Synthesis of furazane conjugated new heterocycles

Article abstract of DOI:10.3987/COM-03-9833

An improved route for the synthesis of 3-(4-aminofurazane-3-yl)-1,2,4-oxadiazole heterocycles using micro-wave irradiation is reported. The preparation of novel 4-(thiazol-4-yl)furazan-3-ylamine, 4-(pyrimidin-4-yl)furazan-3-ylamine and, 4-(pyrazolidin-3-yl)furazan-3-ylamine heterocycles are described.

Full text of DOI:10.3987/COM-03-9833

HETEROCYCLES, Vol. 60, No. 11, 2003, pp. 2417 - 2424
Received, 23rd June, 2003, Accepted, 10th September, 2003, Published online, 16th September, 2003
SYNTHESIS OF FURAZANE CONJUGATED NEW HETEROCYCLES
Renaud Beaudegnies* and Sebastian Wendeborn
Syngenta Crop Protection AG, Optimization Chemistry
CH-4002 Basel, Switzerland
E-mail: renaud.beaudegnies@syngenta.com
Abstract- An improved route for the synthesis of 3-(4-aminofurazane-3-yl)-1,2,4-
oxadiazole heterocycles using micro-wave irradiation is reported. The preparation
of novel 4-(thiazol-4-yl)furazan-3-ylamine, 4-(pyrimidin-4-yl)furazan-3-ylamine
and, 4-(pyrazolidin-3-yl)furazan-3-ylamine heterocycles are described.
1
Furazanes (1,2,5-oxadiazoles) have been reported to exhibit a wide spectrum of biological properties.
In
particular, agrochemical applications of furazanes and their derivatives as herbicides, plant-growth
2
regulators and pesticides have been described. Our biological screening revealed that
3
-(4-aminofurazan-3-yl)-4H-[1,2,4]oxadiazol-5-one (5) exhibits herbicidal activity on broad leaf
(
dicotyledones) weeds. This prompted us to investigate the synthesis of novel 4-aminofurazane
heterocycles.
In the first part of this communication we report the preparation of 5 as well as a new and efficient method
for the high speed synthesis of [3-(4-aminofurazan-3-yl)-4H-[1,2,4]oxadiazol-5-yl]amine derivatives (4).
In the second part, we report the preparation of novel 4-aminofurazane rings conjugated to thiazole,
pyrimidine and pyrazolidine heterocycles.
Few examples have been reported in the literature describing the synthesis of
3
3
-(4-aminofurazan-3-yl)-[1,2,4]oxadiazole heterocycles. 4-(5-Trichloromethyl[1,2,4]oxadiazol-3-yl)-
furazan-3-ylamine (3) appeared to be the intermediate of choice for the preparation of both
-(4-aminofurazan-3-yl)-4H-[1,2,4]oxadiazol-5-one (5) and new [3-(4-aminofurazan-3-yl)-4H-
1,2,4]oxadiazol-5-yl]amine derivatives (4a-p) (Scheme 1). Indeed, it has been reported that the
3
[
trichloromethyl group at the C-5 position of a 1,2,4-oxadiazole ring can be readily substituted by
4
nucleophiles such as guanidines to yield 5-amino-1,2,4-oxadiazole derivatives.
The sequence followed for the preparation of the amide oxime (3) is similar to the one previously published
3d
5
by Andrianov et al. However, their one-pot procedure for the preparation of 3 directly from 1 could not
3
d
be reproduced in our hands (lit., 58%). Our new stepwise pathway involves intermediate (2) and provides
more efficiently from 1 (77% yield two steps).
3

