Synthesis of indolin-2-one, isoindolin-1-one, and indole derivatives from homophthalic acid

Article abstract of DOI:10.1055/s-0030-1260235

We hereby report the preparation of indolin-2-one and isoindolin-1-one and their derivatives starting from 2-(carboxymethyl)benzoic acid, which was first regiospecifically converted into the isomeric half esters. Transformation of the acid functionalities to the acyl azides followed by Curtius rearrangement gave the regioisomeric isocyanates. Reaction of the isocyanates with aniline produced urethane derivatives. Intramolecular cyclization provided the target compounds. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0030-1260235

PAPER
3697
Synthesis of Indolin-2-one, Isoindolin-1-one, and Indole Derivatives from
Homophthalic Acid
S
ynthesis of Indoli
l
n-2-on
p
e
a
nd Isoindo
e
lin-1-one
S
r
keletons A. Kilikli, Cagatay Dengiz, Sevil Özcan, Metin Balci*
Department of Chemistry, Middle East Technical University, 06800 Ankara, Turkey
Fax +90(312)2103200; E-mail: mbalci@metu.edu.tr
Received 21 July 2011; revised 13 August 2011
O
H
H
Abstract: We hereby report the preparation of indolin-2-one and
isoindolin-1-one and their derivatives starting from 2-(carboxy-
methyl)benzoic acid, which was first regiospecifically converted
into the isomeric half esters. Transformation of the acid functional-
N
N
O
NH
ities to the acyl azides followed by Curtius rearrangement gave the
regioisomeric isocyanates. Reaction of the isocyanates with aniline
produced urethane derivatives. Intramolecular cyclization provided
the target compounds.
indole (1)
indolin-2-one (2)
isoindolin-1-one (3)
Figure 1
Key words: amides, azides, fused-ring systems, heterocycles, in-
doles
dolinone systems are useful and important in the field of
medicinal chemistry, the development of simple, conve-
nient, and high-yielding protocols is desirable.
Isoindolinone (3) derivatives also show a wide range of
important biological activity. A series of isoindolinone
derivatives have recently been synthesized9 and screened.
Some substituted isoindolinone derivatives show potent
metabotropic glutamate receptor 1 antagonist activity.10
Moreover, it has been demonstrated that some derivatives
exhibit antipsychotic-like effects in animal models.
Among others, N-substituted isoindolin-1-ones were se-
lected for further evaluation in the treatment of schizo-
phrenia with neuroleptic drugs.11,12 Several methods have
been developed for the synthesis of isoindolinone deriva-
tives.13–19 In this paper we describe a new route for the
synthesis of the indolinone and isoindolinone skeletons
based upon Curtius rearrangement of the azides derived
from isomeric [2-(methoxycarbonyl)phenyl]acetic acid
(4) and 2-(2-methoxy-2-oxoethyl)benzoic acid (5). As the
starting material, homophthalic acid 6 and its derivatives
were used. Our plan for the construction of the desired
heterocyclic ring systems 2 and 3 involved an intramolec-
The indole scaffold is a core nucleus for many biological-
ly active molecules.1,2 Accordingly, after 100 years of in-
tensive research, a variety of methods for elaborating and
functionalizing indoles have been established.3 Substitut-
ed indoles have been referred to as ‘privileged structures’
since they are capable of binding to many receptors with
high affinity.3a Key factors, including starting material
availability and functional group tolerance, often dictate
the most convenient indole synthesis.
Indolin-2-one (2), an oxidation product of 1H-indole (1)
(Figure 1), and its derivatives have been designed as a
novel class of tyrosine kinase inhibitors, which exhibit se-
lectivity towards different receptor tyrosine kinases
(RTKs).4–8 Various indolin-2-ones have been identified as
pharmacologically active compounds in extracts of the
traditional anti-inflammatory herb, Isatis tinctoria.7 Fur-
thermore, it has been shown that they inhibit compound
48/80-induced mast cell degranulation in vitro. Since in-
COOMe
COOH
COOH
COOH
COOH
COOMe
5
4
6
O
R
N=C=O
COOMe
COOMe
N=C=O
N
NR
O
10
8
9
7
Scheme 1 Retrosynthetic analysis of indolinone and isoindolinone derivatives
SYNTHESIS 2011, No. 22, pp 3697–3705
x
x.
x
x
.
2
0
1
1
Advanced online publication: 21.09.2011
DOI: 10.1055/s-0030-1260235; Art ID: T71611SS
© Georg Thieme Verlag Stuttgart · New York

3698
A. A. Kilikli et al.
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ular cyclization reaction of the isocyanates 7 and 9, which chlorides 12 followed by the addition of a solution of so-
can be generated by Curtius rearrangement20 of the corre- dium azide in water. The azide formation was successful
sponding acyl azides. Retrosynthetic analysis, following and provided acyl azides 13a–c in 80–85% yields. When
the sequences outlined in Scheme 1, led us to plan to syn- the acyl azides 13a–c were refluxed in methanol for 12
thesize the regioisomeric half esters 4 and 5 starting from hours, the desired urethane derivatives 15a–c were ob-
diacid 6.
tained in 48–86% yields. Alternately, acyl azides 13a–c
were refluxed in benzene to form isocyanates 14a–c,
which were reacted with aniline in dichloromethane to
give the urea derivatives 16a–c. After satisfactory synthe-
sis of urea and urethanes, we focused on the ring-closure
reactions. When urethanes 15a–c were treated with potas-
sium carbonate in acetonitrile, they cyclized smoothly to
give the isoindolinone derivatives 17 in high yields. Anal-
ysis of 1H and 13C NMR and elemental analysis data sug-
gested that the desired isoindolinones 17a–c were formed.
Accordingly, the reaction of urea derivatives 16a–c with
potassium carbonate afforded isoindolinonecarboxamides
18a–c in 83–85% yields. In the cyclization reaction of 16,
two cyclization products 18 and 19 were expected as a re-
sult of the attack of the two different amide functionalities
on the ester carbonyl group. The formation of five-mem-
bered ring 18 was preferred over the seven-membered
ring 19 (Figure 2).
The starting materials 4a–c were synthesized as described
in the literature.21,22 The esterification of homophthalic
acid derivatives 6a–c was carried out in refluxing metha-
nol in the presence of thionyl chloride to give the diesters
11a–c. Recently, we reported that the reactivity of the es-
ter carbonyl groups in similar systems are different.23 The
ester functionality adjacent to the CH2 group is more reac-
tive than the other. Therefore, the regiospecific hydrolysis
of the ester functionalities in 11a–c was possible. Reac-
tion of 11a–c with potassium carbonate in refluxing meth-
anol–water (1:1) gave the half esters 4a–c in 60–74%
yields (Scheme 2).
