A convenient synthesis of 5-amino-substituted 1,2,4-oxadiazole derivatives via reactions of amidoximes with carbodiimides

Article abstract of DOI:10.3987/COM-08-11340

5-Amino substituted 1,2,4-oxadiazole derivatives were easily prepared, in one step and in high yields, via reactions of a variety of aryl, benzyl, cycloalkyl and alkyl amidoximes with commercially available carbodiimides. Alkyl carbodiimides reacted with amidoximes in toluene to give 5-alkylamino-l,2,4-oxadiazoles, whereas aromatic carbodiimide reacted in DMF to give initially the intermediate O-amidoxime adducts, which were further cyclized to the corresponding 5-arylamino-1,2,4-oxadiazoles.

Full text of DOI:10.3987/COM-08-11340

HETEROCYCLES, Vol. 75, No. 6, 2008
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HETEROCYCLES, Vol. 75, No. 6, 2008, pp. 1321 - 1328. © The Japan Institute of Heterocyclic Chemistry
Received, 16th January, 2008, Accepted, 18th February, 2008, Published online, 22nd February, 2008. COM-08-11340
A CONVENIENT SYNTHESIS OF 5-AMINO-SUBSTITUTED 1,2,4-
OXADIAZOLE DERIVATIVES VIA REACTIONS OF AMIDOXIMES
WITH CARBODIIMIDES†
Maria Ispikoudi,a Konstantinos E. Litinas,b and Konstantina C.
Fylaktakidoua,*
aMolecular Biology and Genetics Department, Democritus University of Thrace,
68100 Alexandroupolis, Greece; E-mail: kfylakta@mbg.duth.gr
bLaboratory of Organic Chemistry, Aristotle University of Thessaloniki, 54124
Thessaloniki, Greece
Abstract - 5-Amino substituted 1,2,4-oxadiazole derivatives were easily prepared,
in one step and in high yields, via reactions of a variety of aryl, benzyl, cycloalkyl
and alkyl amidoximes with commercially available carbodiimides. Alkyl
carbodiimides reacted with amidoximes in toluene to give 5-alkylamino-1,2,4-
oxadiazoles, whereas aromatic carbodiimide reacted in DMF to give initially the
intermediate O-amidoxime adducts, which were further cyclized to the
corresponding 5-arylamino-1,2,4-oxadiazoles.
1,2,4-Oxadiazoles1-3 and specifically their N-substituted (on the 3-, or 5-, or 3,5-positions) derivatives is a
class of heterocyclic compounds evaluated in numerous therapeutic areas. They were found to be potent
antiviral agents,4 muscarinic receptor antagonists,5,6 histamine H2 receptor antagonists,7,8
hypocholesterolemic agents9 and anti-inflammatories.10,11 The variety of their biological activities was
ascribed to the bioisosteric replacement12,13 of an ester or amide functionality and the electronic effects of
the main heterocyclic ring. The latter was interpreted in terms of the hydrogen bonding capacity of the
pharmacophore. A number of structure-activity relationship studies revealed that the attachment of an
additional amine functional group to the heterocyclic core increased the efficacy of the compound, by
increasing the hydrogen bonding capacity of the pharmacophore.5,6 Furthermore, changes in hydrophilici-
ty by introduction of side chains on the nitrogen atom also affected the biological activity.4-6,10,11
† Dedicated to Prof. Emeritus Demetrios N. Nicolaides on the occasion of his 70th birthday

