxypropionic esters and N-substituted amides have been also used
as selective weed killers in the presence of cereal crops. Acids, esters, and amides are
commonly applied in agriculture in compounds such as mecoprop, dichlorprop, clo-
prop, fluazifop-P, diclofop methyl, napropamid, naproanilid, and others.[1] We have
also proved that some phenoxypropionic acid derivatives show fungicidal activity.[2]
Phenoxypropionic acid derivatives and phenoxyacetic acid derivatives are comp-
lementary to each other in their spectrum of herbicidal activity.[3] Phenoxypropionic
acid derivatives also have been investigated as pharmaceutical substances; they
posses analgesic, anti-inflammatory, and hypolipemic activity.[4–6] In addition, they
are important intermediates in many reactions.[7] Aryloxypropionic acid derivatives
are usually applied in agriculture as racemic substances. On the other hand, it is
known that only (R)-enantiomers are responsible for biological activity. Other ones
are usually less active or inactive and cause pollution of the environment.
There are not many methods of obtaining biologically effective (R)-enantiomers
of aryloxypropionic acid derivatives. The most common synthesis of
Received August 7, 2009.
Address correspondence to Zbigniew Ochal, Warsaw University of Technology, Faculty of
Chemistry, Noakowskiego 3, PL-00-664 Warsaw, Poland. E-mail: ochal@ch.pw.edu.pl
3209

3210
Z. OCHAL, K. DURKA, AND Ł. BANACH
(R)-aryloxypropionic acid esters is Effenberger and Burkard’s[8] method, using com-
mercially available (S)-(ꢀ)-ethyl lactate, which was transformed in the first step into
(S)-(ꢀ)-2-sulfonyloxy esters by reaction with various sulfonyl chlorides. (S)-(ꢀ)-2-
Sulfonyloxy lactate was subjected to the SN-2 type reaction with phenols to give (R)
enantiomers of phenoxypropionates.
Many publications describe utilization of this type of reactions to the synthesis
of phenoxypropionic acid esters, changing some conditions of process, such as sol-
vent or base.[9,10] The esters were also prepared by Williamson’s reaction, through
the nucleophilic substitution of halogen in (S)-(ꢀ)-halopropionic esters by aryloxide
anion.[11–14] The first ones are not easily available substances. It was also reported
that (S)-(ꢀ)-ethyl lactate reacts with substituted phenols in conditions of the
Mitsunobu reaction[15,16] to give (R)-aryloxypropionic acid esters, but yields and
enantiomer excess were not satisfactory. Conventional methods of synthesis of
corresponding esters have some disadvantages, such as a long reaction time, poor
yields, large amounts of toxic solvents, and inconvenient workup.
In recent years, the use of microwave irradiation in organic synthesis has received
considerable attention. This technology can enhance the yield, increase the purity of the
resulting products, shorten the reaction time, and eliminate the solvents, which are not
beneficial for the environment. Some phenoxyacetic acid derivatives were successfully
synthesized by Williamson’s reaction under microwave irradiation.[17,18]
This article is part of our work on the synthesis and biological activity of ary-
loxypropionic acid derivatives.[19–21] Herein, we report a convenient, solvent-free,
and high-yielding method for the rapid synthesis of (R)-aryloxypropionic acid ethyl
esters under microwave irradiation. The reactions are shown in Scheme 1.
The starting (S)-(ꢀ)-ethyl tosyloxylactate 2 was synthesized using commercially
available (S)-(ꢀ)-ethyl lactate 1 and tosyl chloride in the presence of triethylamine.
The second step of this synthesis was the subject of our work. We found that ethyl
aryloxypropionates could be prepared in good yields and good enantiomer excess
within several minutes by applying microwave irradiation without solvents. We carried
out parallel reactions that were not subjected to microwave irradiation, but oil bath
heating was applied only. To obtain yields comparable to those achieved by micro-
wave irradiation, it was necessary to run the process for 4–6 h at 125–130 ꢁC. Enatio-
mer excesses (ee) of products in several cases were also lower than to microwave
irradiation (mv) reactions. In the first case, the reactions were irradiated for several
minutes with equimolar amounts of substrates placed in a quartz flask. In searching
Scheme 1. Synthesis of (R)-aryloxypropionic acid ethyl esters under microwave irradiation.

