Preparation of 6-azaoxindole (6-azaindol-2(3H)-one) and substituted derivatives

Article abstract of DOI:10.1002/jhet.5570430107

A general synthesis of 6-azaoxindoles, substituted in the 3- and 5-position, has been developed starting from 4-methoxyearbomethyl-3- nitropyridine, via hydrogenation of the nitro group and cyclisation of the resulting 3-amino-4-methoxyearbomethyl-pyridin

Full text of DOI:10.1002/jhet.5570430107

Preparation of 6-Azaoxindole (6-Azaindol-2(3H)-one)
Jan-Feb 2006
49
and Substituted Derivatives
Einar J. Andreassen and Jan M. Bakke
*
Department of Chemistry, Norwegian University of Science and Technology, Sem Sælandsvei 8, NO-7491, Norway
Received April 13, 2005
A general synthesis of 6-azaoxindoles, substituted in the 3- and 5-position, has been developed starting
from 4-methoxycarbomethyl-3-nitropyridine, via hydrogenation of the nitro group and cyclisation of the
resulting 3-amino-4-methoxycarbomethyl-pyridine.
J. Heterocyclic Chem., 43, 49 (2006).
Introduction.
onate diesters were low [3]. Furthermore, substituted 6-aza-
oxindoles are not easily available by this method.
We have reported the synthesis of 4-methoxycar-
bomethyl-3-nitropyridine (1a) by a vicarious nucleophilic
substitution (VNS) of the readily available 3-nitropyridine.
Furthermore, we showed that the VNS reaction was also
possible with potassium 5-nitropyridine-2-sulfonate [1].
The products from the VNS reactions and their further
substitution products have the "ortho" configuration of the
nitro and ester groups which makes a ring closure possible
after reduction of the nitro group to an amino group.
The products from a ring closure reaction would be 6-aza-
oxindoles (6-azaindol-2(3H)-ones, 3). The azaindole ring
system is part of several pharmaceutical and natural prod-
ucts and several synthetic methods have been reported for
azaindoles, including 6-azaindoles [2]. Azaoxindoles have
been less thoroughly investigated. A few patents for phar-
maceutical products containing the azaoxindoles have
appeared [3] and syntheses for 6-azaoxindole itself have
been reported [3,4]. These started with 4-chloro-3-nitropyri-
dine which was reacted with diethyl [3,4a] or dibenzyl [4b]
malonate. The products were hydrogenated and the diethyl
esters decarboxylated either before [3] or after [4a] the
cyclisation to azaoxindole. With the dibenzyl ester, the
decarboxylation took place during the hydrogenation/ cycli-
sation reaction and 6-azaoxindole was formed in a one-pot
reaction (76% yield). Although the yields in the cyclisation
reaction were satisfactory, the yields in the first steps, espe-
cially the reaction of 4-chloro-3-nitropyridine with the mal-
The new high yield method for the formation of 1a [1]
makes this an attractive compound for the synthesis of 6-
azaoxindole. It might also be possible to prepare substi-
tuted derivatives of 1 and thus obtain a general synthesis of
6-azaoxindoles substituted in the 3- and 5-positions by
reduction of 1 to the 3-aminopyridine, compound 2, fol-
lowed by cyclisation to the 6-azaoxindoles (3).
Results and Discussion.
Preparation of Compounds 1b – 1e.
The possibility of substitution of 1a in the side chain
was explored with a few alkylating agents, methyl and
ethyl iodides and benzyl bromide. The monoalkylation
reaction in MeONa/MeOH gave acceptable yields, 42%,
53% and 41% respectively. However, attempts at dialkyla-
tion failed, both in the reaction of 1b with ethyl iodide and
of 1c with methyl iodide. Attempts at alkylations with 1-
bromo-3-chloropropane and 1-bromo-4-chlorobutane also
failed. With these compounds, the bromide ion apparently
was not a good enough leaving group to facilitate the reac-
tions. Neither were we able to alkylate the 2-methoxy
Scheme 1

50
E. J. Andreassen and J. M. Bakke
Vol. 43
1
compound 1e by the methods above, presumably because
the methoxy group para to the nitro group, mitigates its
electron withdrawing effect.
after 24 h at room temperature ( H NMR). Thus, the cycli-
sation reaction went smoothly under these conditions, but
the isolation of the product was difficult. Although NMR
indicated 3a to be the only product it was only possible to
isolate a low yield of 3a. When 4-(benzyl-methoxycar-
bomethyl)-3-aminopyridine (2d) was reacted under basic
conditions, only one product was obtained in 61% yield.
From MS, NMR and IR spectroscopy this was 3-benzyl-
3-hydroxy-6-azaoxindole (5):
An unexpected reaction took place during these experi-
ments. In an attempt to increase the yield in the prepara-
tion of 1b, 1a was reacted with methyl iodide in
DMSO/NaH. Instead of 1b a deep red compound was iso-
lated in 80% yield, which by MS and NMR spectroscopy
was shown to be the N-methylated 4-pyridone 4a. An
even higher yield of this, 93%, was obtained by reaction
of 1a with dimethyl sulfate and NaH in THF. A small
amount of 4a was also found in the preparation of 1a in
MeOH, showing the fine balance between C- and N-
attack in this reaction. In the reaction of 1a with ethyl
iodide in MeONa/MeOH, a 2% yield of the analogous N-
ethylated 4-pyridone 4b was isolated.
