One-step protection-free synthesis of 3-aryl-5-hydroxyalkyl-1,2,4- oxadiazoles as building blocks

Article abstract of DOI:10.1080/00397911.2012.724757

A simple and straightforward synthesis of 3-aryl-5-hydroxyalkyl-1,2,4- oxadiazoles is described. The reaction among arylamidoximes, ethyl glycolate or ethyl lactate, and potassium carbonate in refluxing toluene afforded the desired 1,2,4-oxadiazoles in moderate to good yields. The synthesis has been accomplished in a single step, avoiding protection-deprotection protocols. Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications to view the free supplemental file.

Full text of DOI:10.1080/00397911.2012.724757

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One-Step Protection-Free Synthesis of 3-
Aryl-5-hydroxyalkyl-1,2,4-oxadiazoles as
Building Blocks
Ricardo A. W. Neves Filho a , Diana C. B. da Silva-Alves a , Janaína V.
dos Anjos a & Rajendra M. Srivastava a
a Departamento de Química Fundamental , Universidade Federal de
Pernambuco , Recife , Brazil
Accepted author version posted online: 26 Mar 2013.Published
online: 26 Jun 2013.
To cite this article: Ricardo A. W. Neves Filho , Diana C. B. da Silva-Alves , Janaína V. dos Anjos &
Rajendra M. Srivastava (2013): One-Step Protection-Free Synthesis of 3-Aryl-5-hydroxyalkyl-1,2,4-
oxadiazoles as Building Blocks, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 43:19, 2596-2602
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Synthetic Communications1, 43: 2596–2602, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2012.724757
ONE-STEP PROTECTION-FREE SYNTHESIS
OF 3-ARYL-5-HYDROXYALKYL-1,2,4-OXADIAZOLES
AS BUILDING BLOCKS
Ricardo A. W. Neves Filho, Diana C. B. da Silva-Alves,
´
Janaına V. dos Anjos, and Rajendra M. Srivastava
Departamento de Quımica Fundamental, Universidade Federal de
´
Pernambuco, Recife, Brazil
GRAPHICAL ABSTRACT
Abstract A simple and straightforward synthesis of 3-aryl-5-hydroxyalkyl-1,2,4-oxadia-
zoles is described. The reaction among arylamidoximes, ethyl glycolate or ethyl lactate,
and potassium carbonate in refluxing toluene afforded the desired 1,2,4-oxadiazoles in
moderate to good yields. The synthesis has been accomplished in a single step, avoiding
protection–deprotection protocols.
Supplemental materials are available for this article. Go to the publisher’s online edition
of Synthetic Communications1 to view the free supplemental file.
Keywords Cyclodehydration; 1,2,4-oxadiazoles; thermal reaction
INTRODUCTION
1,2,4-Oxadiazole-containing compounds have been attracting great attention
because of their applications in therapeutics and materials chemistry.[1–5] When
employed as a pharmacophore, the 1,2,4-oxadiazole ring has been used as anti-
inflammatory,[6] apoptosis inducing,[7] antimicrobial,[8,9] larvicidal,[10] and cytotoxic[11]
agent, for example. In particular, 3-aryl-5-hydroxyalkyl-1,2,4-oxadiazoles are
noteworthy because they were widely employed as 5-lipoxygenase activating protein
inhibitors;[12] N-type calcium channel antagonists;[13] inhibitors of stearoyl-coenzyme-
A delta-9 desaturase;[14] stearoyl-CoA desaturase inhibitors for treatment of obesity,
diabetes, and metabolism-related diseases;[15] and bombesin-2 (BB2) receptor antago-
nists for treating cancer and Alzheimer disease.[16] Furthermore, these compounds
Received July 10, 2012.
Address correspondence to Rajendra M. Srivastava, Departamento de Quımica Fundamental,
´
Universidade Federal de Pernambuco, 50740 540 Recife, PE, Brazil. E-mail: rms@ufpe.br
2596