The most general and versatile synthesis of acyl azides in-
volves the reaction of acyl chlorides with sodium azide in
aqueous medium. The half esters 4 were treated with ox-
alyl chloride in dichloromethane in the presence of a cat-
alytic amount of N,N-dimethylformamide to give acyl
R
COOMe
COOMe
R
COOMe
COOH
R
COOH
K2CO3
SOCl2, MeOH
COOH
reflux, 12 h
92–97%
MeOH–H2O (1:1)
60–74%
11
4
6
a R = H
b R = Br
c R = OMe
(COCl)2
DMF, CH2Cl2
r.t., 90–97%
R
R
R
COOMe
COCl
COOMe
COOMe
CON3
reflux, 12 h
NaN3
N
C
O
acetone–H2O
80–85%
12
14
13
PhNH2
CH2Cl2
41–92%
MeOH
48–86%
O
O
R
COOMe
NHCOOMe
R
K2CO3, MeCN
R
COOMe
N
60 °C, 6 h
88–95%
OMe
17
15
16
NHCONHPh
K2CO3, MeCN
60 °C, 2 h
83–85%
O
O
R
N
NHPh
18
Scheme 2 Synthesis of isoindolin-1-one derivatives 17a–c and 18a–c starting from substituted homophthalic acids 4a–c
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Synthesis of Indolin-2-one and Isoindolin-1-one Skeletons
3699
O
functionalities as shown in Scheme 3. The ring-closure re-
action of 23 was accomplished by treatment with potassi-
um carbonate in acetonitrile. The NMR spectral studies
indicated the formation of two major products, the inter-
molecular condensation products 24 and the fragmenta-
tion products 25. In the case of methoxy derivative 23b,
additionally two minor products 26b and 27 were isolated.
R
NH
N
a R = H
b R = Br
c R = OMe
O
Ph
19
Figure 2
The expected products 28 were not found in the isolated
products. However, we assume that the ring-cyclization
products 28 are generated as intermediates by an intramo-
lecular cyclization reaction of 23 to form a five-membered
ring. Since the methylene protons in 28 are more acidic
than the methylene protons in 18, the reaction proceeds
further and base abstracts an a-proton to form the carban-
ion 29, which can undergo an intermolecular reaction with
indolinone derivatives 28 to form 30 followed by a frag-
mentation reaction to furnish the products 24 and 25
(Scheme 4).
After successful completion of the synthesis of isoindoli-
nones 17 and 18, we turned our attention to the synthesis
of indolinone derivatives 2. Recently, we synthesized the
half ester 5 and studied its ring-closure reactions. As an
extension of this work we have searched the general appli-
cability of this methodology to substituted homophthalic
acid derivatives.24 Synthesis of half esters 5a,b was
achieved through the reaction of methanol at reflux tem-
perature with anhydrides 20a,b,21b,25–27 which were ob-
tained by reaction of the diacids 6 with thionyl chloride
(Scheme 3). Methanol regioselectively attacks the more
reactive carbonyl group which is attached to the methyl-
ene group. The reactivity of the other carbonyl group is
decreased due to conjugation with the benzene ring.
O
O
NHPh
NHPh
MeO
R
N
N
O
The half esters 5a,b were reacted with ethyl chlorofor-
mate in the presence of triethylamine followed by addition
of a solution of sodium azide in water. Azide formation
was successful and provided acyl azides 21a,b in 92%
yield. Curtius rearrangement of acyl azides 21a,b in re-
fluxing benzene furnished isocyanates 22a,b, which were
easily transformed to urea derivatives 23a,b upon treat-
ment with aniline. Finally, we focused our effort on the
ring-closure reaction of 23 already bearing the necessary
O
base
24 and 25
O
29
NHPh
O
NHPh
O
O
N
R
N
R
28
30
Scheme 4 Formation mechanism of the products 24 and 25
O
R
R
COOH
COOMe
R
COOH
COOH
O
SOCl2, CH2Cl2
MeOH
reflux, 12 h
96–97%
reflux, 2 h
86–88%
O
5
20
6
ClCOOEt
a R = Br
b R = OMe
Et3N, NaN3
THF, 73–80%
N
C
O
R
R
CON3
R
NHCONHPh
COOMe
PhNH2
reflux
COOMe
COOMe
CH2Cl2
92%
benzene, 2 h
21
23
22
K2CO3, MeCN
60 °C, 2 h
O
N
NHPh
OH
H
R
O
N
H
R
R
+
N
OH
+
PhHN
NHPh
O
+
27 (2.9%)
NHPh
O
NHPh
O
24a (57%)
24b (56%)
25a (28%)
25b (26%)
26b (2.6%)
Scheme 3 Synthesis of indolin-2-one and some indole derivatives starting from substituted homophthalic acids 4a,b
Synthesis 2011, No. 22, 3697–3705 © Thieme Stuttgart · New York

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A. A. Kilikli et al.
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O
O
H
NHPh
OH
MeO
N
MeO
+
OH
N
PhHN
NHPh
K2CO3, MeCN
60 °C, 2 h
27 (6%)
NHPh
O
NHPh
O
26b (4%)
24b
Scheme 5 Reaction of cyclization product 24b with potassium carbonate
O
O
MeO
MeO
NCONHPh
COOMe
N
MeO
NHCONHPh
COOMe
NaH, THF
+
24b (9%)
OH
+
Ac2O, –5 °C
23b
O
31 (32%)
32 (28%)
Scheme 6 Cyclization of urea derivative 23b in the presence of acetic anhydride
The major product 24b was proposed as an intermediate tives substituted at the benzene ring as well as at the five-
for the formation of the side products 26b and 27 due to a membered ring can be synthesized.
resemblance between their structures. Then the major
Melting points are uncorrected. Infrared spectra were obtained from
product 24b was reacted under identical conditions to
clarify these suspicions (Scheme 5). Treatment of the in-
dole derivative 24b with potassium carbonate in acetoni-
a soln (CHCl3) in 0.1-mm cells or KBr pellets on an FT-IR Bruker
Vertex 70 instrument. 1H and 13C NMR spectra were recorded on a
Bruker-Biospin (DPX-400) instrument. Apparent splitting is given
trile for two hours yielded the same products 26b and 27.
It was proven that these compounds are secondary com-
pounds and that they were formed by a hydrolysis reac-
tion.
in all cases. Column chromatography was performed on silica gel
(60-mesh, Merck), TLC was carried out on Merck 0.2 mm silica gel
60 F254 analytical aluminum plates. Elemental analyses were carried
out on a Leco-932 model CHNS analyzer.
We assume that first carboxamide unit attached to nitro-
gen atom slowly undergoes hydrolysis with potassium
carbonate to form the indole derivative 26b and aniline.
The formed aniline attacks the carboxamide unit in 24b
attached to nitrogen atom to form 26b and N,N¢-diphenyl-
urea 27.
Diesters 11a–c; General Procedure
To a soln of homophthalic acid 6a–c (10.0 mmol) in MeOH (50 mL)
was added SOCl2 (3.57 g, 30.0 mmol) dropwise at r.t.; the mixture
was refluxed for 12 h. After completion of the reaction, the solvent
was evaporated to give diester 11a–c. Chromatography of the resi-
due over a short column (silica gel, CH2Cl2) gave pure diester.
