An efficient synthesis of new spiro[indolo-3(1H),2′(3′H)-oxadiazolyl] and 1-(triazol-4-ylmethyl)isatin derivatives

Article abstract of DOI:10.3987/COM-05-10519

The synthesis and the characterization of new isatin derivatives obtained by 1,3-dipolar cycloaddition reactions on allylisatin and propargylisatin are described. The products thus regiospecifically obtained in good yields bear oxadiazolyles or trizolyles

Full text of DOI:10.3987/COM-05-10519

HETEROCYCLES, Vol. 65, No. 12, 2005
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HETEROCYCLES, Vol. 65, No. 12, 2005, pp. 2949 - 2955
Received, 22nd July, 2005, Accepted, 13th October, 2005, Published online, 14th October, 2005
AN EFFICIENT SYNTHESIS OF NEW SPIRO[INDOLO-3(1H),2’(3’H)-
OXADIAZOLYL] AND 1-(TRIAZOL-4-YLMETHYL)ISATIN
DERIVATIVES
a
b
c
b
Rachid Bouhfid, Nicolas Joly, Mohamed Massoui, Roméo Cecchelli,
b
b
a
Vincent Lequart, Patrick Martin * and El Mokhtar Essassi
a – Heterocyclic Organic Chemistry Laboratory, Mohammed V-Agdal University,
Rabat, Marocco
b – Blood-Brain Barrier Laboratory (EA 2465), IUT of Béthune, University of
Artois, BP 819, F-62408 Béthune
c – Agroressource Chemistry Laboratory, Ibn Tofaïl University, Kenitra, Marocco
*
corresponding author: patrick.martin@univ-artois.fr
Abstract – The synthesis and the characterization of new isatin derivatives
obtained by 1,3-dipolar cycloaddition reactions on allylisatin and propargylisatin
are described. The products thus regiospecifically obtained in good yields bear
oxadiazolyles or trizolyles groups, and were characterized by FT-IR spectroscopy,
NMR spectroscopy and mass spectrometry.
INTRODUCTION
Isatin is well known for its large range of biological activities. Thus, some isatin derivatives (Scheme 1),
1
such as 3-iminoisatin, have found medicinal applications because they possess anticonvulsant,
2
3
4
anti-inflammatory and antimicrobial activities, as well as effects on the central nervous system.
5
Moreover, isatin was reported as a product crossing the blood-brain-barrier.
Preliminary biological tests performed in our laboratory have shown that 1-allylisatin has a very low
6
toxicity (0% death for concentrations less than 1 g per kg). In vivo tests have demonstrated psychotropic,

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HETEROCYCLES, Vol. 65, No. 12, 2005
sedative, anxiolytic and anticonvulsivant properties. Moreover, they have shown an increase in hypnotic
7
effects, compared to native isatin activities, and no cataleptic properties.
R
O
R
N
R'
O
O
O
N
N
N
H
H
H
isatin
3-iminoisatin
oxindole
Scheme 1. Isatin and some isatin derivatives.
Based on these results we engaged the synthesis of 1-allylisatin derivatives to obtain new compounds
bearing an additional heterocycle able to increase biological activities (Scheme 2). Two sorts of
8
N-heterocycles were chosen for their well known biological activities, i.e. oxadiazole and
9
triazolylmethyl derivatives.
Ph
O
O
O
N N
O
O
O
N
N
N
R
N
Ph
N N
2
5-6
7
Scheme 2. General structure of new isatin derivatives keeping 1-allylisatin skeleton.
RESULTS AND DISCUSSION
The first step was the N-alkylation of isatin using corresponding bromides under phase transfer catalysis
conditions (Scheme 3).
2
equiv. R Br
O
O
2
equiv. K CO / DMF / 0.1 equiv. TBAB
2
3
O
O
N
12 h, rt
N
H
R
1
2-4
Product
2
R
Yield (%)
86
CH CH CH2
2
3
4
CH C CH
76
90
2
Bn
Scheme 3. N-Alkylation of isatin.
In a general procedure, isatin was reacted with allyl bromide, propargyl bromide and benzyl bromide
using the mixture K CO / DMF / tetrabutylammonium bromide as catalytic system. After 12 h at room
temperature and recrystallization from ethanol, 1-allylisatin (2) and 1-propargylisatin (3) were isolated in
2
3