In the formation of 5 there must have been an oxidation
stage, most likely an autoxidation of the "enol form" 3d'
under basic conditions. The easy autoxidation of an isomer
of 3d, 3-benzyl-4-azaoxindole has been reported [5].
Reaction under acidic conditions also resulted in com-
plete conversion of 2a to 6-azaoxindole (3a) as indicated
1
by H NMR spectroscopy. In contrast to the product from
Formation of 6-Azaoxindoles.
the reaction under basic conditions, 3a was readily isolated
as its HCl salt. This methodology was then applied to com-
pounds 2b and 2d. In both cases satisfactory yields of the
substituted 6-azaoxindoles 3b and 3d as the HCl salts were
obtained (Table 1).
Late in this investigation, Fiksdahl and Holt [6] found, in
a different project, that methyl 3-aminopyridin-4-yl carba-
mate (6) readily cyclised at 50 °C to 1,3-dihydro-2H-imi-
The cyclisation of 2 might take place under different
conditions. The product from catalytic hydrogenation of 4-
bis(benzyloxycarbo)methyl-3-nitropyridine gave 6-aza-
oxindole in 76% yield upon heating in ethanol solution [4].
A reasonable result from the catalytic hydrogenation
would be the formation of 4-carboxymethyl-3-nitropyri-
dine from reductive cleavage of the benzyl esters followed
by decarboxylation:
dazo[4,5-c]pyridin-2-one (7) with HBF as catalyst.
4
In an attempt to apply this methodology, we hydro-
genated the benzyl ester of 4-(carboxymethyl)-3-nitropyri-
dine. The free acid, 4-(carboxymethyl)-3-aminopyridine
was formed in 65% yield. However, reaction of this in
refluxing ethanol as described for the product from the
hydrogenation of the bisbenzyl ester, gave 4-methyl-3-
aminopyridine as the only product (close to 100% by
NMR). Apparently, the reaction of the bisbenzyl ester did
not proceed by the route above.
This cyclisation reaction had been performed earlier
under more severe conditions, 150 °C in diglyme for 24 h
In an attempt to perform the cyclisation under basic
conditions, 2a was reacted with 1.5 mol eq. NaOEt in
ethanol. The conversion to 6-azaoxindole was complete
[7]. We therefore tried the HBF protocol with 2a as sub-
4
strate. This worked well: in aqueous solution with 3.5 mol

Jan-Feb 2006
Preparation of 6-Azaoxindole (6-Azaindol-2(3H)-one) and Substituted Derivatives
51
Elemental analyses were determined by the Laboratory of
Organic Elemental Analysis, Institute of Chemical Technology,
Prague, Czech Republic. Solvents were purified by standard
methods [8]. Silica gel SDS 60A, 43-60 mesh was used for flash
column chromatography.
eq. HBF , the cyclisation reaction was complete after 0.5 h
4
at reflux temperature. The work up was easy and a 63%
yield of the free base 3a was isolated. We then tried this
method for the other aminopyridines 2b – 2e the yields
were lower then for the cyclisations with HCl but the
reported yields are from the isolation of the free base, not
the acid salts. The results may therefore not be directly
comparable.
We were not able to alkylate the 2-methoxy compound
1e in the side chain. We therefore alkylated the 6-azaoxin-
dole 3e with methyl iodide. The only product from that
reaction was 3,3-dimethyl-5-methoxy-6-azaoxindole 3f.
Even if only 0.5 mol eq. of MeI was reacted, the dimethy-
lated oxindole was the product together with an equivalent
amount of unreacted 3e.
4-(Benzyloxycarbomethyl)-3-nitropyridine.
3-Nitropyridine (1.0 g, 8.1 mmol) and benzyl chloroacetate (2.0
ml, 13.2 mmol) were dissolved in dry DMF (9 ml) and during 5 min-
utes added dropwise to a solution of potassium t-butoxide (3.6 g, 32
mmol) in dry DMF (36 ml) cooled in an ice-water bath. The cooling
bath was removed and the reaction mixture stirred for 35 minutes
before it was quenched by addition of an excess of aqueous ammo-
nium chloride (3 M). The aqueous phase was then extracted with
diethyl ether (4 x 50 ml). The organic phase was washed with brine,
dried (Na SO ) and evaporated to dryness in vacuo to give the crude
2
4
product as a red oil, 2.50 g. Purification by flash chromatography
(ethyl acetate:petroleum ether (80-100 °C) 1:1) gave the pure prod-
uct as a light yellow solid, 1.64 g (75%). mp 64.5-65.5 °C; IR (neat)
Table 1
-1
max/cm : 1727 (s), 1609 (s), 1556 (s), 1455 (m), 1381 (s), 1350 (s),
Formation of 6-Azaoxindoles from 3-Amino-4-methoxycar-
bomethylpyridines
1
1303 (s), 1226 (s); H NMR (400 MHz, d -DMSO): 9.25 (1H, s, H-
6
2), 8.86 (1H, d, J = 4.94 Hz, H-6), 7.68 (1H, d, J = 4.94 Hz, H-5),
7.42-7.30 (5H, m, Ph), 5.14 (2H, s, OCH ), 4.25 (2H, s, CH (CO));
2
2
13
C NMR (100 MHz, d -DMSO): 168.9. 154.1, 145.7, 145.0, 138.8,
6
135.7, 128.5, 128.2, 128.0, 127.9, 66.3, 36.3; m/z (EI) 273.08794
(M+1, C H N O requires 273.08753), 273 (M+1, 0.4), 166 (64),
14 13
2 4
136 (65), 108 (30), 91 (100), 86 (30), 84 (46), 65 (13).