Methyl 2-(2-Methoxy-2-oxoethyl)benzoate (11a)
To prevent the intermolecular condensation shown in
Scheme 5 and as a further support for the formation mech-
anism of 24 and 25, the proposed intermediate 29 shown
in Scheme 4 was trapped with acetic anhydride. For this
purpose, the urea derivative 23b was treated with sodium
hydride in the presence of acetic anhydride in tetrahydro-
furan (Scheme 6). Interestingly, the formation of three
products was observed: an acetylated urea derivative 32,
diacetylated indole 31, along the intermolecular conden-
sation product 24b, which was the major product of the
potassium carbonate based cyclization process.
Colorless oil; yield: 1.93 g (93%).21b,28
Methyl 5-Bromo-2-(2-methoxy-2-oxoethyl)benzoate (11b)
White powder; yield: 2.63 g (92%); mp 101–103 °C.
IR (KBr): 2991, 2951, 1723, 1591, 1288, 1254, 1167 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.06 (d, J6,4 = 2.1 Hz, 1 H, H6),
7.51 (dd, J4,3 = 8.1 Hz, J4,6 = 2.1 Hz, 1 H, H4), 7.05 (d, J3,4 = 8.2 Hz,
1 H, H3), 3.88 (s, 2 H, CH2), 3.79 (s, 3 H, OCH3), 3.61 (s, 3 H,
OCH3).
13C NMR (100 MHz, CDCl3): d = 171.3, 166.1, 135.2, 134.9, 133.9,
133.8, 131.3, 121.1, 52.3, 52.0, 39.8.
The presented results establish that cyclization of acyl
azides is a valuable method for the synthesis of heterocy-
clic compounds. In conclusion, we have developed a new
synthetic methodology for construction of N-substituted
isoindolin-1-one derivatives. Furthermore, by starting
from benzene ring substituted diesters, further substituted
isoindolin-1-one derivatives can be synthesized. By appli-
cation of the same methodology to half esters 5, isoindo-
lin-2-one derivatives 28 are formed as the intermediates.
Due to the acidic methylene protons in 28, they undergo
further condensation reactions. However, if the intermedi-
ate is trapped with electrophiles, various indole deriva-
Anal. Calcd for C11H11BrO4: C, 46.02; H, 3.86. Found: C, 46.23; H,
3.75.
Methyl 5-Methoxy-2-(2-methoxy-2-oxoethyl)benzoate (11c)
Colorless oil; yield: 2.31 g (97%). The analytical data are in accord
with literature values.29
2-(Methoxycarbonyl)phenylacetic Acid (4a); Typical Procedure
To a soln of diester 11a (4.0 g, 19.2 mmol) in MeOH–H2O (1:1, 50
mL) was added K2CO3 (3.98 g, 28.8 mmol) and the mixture was re-
fluxed for 45 min. The mixture was cooled to r.t. and H2O was add-
ed. To remove the unreacted diester 12a, the aqueous phase was
extracted with EtOAc. The aqueous phase was acidified with 1 M
Synthesis 2011, No. 22, 3697–3705 © Thieme Stuttgart · New York

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Synthesis of Indolin-2-one and Isoindolin-1-one Skeletons
3701
HCl and extracted with EtOAc. Evaporation of the solvent gave
pure 4a as a white solid; yield: 2.4 g (64%); mp 147–148 °C (Lit.30
146–148 °C). The analytical data are in accord with literature val-
ues.
IR (KBr): 3002, 2953, 2265, 2139, 1716, 1579, 1435, 1270 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.95 (d, J5,6 = 7.8, J4,6 = 1.4 Hz, 1
H, H6), 7.43 (dt, J5,6 = 7.5 Hz, J = 1.4 Hz, 1 H, H4), 7.32 (d, J = 7.6,
1.2 Hz, 1 H, H5), 7.17 (br d, J = 7.6 Hz, 1 H, H3), 3.96 (s, 2 H, CH2),
3.81 (s, 3 H, OCH3).
[4-Bromo-2-(methoxycarbonyl)phenyl]acetic Acid (4b)
Following the typical procedure for 4a using diester 11b (2.82 g,
9.82 mmol) gave 4b as a colorless viscous liquid; yield: 1.75 g
(73%, based on reacted diester 11b); mp 161–163 °C.
Methyl 2-(2-Azido-2-oxoethyl)-5-bromobenzoate (13b)
Following the typical procedure for 13a using acyl chloride 12b
(1.54 g, 5.28 mmol) gave 13b (1.34 g, 85%) as a yellowish oil.
IR (KBr): 2952, 2316, 1716, 1640, 1289, 1254, 1064, 833 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.12 (d, J3,5 = 2.2 Hz, 1 H, H3),
7.56 (dd, J5,6 = 8.1 Hz, J5,3 = 2.2 Hz, 1 H, H5), 7.05 (d, J6,5 = 8.2 Hz,
1 H, H6), 3.92 (s, 2 H, CH2), 3.83 (s, 3 H, OCH3).
IR (KBr): 3500, 2953, 1706, 1435, 1288, 1255, 1080 cm–1.
1H NMR (400 MHz, CDCl3): d = 11.00–10.20 (br s, 1 H, OH), 8.07
(d, J3,5 = 2.2 Hz, 1 H, H3), 7.52 (dd, J5,6 = 8.2 Hz, J5,3 = 2.2 Hz, 1 H,
H5), 7.05 (d, J6,5 = 8.2 Hz, 1 H, H6), 3.90 (s, 2 H, CH2), 3.80 (s, 3
H, OCH3).
13C NMR (100 MHz, CDCl3): d = 175.5, 165.4, 134.5, 133.3, 133.0,
132.9, 130.1, 120.5, 51.5, 39.0.
13C NMR (100 MHz, CDCl3): d = 176.7, 164.9, 134.5, 133.1, 133.0,
132.9, 130.0, 120.7, 51.4, 41.3.
Methyl 2-(2-Azido-2-oxoethyl)-5-methoxybenzoate (13c)
Following the typical procedure for 13a using acyl chloride 12c
(1.51 g, 6.22 mmol) gave 13c (1.39 g, 89%) as a yellowish oil.
[4-Methoxy-2-(methoxycarbonyl)phenyl]acetic Acid (4c)
Following the typical procedure for 4a using diester 11c (1.45 g,
6.09 mmol) gave 4c as a white solid; yield: 0.82 g (60%, based on
reacted diester 13c); mp 136–137 °C (Lit.30 79–81 °C). The analyt-
ical data are in accord with literature values.30,31
IR (KBr): 2953, 2254, 2138, 1716, 1610, 1504, 1275, 905, 728
cm–1.
1H NMR (400 MHz, CDCl3): d = 7.57 (d, J3,5 = 2.6 Hz, 1 H, H3),
7.16 (d, J6,5 = 8.4 Hz, 1 H, H6), 7.05 (dd, J5,6 = 8.4 Hz, J5,3 = 2.6 Hz,
1 H, H5), 3.96 (s, 2 H, CH2), 3.89 (s, 3 H, OCH3), 3.85 (s, 3 H,
OCH3).