ONE-STEP SYNTHESIS OF HYDROXYALKYL-OXADIAZOLES
2597
Scheme 1. Synthesis of oxadiazoles 3–19 from arylamidoximes 1a–j and esters 2a–b.
have also presented low toxicity (>800 mg=kg of body weight) and sedative action at
doses as low as 50–75 mg=kg when injected in mice or rats intraperitoneally.[17] More-
over, other compounds containing the 3-aryl-5-hydroxymethyl-1,2,4-oxadiazole
moiety have been employed as fungicides, pesticides,[18] and building blocks for
synthesizing biologically active compounds.[19–23]
Because of the great importance of title compounds, there is a vast industrial
interest in this class of oxadiazoles because some of them are commercially available,
but in gram quantities.[24] Therefore, it would be nice to achieve their synthesis in
a simple and cost-effective manner.
The most common method for the preparation of 1,2,4-oxadiazole ring-containing
compounds is the acylation of amidoximes followed by cyclodehydration.[1,25,26] In
addition, all known procedures achieving 3-aryl-5-hydroxymethyl-1,2,4-oxadiazoles
from amidoximes and glycolic acid derivatives involve protection–deprotection
protocols. This is done to avoid the acylation of OH moiety in ethyl glycolate or
ethyl lactate.[17,20,27] Recently, it has been disclosed that the base-catalyzed thermal
reaction between carboxylic acid esters and amidoximes furnishes 1,2,4-oxadia-
zoles.[28–30] Lately, our research group has successfully synthesized functionalized
1,2,4-oxadiazoles by reacting arylamidoximes and methyl levulinate in the presence
of potassium carbonate under solvent-free microwave irradiation.[30] Although it
is well established that transesterification is achieved by heating a carboxylic acid
ester and an alcohol in the presence of a strong base, there is no report concerning
this type of reaction by using a relatively weaker base such as potassium carbonate.
In this article, we report the preparation of title compounds 3–19 by the reaction of
arylamidoximes 1a–j and ethyl glycolate 2a in the presence of K2CO3 in refluxing
toluene. We have also extended this method for synthesizing 3-aryl-5-(hydroxyeth-
1-yl)-1,2,4-oxadiazoles 13–19 by employing S-ethyl lactate 2b (Scheme 1). The
literature does not report such syntheses.
RESULTS AND DISCUSSION
Initially, we tried the reaction of amidoxime 1a and ethyl glycolate 2a using
toluene as a solvent, but the reaction did not proceed, possibly because of the poor
miscibility of ester 2a in this solvent. Therefore, we have used dimethylformamide

2598
R. A. W. NEVES FILHO ET AL.
(DMF) as a cosolvent. Thus, a mixture of toluene–DMF (9:1) worked well for com-
pounds 3–10 and 13–19, but better yields were achieved for compounds 11 and 12
when we changed the ratio of toluene and DMF to 7:3. Water removal during the
reaction by using a Dean–Stark apparatus helped to complete the reaction. It is note-
worthy to find that using K2CO3 as a base results in better chemical yields compared
to the use of Na2CO3. Expensive cesium carbonate can also be used for this end
without any improvement either in the reaction time or yields. We have also inves-
tigated microwave (MW) irradiation for substrates 1a and 2a; the reaction completed
in 10min, but the yield (24%) was quite poor in comparison with the solution pro-
cedure. However, we have also observed the formation of a large quantity of 3,5-
diphenyl-1,2,4-oxadiazole in the MW experiments, probably due to thermal homocou-
pling reaction of two arylamidoxime molecules.[31] After attaining the right conditions,
we succeeded in synthesizing 17 different 1,2,4-oxadiazoles 3–19 containing a hydroxy-
methyl group attached to the C-5 side chain of the heterocyclic ring by the reaction of
aryl amidoximes 1a–j and ethyl glycolate 2a or ethyl lactate 2b (Table 1).
It can be noticed that electron-releasing as well as electron-removing groups
at the para position of the phenyl ring do not influence the reaction. Although this
procedure works well and appears promising, there is one limitation. For example,
when amidoximes containing a nitrogen atom inside or outside the phenyl ring
(e.g., 1i and 1j), were used, the yields were quite poor. Increasing the polarity of
the solvent system (toluene–dimethylformamide, 7:3) improved the yields but to
a lesser extent compared to other arylamidoximes without having a nitrogen atom
(see Table 1).
To verify the application of our method in multigram synthesis, the reaction of
1a with 2a was performed at a 25 mmol scale with impressive results (the yield of the
Table 1. Melting points and yields of compounds 3–19
Compound
Ar
R
Yield (%)
M.p. (ꢀC)
M.p. (ꢀC) Lit.31
3
4
C6H5
H
H
69 (67)a
57
72
59–60
58–59
84–85
93–94
94–95
113–114
155–156
124–125
176–177
152–153
Oil
56–60
–
3-CH3-C6H4
4-CH3-C6H4
4-Cl-C6H4
5
H
–
95–96
6
H
70
73
7
4-Br-C6H4
4-I-C6H4
H
–
8
H
76
68
–
158–159
9
4-CH3O-C6H4
4-NO2-C6H4
4-AcNH-C6H4
4-Pyridyl
H
10
11
12
13
14
15
16
17
18
19
H
56
–
H
22 (45)b
5 (35)b
70
–
N.A.
H
C6H5
CH3
CH3
CH3
CH3
CH3
CH3
CH3
–
–
–
–
–
–
–
3-CH3-C6H4
4-CH3-C6H4
4-Cl-C6H4
66
72
Oil
Oil
68
63
75–76
90–91
83–84
151–152
4-Br-C6H4
4-CH3O-C6H4
4-NO2-C6H4
66
51
aExperiment performed at 25 mmol scale.
bYields in parenthesis indicates the use of 7:3 toluene:DMF (V=V) system during the reaction.