Alkylation Reactions, General Method.
4-(Methoxycarbomethyl)-3-nitropyridine [1] (1a) (5.1 mmol)
and alkyl iodide (5.6 mmol) in dry MeOH or EtOH (15 ml) were
added dropwise to a solution of sodium methoxide (6.3 mmol) in
dry MeOH or EtOH (10 ml) at room temperature under argon
during 5 minutes. After the addition was complete, the mixture
was stirred for 24 hours and quenched with an excess of aqueous
R
Nu
Yields/%
Conditions
a
b
HCl/H O/(C H ) O
HBF /H O
2
2
5 2
4
2
H
Me
Et
Bn
H
Me
H (3a)
H (3b)
H (3c)
H (3d)
MeO (3e)
98
90
-
61
-
63
13
98
51
98
30
NH Cl (3 M).
4
4-(1-Methoxycarboethyl)-3-nitropyridine (1b).
From the reaction of 1a with methyl iodide after quenching
with water, a deep red byproduct (4a) was filtered off from the
reaction mixture. The filtrate was then extracted with CH Cl (3
c
MeO (3f)
2
a
b
Yields of product isolated as HCl salt; Yields of product isolated as
2
2
c
free base; Yield from alkylation of 3e.
x 100 ml). The organic phase was washed with brine, dried
(Na SO ) and stripped of solvent to give the crude product as an
2
4
red oil. Flash chromatography (CH Cl ) gave 1b as an red oil,
2
2
From Table 1 it can be seen that a general method for the
synthesis of 6-azaoxindoles substituted in the 3- and 5-
positions has been elaborated, starting from the readily
available 3-nitropyridine via 4-methoxycarbomethyl-3-
nitropyridine (1a). This may open a new route to a series
of compounds with the potential for biological activity.
-1
455 mg (42%). IR (neat) max/cm : 3360 (bs), 2954 (bs), 1738
1
(s), 1604 (m), 1529 (s), 1436 (m), 1354 (s); H NMR (400 MHz,
CDCl ): 9.17 (1H, s, H-2), 8.79 (1H, d, J = 5.2, H-6), 7.46 (1H, d,
3
J = 5.2, H-5), 4.40 (1H, q, J = 7.2, CH), 3.70 (3H, s, OCH ), 1.63
3
13
(3H, s, J = 7.2, CH CH-); C NMR (100 MHz, CDCl ): 172.2,
3
3
153.7, 146.1, 144.0, 133.1, 123.9, 52.7, 40.9, 17.2; m/z (EI)
210.06405 (M+, C H N O requires 210.06384), 210 (M, 8),
9
10 2 4
179 (21), 164 (100), 150 (36), 104 (38).
EXPERIMENTAL
4-(1-Ethoxycarbopropyl)-3-nitropyridine (1c).
Reaction of 1a with ethyl iodide, extraction of the product with
NMR spectra were recorded on Bruker Avance DPX 300, DPX
400 or DRX 600 instruments with chemical shifts referenced to
Et O, drying (Na SO ) and evaporation of the solvent gave a red
2
2
4
1
13
oil, 972 mg. Purification by flash chromatography (EtOAc:cyclo-
the residual H or C resonances of the deuteriomethanol or deu-
teriodimethylsulfoxide solvent employed. Coupling constants are
given in Hz. IR spectra were recorded on a Thermo Nicolet FT-IR
Nexus spectrometer. EI-MS spectra were obtained on a Finnigan
MAT 95XL spectrometer. Melting points are uncorrected.
hexane = 1:1) gave 1c as a light yellow oil, 644 mg (53%). IR
-1
(neat) max/cm : 2976 (m), 2937 (m), 2878 (m), 1736 (s), 1602
1
(s), 1530 (s), 1461 (m),1354 (s); H NMR (400 MHz, CDCl ):
3
9.12 (1H, s, H-2), 8.76 (1H, d, J = 5.2, H-6), 7.52 (1H, d, J = 5.2,

52
E. J. Andreassen and J. M. Bakke
Vol. 43
H-5), 4.18 (3H, m, OCH , CH CH CH), 2.20 (1H, m,
Formation of the Aminopyridines (2).
2
3
2
CH CH CH), 1.91 (1H, m, CH CH CH),1.22 (3H, t, J = 7.2,
3
2
3
2
The appropiate 3-nitropyridine compound was dissolved in
either methanol or ethyl acetate, Pd/C added (5%, 2.5 mole%)
and the mixture exposed to hydrogen until no starting material
was detectable by TLC (normally overnight). Filtration and evap-
oration gave the crude product in nearly quantitative yield which
was used in subsequent reactions without purification. The prod-
ucts were purified for characterisation purposes.
13
OCH CH ), 0.98 (3H, t, J = 7.2, CH CH CH); C NMR (75
2
3
3
2
MHz, CDCl ): 171.0, 154.0, 147.0, 146.0, 143.5, 124.0, 61.5,
3
47.5, 26.0, 14.0, 12.5; m/z (EI): m/ z (EI) 238.09396 (M+,
C H N O requires 238.09535) 239 (M+1, 1), 193 (61), 192
11 14
2 2
(82), 165 (39), 164 (59), 149 (55), 137 (24), 117 (57), 92 (79).