13C NMR (100 MHz, CDCl3): d = 178.7, 167.1, 158.9, 133.5, 130.2,
127.1, 118.6, 116.1, 55.5, 52.2, 42.2.
Methyl 2-(2-Chloro-2-oxoethyl)benzoate (12a); Typical Proce-
dure
To a stirred suspension of half ester 4a (2.0 g, 10.2 mmol) in CH2Cl2
(25 mL) was added oxalyl chloride (1.57 g, 12.2 mmol) and DMF
(2 drops) as catalyst. The resulting soln was stirred at r.t. for 1 h. Af-
ter completion of the reaction, the solvent was evaporated to give
12a (1.97 g, 90%) as a colorless viscous oil. The analytical data are
in accord with literature values.25
Methyl 2-{[(Methoxycarbonyl)amino]methyl}benzoate (15a);
Typical Procedure
A soln of acyl azide 13a (2.0 g, 9.13 mmol) in MeOH (150 mL) was
refluxed for 12 h with TLC monitoring. After completion of reac-
tion, the solvent was removed under vacuum. Chromatography of
the residue (silica gel, 50 g, EtOAc–hexane–CH2Cl2, 1:1:2) afford-
ed 15a (163 g, 86%) as a pale-yellow solid.
Methyl 5-Bromo-2-(2-chloro-2-oxoethyl)benzoate (12b)
Following the typical procedure for 12a using half ester 4b (0.82 g,
3.0 mmol) gave 12b as a yellowish oil (0.85 g, 97%).
IR (KBr): 2953, 1799, 1721, 1259, 963, 752 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.15 (d, J6,4 = 2.2 Hz, 1 H, H6),
7.58 (dd, J4,3 = 8.1 Hz, J4,6 = 2.2 Hz, 1 H, H4), 7.06 (d, J3,4 = 8.2 Hz,
1 H, H3), 4.42 (s, 2 H, CH2), 3.84 (s, 3 H, OCH3).
IR (KBr): 3349, 2952, 1704, 1650, 1508, 1434, 1252 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.91 (br d, J6,5 = 7.8 Hz, 1 H, H6),
7.43 (m, 2 H, H4, H3), 7.28 (br d, J5,6 = 7.8 Hz, 1 H, H5), 5.75 (br
s, 1 H, NH), 4.48 (d, J1(NH) = 6.6 Hz, 2 H, CH2), 3.87 (s, 3 H, OCH3),
3.56 (s, 3 H, OCH3).
13C NMR (100 MHz, CDCl3): d = 171.3, 165.7, 135.8, 134.4, 133.7,
132.9, 130.7, 122.5, 52.6, 51.9.
13C NMR (100 MHz, CDCl3): d = 167.7, 157.0, 140.5, 132.9, 131.3,
Methyl 2-(2-Chloro-2-oxoethyl)-5-methoxybenzoate (12c)
Following the typical procedure for 12a using half ester 4c (0.79 g,
3.52 mmol) gave 12c as yellowish oil (0.81 g, 95%).
IR (KBr): 2954, 1799, 1716, 1287, 904 cm–1.
131.0, 128.7, 127.7, 52.2, 51.0, 42.3.
Methyl 5-Bromo-2-{[(methoxycarbonyl)amino]methyl}ben-
zoate (15b)
1H NMR (400 MHz, CDCl3): d = 7.61 (d, J6,4 = 2.8 Hz, 1 H, H6),
7.16 (d, J3,4 = 8.5 Hz, 1 H, H3), 7.06 (dd, J3,4 = 8.5 Hz, J6,4 = 2.8 Hz,
1 H, H4), 4.46 (s, 2 H, CH2), 3.91 (s, 3 H, OMe), 3.85 (s, 3 H, OMe).
13C NMR (100 MHz, CDCl3): d = 172.2, 166.8, 159.4, 133.3, 130.1,
126.0, 118.7, 116.3, 55.6, 52.4, 51.9.
Following the typical procedure for 15a using acyl azide 13b (1.54
g, 5.17 mmol) gave 15b as colorless solid (0.75 g, 48%); mp 82–83
°C.
IR (KBr): 3442, 2952, 1708, 1497, 1447, 1246, 996 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.05 (d, J6,4 = 1.9 Hz, 1 H, H6),
7.55 (dd, J4,3 = 8.2 Hz, J4,6 = 2.2 Hz, 1 H, H4), 7.35 (d, J3,4 = 8.2 Hz,
1 H, H3), 5.73 (br s, 1 H, NH), 4.43 (d, J1(NH) = 6.8 Hz, 2 H, CH2),
3.85 (s, 3 H, OCH3), 3.56 (s, 3 H, OCH3).
Methyl 2-(2-Azido-2-oxoethyl)benzoate (13a); Typical Proce-
dure
To a soln of acyl chloride 12a (1.8 g, 8.25 mmol) in acetone (30 mL)
was added a soln of NaN3 (1.66 g, 25.5 mmol) in H2O (10 mL) drop-
wise at 0 °C and the mixture was stirred at 0 °C for 1 h. After the
addition of H2O (25 mL) the mixture was extracted with EtOAc
(3 × 25 mL), and the combined extracts were washed with sat.
NaHCO3 and H2O, and dried (MgSO4). After concentration of the
solvent, acyl azide 13a (1.58 g, 85%), unstable at r.t., was obtained
as a pale-yellow solid, which was used for the next step without pu-
rification.
13C NMR (100 MHz, CDCl3): d = 166.4, 157.0, 139.5, 135.7, 133.9,
132.8, 130.2, 121.4, 52.5, 52.1, 43.6.
HRMS: m/z [M + Na]+ calcd for C11H12NO4Na: 323.9842; found:
323.9842.
Methyl 5-Methoxy-2-{[(methoxycarbonyl)amino]methyl}ben-
zoate (15c)
Following the typical procedure for 15a using acyl azide 13c (1.15
g, 4.61 mmol) gave 15c (0.88 g, 75%) as a colorless oil.
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A. A. Kilikli et al.
PAPER
IR (KBr): 3349, 2952, 1707, 1608, 1500, 1217, 1074, 1036 cm–1.
13C NMR (100 MHz, CDCl3): d = 167.9, 158.7, 155.4, 138.7, 133.1,
133.0, 129.7, 129.1, 123.5, 120.7, 118.4, 116.1, 55.5, 52.3, 42.7.
1H NMR (400 MHz, CDCl3): d = 7.49 (d, J4,6 = 2.7 Hz, 1 H, H6),
7.45 (d, J3,4 = 8.5 Hz, 1 H, H3), 7.03 (dd, J3,4 = 8.5 Hz, J4,6 = 2.7 Hz,
1 H, H4), 5.82 (br s, 1 H, NH), 4.47 (br d, J = 6.6 Hz, 2 H, CH2),
3.91 (s, 3 H, OCH3), 3.83 (s, 3 H, OCH3), 3.62 (s, 3 H, OCH3).