(R)-ARYLOXYPROPIONIC ACID ESTERS
3211
Table 1. Properties and yields of (R)-2-phenoxypropionic acid derivatives obtained under microwave
irradiation
25
Power of
microwave
(W)
Temp. of
reaction
(ꢁC)
Time of
irradiation
(min)
½aꢂD
(CH2Cl2),
c ¼ 5
Yield
(%)
ee
(%)
Compound
R
4a
4b
4c
4d
4e
4f
H
2-Cl
75
75
80
75
75
75
75
75
90
75
60
60
75
75
75
90
100
112
104
105
99
12
15
12
20
15
18
15
15
15
15
15
15
18
15
15
20
93.9
86.2
88.7
91.7
94.2
90.1
94.6
91.7
92.1
83.0
81.7
80.0
79.5
76.0
74.8
88.9
35.30
32.10
32.60
28.20
24.10
29.90
36.85
35.80
27.65
32.70
31.90
33.55
24.70
36.30
38.90
29.30
92.2
—
4-Cl
93.3
92.9a
88.7
—
4-Cl-2-CH3
2,3,5-(CH3)3
2,4-Cl2
102
104
110
96
4g
4h
4i
3,4-Cl2
3,5-Cl2
91.8
93.6
92.6
91.4
93.2
92.2
—
4-Cl-3-CH3
4-Cl-3,5-(CH3)2
3-Br
4j
108
98
4k
4l
4-Br
2,4-Br2
96
4m
4n
4o
4p
105
109
106
104
3-NO2
4-NO2
2,6-(OCH3)2
89.7
90.4
—
aEnantiomeric excess of acid obtained by alkaline hydrolysis of ester determined by HPLC using an S, S
Whelk 01 column.
for the best reaction conditions, we carried out a series of experiments, changing the
time and power of irradiation. The reaction mixture was subjected to microwave
irradiation (100–150W), and every 5 min of irradiation was followed by a 1-min inter-
val. After 10–15 min, the reaction was completed. Products were isolated by filtration
or extraction. The ee of products was determined by high-performance liquid chroma-
tography (HPLC) using chiral column Chiracel OD-H. In some cases, this column did
not give satisfactory results. Parameters of each reaction were optimized for each
phenol. The reaction time, power of irradiation, yields, and properties of obtained
compounds are summarized in Table 1.
In conclusion,
a
good method was found for the synthesis of
(R)-aryloxypropionic acid ethyl esters under microwave irradiation. The method
possesses the advantages of speed, high yield, good enantiomer excess, and ease of
workup over the reported methods without the toxic solvents.
EXPERIMENTAL
Microwave irradiation was carried out with a commercial microwave oven, type
Maxidigest MX-350 Prolabo. Optical rotations were measured at D wavelength with
a P-20 Bellingham and Stanley polarimeter; c is expressed as g=100 ml of solvent.

3212
Z. OCHAL, K. DURKA, AND Ł. BANACH
HPLC analyses were conducted by employing a Spectra Series P-100 Thermo-
Separation Products chromatograph equipped with chiral column (Chiracel OD-H,
150 ꢃ 4.6 mm, from Daicel Chemical Industries). Hexane and 2-propanol 98:2 (v=v)
were as a mobile phase. Flow rates varied from 0.6 to 1.0 ml=min.
General Procedure
(S)-(ꢀ)-Ethyl tosyloxypropionate (3 mmol), proper phenol (3 mmol), and
anhydrous K2CO3 (3 mmol) were placed in quartz round-bottomed tube reactor
(20 mL) equipped with mechanical stirrer. The mixture was stirred and irradiated
by microwaves (100–150 W) for 10–15 min. Every 5 min of irradiation were followed
by 1-min intervals. When the reaction completed, as monitored by thin-layer
chromatography (TLC), the mixture was cooled, the product was filtered off, and
the precipitate was washed by methylene chloride to give, after evaporating the
solvent, the second part of product.
ACKNOWLEDGMENT
This work was financially supported by the Polish State Committee for
Scientific Research Grant No. N N209 119937 and Warsaw Technical University.
REFERENCES
1. Tomlin, C. D. S. The Pesticide Manual: A World Compendium, 13th ed. British Crop
Protection Council, Farnham, UK, 2003.
´
2. Bakuniak, E.; Ptaszkowska, J.; Ziminska, Z.; Tippe, A.; Ejmocki, Z.; Ochal, Z.
Compounds with fungicidal and herbicidal activity. PL Patent 171529 B1, 1997; Chem.
Abstr. 1997, 127, 157949e.
3. Wegler, R. Chemie der Pflanzenschutz und Schadlingsbekampfungsmittel, band 8;
Springer-Verlag: Berlin, 1982.