Treatment with p-toluidine was required for the selective removal of the trichloroacetyl group of the
intermediate (2) which provides 3 in 81% yield. The ammonolysis of 3 in the presence of NH OH gave 5
87% yield).
4
(
In order to access a number of structurally diverse analogs of 5, a small library was prepared by treating 3
with a series of both primary and secondary amines. When the reaction was performed in EtOH/THF at
70°C (method A), the reaction was slow (2-3 days) and low yielding, but nonetheless provided a number of
pure [3-(4-aminofurazan-3-yl)-4H-[1,2,4]oxadiazol-5-yl]amines after crystallisation.
The efficiency of the process could be drastically improved when 3 and 1.2 eq. of amine were adsorbed
together on neutral alumina and irradiated in the microwave oven at 400 W (method B). Under these
conditions, the reactions were much faster (< 20 min) and substantially cleaner.
The compounds prepared by these two methods are summarized in Table 1.
O
O
N
N
N
N
a) - c)
d)
O
N
N
N
H N
N
2
N
H
OH
CCl3
H N
N
2
O
1
(43%; 3 steps)
2 (96%)
CCl3
f)
e)
X
O
O
N
O
N
N
N
N
N
g) or h)
i)
H N
H N
H N
2
2
N
2
N
N
N
O
N
HN
O
O
NR R
CCl3
3 (81%)
O
1
2
4
a-p
5 (87%)
Scheme 1. a) NaNO
2
(2 eq.), HCl (2N), rt, 5 h; b) NH
2
OH.HCl (2.2 eq.), NaOH (pH=10), rt; c) reflux, 3 h;
2
d
d) (CCl CO) O, 120°C, 5 h; e) p-toluidine (2 eq.), C
3
2
2
5 3 2
H OH, 80°C, 19 h; f) (CCl CO) O, 60-80°C (lit.,
5
8%); g) method A : amine (3-5 eq.), C H OH, 70°C, 2-3 d.; h) method B : amine (1.2 eq.) on neutral
2 5
4
alumina, microwave (400W), 2x10 min.; i) 25% NH OH.

Table 1. Transformation of 3 into 4
entry
amine
NH2
method product
yield
entry
amine
method product
yield
H N
2
Cl
1
A
B
4a
4a
<5%
12
B
A
4f
90%
F
NH2
NH2
2
quant. 13
4g
44%
CH O
3
OCH3
H N
H N
2
2
3
4
A
B
4b
4b
15%
14
A
A
4h
4i
81%
90%
CF3
H N
H N
2
2
quant. 15
F
H N
2
H N
2
CF3
5
6
7
A
B
A
4c
4c
4d
65%
95%
30%
16
17
18
A
A
A
4j
4k
4l
88%
79%
43%
F
NH2
H N
2
F
NH2
H N
2
OCH3
OCH3
CF3
H N
2
H N
2
O
8
9
B
A
B
4d
4e
4e
88%
33%
86%
19
20
21
A
A
B
4m 57%
H N
2
NH2
4n
4o
70%
96%
H N
2
H N
2
CF3
1
1
0
1
OCH3
H N
2
H
N
Cl
A
4f
39%
22
A
4p
36%
F

6
We also report the preparation of novel 4-aminofurazanes bearing 5- or 6- membered ring heterocycles.
7
,8
Their syntheses use 1-(4-aminofurazan-3-yl)ethanone (10) as a key intermediate (Schemes 3 and 4). It
has been reported that such 3-acylated furazane rings can be prepared through the reduction of the
7
corresponding carbonyl-substituted furoxans. We report here a new synthesis of 10 as depicted in Scheme
2
in which the key step is the mild and regioselective cyclisation of 8 induced by the treatment with NaOAc
in dioxane at 60°C, to give 9 in high yield.
O
O
NOH
a) , b)
c)
CN
NOH
(30%; 2 steps)
NOH
NOH
Cl
H N
2
6
7
(70%)
d)
O
NOAc
NOAc
NOAc
NOAc
N
N
f)
e)
O
O
N
N
H N
H N
H N
2
2
2
10 (97%)
9 (90%)
8 (90%)
Scheme 2. a) isopentyl nitrite, (C
NaOH, H O, rt ; d) Ac O, O°C-rt ; e) NaOAc (4 eq.), dioxane, 60°C; f) 20% HCl, H
distillation.
2
H
5
)
2
O, HCl; b) KCN (1.8 eq.), (C
2
H
5
)
2
O, H
2
O, 45°C ; c) H
2
NOH.HCl,
2
2
2
O, reflux, steam
8
b
1
-(4-Aminofurazan-3-yl)ethanone (10) was brominated according to reported conditions. Thiazole
8b
derivatives (12 and 13) were prepared in 26 to 99% yields through the Hantzsch reaction of bromide (11)
9
and the corresponding thioamides or thioureas (Scheme 3 and Table 2).
O
N
N
S
H N
2
N
R1
NH2
b)
R1
S
O
O
12 a-d
N
N
N
N
a)
(
26-93%)
H N
O
H N
O
2
2
c)
O
N
10
11 (45%)
Br
N
S
R2
H N
N
H
NH2
2
N
R2
S
N
H
13 a-l
(70-99%)
Scheme 3. a) Br
2
(1.05 eq.), AcOH (100%), 55°C; b) method A: 1.1 eq. nucleophile, benzene, reflux, 2-3
OH, reflux, 2-3 h.
h, Dean-Stark; c) method B: 1.1 eq. nucleophile, C
2
H
5