HRMS: m/z [M + Na]+ calcd for C17H18N2O4Na: 337.1159; found:
337.1141.
Methyl 1-Oxo-1,3-dihydro-2H-isoindole-2-carboxylate (17a);
Typical Procedure
13C NMR (100 MHz, CDCl3): d = 167.5, 158.8, 157.00, 132.8,
129.6, 118.4, 116.1, 55.5, 52.3, 51.9, 43.6.
To a soln of urethane 15a (1.8 g, 8 mmol) in MeCN (40 mL) was
added excess K2CO3 (1.8 g, 13 mmol) and the resulting mixture was
stirred at 60 °C for 6 h. After completion of the reaction, excess
K2CO3 was filtered off and washed with MeCN (10 mL). After
evaporation of the solvent, the residue was purified by column chro-
matography (silica gel, 20 g, EtOAc–hexane, 8:2) to give 17a (1.35
g, 88%) as a white solid; mp 135–136 °C (Lit.26 136–138 °C).The
analytical data are in accord with literature values.26
HRMS: m/z [M + Na]+ calcd for C12H15NO5Na: 276.0842; found:
276.0843.
Methyl 2-{[(Anilinocarbonyl)amino]methyl}benzoate (16a);
Typical Procedure
A soln of acyl azide 13a (1.4 g, 6.4 mmol) in anhyd benzene (50
mL) was refluxed for 1 h. After completion of the reaction, the mix-
ture was cooled to r.t. and the solvent was removed under vacuum.
The formed isocyanate 14a was dissolved in CH2Cl2 (50 mL). A
soln of aniline (700 mg, 7.5 mmol) in CH2Cl2 (5 mL) was added
dropwise at r.t. The resulting mixture was stirred at r.t. for 2 h. The
organic phase was extracted with 10% HCl soln and H2O. Evapora-
tion of the solvent gave urea derivative 16a (1.67 g, 92%). Crystal-
lization (EtOAc–n-hexane, 10:2) gave analytical pure 16a; mp 136–
137 °C.
Methyl 6-Bromo-1-oxo-1,3-dihydro-2H-isoindole-2-carboxy-
late (17b)
Following the typical procedure for 17a using urethane 15b (0.48
mg, 1.59 mmol) gave 17b (0.41 g, 95%) as a colorless solid; mp
164–165 °C (EtOAc–n-hexane).
IR (KBr): 2949, 1767, 1695, 1438, 1363, 1320, 1208, 842 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.06 (d, J7,5 = 1.7 Hz, 1 H, H7),
7.77 (dd, J5,4 = 8.1 Hz, J7,5 = 1.7 Hz, 1 H, H5), 7.39 (d, J5,4 = 8.1 Hz,
1 H, H4), 4.78 (s, 2 H, CH2), 3.97 (s, 3 H, OCH3).
13C NMR (100 MHz, CDCl3): d = 164.7, 152.3, 139.4, 136.8, 133.0,
128.2, 124.8, 122.7, 53.9, 48.9.
IR (KBr): 3367, 1718, 1650, 1600, 1552, 1440, 1270, 1084 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.83 (br d, J6,5 = 7.7 Hz, 1 H, H6),
7.43 (br d, J3,4 = 7.5 Hz, 1 H, H3), 7.32 (dd, J4,5 = 7.4 Hz, J4,3 = 7.5
Hz, 1 H, H4), 7.09–7.22 (m, 6 H, Harom, NH), 6.90 (dd, J4a3a = 7.1
Hz, J4a5a = 7.0 Hz, 1 H, H4a), 6.22 (br d, 1 H, NH), 4.53 (d, J = 6.2
Hz, 2 H, CH2), 3.73 (s, 3 H, OCH3).
HRMS: m/z [M + Na]+ calcd for C10H8NO3Na: 291.9585; found:
291.9587.
13C NMR (100 MHz, CDCl3): d = 167.9, 156.2, 141.0, 139.0, 132.8,
130.9, 130.5, 128.9, (2 C), 128.6, 127.3, 123.1, 120.4 (2 C), 52.1,
42.9.
Methyl 6-Methoxy-1-oxo-1,3-dihydro-2Hisoindole-2-carboxy-
late (17c)
Following the typical procedure for 17a using urethane 15c (0.42 g,
1.66 mmol) gave 17c (0.34 g, 92%) as a white solid; mp 161–163
°C (EtOAc–n-hexane).
Anal. Calcd for C16H16N2O3: C, 67.59; H, 5.67; N, 9.85. Found: C,
67.33; H, 5.75; N, 10.04.
Methyl 2-{[(Anilinocarbonyl)amino]methyl}-5-bromobenzoate
(16b)
Following the typical procedure for 16a using acyl azide 13b (1.5 g,
13.44 mmol) gave 16b (0.840 g, 46%) as a colorless solid; mp 170–
172 °C.
IR (KBr): 3303, 1709, 1626, 1557, 1247, 1073 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.01 (d, J6,4 = 2.1 Hz, 1 H, H6),
7.52 (dd, J3,4 = 8.2 Hz, J6,4 = 2.1 Hz, 1 H, H4), 7.39 (d, J3,4 = 8.2 Hz,
1 H, H3), 7.30–7.10 (m, 4 H), 7.05–6.90 (m, 1 H), 6.51 (br s, 1 H,
NH), 5.94 (br t, J = 6.3 Hz, 1 H, NH), 4.50 (d, J = 6.5 Hz, 2 H, CH2),
3.81 (s, 3 H, OCH3).
IR (KBr): 1771, 1690, 1494, 1423, 1272, 1250, 1002, 779 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.37 (d, J4,5 = 8.3 Hz, 1 H, H4),
7.36 (d, J7,5 = 2.5 Hz, 1 H, H7), 7.22 (dd, J5,4 = 8.3 Hz, J5,7 = 2.5 Hz,
1 H, H5), 4.75 (s, 2 H, CH2), 3.97 (s, 3 H, OCH3), 3.88 (s, 3 H,
OCH3).
13C NMR (100 MHz, CDCl3): d = 166.3, 160.3, 152.5, 133.2, 132.2,
124.0, 122.8, 107.1, 55.7, 53.7, 48.7.
HRMS: m/z [M + Na]+ calcd for C11H11NO4Na: 244.0580; found:
244.0580.
1-Oxo-N-phenyl-1,3-dihydro-2H-isoindole-2-carboxamide
(18a); Typical Procedure
13C NMR (100 MHz, CDCl3): d = 166.7, 155.8, 139.9, 138.6, 135.7,
133.8, 133.7, 130.2, 129.2, 123.6, 121.5, 121.2, 120.7, 52.5, 42.6.
