A Convenient 1,3-Dipolar Cycloaddition Reaction for the Synthesis of Spirooxindoles and Some Other Spirocompounds Containing the 1,3,4-Oxadiazole Moiety

Article abstract of DOI:10.1002/hlca.201500515

A series of spiro[indoline-3,2′-[1,3,4]oxadiazol]-2-ones were prepared from the reaction of isatin derivatives and hydrazonoyl chlorides through the 1,3-dipolar cycloaddition reaction. This method has some important aspects, such as mild reaction condition, easy purification, and high yield of products. Also, the synthesis of spiro[acenaphthylene-1,2′-[1,3,4]oxadiazol]-2-one and spiro[[1,3,4]oxadiazole-2,9′-phenanthren]-10′-one were studied under the same condition. The structures were confirmed spectroscopically (IR,¹H- and¹³C-NMR, and EI-MS) and by elemental analyses. A plausible mechanism for this reaction is proposed.

Full text of DOI:10.1002/hlca.201500515

Helv. Chim. Acta 2016, 99, 457 – 461
457
FULL PAPER
A Convenient 1,3-Dipolar Cycloaddition Reaction for the Synthesis of Spirooxindoles
and Some Other Spirocompounds Containing the 1,3,4-Oxadiazole Moiety
by Abdolali Alizadeh*, and Leila Moafi
Department of Chemistry, Tarbiat Modares University, P.O. Box 14115-175, Tehran, Iran (phone: +98-21-88006631;
fax: +98-21-88006544; e-mails: abdol_alizad@yahoo.com, aalizadeh@Modares.ac.ir)
0
A series of spiro[indoline-3,2 -[1,3,4]oxadiazol]-2-ones were prepared from the reaction of isatin derivatives and
hydrazonoyl chlorides through the 1,3-dipolar cycloaddition reaction. This method has some important aspects, such as mild
0
reaction condition, easy purification, and high yield of products. Also, the synthesis of spiro[acenaphthylene-1,2 -[1,3,4]
0
0
13
oxadiazol]-2-one and spiro[[1,3,4]oxadiazole-2,9 -phenanthren]-10 -one were studied under the same condition. The structures
1
were confirmed spectroscopically (IR, H- and C-NMR, and EI-MS) and by elemental analyses. A plausible mechanism for
this reaction is proposed.
Keywords: Isatin, Hydrazonoyl chloride, Nitrile imine, Spirooxindole, 1,3,4-Oxadiazole, 1,3-Dipolar cycloaddition reaction.
compounds through a relatively simple procedure [17]
[18]. Among the 1,3-dipoles, nitrile imines are widely used
Introduction
The spirooxindole framework has been found as a core
structure of many pharmacological agents and natural
alkaloids such, as welwitindolinone A [1], coerulescine
in 1,3-dipolar cycloaddition reaction [19][20]. One of the
convenient methods for the synthesis of nitrile imines
involves dehydrohalogenation of hydrazonoyl chloride in
the presence of a base [21] (Fig. 2).
[2], and (+)-elacomine [3] (Fig. 1).
The biological activity of spirooxindole derivatives is
Cycloaddition of nitrile imine to C=O groups repre-
fully established ranging from antimicrobial [4], antibac-
sents an efficient method for the construction of the oxa-
terial [5], antifungal [6], antitumor [7], antitubercular diazole structure [22].
[
8], and antimalarial [9] to antioxidant activities [10].
Similar to spirooxindoles, heterocycles containing
,3,4-oxadiazole moiety have considerable synthetic
interest due to significant biological activities, such as
Although various procedures are found in the litera-
ture for the synthesis of spirooxindole scaffolds [23][24],
methods for the synthesis of molecules having both the
spirooxindole and oxadiazole moieties are still limited.
a
1
antibacterial [11], antifungal [12], anti-inflammatory [13], Bouhfid et al. [25] have reported a two-component reac-
anticancer [14], and anticonvulsant [15]. Also oxadia- tion of allylisatin and hydrazonoyl bromide for the syn-
zoles are employed as fluorescent whiteners and act as
muscle relaxants [16].
thesis of the mentioned compounds with moderate yield
after extended reaction time.
The 1,3-dipolar cycloaddition reactions has been
studied extensively to construct important heterocyclic
The most common approaches to the synthesis of
spirooxindole containing 1,3,4-oxadiazole derivatives are
the reaction of isatins with carbohydrazide [26] or
cyanoacetic acid hydrazide [27] by a multistep procedure.
These methods are associated with several disadvantages,
such as extended reaction time, moderate yield of products,
high temperature, and harsh reaction conditions.
In continuation of our efforts for the synthesis of
spirooxindole scaffolds [28][29], we describe in this paper
a simple procedure for the construction of spiro[indoline-
0
3
cycloaddition reaction of isatins
,2 -[1,3,4]oxadiazol]-2-one derivatives 3 via 1,3-dipolar
1 and hydrazonoyl
chlorides 2 in the presence of Et N in EtOH at room
temperature (Scheme 1).