4. Azzolina, O.; Collina, S.; Vercesi, D.; Ghislandi, V.; Bonabello, A.; Galmozzi, M. R.
Chiral resolution, configurational study, and pharmacological profile of 2-phenoxypro-
pionic acids. Farmaco 1997, 52, 449–456.
5. Astoin, J.; Lepage, F.; Fromantin, J. P.; Poisson, M. Proprietes analgesiques et
anti-inflammatoires d’acides m-benzoyl phenoxy alcanoiques. Eur. J. Med. Chem. 1980,
15, 457–462.
6. Metz, G.; Specker, M. Hypolipemic activity of clofibrate-related compounds. Arzneim.
Forsch. (Drug Res.) 1975, 25, 1686–1692.
7. Ochal, Z.; Krawczyk, M.; Wyrzykowska, U. Use of 2-phenoxypropionates for synthesis of
1,3-pentanedione derivatives. Przem. Chem. 2007, 86(6), 501–505.
8. Burkard, U.; Effenberger, F. Racemisierungsfreie Substitution von 2-(Sulfonyloxy)
carbonsaureestern mit Sauerstoff- und Schwefelnucleophilen. Chem. Ber. 1986, 119,
1594–1601.
9. Villa, L.; Valoti, E.; Villa, A. M.; Pallavicini, M.; Ferri, V.; Iuliano, E.; Brunello, N.
Molecular properties of the WB141 enantiomers and of its chiral methyl derivatives for
alpha 1-adrenoceptor recognition. Farmaco 1994, 49, 587–606.
10. Otera, J.; Nakazawa, K.; Sekoguchi, K.; Orita, A. CsF in organic synthesis: Inversion of
secondary mesylates and tosylates. Tetrahedron 1997, 53, 13633–13640.

(R)-ARYLOXYPROPIONIC ACID ESTERS
3213
11. Koch, M. Optically active D-(phenoxy- or benzyl) phenoxypropionic acids and their alkali
metal salts. Ger. Patent 2,854,542 A1, 1980; Chem. Abstr. 1980, 93, 204280w.
12. Tai, J. J. Process for the preparation of optically active 2-[4-(20,40-
dihalophenoxy)phenoxy]propionic acids. US Patent 4,757,155, 1988; Chem Abstr. 1988,
109, 170039f.
13. Suzuki, K.; Hashiba, I.; Tsuchiya, S.; Takakuwa, Y. Optically active
2-(4-hydroxyphenoxy)propionic acid as herbicide intermediate. Jpn. Patent 6,216,446,
1987; Chem. Abstr. 1987, 107, 39415s.
14. Metivier, J.; Sauli, M. 2-Phenoxypropionic acids. Fr. Patent 1,479,271, 1967; Chem. Abstr.
1968, 68, 95549b.
15. Varasi, M.; Walker, K. A. M.; Maddox, M. L. A revised mechanism for the Mitsunobu
reaction. J. Org. Chem. 1987, 52, 4235–4238.
16. Heumann, A.; Faure, R. Fluorinated lactic acids: Easily accessible reagents for the analy-
sis of chiral compounds by fluorine-19 NMR spectroscopy: 19F NMR separation of the
eight isomers of menthol. J. Org. Chem. 1993, 58, 1276–1279.
17. Villemin, D.; Hammadi, M. Environmentally desirable synthesis without use of organic
solvent: Synthesis of aryloxyacetic acids. Synth. Commun. 1996, 26, 4337–4341.
18. Wei, T.-B.; Liu, H.; Li, M.-L.; Zhang, Y.-M. Rapid and high yield synthesis of aryloxya-
cetates under microwave irradiation and phase-transfer catalysis conditions. Synth.
Commun. 2005, 35, 1759–1766.
19. Ejmocki, Z.; Gajadhur, A.; Mizerski, A.; Ochal, Z. (R)-2-Phenoxy-N-phenylpropiona-
mide derivatives with fluoro-, difluoro-, and trifluoromethylsulfonyl groups. PL Patent
192013 B1, 2006; Chem Abstr. 2007, 147, 257549f.
20. Ochal, Z.; Gajadhur, A. Synthesis of (R)- and (S)-2-phenoxypropionamide derivatives as
new compounds with promising pesticidal activity. Pol. J. Appl. Chem. 2004, 47, 33–43.
21. Ochal, Z.; Gała˛zka, J. Synthesis of (R)- and (S)-2-[4-(40-difluoromethylsulfonyl-
20-nitrophenylamino)phenoxy] propionic acid derivatives as new pesticides. Pol. J. Appl.
Chem. 2006, 50, 13–27.