To a soln urea derivative 16a (3.0 g, 11 mmol) in MeCN (150 mL)
was added K2CO3 (3.0 g, 22 mmol). The resulting mixture was
stirred at 60 °C for 2 h. After completion of the reaction, excess
K2CO3 was filtered and washed with MeCN (10 mL). The solvent
was evaporated and the residue was chromatographed (silica gel,
EtOAc–hexane, 1:1) to give 18a (2.23 g, 84%) as a white crystalline
compound; mp 178–179 °C.
HRMS: m/z [M + Na]+ calcd for C16H15BrN2O3Na: 385.0164;
found: 385.0168.
Methyl 2-{[(Anilinocarbonyl)amino]methyl}-5-methoxyben-
zoate (16c)
Following the typical procedure for 16a using acyl azide 13c (0.65
mg, 2.6 mmol) gave 16c (0.336 g, 41%) as colorless solid; mp 142–
144 °C.
IR (KBr): 3390, 1711, 1604, 1440, 1305, 1242 cm–1.
1H NMR (400 MHz, CDCl3): d = 10.66 (br s, 1 H, NH), 7.86 (br d,
J7,6 = 7.7 Hz, 1 H, H7), 7.61 (dd, J6,5 = 7.4 Hz, J6,7 = 7.6 Hz, 1 H,
H6), 7.54–7.45 (m, 4 H, Harom), 7.28 (m, 2 H, H3a, H5a), 7.04 (m, 1
H, H4a), 4.85 (s, 2 H, CH2).
13C NMR (100 MHz, CDCl3): d = 169.5, 150.3, 141.1, 137.6, 134.0,
131.0, 129.1 (2 C), 128.7, 124.9, 124.1, 123.4, 120.1 (2 C), 48.6.
IR (KBr): 3310, 3056, 1718, 1627, 1597, 1357, 1177, 1066, 784
cm–1.
1H NMR (400 MHz, CDCl3): d = 7.49 (d, J3,4 = 8.5 Hz, 1 H, H3),
7.46 (d, J4,6 = 2.8 Hz, 1 H, H6), 7.40–7.20 (m, 4 H), 7.10–6.90 (m,
2 H), 6.58 (br s, 1 H, NH), 6.03 (br s, 1 H, NH), 4.55 (br d, J = 5.62
Hz, 2 H, CH2), 3.87 (s, 3 H, OCH3), 3.81 (s, 3 H, OCH3).
Synthesis 2011, No. 22, 3697–3705 © Thieme Stuttgart · New York

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Synthesis of Indolin-2-one and Isoindolin-1-one Skeletons
3703
Anal. Calcd for C15H12N2O2: C, 71.42; H, 4.79; N, 11.10. Found: C,
71.44; H, 5.04; N, 10.82.
Anal. Calcd for C10H9BrO4; C, 43.98; H, 3.32. Found: C, 43.66; H,
3.29.
6-Bromo-1-oxo-N-phenyl-1,3-dihydro-2H-isoindole-2-carbox-
amide (18b)
Following the typical procedure for 18a using urea 16b (0.60 g,
1.65 mmol) gave 18b (0.47 g, 85%) as a white powder; mp 241–243
°C (EtOAc–n-hexane).
5-Methoxy-2-(2-methoxy-2-oxoethyl)benzoic Acid (5b)
Following the typical procedure for 5a using anhydride 20b (4.4 g,
22.8 mmol) gave 20b (4.50 g, 20.1 mmol, 88%) as a light-yellow
solid; mp 112–113 °C (EtOAc–hexane, 3:1). The analytical data are
in accord with literature values.35
IR (KBr): 1702, 1678, 1444, 1368, 1311 cm–1.
Methyl [2-(Azidocarbonyl)-4-bromophenyl]acetate (21a); Typ-
ical Procedure
1H NMR (400 MHz, CDCl3): d = 10.55 (br s, 1 H, NH), 8.00 (d,
J7,5 = 1.7 Hz, 1 H, H7), 7.74 (dd, J5,4 = 8.1 Hz, J5,7 = 1.7 Hz, 1 H,
H5), 7.53 (d, J = 7.6 Hz, 2 H), 7.40 (d, J4,5 = 8.1 Hz, 1 H), 7.29 (t,
J = 7.4 Hz, 2 H), 7.07 (t, J = 7.4 Hz, 1 H), 4.83 (s, 2 H, CH2).
13C NMR (100 MHz, CDCl3): d = 168.0, 149.9, 139.7, 137.3, 137.0,
133.0, 129.1, 127.9, 125.0, 124.3, 122.7, 120.2, 48.4.
To a soln of half ester 5a (2.0 g, 7.3 mmol) in freshly distilled THF
(10 mL) at –5 °C was added a soln of Et3N (1.22 mL, 8.7 mmol) in
THF (6 mL) dropwise and the resulting mixture was stirred for 30
min. This was followed by slow addition of a soln of ethyl chloro-
formate (0.82 mL, 8.7 mmol) in THF (10 mL) to the mixture, which
was continuously stirred for 30 min at this temperature. Then, NaN3
(0.56 g, 8.7 mmol) dissolved in H2O (10 mL) was added dropwise
and the mixture was stirred at this temperature overnight. After re-
moval of the solvent under reduced pressure, H2O was added and
the mixture was extracted with EtOAc (2 × 30 mL) and the organic
phase was washed with sat. NaHCO3 and dried (MgSO4). Evapora-
tion of the solvent gave azide 21a (1.59 g, 73%) as a viscous liquid.
Anal. Calcd for C15H11BrN2O2: C, 54.40; H, 3.35; N 8.46. Found:
C, 54.09; H, 3.41; N, 8.35.
6-Methoxy-1-oxo-N-phenyl-1,3-dihydro-2H-isoindole-2-car-
boxamide (18c)
Following the typical procedure for 18a using urea 16c (0.32 g, 1.02
mmol) gave 18c (0.24 g, 83%) as a white powder; mp 193–195 °C
(EtOAc–n-hexane).
IR (KBr): 2952, 2273, 2141, 1740, 1691, 1230, 1169 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.06 (d, J6,2 = 1.9 Hz, 1 H, H6),
7.57 (br dd, J2,3 = 8.0 Hz, J2,6 = 1.9 Hz, 1 H, H2), 7.07 (br d,
J3,2 = 8.1 Hz, 1 H, H3), 3.91 (s, 2 H, CH2), 3.62 (s, 3 H, OCH3).
13C NMR (100 MHz, CDCl3): d = 172.0, 171.0, 136.4, 135.5, 134.1,
133.7, 131.2, 121.2, 52.0, 39.7.
IR (KBr): 3242, 3220, 3034, 1710, 1674, 1339, 1257, 1145, 749
cm–1.
1H NMR (400 MHz, CDCl3): d = 10.7 (br s, 1 H, NH), 7.53 (d,
J = 7.6 Hz, 2 H), 7.38 (br d, J4,5 = 8.3 Hz, 1 H, H4), 7.33–7.25 (m,
3 H), 7.18 (dd, J5,4 = 8.4, J5,7 = 2.5 Hz, 1 H, H5), 7.05 (br t, J = 7.4
Hz, 1 H), 4.79 (s, 2 H, CH2), 3.82 (s, 3 H, OCH3).