Table 2. Synthesis of 4-(thiazol-4-yl)furazan-3-ylamine derivatives (12) and (13)
entry
reagent
product
yield
entry
reagent
product
yield
Cl
S
S
1
NC
12a
60%
9
13e
70%
NH2
NH2
N
NH2
H
S
S
2
12b
26% 10
13f
79%
H N
NH2
2
N
S
S
3
4
12c
12d
34% 11
93% 12
13g
13h
91%
98%
N
NH2
NH2
H
S
S
NH2
N
NH2
H
S
S
5
6
13a
13b
87% 13
75% 14
13i
13j
94%
85%
N
N
H
NH2
N
H
NH2
Cl
S
Cl
S
CF3
N
NH2
H
N
NH2
H
Cl
CF3
CF3
S
S
7
8
13c
13d
99% 15
88% 16
N
H
NH2
13k
13l
90%
96%
N
NH2
H
CF3
N
Cl
S
S
N
NH2
N
H
NH2
H
Cl
Cl
Cl
4
-(Pyrimidin-4-yl)furazan-3-ylamine and 4-(pyrazolidin-3-yl)furazan-3-ylamine heterocycles (18-23 and
4 to 31) respectively are available in three steps from 10 via the reaction of 15 with ambident nucleophiles
2
such as amidines, guanidines or hydrazines (Scheme 4 and Table 3).
As shown in the Scheme 4, triphenylphosphorane (14) did not react with aldehydes and only starting
materials were recovered. In contrast, piperidine catalyzed aldol condensations between 10 and various
aldehydes proceeded in satisfactory to excellent yields (Scheme 4).
The resulting α,β-unsaturated ketones (15, 16, and 17) were allowed to react with amidines and guanidines
in the presence of oxygen to give 4-(pyrimidin-4-yl)furazan-3-ylamine derivatives (24 to 31) in low to
moderate yields. Compounds (15 and 17) underwent reaction with hydrazine to give oxygen sensitive