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HETEROCYCLES, Vol. 75, No. 6, 2008
For the synthesis of N-substituted 1,2,4-oxadiazole derivatives Eloy and Lenaers14-16 have reported a two
step procedure: initially, formation of the 5-trichloromethyl- or 5-chloro-1,2,4-oxadiazole derivatives
from a proper amidoxime and then, nucleophilic substitution of the trichloromethyl or chloro substituent
by the desired amine. The same team discovered14,15 the formation of primary or secondary amine
derivatives upon the reaction of hydroximoyl chlorides with guanidine derivatives. These are widely used
methodologies for the synthesis of the above mentioned heterocycles in the area of medicinal chemistry,
though, in most of the cases, the first step is usually low to moderate yielded.
A straightforward formation of 5-amino-substituted 1,2,4-oxadiazoles from amidoximes, relies on
condensation with cyanoguanidine,17 N,N-dialkylcyanamides,18 diphenyl cyanocarbonimidate,11
phosphorous ylides,19 and N,N΄-dicyclohexylcarbodiimide (DCC),20 methodologies which suffer
generality or provide the products in low yields. Interestingly, to the best of our knowledge, the procedure
involving the DCC was demonstrated only with the reaction with benzamidoxime, under dry conditions
and the yield did not exceeded 54%, even when a biequimolar quantity of the carbodiimide was
employed.20
Our interest in the chemistry and biology of amidoximes19,21-24 has prompted us to investigate thoroughly
this reaction, taking into account that a relatively large number of carbodiimides, as well as amidoximes
(or their precursors, nitriles) are nowadays commercially available. We envisaged that the construction in
a single step of the 1,2,4-oxadiazole heterocyclic ring bearing an N-substituent at position 5 and a variety
of alkyl or aryl substituents at position 3, could be a useful synthetic tool in the area of medicinal
chemistry.
To our delight, when aryl-, benzyl-, cycloalkyl- and alkyl- amidoximes 1-1125 reacted, in each case, with
diisopropylcarbodiimide (DIC, 12a), DCC (12b) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide
20
(EDC, 12c), in refluxing toluene and under air (instead of dry CHCl3 ), the heterocycles 13-23 were
smoothly obtained,26,27 as exemplified in Table 1. For solubility reasons the reaction of bis(4-nitro-
o
phenyl)-carbodiimide (NPC, 12d) was performed in DMF at 120 C.28 Under these simple and direct
conditions, the previously reported20 5-cyclohexylamino-3-phenyl-1,2,4-oxadiazole derivative 13b was
formed in an optimized yield (81%), whereas in general, all combinations of amidoximes and
carbodiimides examined showed a rather fast conversion of the reactants, leading to the desired products
in very good yields (>65%).
An exception was observed regarding the reaction of amidoxime 1 with 12d (Entry 24). In this case 13d

HETEROCYCLES, Vol. 75, No. 6, 2008
1323
was obtained in a low yield although some starting amidoxime remained unreacted. This event is
probably a result of the sensitivity of aromatic carbodiimides, which are vulnerable to polymerization
when an electron withdrawing group is attached on them.29
Table. Reactions of amidoximes with carbodiimides
1: R1 = phenyl
N
O
2: R1 = p-methoxyphenyl
3: R1 = p-methylphenyl
4: R1 = p-nitrophenyl
5: R1 = m-nitrophenyl
6: R1 = o-nitrophenyl
7: R1 = benzyl
N OH
R1
R1
+ R2 N C N R3
R
N
N
H
NH2
1-11
12a-d
13-23
R = R2 or R3
12a: R2 = R3 = isopropyl
12b: R2 = R3 = cyclohexyl
12c: R2 = ethyl,
8: R1 = p-chlorobenzyl
9: R1 = p-nitrobenzyl
10: R1 = cyclohexyl
11: R1 = propyl
R3 = 3-(dimethylamino)propyl
12d: R2 = R3 = p-nitrophenyl
Entry
Amidoxime
Carbodiimide
Product
Reaction
Time (h)
Yield %a
1
2
DIC (12a)
13a
14a
6
6
81
74
78
80
72
67
75
72
68
65
65
81
89
85
97
84
65
68
1
2
“
3
“
15a
6
3
4
“
16a
6
4
5
“
17a
7
5
6
“
18a
8
6
7
“
19a
7
7
8
“
20a
7
8
9
“
21a
7
9
10
11
1
“
22a
10
10
7
10
11
12
13
14
15
16
17
18
19
20
21
“
23a
DCC (12b)
13b
2
“
14b
7
3
“
15b
7
4
“
16b
7
5
“
17b
9
7
“
19b
8
8
“
20b
8
9
“
21b
8
8
4
72
65
10
1
“
22b
13c (R = R2
EDC (12c)
)
60
13c΄ (R = R3)
14c (R = R2)
14c΄ (R = R3)
15c (R = R2)
15c΄ (R = R3)
13d
31
22
23
24
2
3
1
“
4
4
55
25
“
61
27
14 (35)b
NPC (12d)
24
a Yields obtained after column chromatography purification.
b Yield in parenthesis is based on the reacted starting material.