Methyl [2-(Azidocarbonyl)-4-methoxyphenyl]acetate (21b)
Following the typical procedure for 21a using half ester 5b (2.0 g,
8.9 mmol) gave 23b (1.77 g, 80%) as an oily product.
13C NMR (100 MHz, CDCl3): d = 168.5, 159.3, 149.3, 136.5, 132.5,
131.1, 128.1, 123.3, 123.1, 121.8, 119.1, 105.9, 54.7, 47.2.
HRMS: m/z [M + Na]+ calcd for C16H14N2O3Na: 305.0902; found:
305.0926.
IR (KBr): 2887, 2278, 2144, 1740, 1691, 1270, 1209, 913, 743
cm–1.
1H NMR (400 MHz, CDCl3): d = 7.54 (d, J6,2 = 2.8 Hz, 1 H, H6),
7.19 (br d, J3,2 = 8.4 Hz, 1 H, H3), 7.09 (br dd, J2,3 = 8.4 Hz,
J2,6 = 2.8 Hz, 1 H, H2), 3.97 (s, 2 H, CH2), 3.84 (s, 3 H, OCH3), 3.71
(s, 3 H, OCH3).
13C NMR (100 MHz, CDCl3): d = 172.9, 171.9, 158.6, 133.7, 130.3,
128.7, 119.5, 116.1, 55.5, 55.4, 39.5.
7-Bromo-1H-isochromene-1,3(4H)-dione (20a); Typical Proce-
dure
To a suspension of bromohomophthalic acid 6b (5.0 g, 19 mmol) in
CH2Cl2 (100 mL), excess SOCl2 (5 mL, 68 mmol) was added at r.t.
and the mixture was refluxed overnight. After completion of the re-
action (observation of a clear soln), solvent and excess SOCl2 were
removed under vacuum pressure to give 20a (4.5 g, 97%) as a light-
yellow solid; mp 171–173 °C (CH2Cl2). The analytical data are in
accord with literature values.32–34
Methyl {2-[(Anilinocarbonyl)amino]-4-bromophenyl}acetate
(23a); Typical Procedure
The acyl azide 21a (1.59 g, 5.3 mmol) was dissolved in anhyd ben-
zene and refluxed for 1 h. Evaporation of solvent gave isocyanate
22a (1.41 g, 5.2 mmol, 98%), which was used for further reactions.
The residue was dissolved in CH2Cl2 and aniline (0.56 mL, 6.2
mmol) was added and the soln was stirred at r.t. for 2 h. Filtration
of the precipitate yielded the urea derivative 23a (1.77 g, 92%) as a
white solid; mp 179–181 °C (EtOAc).
7-Methoxy-1H-isochromene-1,3(4H)-dione (20b)
Following the typical procedure for 20a using methoxyhomoph-
thalic acid 6c (5.0 g, 23.8 mmol) gave 20b (4.4 g, 96%) as a color-
less liquid. The analytical data are in accord with literature values.32
5-Bromo-2-(2-methoxy-2-oxoethyl)benzoic Acid (5a); Typical
Procedure
The anhydride 20a (4.5 g, 18.7 mmol) was dissolved in MeOH (100
mL) and refluxed for 2 h. After evaporation of the solvent, 5a (4.41
g, 86%) was obtained as a light-yellow solid; mp 135–138 °C
(EtOAc–hexane, 4:1).
IR (KBr): 3277, 1733, 1640, 1597, 1578, 1533, 1445, 1236, 1154
cm–1.
1H NMR (400 MHz, CDCl3): d = 7.83 (d, J5,3 = 1.6 Hz, 1 H, H5),
7.74 (br s, 1 H, NH), 7.32 (br s, 1 H, NH), 7.32–7.19 (m, 4 H, Harom),
7.19 (br dd, J3,2 = 8.0 Hz, J3,5 = 1.6 Hz, 1 H, H3), 7.06 (br t, J = 6.8
Hz, 1 H, Harom), 7.02 (br d, J3,2 = 8.0 Hz, 1 H, H3), 3.60 (s, 3 H,
OCH3), 3.54 (s, 2 H, CH2).
13C NMR (100 MHz, CDCl3): d = 172.4, 153.8, 138.1, 138.0, 132.0,
129.1, 128.4, 128.2, 126.2, 124.0, 121.7, 120.9, 52.5, 37.6.
IR (KBr): 2923, 1728, 1685, 1591, 1437, 1259, 1213 cm–1.
1H NMR (400 MHz, CDCl3): d = 9.77 (br s, 1 H, OH), 8.26 (d,
J6,2 = 2.4 Hz, 1 H, H6), 7.65 (br dd, J2,3 = 8.0 Hz, J2,6 = 2.4 Hz, 1 H,
H2), 7.16 (br d, J3,2 = 8.0 Hz, 1 H, H3), 4.01 (s, 2 H, CH2), 3.70 (s,
3 H, OCH3).
Anal. Calcd for C16H15BrN2O3; C, 52.91; H, 4.16; N, 7.71. Found:
C, 52.49; H, 4.12; N, 7.66.
13C NMR (100 MHz, CDCl3): d = 171.5, 170.8, 136.1, 135.6, 134.7,
133.9, 130.3, 121.3, 52.1, 39.9.
Synthesis 2011, No. 22, 3697–3705 © Thieme Stuttgart · New York

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A. A. Kilikli et al.
PAPER
Methyl {2-[(Anilinocarbonyl)amino]-4-methoxyphenyl}acetate
(23b)
IR (KBr): 3629, 3201, 3033, 1678, 1596, 1583, 1550, 1443, 1414
cm–1.
Following the typical procedure for 23a using acyl azide 21b (1.77
g, 7.1 mmol) gave 23b (2.05 g, 92%) as a white solid; mp 168–170
°C (EtOAc).
1H NMR (400 MHz, DMSO-d6): d = 12.69 (br s, 1 H, NH), 10.58
(br s, 1 H, NH), 7.87 (d, J6,8 = 2.4 Hz, 1 H, H6), 7.80 (br d, J9,8 = 8.4
Hz, 1 H, H9), 7.67 (br d, J = 7.6 Hz, 2 H, Harom), 7.65 (br d, J = 7.6
Hz, 2 H, Harom), 7.37 (br t, J = 7.6 Hz, 2 H, Harom), 7.27 (br t, J = 7.6
Hz, 2 H, Harom), 7.08 (br t, J = 7.2 Hz, 1 H, Harom), 6.9 (br t, J = 7.2
Hz, 1 H, Harom), 6.65 (br dd, J8,9 = 8.4 Hz, J8,6 = 2.4 Hz, 1 H, H8),
3.74 (s, 3 H, -OCH3).
13C NMR (100 MHz, DMSO-d6): d = 164.3, 164.1, 153.2, 151.8,
140.9, 138.6, 130.5, 129.0, 128.6, 122.9, 122.8, 120.7, 119.4, 118.1,
116.8, 108.5, 100.7, 84.6, 55.3.