HETEROCYCLES, Vol. 65, No. 12, 2005
2951
8
6% and 76% yields respectively. 1-Benzylisatin (4) was also synthesized by the same experimental
procedure in order to check the importance of the grafting of a heterocycle on biological activity. The
product (4) was isolated in 90% yield. Each product structure was characterized by traditional
spectroscopic methods. FT-IR spectrometry has shown characteristic bands of the grafted moieties
(double bound, triple bound or aromatics), and NMR spectrometry confirmed the presence of the allyl,
propargyl or benzyl group N-grafted on isatin block.
The 1,3-dipolar cycloaddition reactions were first carried out on 1-allylisatin (2) (Scheme 4).
C H -p-CH
3
R
6
4
O
2
2
equiv. p-CH -C H NH N C
O
O
3
6
4
N N
N
Br
N
R
O
2
equiv. (C H ) N, THF
2 5 3
refluxing, 24 h
5-6
Product
R
Ph
Yield (%)
5
6
45
58
CO2C2H5
Scheme 4. Synthesis of oxadiazolyl isatin derivatives from 1-allylisatin (2).
The cycloaddition was achieved by refluxing 2 in THF with the N-tolyl-C-phenylnitrilimine generated in
situ by the reaction of N-tolyl-1-phenylhydrazonyl bromide with triethylamine. The precipitate was
purified
-allyl-5’-phenyl-3’-(p-tolyl)-2H-spiro[indolo-3(1H),2’(3’H)-1,3,4-oxadiazol]-2-one (5) was thus
obtained in 45% yield.
by
recrystallization
from
ethanol.
The
desired
product
1
We performed the same reaction using 2 equiv. of α-bromo-N-tolylhydrazonylcarboxylate in the same
condition as previously described for the synthesis of 5. The compound (6), ethyl
1-allyl-2-oxo-3’-(p-tolyl)spiro[indolo-3(1H),2’(3’H)-1,3,4-oxadiazole]-5’-carboxylate was isolated in
5
8% yield. The ethoxycarbonyl substituent of the dipole may have a high mesomeric effect on hydrazone
function allowing an easier dipolar attack to 3-carbonyl function of isatin, which could explain the
difference in yields between both syntheses. It is important to notice that both reactions leading to the
compounds (5) and (6) have shown a high periselectivity; only the 3-carbonyl group of isatin was
attacked, leaving unchanged the carbon-carbon double bond of allylic group. The presence of the double
bound was confirmed by FT-IR spectroscopy and NMR spectroscopy, showing the characteristic signals
of protons and corresponding carbons of the vinylic function. Moreover, these reactions are regiospecific
because the heteroatom of the dipole attacked specifically the 3-carbonyl group of isatin skeleton.
Concerning 1-propargylisatin (3), an additional heterocyclic substituent was introduced on its structure by
the reaction between the carbon-carbon triple bound and an azide derivative, leading to the isatin
derivative (7) bearing a triazolyl group (Scheme 5).

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HETEROCYCLES, Vol. 65, No. 12, 2005
O
3
O
2
equiv. Ph CH2 N3
in ethanol
O
O
N
N
N
N N
Ph
refluxing, 24 h
7
3
4%
Scheme 5. Synthesis of triazolyl isatin derivative starting from propargylisatin (3).
The azide derivative used in this synthesis was benzyl azide, which was prepared as described by Lindsay
1
0
et al. The desired product 1-(1-benzyl-1,2,3-triazol-4-ylmethyl)indol-2,3-dione (7) was obtained in 34%
yield. The disappearance of the carbon-carbon triple bond was confirmed by the absence of its FT-IR and
1
13
H and C NMR spectra. Again this reaction has shown a high regioselectivity because the compound (7)
1
3
is the only product. This regioselectivity of this 1,3-dipolar cycloaddition reaction was confirmed by C
NMR spectrum, showing the characteristic signal at 128.2 ppm assigned to C-5 triazolyl carbon, which is
1
1-13
in agreement with values found in literature.
The structure of 7 was also confirmed by NOE
experiments showing interactions between hydrogen of CH
cycle.
2
groups and the hydrogen of the triazolyl
ACKNOLEDGEMENT
We wish to thank the “Institut Universitaire de Technologie” of Béthune and its Director Dr Pierre Boulet
for financial support and Beatrice Herbaux for help in manuscript preparation.
EXPERIMENTAL
General
®
Melting points were determined by differential scanning calorimetry using a Perkin Elmer DSC Pyris 1 .
NMR spectra were recorded in CDCl (internal Me Si) with a Bruker DRX-300 Spectrometer (operating
3
4
at 300.13 MHz). Elemental analyses were performed by the IUT of Bethune, Departement of Chemistry
Bethune, France). Analytical TLC were performed on Merck aluminium backed silica gel (Silica Gel
(
F254), spots were visualized in UV light. Infra-red spectroscopy was performed using a FT-IR Bruker
Vector 22 apparatus equipped with a diamond reflection accessory.
N-Alkylation of isatin
In a general procedure, isatin (1.47 g, 0.01 mol) was reacted with alkyl bromide (0.02 mol) in the
2 3
presence of K CO (2.76 g, 0.02 mol) and tetrabutylammonium bromide (0.32 g, 0.001 mol) in DMF (60
mL). After 12 h stirring at rt, the precipitate was removed by filtration and purified by recrystallization
from ethanol.