ONE-STEP SYNTHESIS OF HYDROXYALKYL-OXADIAZOLES
2599
product 3 was 69%). These findings show that it could be possible to scale up the
newly developed protocol at a much larger scale.
Next, we tried to perform the same reaction by using ethyl lactate. The method
has worked well in all cases. We also observed total racemization of the products, as
verified by optical rotation measurements.
Because the final products 13–19 have been found as racemic, it is obvious that
potassium carbonate in refluxing toluene did the job. At the moment, it is not clear if
optically active ethyl lactate suffered any racemization (partial or total) before react-
ing with arylamidoximes. Even if the optically active ester reacted as such with ary-
lamidoximes to form the intermediates possessing an asymmetric carbon atom, the
latter could undergo racemization before cyclization or after cyclization to provide
inactive 5-(hydroxyeth-1-yl)-3-aryl-1,2,4-oxadiazoles 13–19. It appears to us that it
has been a gradual process from the beginning until the end of the reaction, although
we cannot be sure about it.
We also employed the same reaction protocol employing thioglycolic acid
methyl ester instead of 2. In this reaction, we have observed the formation of a com-
plex mixture of products and decomposition of the starting materials.
The key to success for the reaction between 1 and 2 is the quick formation of a
resonance-stabilized anion at the oxygen atom of arylamidoxime in the presence of
K2CO3, which consequently attacks the carbonyl carbon atom of the ester group fol-
lowed by the ejection of the ethoxy group with the formation of O-acyl derivative of
aryl amidoxime. The O-acyl derivative then cyclodehydrates to furnish the product
(Scheme 2).
As observed, the unprotected –OH group of ethyl glycolate and ethyl lactate
did not cause any significant difficulty in the reaction in the presence of K2CO3. Even
if it has removed the proton from the –OH group, the oxygen atom would not be
Scheme 2. Mechanism of formation of 1,2,4-oxadiazoles 3–19 from compounds 1 and 2.
Figure 1. Complexation of potassium cation with negatively charged esters 2a and 2b.