4-(Methoxycarbo-benzylmethyl)-3-nitropyridine (1d).
The crude product from the reaction of 1a with benzyl bromide
was isolated from the quenched (water) reaction mixture by filtra-
3-Amino-4-(carboxymethyl)pyridine.
4-(Benzyloxycarbomethyl)-3-nitropyridine (500 mg, 1.84
mmol) was dissolved in methanol (30 ml), Pd/C 5% was
added (78 mg, 2.0 mol%) and the mixture exposed to hydro-
gen for 4 hours. Filtering off the catalyst and removing the
solvent in vacuo gave the crude product as a yellow solid, 188
mg (65 %). mp 136.0-137.0 °C, identified as the free car-
tion to give pale brown crystals. One recrystallization (CHCl )
gave pure 1d, 595 mg (41%). mp 92.5-93.0 °C; Found: C, 62.5; H,
3
4.8; N, 9.5. C H N O requires: C, 62.9; H, 4.9; N, 9.8; IR (KBr)
15 14
2 4
-1
max/cm : 3444 (m), 3033 (m), 2952 (m), 1731 (s), 1599 (s), 1548
(m), 1523 (s), 1495 (m), 1355 (s); H NMR (400 MHz, d -
1
6
DMSO): 9.10 (1H, s, H-2), 8.72 (1H, d, J = 5.2, H-6), 7.44 (1H, d,
J = 5.2, H-5), 7.27-7.10 (5H, m, Ph), 4.61 (1H, dd, J = 7.6, 7.6,
-1
boxylic acid: IR (neat) max/cm : 3334 (s), 3186 (s), 1652 (s),
1
1500 (s), 1443 (m), 1352 (s), 1257 (s); H NMR (400 MHz,
BnCH), 3.67 (3H, s, OCH ), 3.50 (1H, dd, J = 13.8, 7.7, -CH -),
3
2
d -DMSO): 7.95 (1H, s, H-2), 7.71 (1H, d, J = 4.94 Hz, H-6),
13
6
3.14 (1H, dd, J = 13.8, 7.7, -CH -); C NMR (100 MHz, d -
2
6
13
6.94 (1H, d, J = 4.94 Hz, H-5), 3.34 (2H, s, CH (CO));
C
2
DMSO): 171.2, 153.3, 146.0, 145.4, 141.9, 137.2, 128.9, 128.6,
127.0, 124.4, 52.6, 48.1, 38.7; m/z (EI) 286 (M, 0.05%), 268 (3.5),
209 (18), 180 (17), 152 (9), 121 (34), 105 (11), 91 (100).
NMR (100 MHz, d -DMSO): 171.8. 143.4, 137.3, 137.0,
6
125.9, 124.7, 36.0; m/z (EI) 152.05894 (M+, C H N O
7
8
2
2
requires 152.05857), 152 (M+, 18), 134 (30), 108 (100), 107
(38), 80 (50). When cyclisation of this compound was
attempted under acidic conditions (see below) the only prod-
uct was 3-amino-4-methylpyridine.
Methyl (1-Methyl-3-nitro-1H-pyridine-4-ylidene)acetate (4a).
The red compound was filtered off from the crude reaction mix-
ture from the reaction of 1a with methyl iodide after quenching
with water. Recrystallisation (CHCl ) gave 4a as a cotton like
3
3-Amino-4-(methoxycarbomethyl)pyridine (2a).
solid, 31mg (3%). mp 200.0-201.0 °C; Found: C, 50.9; H, 4.8; N,
13.3. C H N O requires: C, 51.4; H, 4.8; N, 13.3; IR (KBr)
A pure sample was obtained by recrystallization from CHCl
3
9
10 2 4
-1
to give colorless crystals, mp 82.5-83.0 °C; Found: C, 57.53; H:
6.22; N: 16.51; C H N O requires: C, 57.82; H, 6.07; N, 16.86.
max/cm : 3430 (bs), 3089 (m), 2944 (m), 1739 (m), 1686 (s),
1653 (s), 1560 (s), 1526 (m), 1438 (s), 1403 (s), 1324 (s); H
1
8
10
-1
2 2
IR (KBr) max/cm : 3333 (bs), 3211 (bs), 2953 (m), 1731 (s),
NMR (400 MHz, CDCl ): 8.43 (1H, d, J = 7.9, H-6), 8.30 (1H, d,
3
1
1644 (s), 1597 (m), 1567 (s), 1503 (s), 1428 (s), 1341 (s); H
J = 2.0, H-2), 6.54 (1H, ddd, J = 8.0, 1.5, 1.5, H-5), 6.39 (1H, d, J
13
NMR (400 MHz, d -DMSO): 7.96 (s, 1H, H-2), 7.70 (d, 1H, J =
= 1.0, COCH), 3.69 (3H, s, NCH ), 3.56 (3H, s, OCH );
C
6
3
3
4.9, H-6), 6.92 (d, 1H, J = 4.9, H-5), 5.15 (2H, bs, NH ), 3.61
NMR (100 MHz, CDCl ): 168.5, 143.0, 138.0 , 134.5, 129.9,
2
3
13
(3H, s, OCH ), 3.58 (2H, s, CH (CO)); C NMR (100 MHz,
117.0, 89.8, 50.0, 43.0; m/z (EI): 211 (M+1, 5), 210 (M, 50), 179
(33, 151 (100), 133 (17), 121 (74), 105 (17), 93 (51), 92 (14). This
compound was prepared in high yield by slowly adding a mixture
of 1a (0.27 g, 1.4 mmol) and dimethyl sulfate (0. 18 ml, 2 mmol)
in dry THF (15 ml) to NaH (45 mg, 2 mmol) in dry THF (15 ml)
3
2
CHCl ): 170.8, 142.1, 139.5, 138.2, 126.6, 125.0, 52.3, 37.1; m/
3
z (EI) 167.1 (M+1, 11%),166.1 (100), 134.1 (93), 107.1 (94), 106
(48), 80.1 (19).