Fig. 1. Selected examples of natural products with spiro-fused oxindoles
motif.
3
DOI: 10.1002/hlca.201500515
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458
Helv. Chim. Acta 2016, 99, 457 – 461
Fig. 2. Synthesis of nitrile imine from hydrazonoyl chloride.
Scheme 1. Convenient synthesis of spirooxindoles 3.
expected, spirocompounds 5 and 7 were obtained in high
yields (Scheme 2).
The mechanism of this reaction involves formation of
Results and Discussion
Reaction of isatin 1a (X, R = H) with nitrile imine A
(
generated in situ from the corresponding hydrazonoyl nitrile imine A from the reaction of hydrazonoyl chloride
chloride 2a (Ar = Ph) and Et N) in EtOH proceeds at and Et N. 1,3-Dipolar cycloaddition reaction of interme-
3
3
0
0
0
room temperature for 5 h to afford 3 ,5 -diphenyl-3 H- diate A onto the C=O group of isatin (1a) generates pro-
0
spiro[indoline-3,2 -[1,3,4]oxadiazol]-2-one (3a) in 83% duct 3a (Scheme 3). Analogously, the reaction of A with
yield.
a C=O group of 4 and 6 leads to the spirocompounds 5
The IR spectrum of 3a displayed absorption peaks at and 7, respectively.
ꢀ
1
3
432 and 1736 cm
1
for NH and C=O groups, respec-
tively. The H-NMR spectrum of 3a consists of one sin- synthesis of spiro[indoline-3,2 -[1,3,4]oxadiazol]-2-one
In brief, we have developed an efficient method for the
0
glet at 11.14 ppm due to the NH group and characteristic
signals for 14 aromatic H-atoms, which is consistent with
derivatives by treatment of various isatins with hydrazonoyl
chlorides in the presence of Et N. This protocol has some
3
1
3
the proposed structure. The proton-decoupled C-NMR
advantages compared to previous method [25] like using
available starting materials, mild reaction condition, rela-
ment with the proposed structure. The characteristic sig- tively short reaction time, and high yields of product.
spectrum of 3a showed 17 distinct resonances in agree-
nals for the spiro-C-atom and the C=O group were
observed at 95.5 and 169.8 ppm, respectively.
We extended the scope of this reaction to different
isatins 1 and hydrazonoyl chlorides 2 under the same con-
dition. The corresponding spirooxindoles 3 were synthe-
sized in high yields (Table).
Financial support of this research from Tarbiat Modares
University, Iran is gratefully acknowledged.
Experimental Part
1
,3-Dipolar cycloaddition reactions of various 1,3-
dipoles, such as nitrile ylide and nitrile oxide, with ace-
General
naphthoquinone (4) and 9,10-phenanthraquinone (6) have Isatin, acenaphthoquinone, and 9,10-phenanthraquinone
were obtained from Merck (Darmstadt, Germany) and
Fluka (Buchs, Switzerland) and were used without further
been reported [30][31]. In the present study, a nitrile
imine was used as 1,3-dipole and reacted with 4 and 6. As
Table. Results of the synthesis of 3
Entry
X
R
Ar
Time [h]
Yield of 3 [%]
a
b
c
H
H
Ph
5
3
5
3
4
83
87
85
88
83
H
Me
Et
H
p-Cl–Ph
p-Cl–Ph
p-Cl–Ph
Ph
H
d
e
Br
Br
Me
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Helv. Chim. Acta 2016, 99, 457 – 461
459
Scheme 2. Synthesis of spirocompounds 5 and 7.
Scheme 3. Mechanism of the reaction.
purification. M.p.: Electrothermal 9100 instrument (Bibby 80% yield. Then a mixture of CCl (1.46 ml, 15 mmol),
4
Scientific Ltd., Stone, UK). IR Spectra: as KBr pellets on a Ph P (4.91 g, 18.75 mmol), and benzoyl phenylhydrazine
3
NICOLET FT-IR 100 spectrometer (Thermo Fisher, Wal- (3.18 g, 15 mmol) in MeCN (40 ml) was stirred at r.t. for
ꢀ
1 1
tham, MA, USA); in cm . H-NMR (400 MHz, 300 MHz) 6 h. After completion of reaction, the solid was filtered
1
and C-NMR (100 MHz, 75 MHz) spectra: Bruker DRX- and washed with Et O to afford hydrazonoyl chloride 2a
3
2
400 and Bruker DRX-300 AVANCE spectrometers (Bru- in 50% yield.
ker, Bremen, Germany). MS: FINNIGAN-MAT 8430 mass Synthesis of Compounds 3 (exemplified for 3a). A
spectrometer (FINNIGAN, Nevada, USA) operating at an mixture of isatin (1a; 1 mmol), hydrazonoyl chloride (2a;
ionization potential of 70 eV. Elemental analyses for C, H, 1 mmol), and Et N (1 mmol) in EtOH (5 ml) was stirred
3
and N: Heraeus CHN–O–Rapid analyzer.
at r.t. for the time given in Table. After completion of the
Synthesis of Compounds 2 (exemplified for 2a). Com- reaction (TLC), the mixture was filtered and the precipi-
pound 2 was synthesized according to previous reports tate washed with EtOH to afford the pure product 3a in
[
21][32]. To a stirred soln. of 2.16 g (20 mmol) phenylhy-
83% yield.