HETEROCYCLES, Vol. 65, No. 12, 2005
2953
1
1
-Allylisatin (2) was obtained in 86% yield as red crystals, (mp 89-91°C, ethanol). H NMR (300 MHz,
CDCl ): δ (ppm) 4.30 (dd, J = 7.0 and 1.7 Hz, 2H, N-CH ), 5.24 (m, 2H, CH =), 5.78 (m, 1H, -CH=),
.83-7.51 (m, 4H, HAr). C NMR (300 MHz, CDCl ): δ (ppm) 42.4 (N-CH ), 110.9, 123.8, 125.2, 138.4
4 CArH), 117.5 (CAr-C=O), 118.5 (=CH ), 130.2 (-CH=), 150.8 (CAr-N-C=O), 157.9 (N-C=O), 183.2
3
2
2
1
3
6
3
2
(
(
2
-1
C=O ketone) ; IR: υ (cm ) 3093, 1735, 1645, 1601. Anal. Calcd for C11
H
9
NO
2
: C; 70.58, H; 4.85, N;
+
7
.48. Found: C; 70.42, H; 4.95, N; 7.60. EIMS [M] m/z 187.
1
1
-Propargylisatin (3) was obtained in 76% yield as orange crystals (mp 156-158°C, ethanol). H NMR
(
300 MHz, CDCl ): δ (ppm) 4.50 (d, J = 2.6 Hz, 2H, N-CH ), 2.32 (t, J=2.6 Hz, 1H, ≡CH), 7.20-7.63 (m,
3
2
1
3
4
H, HAr). C NMR (300 MHz, CDCl
3
): δ (ppm) 29.8 (N-CH ), 73.9 (≡CH), 74.5 (-C≡), 111.7, 125.8,
2
1
26.2, 139.3 (4 CAr-H), 117.4 (CAr-C=O), 149.0 (CAr-N-C=O), 158.6 (N-C=O), 183.0 (C=O ketone) ; IR:
-1
υ (cm ) 3243, 2117, 1728, 1601. Anal. Calcd for C11
H
7
NO
2
: C; 71.35, H; 3.81, N; 7.56. Found: C; 71.50,
+
H; 3.72, N; 7.75. EIMS [M] m/z 185.
1
N-Benzylisatin (4) was obtained in 80% yield as orange crystals (mp 133-135°C, ethanol). H NMR (300
1
3
MHz, CDCl
3
): δ (ppm) 4.86 (s, 2H, N-CH
2 3
), 6.70-7.55 (m, 9H, Har) ; C NMR (300 MHz, CDCl ): δ
(
ppm) 44.0 (N-CH ), 111.0, 123.9, 125.4, 138.3 (4 C ), 127.4, 128.2, 129.1 (3 C ), 117.7, (C -C=O),

2
Ar
Bn
Ar
-1
1
34.5 (CqBn), 150.7 (CAr-N-C=O), 158.3 (N-C=O), 183.3 (C=O ketone) ; IR: υ (cm ) 3030, 1727, 1608.
+
Anal. Calcd for C15
m/z 237.
2
H11NO : C; 75.94, H; 4.67, N, 5.90. Found: C; 76.08, H; 4.52, N; 6.05. EIMS [M]
1
1
,3-Dipolar cycloaddition reactions starting from compound (2)
-Allyl-5'-phenyl-3'-(p-tolyl)-2H-spiro[indolo-3(1H),2'(3'H)-1,3,4-oxadiazol]-2-one (5) was obtained
by refluxing compound (2) (1.87 g, 0.01 mol) for 24 h with N-tolyl-1-phenylhydrazonyl bromide (5.48 g,
.02 mol) and triethylamine (2.02 g, 0.02 mol) in THF (60 mL). The precipitate was recovered by
0
filtration and was purified by recrystallization from ethanol. Product (5) was thus obtained in 45% yield
1
as yellow crystals (mp 176-178°C, ethanol). H NMR (300 MHz, CDCl ): δ (ppm) 2.36 (s, 3H, C -CH ),
3
Ar
3
3
.87 (dd, J = 6.9 and 1.8 Hz, 2H, N-CH
2
), 5.26 (m, 2H, =CH
2
), 6.02 (m, 1H, =CH), 6.35-7.50 (m, 13H,
), 109.8, 116.3, 135.7, 139.7, 145.1,
),
29.0 (=CH-), 154.7 (C=O amide) ; IR: υ (cm ) 3085, 3029, 2975-2831, 1643, 1612. Anal. Calcd for
1
3
H
Ar).