3-Amino-4-(methoxycarboethyl)pyridine (2b).
under N at 20 °C. The mixture was stirred for 48 h and quenched
2
A pure sample was obtained by flash chromatography (EtOAc)
to give a light brown solid, mp 89.0-90.0 °C; IR (KBr) max/cm :
3427 (s), 3356 (s), 3252 (m), 2980 (m), 1723 (s), 1644 (s), 1586
(s), 1563 (s), 1531 (m), 1494 (s), 1413 (s), 1354 (s), 1221 (s); H
with water (20 ml). The red precipitate (4a) was collected by fil-
tration, washed and dried. Yield 0.27 g, 1.28 mmol, 93%) [9].
-1
Methyl (1-Ethyl-3-nitro-1,4-dihydropyridine-4-ylidene)acetate
(4b).
1
NMR (400 MHz, d -DMSO): 7,97 (1H, s, H-2), 7.72 (1H, d, J =
6
5.2, H-6), 6.85 (1H, d, J = 5.2, H-5), 5.23 (2H, s, NH ), 3.92 (1H,
The red compound was filtered off from the crude reaction
2
q, J = 8.0, CH CH), 3.60 (3H, s, OCH ), 1.30 (3H, d, J = 8.0,
mixture from 1a and ethyl iodide after quenching with water.
3
3
13
CH CH); C NMR (100 MHz, d -DMSO): 173.8, 142.3, 137.7,
Recrystallisation (CHCl ) gave 4b as red needles, 18mg (2%).
3
6
3
+
137.6, 130.9, 121.2, 51.9, 38.1, 16.4; m/z (EI) 180.08992 (M ,
C H N O requires 180.08988) 181 (M+1, 9%), 180 (M, 81),
mp 159.0-160.0°C; Found: C, 53.2; H, 5.6; N, 12.4. C H N O
10 12
-1
2 4
requires: C, 53.6; H, 5.4; N, 12.5; IR (KBr) max/cm : 3421(bs),
3089 (s), 2984 (s), 2946 (s), 1679 (s), 1649 (s), 1555 (s), 1527 (s),
9
12 2 2
148 (47), 121 (100), 120 (46), 104 (13).
1
1492 (m), 1471 (s), 1354 (s), 1319 (s), 1319 (s), 1268 (s); H
3-Amino-4-(1-ethoxycarbopropyl)pyridine (2c).
A pure sample was obtained by flash chromatograpy
NMR (400 MHz, CDCl ): 8.43 (1H, d, J = 7.9, H-6), 8.33 (1H, d,
3
J = 1.9, H-2), 6.58 (1H, ddd, J = 8.0, 1.6, 1.6, H-5), 6.39 (1H, d, J
-1
(MeOH:CH Cl =1:20) to give a yellow oil. IR (KBr) max/cm :
= 1.6, COCH), 3.75 (2H, q, J = 7.6,NCH ), 3.69 (3H, s, OCH ),
2
2
2
3
13
3353 (bs), 3221 (bs), 2970 (bs), 1724 (s), 1641 (s), 1591 (m),
1562 (m), 1500 (m), 1460 (m), 1422 (s), 1370 (s), 1327 (m), 1262
1.46 (3H, t, J = 7.6, NCH CH ); C NMR (100 MHz, CDCl ):
2
3
3
169.4, 140.6, 137.2, 130.3, 131.5, 119.4, 94.0, 51.8, 50.6, 15.5;
m/z (EI): 225 (M+1, 4), 224 (M, 38), 193 (34), 165 (100), 135
(95), 107 (77), 106 (17).
1
(s); H NMR (400 MHz, d -DMSO): 7.97 (1H, s, H-2), 7.73 (1H,
6
d, J = 4.8, H-6), 6.90 (1H, d, J = 4.8, H-5), 5.26 (2H, bs, NH ),
2

Jan-Feb 2006
Preparation of 6-Azaoxindole (6-Azaindol-2(3H)-one) and Substituted Derivatives
53
4.08 (2H, m, OCH ), 3.73 (1H, t, J = 7.5, CH CH CH), 1.87 (1H,
Formation of 6-Azaoxindoles (3) Under Acidic Conditions.
2
3
2
m, CH CH CH), 1.65 (1H, m, CH CH CH), 1.14 (3H, t, J = 7.2,
3
2
3
2
a) with HCl.
13
OCH CH ), 0.88 (3H, t, J = 7.2, CHCH CH ); C NMR (100
2
3
2
3
The appropriate 3-amino-4-substituted pyridine (2.0 mmol)
was dissolved in diethylether (15 ml) and HCl (10 ml, 10%
aqueous). The resulting biphasic solution was stirred at room
temperature over night. The two phases were separated and the
organic phase washed with water. The combined aqueous
phases were evaporated to give the crude 6-azaoxindole
hydrochloride. There can be keto-enol tautomerism in all 6-aza-
oxindole products, but the spectroscopic data showed the salts
to exist in the enol form only.