4
-(pyrazolidin-3-yl)furazan-3-ylamine heterocycles which were directly acylated with various acid
chlorides in good yields, thus allowing the introduction of additional points of diversity.
O
O
N
N
N
N
H N
O
H N
N
2
2
NH
R2
10
N
R2
NH2
a)
N
18-23
R1
b)
f)
O
O
N
N
N
O
N
N
g)
H N
N
H N
O
2
2
1
1
N
24
(
45%)
H N
2
Br
R1
e)
O
R1
c),d)
N
1
5 (R1 = cyclopropyl ; 94%)
X
16 (R1 = 4-CH OC H ; 30%)
3 6 4
17 (R1 = furyl ; 39%)
O
O
O
N
N
N
N
N
h)
i)
H N
O
H N
N
H N
N
2
2
2
O
14
NH
N
(74%, 2 steps)
2
2
5 (R1 = cyclopropyl)
6 (R1 = furyl)
27- 31
PPh3
R3
R1
R1
1
Scheme 4. a) Br
2
(1.05 eq.), AcOH (100%), 55°C; b) R CHO (2.0 eq.), piperidine (0.1 eq.), C
2
5
H OH /THF:
1
5
/1, 50°C; c) PPh
3
(1.0 eq.), toluene, 100°C; d) NaOH (2N), CH
3
OH, 0°C; e) R CHO (1.2 eq.), piperidine
2 2
(0.1 eq.), 60°C; f) amidine or guanidine (1.1 eq.), N,N-dimethylacetamide, 60°C, O (gas); g) PhNHNH
3
(
2.0 eq.), THF/ C H OH: 1/20, rt; h) H NNH .H O (10 eq.), THF, rt; i) R COCl (1.2 eq.), pyridine (3.0 eq.),
2
5
2
2
2
2 2
CH Cl , rt.
Table 3. Synthesis of compounds (18 to 31)
entry educt
R1
R2
product yield entry educt
R1
R3
product yield
*
1
5
cyclopropyl
methyl
18
29%
8
15 cyclopropyl
25
92%
1
2
15
15
15
15
cyclopropyl
cyclopropyl
cyclopropyl
cyclopropyl
p-methoxyphenyl
phenyl
19
20
21
22
23
24
14%
9
17
2-furyl
26
27
28
29
30
31
99%
74%
92%
76%
73%
79%
3
4
5
6
7
26% 10
16% 11
25% 12
56% 13
26% 14
25 cyclopropyl
methyl
aniline
26
26
26
26
2-furyl
2,4-dichlorophenyl
benzylamine
2-furyl (4-chlorophenoxy)methyl
16 p-methoxyphenyl m-methylaniline
17
2-furyl
2-furyl
2-furyl
2-furyl
cyclopropyl
(
*) Performed in the presence of 1.1 eq. of DBU.