Synthesis of Compound 5. A mixture of acenaphtho-
quinone (4; 1 mmol), hydrazonoyl chloride (2a; 1 mmol),
drazine in 20 ml pyridine was slowly added dropwise ben-
zoyl chloride (2.8 g, 20 mmol) under the ice bath over a
period of 20 min. Upon completion of addition, ice bath and Et N (1 mmol) in EtOH (5 ml) was stirred at r.t. for
3
was taken away, and the stirring was continued for
another 15 h at the r.t. After this time, H O (15 ml) was
3 h. After completion of the reaction (TLC), the mixture
was filtered and the precipitate was washed with EtOH
(4 ml) to afford the pure product 5.
Synthesis of Compound 7. A mixture of 9,10-phenan-
thraquinone (6; 1 mmol), hydrazonoyl chloride (2a;
2
added to the above mixture and the precipitate was col-
lected by filtration, washed with H O, dried, and recrys-
tallized with MeOH to give benzoyl phenylhydrazine in
2
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2016 Verlag Helvetica Chimica Acta AG, Z u€ rich
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460
Helv. Chim. Acta 2016, 99, 457 – 461
1
1
mmol), and Et N (1 mmol) in EtOH (5 ml) was stirred
3
(C=O), 1602 and 1488 (Ar). H-NMR (300 MHz, (D )
6
3
at r.t. for 4 h. After completion of the reaction (TLC),
the mixture was filtered and the precipitate was washed
with EtOH (4 ml) to afford the pure product 7.
DMSO): 3.2 (s, 3 H); 6.68 (d, J = 7.3, 2 H); 6.82 (t,
J = 7.1, 1 H); 7.17 (t, J = 7.8, 2 H) 7.55 – 7.78 (m, 7 H).
C-NMR (75 MHz, (D )DMSO): 27.0; 94.6; 113.1; 113.8;
3
3
1
3
6
0
0
0
0
3
(
,5 -Diphenyl-3 H-spiro[indole-3,2 -[1,3,4]oxadiazol]-2
1H)-one (3a). Yield: 0.283 g (83%). Yellow powder.
M.p. 227 – 229 °C. IR: 3432 (NH), 1736 (C=O), 1599,
116.2; 121.5; 123.2; 124.9; 128.2; 128.9; 129.6; 129.7; 129.8;
136.1; 141.7; 143.6; 151.1; 169.3. Anal. calc. for
C H BrClN O (468.73): C 56.37, H 3.23, N 8.96; found:
2
2
15
3
2
1
1
486 (Ar), 1129 (C–O). H-NMR (400 MHz, (D6) C 56.31, H 3.18, N 8.89.
3
3
0
0
0
0
DMSO): 6.75 (d, J = 7.6, 2 H); 6.83 (t, J = 7.2, 1 H); 3 ,5 -Diphenyl-2H,3 H-spiro[acenaphthylene-1,2 -[1,3,4]
.06 (d, J = 8.0, 1 H); 7.10 (t, J = 7.6, 1 H); 7.19 (d, oxadiazol]-2-one (5). Yield: 0.338 g (90%). Gray powder.
J = 8.4, 2 H); 7.47 – 7.56 (m, 5 H); 7.82 (d, J = 8.0, 2 M.p. 190 – 192 °C. IR: 1732 (C=O), 1594, 1493 (Ar), 1196
H); 11.14 (s, 1 H). C-NMR (75 MHz, (D )DMSO): 95.5; (C–O). H-NMR (300 MHz, (D )DMSO): 6.52 (d,
J = 5.7, 2 H); 6.71 (t, J = 8.1, 1 H); 7.00 (t, J = 8.1, 2
29.1; 129.3; 131.1; 132.9; 141.8; 143.7; 151.5; 169.8. EI-MS H); 7.51 – 7.53 (m, 3 H); 7.81 – 7.83 (m, 3 H); 7.91 (d,
J = 8.1, 1 H); 8.01 (t, J = 8.9, 1 H); 8.17 (d, J = 4.8, 1
65), 77 (96). Anal. calc. for C H N O (341.36): C H); 8.28 (d, J = 7.2, 1 H); 8.54 (d, J = 6.9, 1 H). C-
3
3
7
3
3
1
3
1
6
6
3
3
3
1
1
11.5; 113.3; 120.6; 122.9; 123.4; 124.0; 125.95; 125.98;
+
70 eV): 341 (M , 80), 313 (100), 208 (49), 105 (69), 91
3
3
3
(
3
3
13
(
2
1
15
3
2
7
5
3
3.89, H 4.43, N 12.31; found: C 73.96, H 4.39, N 12.36.