MHz, d -DMSO): 172.7, 142.6, 137.6, 137.5, 129.1, 121.3, 60.3,
6
45.3, 24.5, 14.0, 11.7; m/z (EI) 208.12072 (M+, C H N O
11 16
2 2
requires 208.12117) 209 (M+1, 11), 208 (M, 61), 180 (15), 135
(65), 134 (100), 133 (30), 119 (28), 107 (46).
3-Amino-4-(methoxycarbo-benzylmethyl)pyridine (2d).
A pure sample was obtained by flash chromatography
(MeOH:CH Cl =1:50) to give a light yellow solid. mp 155.0-
2
2
-1
157.0 °C; IR (KBr) max/cm : 3398 (s), 3323 (m), 3214 (s), 3020
(m), 2928 (m), 2867 (m), 1636 (s), 1595 (m), 1562 (s), 1495 (s),
6-Azaoxindole Hydrochloride (3a•HCl).
1
1423 (s), 1299 (m); H NMR (400 MHz, d -DMSO): 7.95 (1H, s,
6
The product was obtained as a white solid, 340 mg (98%), mp
H-2), 7.71 (1H, d, J = 5.0, H-6), 7.24-7.15 (5H, m, Ph), 7.00 (1H,
-1
225 °C (dec.). IR (KBr) max/cm : 3380 (bs), 3018 (bs), 1780 (s),
d, J = 5.0, H-5), 5.29 (2H, bs, NH ), 4.22 (1H, dd, J = 8.7, 6.7,
2
1644 (m), 1606 (s), 1524 (m), 1476 (s), 1445 (m), 1346 (m), 1250
BnCH), 3.53 (3H, s, OCH ), 3.20 (1H, dd, J = 14.0, 8.8, PhCH ),
3
2
1
13
(m), 1225 (m); H NMR (400 MHz, d -DMSO):13.80 (1H, bs,
3.00 (1H, dd, J = 14.0, 6.6, PhCH ); C NMR (100 MHz, d -
6
2
6
NH), 12.50 (1H, s, OH), 8.48 (1H, s, H-7), 8.01 (1H, d, J = 6.2,
H-5), 7.58 (1H, d, J = 6.4, H-4), 5.90 (s, H-3); C NMR (100
DMSO): 173.5, 143.4, 139.5, 138.7, 138.4, 129.7, 129.3, 129.0,
13
+
127.1, 122.5, 52.7, 46.0, 37.3; m/z (EI): 256.12128 (M ,
MHz, d -DMSO): 162.9, 139.3, 128.9, 126.5, 121.4, 112.0, 83.1.
C
H N O requires 256.12117) 257 (M+1, 44%), 256 (M,
6
15 16 2 2
100), 225 (42), 200 (33), 166 (11), 165 (79), 133 (93), 91 (97).
3-Amino-4-(methoxycarbomethyl)-6-methoxypyridine (2e).
A pure sample was obtained by flash chromatography
3-Methyl-6-azaoxindole Hydrochloride (3b•HCl).
The product was obtained as a white solid, 332 mg (90%), mp
-1
232-234 °C. IR (KBr) max/cm : 3170 (bs), 1667 (m), 1590 (s),
1
1444 (s), 1383 (s), 1349 (m), 1307 (m), 1262 (m), 1222 (m); H
(MeOH:CH Cl 1:20) to give 2e as a light brown solid. mp 51.5-
2
2
-1
NMR (400 MHz, d -DMSO): 13.8 (1H, bs, NH), 12.2 (1H, s,
52.5°C; IR (KBr) max/cm : 3418 (s), 3349 (s), 2986 (m), 2948
6
OH), 8.42 (1H, d, J = 5.4, H-7), 7.99 (1H, dd, J = 6.2, 5.4, H-5),
(m), 1724 (s), 1635 (m), 1612 (m), 1502 (s), 1459 (m), 1442 (s),
13
1
7.53 (1H, d, J = 6.2, H-4), 2.11 (s, CH ); C NMR (100 MHz,
1413 (s), 1395 (s), 1337 (m), 1314 (m), 1251 (s); H NMR (400
3
d -DMSO: 159.9 (s), 137.9 (s), 128.2 (d), 125.5 (s), 121.0 (d),
MHz, d -DMSO): 7.57 (1H, s, H-2), 6.50 (1H, s, H-5), 4.57 (2H,
6
6
+
110.4 (d), 91.0 (s), 6.6 (q); m/z (EI) 148.06333 (M , C H N O
requires 148.06366), 183 (M-1, 26%), 164 (18), 148 (100), 129
(35), 120 (49), 105 (71).
bs, NH ), 3.71 (3H, s, OCH ), 3.61 (3H, s, OCH ), 3.59 (2H, s,
8
8 2
2
3
3
13
CH ); C NMR (100 MHz, d -DMSO): 170.5, 156.2, 138.0,
2
6
132.4, 132.3, 110.9, 52.7, 51.8, 35.7; m/z (EI) 196.08463 (M+,
C H N O requires 196.08479) 197 (M+1, 7), 196 (M, 64),
195 (M-1, 23), 164 (21), 163 (48), 137 (21), 135 (45), 134 (22),
110 (18), 94 (26), 93 (29).