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HETEROCYCLES, Vol. 75, No. 6, 2008
We have observed that all reactions required two equivalents of carbodiimide in order to achieve the
complete consumption of starting amidoxime. This fact is easily explained by accepting the mechanistic
pathway proposed earlier.20 A nucleophilic attack, Scheme 1, of the hydroxyl group of amidoxime (I) to
the electrophilic centre of carbodiimide (II) occurs initially, leading to the O-amidoxime adducts (III),
which subsequently undergo an intramolecular attack by the amino group attached to the parent
amidoxime. A second molecule of carbodiimide facilitates the latter transformation by abstracting the
remaining alkyl- or aryl-amino moiety of carbodiimide. Thus, the 1,2,4-oxadiazole derivative (IV) is
produced along with a guanidine type intermediate (V), which under air is hydrolyzed and delivers the
corresponding urea derivative (VI).
R2
R2
R2
N
C
N
N
C
N
N
N O
NH
OH
+
R1
R1
+
N
+
NH2
NH2
R2
R2
R2
I
II
II
III
H
N
H
H
N
H
N
N
N
O
H2O
R1
R2
R2
R2
N
R2
R2
R2
N
N
H
O
IV
VI
V
Scheme 1. Mechanistic pathway for the formation of 5-amino substituted 1,2,4-oxadiazole derivatives.
A two step procedure, was adopted in order to verify the mechanism of the reaction. We first examined
the reaction of benzamidoxime 1 with an equimolar amount of DCC (12b) in toluene at room temperature.
The reaction mixture was stirred for a longer period (24 h), to give only product 13b in 42% yield,
whereas almost half of 1 remained unreacted. However, when DMF was used as the solvent under the
same reaction conditions, the isolated products were 13b and the intermediate O-adduct (III, R2 =
cyclohexyl, Scheme 1) in 20% and 45% yields, respectively. The isolation of the intermediate O-adducts
in DMF is probably due to the stabilization of the polar intermediates by the more polar solvent.
Similarly, when NPC (12d) reacted with amidoximes (1, 3 and 11) in DMF at rt, all O-amidoxime
adducts 24-2630 were isolated in 42-60% yields (Scheme 2). These derivatives having an extensive
conjugation and, thus, a less nucleophilic secondary amino group were rather reluctant to react further at
room temperature with another molecule of carbodiimide and deliver the corresponding 1,2,4-oxadiazole
ring. Nevertheless, upon heating at 120 oC in the presence of 12d, all three oxadiazoles 13d, 15d and 23d
were obtained in 27-33% yield.
Another point of interest was the observed preference for the formation of one of the N-substituted