0
NMR (75 MHz, (D )DMSO): 97.6; 113.9; 121.1; 123.4;
6
0
0
-(4-Chlorophenyl)-1-methyl-3 -phenyl-3 H-spiro[indole-
0
123.7; 124.5; 126.5; 128.4; 128.9; 129.5; 129.7; 129.90;
129.95; 130.8; 131.6; 131.9; 134.4; 141.9; 142.2; 151.9; 192.1.
,2 -[1,3,4]oxadiazol]-2(1H)-one (3b). Yield: 0.339 g
(
(
(
87%). Orange powder. M.p. 215 – 217 °C. IR: 1731 Anal. calc. for C H N O (376.41): C 79.77, H 4.28, N
2
5
16
2
2
1
C=O), 1605 and 1486 (Ar), 1120 (C–O). H-NMR
7.44; found: C 79.72, H 4.36, N 7.48.
0
3
0
300 MHz, (D )DMSO): 3.22 (s, 3 H); 6.70 (d, J = 7.6, 2
3,5-Diphenyl-3H,10 H-spiro[1,3,4-oxadiazole-2,9 -phe-
0
6
3
H); 6.82 (t, J = 7.2, 1 H); 7.15 – 7.27 (m, 4 H); nanthren]-10 -one (7). Yield: 0.354 g (88%). Orange pow-
7
3
13
.50 – 7.57 (m, 4 H); 7.81 (d, J = 8.0, 2 H). C-NMR
der. M.p. 226 – 227 °C. IR: 1699 (C=O), 1595, 1495 (Ar),
1
(
75 MHz, (D )DMSO): 26.9; 95.2; 111.0; 113.9; 121.4; 1162 (C–O). H-NMR (300 MHz, (D )DMSO): 6.67 (d,
6
6
3
3
3
1
1
22.8; 123.3; 124.5; 126.1; 128.2; 129.7; 129.8; 133.5; 136.1;
41.9; 144.4; 151.2; 169.7. Anal. calc. for C H ClN O
2
J = 7.2, 2 H); 6.72 (t, J = 5.2, 1 H); 7.08 (t, J = 6.9, 2
H); 7.46 – 7.49 (m, 3 H); 7.56 – 7.65 (m, 3 H); 7.76 (d,
2
2
16
3
3
3
3
(389.83): C 67.78, H 4.14, N 10.78; found: C 67.83, H 4.18,
N 10.73.
J = 5.4, 2 H); 7.94 (t, J = 6.0, 1 H); 7.99 (d, J = 7.8, 2
3
13
H); 8.42 (d, J = 7.2, 2 H). C-NMR (75 MHz, (D6)
DMSO): 93.0; 114.0; 120.4; 124.6; 125.1; 125.6; 126.3;
0
0
0
0
5
[
-(4-Chlorophenyl)-1-ethyl-3 -phenyl-3 H-spiro[indole-3,2 -
1,3,4]oxadiazol]-2(1H)-one (3c). Yield: 0.343 g (85%). 127.7; 128.6; 129.5; 129.6; 129.9; 130.2; 130.9; 131.4; 131.6;
Orange powder. M.p. 220 – 222 °C. IR: 1732 (C=O), 1641 132.3; 133.4; 136.5; 137.5; 142.0; 150.6; 191.0. Anal. calc.
1
(
(
C=N), 1602, 1535 and 1484 (Ar), 1122 (C–O). H-NMR
for C H N O (402.44): C 80.58, H 4.51, N 6.96; found:
27 18 2 2
3
300 MHz, (D )DMSO): 1.18 (t, J = 6.9, 3 H); 3.77 (m, 2
H); 6.71 (d, J = 8.0, 2 H); 6.80 (t, J = 8.7, 1 H); 6.83 (t,
J = 6.9, 1 H); 7.16 (t, J = 8.0, 2 H); 7.33 (d, J = 8.4, 1
H); 7.55 – 7.57 (m, 1 H); 7.59 (d, J = 8.1, 2 H); 7.83 (d,
J = 8.4, 2 H); 7.94 (d, J = 8.1, 1 H). C-NMR (75 MHz,
D )DMSO): 12.6; 35.1; 95.3; 111.0; 114.0; 121.5; 123.1;
C 80.65, H 4.56, N 6.90.
6
3
3
3
3
3
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5
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(
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