CONCLUSION
We have developed a new and efficient method for the synthesis of [3-(4-aminofurazan-3-yl)-4H-[1,2,4]-
oxadiazol-5-yl]amine derivatives. We have also enlarged the scope of the 4-aminofurazane chemistry to
novel 4-(thiazol-4-yl)furazan-3-ylamine, 4-(pyrimidin-4-yl)furazan-3-ylamine and, 4-(pyrazolidin-3-yl)-
furazan-3-ylamine heterocycles.
REFERENCES
1
2
. R.M. Paton, Comprehensive Heterocyclic Chemistry II, ed. by A.R. Katritsky, C.W. Rees, and E.F.V.
Scriven, Pergamon, Oxford, 1996, 4, 229 and references cited therein.
. (a) J.C. Bottaro, M.A. Petrie, P.E. Penwell, and D.C. Bomberger, PCT Int. Appl., 2003, WO
0306371A1 (Chem. Abstr., 2003, 138, 126950); (b) H. Cerecetto, E. Dias, R. Di Maio, M.Gonzalez,
S. Pacce, P. Saenz, G. Seoane, L. Suescun, A. Mombru, G. Fernandez, M. Lema, and J. Villalba, J.
Agric. Food Chem., 2000, 48, 2995; (c) Ger. Offen.,1985, DE 3326509A1 (Chem. Abstr., 1985, 102,
2
20879h); (d) R.W.W. Baldwin, U.S. Patent, 1970, US 3501285 (Chem. Abstr., 1970, 72, 111477s);
(
e) French Patent, 1969, FR 1576140 (Chem. Abstr., 1970, 72,110178h); (f) W.E. Buting and C.
Ainsworth, U.S. Patent, 1966, US 3279988 (Chem. Abstr., 1967, 66, 28776u).
3
. (a) S.D. Shaposhnikov, N.V. Korobov, A.V. Sergievskii, S.V. Pirogov, S.F. Mel'nikova, and I.V.
Tselinskii, Russian J. Org. Chem., 2002, 38, 1351; (b) S. Bailey, P.V. Fish, K. James, and G.A.
Whitlock, PCT Int. Appl., 2002, WO 0279200A1 (Chem. Abstr., 2002, 137, 294960); (c) V.N.
Yarovenko, V.Z. Shirinyan, I.V. Zavarzin, and M.M. Krayushkin, Izv. Akad. Nauk, Ser. Khim. 1994,
1
18; (d) V.G. Andrianov, E.N. Rozhkov, and A.V. Eremeev, Khim. Geterotsikl. Soedin., 1994, 534;
(
e) V.G. Andrianov, V.G. Semenikhina, and A.V. Eremeev, Khim. Geterotsikl. Soedin., 1994, 539; f)
O.A. Rakitin, V.A. Ogurtsov, E.A. Khaibullina, T.I. Godovikova, and L.I. Khmel’nitskii, Khim.
Geterotsikl. Soedin., 1993, 1283; (g) V.G. Andrianov, V.G. Semenikhina, and A.V. Eremeev, Khim.
Geterotsikl. Soedin., 1992, 687; (h) V.N. Yarovenko, V.Z. Shirinyan, I.V. Zavarzin, and M.M
Krayushkin, Izv. Akad. Nauk, Ser. Khim. 1991, 2166; i) V.N. Yarovenko, V.K.Taralashvili, I.V.
Zavarzin, and M.M Krayushkin, Tetrahedron, 1990, 46, 3941.
4
. (a) I. Kumita, A. Niwa, C. Sano, and M. Takagi, Jpn. Kokai Tokkyo Koho, 1993, JP 05117255A2
(
4
Chem. Abstr., 1993, 119 : P271167h); (b) J.L. LaMattina and C.J. Mularski, J. Org. Chem., 1984, 49,
800.
5
6
7
8
. (a) V.G. Andrianov, A.V. Eremeev, and Y.B. Sheremet, Khim. Geterotsikl. Soedin.,1988, 856; (b) T.
Ichikawa, T. Kato, and T. Takenishi, J. Heterocycl. Chem., 1965, 2, 253.
. For reviews on Furazanes fused to 5-, 6-, and 7-membered rings see: (a) A.B. Sheremetev, J.
Heterocycl. Chem., 1995, 32, 371; (b) A.B. Sheremetev, Russian Chemical Reviews, 1999, 68, 137.
. A.S. Kulikov, N.N. Makhova, T.I. Godovikova, S.P. Golova, and L.I. Khmel'nitskii, Izv. Akad. Nauk,
Ser. Khim., 1994, 679.
. (a) T.S. Novikova, T. M. Mel'nikova, O.V. Kharitonova, V.O. Kulagina, N.S. Aleksandrova, A.B.
Sheremetev, T.S. Pivina, L.I. Khmel'nitskii, and S.S. Novikov, Mendeleev Commun., 1994, 138; (b)
A.B. Sheremetev, A.S. Kulikov, and L.I. Khmel'nitskii, Izv. Akad. Nauk, Ser. Khim., 1993, 744; (c) E.
Borello, A. Zecchina, and E. Guglielminotti, Gazz. Chim. Ital., 1965, 95, 1465.
9
.
For similar reaction see : A.S. Kulikov and N.N. Makhova, Izv. Akad. Nauk, Ser. Khim., 1998, 137.
5
b
1
0. Analytical and spectroscopic data are shown in the following. 1: mp 190-192°C (H O), (lit.,
2
1
13
190-191°C); H NMR (300 MHz, CD
45.80, 141.19; Anal. Calcd for C
3
OD) δ= 4.90 (br s); C NMR (75 MHz, CD
3
OD) δ= 155.92,
: C, 25.18; H, 3.52; N, 48.94. Found: C, 25.25; H, 3.48; N,
1
3
H N
5 5
O
2