HETEROCYCLES, Vol. 75, No. 6, 2008
1325
oxadiazole derivatives when a non symmetrical carbodiimide was used (e.g. EDC, Entries 21-23). These
reactions afforded in all cases the two possible products in a ratio of ca 2:1, favoring the ethyl one. A
result like this could be explained accepting a stabilization of one of the two equilibrated tautomers of
type III (Scheme 1) through an intramolecular hydrogen bond, (Figure 1), an event which again supports
the proposed mechanistic pathway.
C6H4-p-NO2
N O
NH
13d (33%)
15d (27%)
23d (31%)
1
3
11
12d
R1
12d
+
N
NH2
24-26
C6H4-p-NO2
24: R1 = Ph (45%)
25: R1 = p-Me-Ph (42%)
26: R1 = propyl (60%)
Scheme 2. Formation of the intermediate O-amidoxime adducts 24-26 and the 1,2,4-oxadiazoles 13d,
15d and 23d.
N O
NH2
N
N
N O
NH2
N
N
R1
R1
H
N
NH
Figure 1. Structures of the intermediate O-amidoxime adducts related to EDC.
As a conclusion, we provide a facile and convenient methodology for the preparation in one step and in
very good yields of 3-substituted-5-alkyl-, cycloalkyl- or aryl- amino-1,2,4-oxadiazoles. Clarification of
the proposed mechanism was achieved with the isolation of some initially formed aducts. Furthermore,
the obtained compounds bearing a secondary amino group maybe be used as key synthons to reach the
corresponding N,N-bis-substituted derivatives, as it had been earlier demonstrated by us.19
REFERENCES AND NOTES
1.L. B. Clapp, ‘Advances in Heterocyclic Chemistry’, Vol. 20, ed. by A. R. Katritzky and A. J. Boulton,
Academic Press, Inc., New York, 1976, pp. 65–116.
2.L. B. Clapp, ‘Comprehensive Heterocyclic Chemistry’, Vol. 6, 1st ed. by K. T. Potts, Pergamon Press,
Oxford, 1984, pp. 365–392.
3.J. C. Jochims, ‘Comprehensive Heterocyclic Chemistry’, Vol. 4, 2nd ed. by A. R. Katritzky, C. W.
Rees, and E. F. V. Scriven, Pergamon Press, Oxford, 1996, pp. 179–228.
4.G. D. Diana, D. L. Volkots, T. J. Nitz, T. R. Bailey, M. A. Long, N. Vescio, S. Aldous, D. C. Pevear,
and F. J. Dutko, J. Med. Chem., 1994, 37, 2421.
5.G. A. Showell, T. L. Gibbons, C. O. Kneen, A. M. MacLeod, K. Merchant, J. Saunders, S. B.

1326
HETEROCYCLES, Vol. 75, No. 6, 2008
Freedman, S. Patel, and R. Baker, J. Med. Chem., 1991, 34, 1086.
6.L. J. Street, R. Baker, T. Book, C. O. Kneen, A. M. MacLeod, K. J. Merchant, G. A. Showell, J.
Saunders, R. H. Herbert, S. B. Freedman, and E. A. Harley, J. Med. Chem., 1990, 33, 2690.
7.I. Krämer and W. Schunack, Arch. Pharm. (Weinheim), 1985, 318, 888.
8.I. Krämer and W. Schunack, Arzheim.-Forsch./Drug Res., 1986, 36, 1011.
9.S. Yugugi, A. Miyake, T. Fushimi, E. Imamiya, H. Matsamura, and Y. Imai, Chem. Pharm. Bull.,
1973, 21, 1641.
10.P. C. Unangst, G. P. Shrum, D. T. Connor, R. D. Dyer, and D. J. Schrier, J. Med. Chem., 1992, 35,
3691.
11.Y. Song, D. T. Connor, A. D. Sercel, R. J. Sorenson, R. Doubleday, P. C. Unangst, B. D. Roth, V. G.
Beylin, R. B. Gilbertsen, K. Chan, D. J. Schrier, A. Guglietta, D. A. Bornemeier, and R. D. Dyer, J.
Med. Chem., 1999, 42, 1161.
12.K. E. Andersen, B. F. Lundt, A. S. Jørgensen, and C. Braestrup, Eur. J. Med. Chem., 1996, 31, 417.
13.J.-M.Ahn, N. A. Boyle, M. T. MacDonald, and K. D. Janda, Mini Rev. Med. Chem., 2002, 2, 463.
14.R. Lenaers and F. Eloy, Helv. Chim. Acta, 1963, 46, 1067.
15.F. Eloy and R. Lenaers, Helv. Chim. Acta, 1966, 49, 1430.
16.C. Moussebois and F. Eloy, Helv. Chim. Acta, 1964, 47, 838.
17.V. N. Yarovenko, V. Z. Shirinyan, I. V. Zavarzin, and M. M. Krayushkin, Russ. Chem. Bull., Int. Ed.,
1994, 43, 114.
18.M. Yasumoto, K. Yanagiya, I. Shibuya, and M. Goto, Nippon Kagaku Kaishi, 1987, 10, 1807.
19.D. N. Nicolaides, K. E. Litinas, I. Vrasidas, and K. C. Fylaktakidou, J. Heterocycl. Chem., 2004, 41,
499.
20.E. Kawashima and K. Tabei, J. Heterocycl. Chem., 1986, 23, 1657.
21.D. N. Nicolaides, K. C. Fylaktakidou, K. E. Litinas, and D. Hadjipavlou-Litina, Eur. J. Med. Chem.,
1998, 33, 715.
22.D. N. Nicolaides, K. E. Litinas, T. Papamehael, H. Grzeskowiak, D. R. Gautam, and K. C.
Fylaktakidou, Synthesis, 2005, 407.
23.K. C. Fylaktakidou, K. E. Litinas, A. Saragliadis, S. G. Adamopoulos, and D. N. Nicolaides, J.
Heterocycl. Chem., 2006, 43, 579.
24.K. C. Fylaktakidou, D. J. Hadjipavlou-Litina, K. E. Litinas, E. Varella, and D. N. Nicolaides, Curr.
Pharm. Design, 2008, in press.
25.All amidoximes were prepared according to procedures described in: F. Eloy and R. Lenaers, Chem.
Rev., 1962, 62, 153.
26.General procedure for the reactions of amidoximes with carbodiimides 12a,b: Amidoxime was