C NMR (300 MHz, CDCl
3
): δ (ppm) 14.3 (CH ), 46.2 (N-CH
3
2
1
1
47.6, 153.6 (Cq), 112.0, 125.5, 126.8, 127.9, 130.2, 130.6, 132.0, 135.1, 137.4 (CArH), 115.7 (=CH
2
-1
21 3 2
Elemental Analysis C25H N O : C; 75.93, H; 5.35, N: 10.63. Found: C; 75.72, H; 5.43, N; 10.70. EIMS
+
[
M] m/z 395.
Ethyl 1-allyl-2-oxo-3'-(p-tolyl)spiro[indolo-3(1H),2'(3'H)-1,3,4-oxadiazole]-5'-carboxylate (6) was
obtained using the same procedure as previously, by reaction of (2) (1.87 g, 0.01 mol) with
α-bromo-N-tolyl-hydrazonylcarboxylate (5.40 g, 0.02 mol). Product (6) was purified by recrystallization

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HETEROCYCLES, Vol. 65, No. 12, 2005
1
from ethanol and obtained in 58% yield as yellow crystals (mp 187-189°C, ethanol). H NMR (300 MHz,
CDCl ): δ (ppm) 1.42 (t, J = 7.1 Hz, 3H, O-C-CH ), 2.38 (s, 3H, CAr-CH ), 3.85 (dd, J = 7.1 and 1.7 Hz,
N-CH ), 4.56 (q, J = 7.1 Hz, 2H, O-CH ), 5.28 (m, 2H, =CH ), 6.05 (m, 1H, =CH), 6.45-7.40 (m, 8H,
C NMR (300 MHz, CDCl ): δ (ppm) 14.7 (CH ), 21.6 (CH -C-O), 46.1 (N-CH ), 62.4 (O-CH ),
3
3
3
2
2
2
1
3
H ).

Ar
3
3
3
2
2
1
q
09.9, 116.3, 135.9, 139.8, 147.6, 153.8 (C ), 112.1, 125.6, 130.3, 130.7, 132.1, 135.1 (CArH), 115.7
(
=CH ), 129.1 (=CH-), 160.3 (C=O ester), 154.6 (C=O amide) ; IR: υ (cm-1) 3080, 2982-2820, 1726,
2
1
21 3 4
644, 1609. Anal. Calcd for C22H N O : C; 67.51, H; 5.41, N; 10.74, Found: C; 67.62, H; 5.28, N; 10.85.
+
EIMS [M] m/z 391.
1
1
,3-Dipolar cycloaddition reactions starting from compound (3)
-(-1-Benzyl-1,2,3-triazol-4-ylmethyl)indol-2,3-dione (7) was obtained by refluxing (3) (1.85 g, 0.01
mol) with benzyl azide (2.66 g, 0.02 mol) in ethanol (30 mL) for 24 h. After cooling the reaction medium
to rt, the precipitate was washed with ethanol. The desired product (7) was obtained with 34% yield as a
1
yellow crystals (mp 139-141°C, ethanol). H NMR (300 MHz, CDCl
3
): δ (ppm) 4.95 (s, 2H, OC-N-CH
2
),
): δ
-Ph), 111.9, 124.4, 125.6, 139.0 (CArH isatin), 117.9 (CAr-CO),
28.2 (CtriazoleH), 128.6, 139.3, 129.6 (CArH benzyl), 134.4 (Cq benzyl), 150.6 (CAr-N), 158.3 (C=O
1
3
5
.46 (s, 2H, N-CH
2
-Ph), 7.20-7.60 (m, 9H, HAr), 7.54 (s, 1H, CHtriazole).
), 54.8 (N-CH
 C NMR (300 MHz, CDCl
3
(
ppm) 35.8 (OC-N-CH
2
2
1
-1
14 4 2
amide), 183.5 (C=O ketone) ; IR: υ (cm ) 3126, 1737, 1609. Anal. Calcd for C18H N O : C; 67.91; H;
+
4
.43, N; 17.60%. Found: C; 68.07, H; 4.27, N; 17.45. EIMS [M] m/z 318.
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