2600
R. A. W. NEVES FILHO ET AL.
able to stabilize the negative charge on it, although it would form a five-membered
complex with potassium cation (Fig. 1). This unique situation could allow the reac-
tion to proceed without protection of –OH in 2a and 2b, respectively.
In summary, we have developed a direct protection–deprotection-free approach
for synthesizing 3-aryl-5-hydroxyalkyl-1,2,4-oxadiazoles (3–19). The base-mediated
reaction between amidoximes 1a–j and esters 2a and 2b furnished the desired
products in good yields and presented a large scope of applications. This protocol
has successfully been scaled up to 25 mmol quantity. Thus this procedure appears
to be suitable for further applications at larger scales.
EXPERIMENTAL
All reagents were obtained from commercial sources and used without further
purification. Infrared (IR) spectra of the compounds were recorded on a Perkin-Elmer
model 283 spectrometer employing KBr pellets. 1H NMR spectra were obtained with
a Varian 300-MHz instrument using tetramethylsilane (TMS) as the internal standard.
13C NMR spectra were recorded on a Varian 75-MHz spectrometer. Elemental analysis
was performed with a Carlo Erba instrument model E-1110. Optical rotations were
recorded using a Jasco P2000 polarimeter. Thin-layer chromatography (TLC) was
performed on plates coated with silica gel containing GF254 as fluorescent indicator.
The solvent system for the development was CHCl3–EtOAc (7:3).
Typical Experimental Procedure
In a round bottom flask equipped with a reflux condenser and a Dean–Stark
trap, the suitable arylamidoxime 1a–j (5 mmol) and carboxylic acid ethyl ester 2a
or 2b (7.5 mmol) were dissolved in a mixture of toluene:DMF (9:1, v=v) (80 mL).
Then, potassium carbonate (0.83 g, 6 mmol) was added. The contents were stirred
under reflux for 8 h. The contents in the flask were diluted with ethyl acetate
(40 mL) and water (40 mL). The phases were separated and the organic layer was
washed with 1 M aqueous hydrochloric acid solution (40 mL), saturated NaHCO3
solution (40 mL) and then with a saturated brine solution (40 mL). The resulting
organic phase was dried over anhydrous sodium sulfate. Solvent removal under
reduced pressure provided the crude product, which could be purified either by
crystallization or by column chromatography.
5-Hydroxymethyl-3-phenyl-1,2,4-oxadiazole (3)
Colorless crystals (69%), crystallized from EtOAc and n-hexane, mp: 59–60 ꢀC.
1
(lit.[16]): 58–60 ꢀC. IR (KBr): 3293, 2909, 1598 cmꢁ1. H NMR (300 MHz, CDCl3) d
(ppm): 4.01 (bs, 1H), 4.5 (s, 2H), 7.43–7.53 (m, 3H), 8.02 (d, J ¼ 9.6 Hz, 2H), 13C
NMR (75 MHz, CDCl3): 56.3, 126.0, 127.3, 128.9, 131.5, 168, 178.5.
SUPPORTING INFORMATION
Full experimental details and spectroscopic data (1H and 13C NMR spectra)
for compounds 3–19 can be found via the Supplementary Content section of this
article’s Web page.

ONE-STEP SYNTHESIS OF HYDROXYALKYL-OXADIAZOLES
2601
ACKNOWLEDGMENTS
Our thanks go to the Brazilian National Research Council (CNPq) and Pernam-
buco State’s Scientific and Research Foundation (FACEPE, PRONEX-0788-1.06=08
CNPq) for providing financial assistance. One of us (R. A. W. N. F.) is grateful to
CNPq for a technician’s fellowship.
REFERENCES
1. Jakopin, Z.; Dolenc, M. S. Curr. Org. Chem. 2008, 12, 850–898.
2. Tiwari, S. B.; Kohli, D. V. Med. Chem. Res. 2008, 17, 386–398.
3. Lankau, H. J.; Unverferth, K.; Grunwald, C.; Hartenhauer, H.; Heinecke, K.; Bernoster,
K.; Dost, R.; Egerland, U.; Rundfeldt, C. Eur. J. Med. Chem. 2007, 42, 873–879.
4. Gallardo, H.; Cristiano, R.; Vieira, A. A.; Neves Filho, R. A. W.; Srivastava, R. M.;
Bechtold, I. H. Liq. Cryst. 2008, 35, 857–863.
5. Gallardo, H.; Cristiano, R.; Vieira, A. A.; Neves Filho, R. A. W.; Srivastava, R. M.
Synthesis 2008, 605–609.
6. Ispikoudi, M.; Amvrazis, M.; Kontogiorgis, C.; Koumbis, A. E.; Litinas, K. E.;
Hadjipavlou-Litina, D.; Fylaktakidou, K. C. Eur J. Med. Chem. 2010, 45, 5635–5645.
7. Ziedan, N. I.; Stefanelli, F.; Fogli, S.; Westwell, A. D. Eur J. Med. Chem. 2010, 45,
4523–4530.
8. Rai, N. P.; Narayanaswamy, V. K.; Govender, T.; Manuprasad, B. K.; Shashikanth, S.;
Arunachalam, P. N. Eur J. Med. Chem. 2010, 45, 2677–2682.
9. Tka, N.; Hassine, N. B. Synth. Commun. 2010, 40, 3168–3176.
10. Neves Filho, R. A. W.; Silva, C. A.; Silva, C. S.; Brustein, V. P.; Navarro, D. M. A. F.;
dos Santos, F. A.; Alves, L. C.; Cavalcanti, M. G. S.; Srivastava, R. M.; Carneiro-
Da-Cunha, M. G. Chem. Pharm. Bull. 2009, 57, 819–825.
11. dos Anjos, J. V.; Neves Filho, R. A. W.; Nascimento, S. C.; Srivastava, R. M.; Melo,
S. J.; Sinou, D. Eur. J. Med. Chem. 2009, 44, 3571–3576.
12. Chu, L.; Li, B.; Ogawa, A. K.; Ok, H. O.; Ondeyka, D. L.; Patel, M.; Sisco, R.;
Ujjainwalla, F.; Xu, J. PCT Int. Appl. 2007, WO patent 2007120574 A2; Chem. Abstr.
2007, 147, 486423.
13. Hobbs, C. J.; Lynch, R.; Mellor, S. L.; Radford, F.; Gilbert, J. C.; Stokes, S.; Glen, A.;
Fuimana, A.; Earnshaw, C. G.; Lars, J. S.; Dean, K. E. S. PCT Int. Appl. 2006, WO
patent 2006030211 A2; Chem. Abstr. 2006, 144, 390924.
14. Li, C. S.; Ramtohul, Y. K. PCT Int. Appl. 2007, WO patent 2007143824 A1; Chem. Abstr.
2007, 148, 78875.
15. Taniguchi, T.; Miyata, K.; Kubo, O. PCT Int. Appl. 2008, WO patent 2008044767 A1;
Chem. Abstr. 2008, 148, 42912.
16. Galley, G.; Kitas, E. A.; Jakob-Roetne, R. PCT Int. Appl. 2006, WO patent 2006005486
A1; Chem. Abstr. 2006, 144, 128869.
17. Palazzo, G.; Silvestrini, B. Boll. Chim. Farm. 1962, 101, 251–253.
18. Oh, C. H.; Dong, H. G.; Lee, J. S.; Lee, S. C.; Hong, J. H.; Cho, J. H. Arch. Pharm. 2003,
336, 567–572.
19. Rhee, J. K.; Im, W. B.; Cho, C. H.; Choi, S. H.; Lee, T. H. PCT Int. Appl. 2005, WO
patent 2005058886 A1; Chem. Abstr. 2005, 143, 97343.
20. Fyfe, M.; Gardner, L.; King-Underwood, J.; Procter, M.; Rasamison, C.; Schofield, K.;
Thomas, G. H. PCT Int. Appl. 2005, WO patent 2005061489 A1; Chem. Abstr. 2005,
143, 115543.