HETEROCYCLES, Vol. 75, No. 6, 2008
1327
dissolved in toluene (0.15 M) and 2.1 equivalents of DIC or DCC were added in one portion. The
mixture was refluxed for 6-10 h, cooled to rt, concentrated and the residue was subjected to column
o
chromatography with hexanes/EtOAc. 16a: pale yellow crystals, mp 183.5-184 C (hexanes/EtOAc);
1Η NMR (300 ΜΗz, CDCl3) δ 1.36 (d, J = 6.7 Hz, 6H), 4.05 (m, 1H), 5.12 (bd, J = 7.9 Hz, 1H, NH),
13
8.18 (d, J = 8.5 Hz, 2H), 8.31 (d, J = 8.5 Hz, 2H); C NMR (75 ΜΗz, CDCl3) δ 22.9, 46.6, 123.8,
128.1, 151.2, 153.8, 159.6, 160.8; IR (neat): 3316, 2978, 2939, 1632, 1610; HRMS: calcd for
o
C11H12N4NaO3 m/z: (M+Na)+ 271.0802, found 271.0803. 15b: white crystals, mp 146-147 C
(CHCl3/hexanes); 1Η NMR (300 ΜΗz, CDCl3) δ 1.20-1.49 (m, 5H), 1.60-1.68 (m, 1H), 1.75-1.80 (m,
2H), 2.10 (bd, J = 11.8 Hz, 2H), 2.39 (s, 3H), 3.63-3.74 (m, 1H), 5.12 (bd, J = 8.2 Hz, 1H, NH), 7.25
(d, J = 8.2 Hz, 2H), 7.87 (d, J = 8.2 Hz, 2H); 13C NMR (75 ΜΗz, CDCl3) δ 21.5, 24.6, 25.3, 33.2, 52.8,
124.8, 127.1, 129.3, 140.9, 163.7, 170.4; IR (neat): 3285, 3235, 2938, 2913, 2853, 1641, 1613;
HRMS: calcd for C15H19N3NaO m/z: (M+Na)+ 280.1420, found 280.1402.
27.General procedure for the reactions of amidoximes with carbodiimide 12c: EDC.HCl and an equimolar
amount of Na2CO3 were added in water and an equal volume of toluene was added. This biphasial
system was stirred vigorously for 5 min, then the two phases were separated, the aqueous phase was
washed with toluene, the combined organic phases were dried with Na2SO4 and the filtrate was added
to a flask containing the amidoxime (concentration approximately 0.15 M). The mixture was heated at
reflux for 4 h, concentrated and the residue was subjected to column chromatography with
hexanes/EtOAc for the elution of the ethyl derivative. The 3-dimethylaminopropyl product was eluted
1
with CH2Cl2/MeOH/Et3N (90/5/5). 13c: white crystals, mp 74-75 oC (heptanes); Η NMR (400 ΜΗz,
CDCl3) δ 1.24 (t, J = 7.2 Hz, 3H), 3.48 (dq, J = 7.2, 5.6 Hz, 2H), 6.95 (bs, 1H, NH), 7.43-7.50 (m, 3H),
8.01 (dd, J = 7.9, 1.8 Hz, 2H); 13C NMR (100 ΜΗz, CDCl3) δ 14.9, 38.2, 127.0, 127.5, 128.5, 130.6,
168.1, 171.2; IR (neat): 3198, 3073, 2980, 2934, 1654, 1629; HRMS: calcd for C10H11N3NaO m/z:
(M+Na)+ 212.0794, found 212.0810. 13c΄: oil; 1Η NMR (400 ΜΗz, CDCl3) δ 1.78 (quintet, J = 6.3 Hz,
2H), 2.24 (s, 6H), 2.46 (t, J = 6.3 Hz, 2H), 3.52 (t, J = 6.3 Hz, 2H), 7.35-7.48 (m, 3H), 7.63 (bs, 1H,
13
NH), 7.95 (dd, J = 7.8, 2.1 Hz, 2H); C NMR (100 ΜΗz, CDCl3) δ 25.5, 43.6, 45.0, 58.2, 127.0,
127.7, 128.5, 130.5, 168.3, 171.2; IR (neat): 3229, 2946, 2819, 1635; HRMS: calcd for C13H19N4O
m/z: (M+H)+: 247.1553, found 247.1565.
28.Amidoxime 1 was dissolved in DMF (0.15 M) and 2.1 equivalents of NPC 12d were added in one
portion. The mixture was stirred at 120 oC for 24 h, concentrated and the residue subjected to column
o
1
chromatography with hexanes/EtOAc. 13d: yellow crystals, mp 226-227 C (hexanes/EtOAc); Η
NMR (400 ΜΗz, DMSO-d6) δ 7.54-7.60 (m, 3H), 7.80 (d, J = 8.7 Hz, 2H), 8.03 (d, J = 6.4 Hz, 2H),
8.31 (d, J = 8.7 Hz, 2H); 13C NMR (100 ΜΗz, DMSO-d6) δ 118.1, 125.9, 127.1, 127.4, 129.6, 131.9,
142.5, 144.5, 167.9, 168.0; IR (neat): 3359, 3117, 1629, 1583; HRMS: calcd for C14H9N4O3 m/z: (M-