+
1
4
9
1
(
2
8.91; MS (electrospray): 142 (M-H ). 4m: amorphous powder; H NMR (300 MHz, DMSO d
6
) δ=
1
3
.00 (s, 1H), 6.35 (s, 2H), 3.50 (m, 2x2H), 3.28 (s, 3H); C NMR (75 MHz, DMSO d
58.89, 155.31, 137.34, 69.94, 57.88, 42.85; MS (electrospray): 225 (M-H ), 261 (M+Cl ), 451
2M-H ). 5: mp 208-210°C (decomp), (isopropanol); H NMR (300 MHz, DMSO d
H), 6.80 (br s, 1H); C NMR (75 MHz, DMSO d ) δ= 172.46, 159.23, 155.29, 138.99; HRMS (EI):
6
) δ= 171.61,
+
-
+
1
6
) δ= 7.30 (br s,
1
3
6
1
Calcd 169.0236 Found: 169.0233. 9: mp 136-138°C (CH
3
OH); H NMR (300 MHz, CDCl
.50 (br s, 2H), 2.51 (s, 3H), 2.30 (s, 3H); C NMR (75 MHz, CDCl ) δ= 166.87, 155.10, 154.38,
), (lit., 96°C); H NMR (300 MHz, CDCl ) δ= 5.20
) δ= 192.84, 155.17, 143.49, 28.16; MS (EI) 127
3
) δ=
1
3
5
1
(
3
7
1
42.69, 19.28, 13.50. 10: mp 94-95°C (CH
2
Cl
2
3
1
3
s, 2H), 2.74 (s, 3H); C NMR (75 MHz, CDCl
3
+.
8b
1
(
M ). 11: mp 162°C (CH
2
Cl
2 6
), (lit., 162-163°C); H NMR (300 MHz, DMSO d ) δ= 6.50 (br s,
H), 4.87 (s, 2H); C NMR (75 MHz, DMSO d ) δ= 184.72, 155.67, 141.91, 34.34; MS (EI) 207,
05 (M ). 13f: amorphous powder; H NMR (300 MHz, CD
OD) δ= 171.70, 156.40, 142.38, 136.42, 109.07; MS (electrospray): 182
M-H ), 228(M+HCOO ), 262, 264 (M+Br ); MS (electrospray): 184 (M+H ), 225 (M+CH
5: mp 109°C (ethyl acetate); H NMR (300 MHz, CDCl ) δ= 7.10 (d, J = 15.6 Hz, 1H), 6.80 (dd, J
15.6 and 11.3 Hz, 1H), 5.20 (br s, 1H), 1.75 (m, 1H), 1.15 (m, 2H), 0.85 (m, 2H); C NMR (75
1
3
2
2
6
+
1
3
OD) δ= 7.20 (s, 1H), 4.80 (br s, 4H);
1
3
C NMR (75 MHz, CD
3
+
-
-
+
+
(
1
=
3
CN+H ).
1
3
1
3
MHz, CDCl
3
) δ= 182.11, 158.81, 156.05, 143.32, 123.09, 15.98, 10.25; MS (electrospray): 180
+
1
(
M+H ). 22: mp 122-124°C (Hexane); H NMR (300 MHz, CDCl
3
) δ= 7.40-7.20 (m, 6H), 5.55 (br
s, 1H), 5.20 (br s, 2H), 4.58 (d, J = 6.2 Hz, 2H), 1.95 (m, 1H), 1.15 (m, 2H), 1.05 (m, 2H); MS
+
+
-
-
(
(
(
electrospray): 309 (M+H ); MS (electrospray): 307 (M-H ), 343 (M+Cl ), 367 (M+CH COO ), 651
3
-
1
2M+Cl ). 27: amorphous powder; H NMR (300 MHz, CDCl
m, 1H), 5.71 (m, 1H), 5.20 (br s, 2H), 3.15 (m, 2H), 2.39 (s, 3H); C NMR (75 MHz, CDCl
68.65, 154.27, 150.83, 142.52, 142.43, 140.24, 110.70, 108.53, 53.20, 38.32, 22.01.
3
) δ= 7.32 (s, 1H), 6.38 (m, 1H), 6.34
1
3
3
) δ=
1