11 16
2 2
3-Benzyl-6-azaoxindole Hydrochloride (3d•HCl).
The product precipitated from the reaction mixture, and was
isolated by filtration to give a white solid, 230 mg (42%), mp
Formation of 6-Azaoxindoles (3) Under Basic Conditions.
-1
219.221 °C. IR (KBr) max/cm : 3291 (m), 3215 (m), 3059 (m),
1670 (s), 1566 (s), 1533 (s), 1517 (s), 1494 (m), 1430 (s), 1350
The appropriate 3-amino-4-substituted pyridine (2.0 mmol)
was dissolved in ethanol (70 ml) and sodium hydride (3.0 mmol)
in ethanol (6 ml) was added. The purple solution was stirred at
roomtemperature over night before water (75 ml) was added and
the ethanol stripped off. Generally, the products were difficult to
isolate from the aqueous solution by continous extraction and
pH-adjustment to pH 7 - 8.
1
(m), 1316 (m); H NMR (400 MHz, d -DMSO): 13.65 (1H, bs,
6
NH), 12.15 (1H, s, OH), 8.40 (1H, d, J = 5.6, H-7), 7.93 (1H, dd,
J = 6.0, 6.4, H-5), 7.41 (1H, d, J = 6.4, H-4), 7.30-7.10 (5H, Ph),
13
4.00 (2H, s, PhCH ); C NMR (100 MHz, d -DMSO: 160.0,
2
6
141.6, 137.5, 128.5, 128.3, 128.1, 125.9, 125.7, 121.1, 110.2,
+
95.2, 27.2; m/z (EI) 224.09486 (M , C
H N O requires
14 12 2
224.09496), 224.1 (M+, 41%), 147.1 (4), 91.1 (100).
3-Hydroxy-3-benzyl-6-azaoxindole (5).
3,3-Dimethyl-5-methoxy-6-azaoxindole (3f).
The evaporated reaction mixture was stirred with methanol (30
ml) for 2 hours before it was passed through a short column of
silica. Evaporation of the solvent gave 5 (183 mg, 61%) as a yel-
5-Methoxy-6-azaoxindole (3e) (100 mg, 0.61 mmol) was dis-
solved in dry DMF (10 ml), sodium hydride (17 mg, 0.71 mmol)
was added and the mixture stirred for 5 minutes. Methyl iodide
(47 µl, 0.76 mmol) was added and the reaction mixture stirred at
room temperature. After 24 hours another batch of sodium
hydride and methyl iodide was added and stirring continued for
another 24 hours. The reaction mixture was then evaporated to
dryness, dissolved in ammonium chloride (15 ml, 3 M) and
extraced with ethyl acetate (3 x 30 ml). Drying and evaporation
gave the crude product as a light brown solid. One recrystalliza-
low solid. Recrystallization (MeOH/H O) gave pure 5, mp
2
-1
220.0-222.0 °C; IR (KBr) max/cm : 3281 (s), 1740 (s), 1705 (s),
1
1622 (m), 1495 (m), 1453 (s), 1302 (m), 1208 (s); H NMR (400
MHz, d -DMSO): 10.28 (1H, bs, NH), 8.20 (1H, d, J = 4.9, H-6),
6
7.92 (1H, s, H-2), 7.13 (1H, d, J = 4.9, H-5), 7.12-6.85 (5H, m,
Ph), 6.4 (1H, s, OH), 3.18 (1H, d, J =12.8 Hz, -CH -), 3.02 (1H,
2
13
d, J = 12.8 Hz, -CH -); C NMR (100 MHz, d -DMSO): 178.2,
2
6
143.5, 139.2, 138.2, 134.4, 130.5, 130.1, 127.6, 126.6, 119.5,
76.4, 42.8; m/z (EI) 240.08976 (M+, C N O requires
240.08987) 226 (M+, 2%), 225 (M-1,8%), 209 (28), 195 (12),
179 (41), 165 (17), 149 (32), 131 (9), 119 (26),91 (100).
H
tion (CHCl ) gave pure 3f as a light brown solid, 35 mg (30 %).
14 12
2
2
3
-1
1
mp 194.0-195.0 °C; IR (KBr) max/cm : H NMR (400 MHz,
CDCl ): 8.01 (1H, bs, NH), 7.75 (1H, s, H-7), 6.64 (1H, s, H-4),
3

54
E. J. Andreassen and J. M. Bakke
Vol. 43
13
5-Methoxy-6-azaoxindole (3e).
3.92 (3H, s, OCH ), 1.41 (6H, s, 2xCH ); C NMR (100 MHz,
3
3
CDCl ): 182.0, 160.3, 149.4, 131.4, 125.4, 106.1, 53.6, 44.7,
3
The product was obtained as a white solid, 328 mg (98%), mp
246-247 °C. IR (KBr) max/cm : 3314 (bs), 3042 (s), 2956 (s),
23.9; m/z (EI) 192.08979 (M+, C H N O requires 192.08987)
-1
10 12
2
2
193 (M+1, 14), 192 (M, 100), 191 (M-1, 86), 177 (12), 163 (53),
162 (16).