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HETEROCYCLES, Vol. 75, No. 6, 2008
H)+ 281.0669, found 281.0681.
29.F. Kurzer and K. Douraghi-Zadeh, Chem. Rev., 1967, 67, 107.
30.General procedure for the synthesis of the intermediate O-substituted amidoxime derivatives:
Amidoxime was dissolved in DMF (0.15 M) and 2.1 equivalents of NPC 12d were added in one
portion. The mixture was stirred at rt for 24 h, concentrated and the residue was subjected to column
chromatography with hexanes/EtOAc. 26: yellow crystals, mp 189-190 oC (hexanes/EtOAc); 1Η NMR
(400 ΜΗz, DMSO-d6) δ 0.82 (t, J = 7.4 Hz, 3H), 1.46 (sixtet, J = 7.6 Hz, 2H), 1.97 (t, J = 7.6 Hz, 2H),
7.19 (d, J = 8.9 Hz, 2H), 7.99 (d, J = 9.2 Hz, 2H), 8.11 (d, J = 8.9 Hz, 2H), 8.21 (d, J = 9.2 Hz, 2H),
13
9.69 (bs, 1H); C NMR (100 ΜΗz, DMSO-d6) δ 13.3, 19.6, 31.9, 118.9, 123.4, 124.3, 124.6, 141.5,
145.4, 148.1, 154.2, 158.4; IR (neat): 3497, 3380, 3319, 2966, 1654, 1609, 1595; HRMS: calcd for
C17H18LiN6O5 m/z: (M+Li)+ 393.1493, found 393.1492.