2602
R. A. W. NEVES FILHO ET AL.
21. Aldous, D. J.; Smith, G. F.; Astles, P. C.; Pickett, S. D.; McLay, I. M.; Stuttle, K. A. J.;
Ratcliffe, A. J. PCT Int. Appl. 1997, WO patent 9703967 A1; Chem. Abstr. 1997, 126,
212048.
22. Palazzo, G.; Baiocchi, L.; Picconi, G. J. Heterocycl. Chem. 1979, 16, 1469–1475.
23. Kuduk, S. D.; Bock, M. G.; Feng, D.-M.; Wai, J. M.-C. U. S. Pat. Appl. Publ. 2004,
US 20040063761 A1; Chem. Abstr. 2004, 140, 303540.
24. UkrOrgSynthesis Building Blocks, Alinda Chemical Ltd. Building Blocks, ChemBridge
Building Block Library, AKos Building Blocks Product List, and Bio-Farma Product List.
25. Braga, V. M. L.; Melo, S. J.; Srivastava, R. M.; Falca˜o, E. P. S. J. Braz. Chem. Soc. 2004,
15, 603–607.
26. Melo, S. J.; Sobral, A. D.; Lopes, H. L.; Srivastava, R. M. J. Braz. Chem. Soc. 1998,
9, 465–468.
27. Palazzo, G. US 3270028, 1966; Chem. Abstr. 1966, 65, 108075.
28. Amarasinghe, K. K. D.; Maier, M. B.; Srivastava, A.; Gray, J. L. Tetrahedron Lett. 2006,
47, 3629–3631.
29. Du, W.; Truong, Q.; Qi, H. B.; Guo, Y.; Chobanian, H. R.; Hagmann, W. K.; Hale, J. J.
Tetrahedron Lett. 2007, 48, 2231–2235.
30. de Freitas, J. J. R.; Freitas, J. C. R.; da Silva, L. P.; de Freitas, J. R.; Kimura, G. Y. V.;
Srivastava, R. M. Tetrahedron Lett. 2007, 48, 6195–6198.
31. Leite, L. F. C. C.; Srivastava, R. M.; Cavalcanti, A. P. Bull. Soc. Chim. Belg. 1989, 98,
203–210.