2919 (s), 1712 (s), 1689 (s), 1483 (s), 1445 (s), 1367 (s), 1295 (s),
1
1246 (m), 1192 (m); H NMR (400 MHz, d -DMSO): 10.37 (1H,
6
bs, NH), 7.59 (1H, s, H-7), 6.74 (1H, s, H-4), 3.77 (3H, s, OCH ),
3
b) with Tetrafluorohydroboric Acid
13
3.52 (2H, s, H-3); C NMR (100 MHz, d -DMSO: 175.0, 158.8,
6
The appropriate 3-amino-4-substituted pyridine (2.0 mmol)
was dissolved in water (15 ml), HBF (0.88 ml, 3.5 moleq,
50wt% in water) was added and the mixture heated at reflux for
30 minutes. When the solution had reached room temperature, it
was neutralized with solid NaHCO and extracted with ethyl
+
139.9, 135.7, 124.3, 107.3, 53.0, 35.7; m/z (EI) 164.05802 (M ,
C H N O requires 164,05857), 165 (M+1, 30), 164 (M, 100), 163
4
8
8 2 2
(M-1, 94), 136 (22), 135 (88), 134 (63), 107 (32), 94 (34), 67 (30).
Acknowledgemets.
3
acetate. Drying (Na SO ) and evaporation gave the product as a
white solid.
2
4
The generous support from the Norwegian Research Counsil
and from Department of Chemistry, NTNU are gratefully
acknowledged.
6-Azaoxindole (3a).
The product was obtained as a white solid, 169 mg (63%), mp
232 °C (dec.). IR (KBr) max/cm : 3085 (bs), 2715 (s), 1675 (s),
-1
REFERENCES AND NOTES
1584 (s), 1456 (s), 1338 (m), 1281 (m), 1209 (m), 1167 (m), 1120
1
(m); H NMR (400 MHz, d -DMSO): 11.40 (0.5H, bs, enol NH),
[1] E. J. Andreassen, J. M. Bakke, I. Sletvold and H. Svensen..
Org. Biomol. Chem., 2, 2671 (2004).
6
10.55 (0.7H, bs, keto NH), 9.89 (0.7H, bs, enol-OH), 8.20 (1H, d,
J = 4.8, keto H-5), 8.09 (1H, s, keto H-7), 7.30 (0.7H, d, J = 6.8,
enol H-5), 7.27 (1H, d, keto H-4), 7.22 (0.7H, s, enol H-7), 6.58
(0.7H, d, J = 6.8, enol H-4), 4.94 (0.7H, s, enol H-3), 3.56 (2H, s,
keto H-3); C NMR (100 MHz, d -DMSO) : 175.5, 170.6,
143.0, 141.1, 140.2, 135.0, 129.9, 127.5, 127.4, 119.8, 110.0,
103.7, 85.9, 35.5; m/ z (EI) 134,04807 (M+, C H N O requires
134.04801) 135 (13), 134 (100), 106 (30), 105 (69), 79 (24).
[2] Z. Zhang, Z. Yang, N. A. Meanwell, J. F. Kadow and T.
Wang, J. Org. Chem,. 67, 2335 (2002) and references cited therein.
[3] P.A. Harris, L. F. Kuyper, K. E. Lackey and J. M. Veal, PCT
Int. Appl. (2000), CODEN: PIXXD2 WO 20000555159 A2
20000921; A. Marfat and R. P. Robinson, U.S. (1998) CODEN:
USXXAM US 5811432 A 19980922.
[4a] B. A. J. Clark, M. M. S. El-Bakoush, J. Parrick, J. Chem.
Soc., Perkin Trans. 1, 1531 (1974); [b] R. W. Daisley and J. R.
Hanbali, Synth. Comm., 11, 743 (1981).
13
6
7
6 2
3-Ethyl-6-azaoxindole (3c).
[5] N. Finch, M. R. Robinson and M. P. Valerio, J. Org. Chem.,
37, 51 (1972).
[6] A. Fiksdahl and J. Holt, The 20th Norwegian Organic
Winter meeting, 2005.
[7] J. M. Bakke, H. S. H. Gautun and H. Svensen, J.
Heterocyclic Chem., 40, 585 (2003).
The product was obtained as a white solid, 317 mg (98%), mp
-1
220 °C (dec.). IR (KBr) max/cm : 3257 (bs), 2966 (bs), 1704 (s),
1
1507 (s), 1560 (s), 1425 (s), 1355 (m), 1318 (m), 1276 (s); H
NMR (400 MHz, d -DMSO): 9.90 (1H, bs, NH), 7.23 (1H, d, J =
6
6.9, H-5), 7.15 (1H, s, H-7), 6.50 (1H, d, J = 6.9, H-4), 2.28 (2H,
13
q, J = 7.5, -CH -), 1.00 (3H, t, J = 7.5, CH -); C NMR (75
2
3
[8] D. D. Perrin and W. L. F. Armarego, Purification of
MHz, d -DMSO: 169.8, 135.8, 126.8, 125.9, 109.1, 101.6, 99.7,
rd
Laboratory Chemicals, 3 . edn,. Pergamon Press, Oxford, 1988.
6
16.0, 14.2; m/z (EI) 162.07873 (M+, C H N O requires
[9] A. Fagerbakk, Master Thesis, Department of chemistry,
Norwegian University of Science and Technology, Trondheim,
Norway, 2003.
9
10
2
162.07931) 163 (M+1, 6), 162 (M, 47), 134 (100), 133 (28), 119
(54), 106 (13), 105 (12).