IR (KBr): 3265, 2896, 1723, 1618, 1553, 1462, 1260, 1243, 1150,
989 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.45 (br s, 1 H, NH), 7.30 (br d,
J = 7.6 Hz, 2 H, Harom), 7.22 (m, 3 H, Harom), 7.04 (br d, J2,3 = 8.4
Hz, 1 H, H2), 7.00 (br t, J = 7.6 Hz, 1 H, Harom), 6.71 (br s, 1 H, NH),
6.63 (br dd, J3,2 = 8.4 Hz, J3,5 = 2.4 Hz, 1 H, H3), 3.72 (s, 3 H,
OCH3), 3.56 (s, 3 H, OCH3), 3.52 (s, 2 H, CH2).
13C NMR (100 MHz, CDCl3): d = 173.1, 159.7, 153.9, 138.2, 137.7,
131.7, 129.1, 123.9, 120.7, 119.5, 111.9, 110.7, 55.4, 52.4, 37.3.
HRMS: m/z [M + K]+ calcd for C23H19N3O4K: 440.1012; found:
410.1007.
Anal. Calcd for C17H18N2O4; C, 62.96; H, 5.77; N, 8.91. Found: C,
63.29; H, 5.56; N, 8.62.
6-Methoxy-1,3-dihydro-2H-indol-2-one (25b)
Light-red solid; mp 157–159 °C (Lit.37 162 °C). The analytical data
are in accord with literature values.
6-Bromo-2-hydroxy-N1,N3-diphenyl-1H-indole-1,3-dicarbox-
amide (24a) and 6-Bromo-1,3-dihydro-2H-indol-2-one (25a);
Typical Procedure
2-Hydroxy-6-methoxy-N-phenyl-1H-indole-3-carboxamide
(26b)
White crystalline solid; mp 250–252 °C.
To a soln of urea derivative 23a (1.5 g, 4.13 mmol) in MeCN (50
mL) at 60 °C was added excess K2CO3 (5.0 g, 36 mmol). After stir-
ring for 1.5 h, excess K2CO3 was filtered and solvent was evaporat-
ed under reduced pressure. The formed products were separated by
treatment of the mixture with CHCl3. The major product 24a was in-
soluble in CHCl3 and was separated by filtration (0.51 g, 57%). The
solvent was removed and the residue was purified by column chro-
matography (silica gel, EtOAc–hexane, 7:3) to give the minor prod-
uct 25a (0.25 g, 28%).
IR (KBr): 3446, 3268, 3006, 1715, 1668, 1626, 1598, 1217, 1162,
1005 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 11.98 (br s, 1 H, NH), 11.47
(br s, 1 H, NH), 7.44 (m, 3 H, Harom), 7.30 (br t, J = 7.6 Hz, 2 H,
Harom), 7.08 (br t, J = 7.6 Hz, 1 H, Harom), 6.58 (br dd, J8,9 = 8.4 Hz,
J8,6 = 2.4 Hz, 1 H, H8), 6.33 (d, J6,8 = 2.4 Hz, 1 H, H6), 3.69 (s, 3 H,
OCH3).
13C NMR (100 MHz, DMSO-d6): d = 176.5, 165.4, 160.7, 143.7,
138.0, 129.0, 128.8, 126.0, 124.3, 120.2, 119.7, 116.6, 108.1, 97.1,
63.9, 55.3.
6-Bromo-2-hydroxy-N1,N3-diphenyl-1H-indole-1,3-dicarbox-
amide (24a)
Purple solid; mp >320 °C.
IR (KBr): 3604, 3289, 1679, 1594, 1583, 1559, 1445, 1403 cm–1.
Anal. Calcd for C16H14N2O3; C, 68.07; H, 5.00; N, 9.92; O, 17.00.
Found: C, 68.19; H, 4.74; N, 9.93.
1H NMR (400 MHz, DMSO-d6): d = 12.8 (br s, 1 H, NH), 10.74 (br
s, 1 H, NH), 8.4 (d, J6,8 = 1.4 Hz, 1 H, H6), 8.02 (br d, J9,8 = 8.1 Hz,
1 H, H9), 7.78 (br d, J = 7.9 Hz, 2 H, Harom), 7.72 (br d, J = 7.8 Hz,
2 H, Harom), 7.35 (br t, J = 7.8 Hz, 2 H, Harom), 7.24 (br t, J = 7.8 Hz,
2 H, Harom), 7.10 (br dd, J8,9 = 8.1 Hz, J8,6 = 1.6 Hz, 1 H, H8), 7.05
(br t, J = 7.3 Hz, 1 H, Harom), 6.89 (br t, J = 7.3 Hz, 1 H, Harom).
13C NMR (100 MHz, DMSO-d6): d = 166.0, 165.9, 152.9, 142.4,
140.3, 132.3, 130.3, 129.7, 129.4, 125.3, 123.5, 121.6, 120.4, 119.3,
119.1, 117.3, 111.1, 86.6.
1,3-Diphenylurea (27)
White crystals; mp 238–240 °C (Lit.38 231–235 °C).
Reaction of Indole Derivative 24b with Potassium Carbonate
Following the typical procedure for 24a and 25a using 24b (0.3 g,
4.13 mmol), MeCN (20 mL), and K2CO3 for 2 h. Analysis of the
product mixture by NMR spectroscopy indicated the formation of
26b and 27 in 4 and 6% yields, respectively, where the most of the
starting material remained unreacted.
HRMS: m/z [M]+ calcd for C22H16BrN3O3: 448.0296; found:
448.0309.
1,1¢-(2-Hydroxy-6-methoxy-1H-indole-1,3-diyl)diethanone
(31), Methyl {4-Methoxy-2-[N-(anilinocarbonyl)acet-
6-Bromo-1,3-dihydro-2H-indol-2-one (25a)
amido]phenyl}acetate (32), and 2-Hydroxy-6-methoxy-N1,N3-
diphenyl-1H-indole-1,3-dicarboxamide (24b)
Orange solid; mp 208–212 °C (Lit.36 214–215 °C). The analytical
data are in accord with literature values.
The urea derivative 23b (1.2 g, 3.81 mmol) was dissolved in freshly
distilled THF (20 mL) and the mixture was cooled to –5 °C. At this
temperature NaH (0.175 g, 7.63 mmol) was added and the mixture
was stirred for 30 min. Then Ac2O (0.8 g, 7.84 mmol) added to the
soln which was further stirred overnight at r.t. After removal of sol-
vent, H2O was added and extracted with EtOAc (2 × 30 mL) and the
organic phase was dried (MgSO4). After removal of solvent the res-
idue was submitted to column chromatography (silica gel, EtOAc–
hexane, 3:2) to give in the following order the products 32 (0.38 g,
28%), 31 (0.27 g, 32%), and 24b (0.07 g, 9%).
2-Hydroxy-6-methoxy-N1,N3-diphenyl-1H-indole-1,3-dicarbox-
amide (24b), 6-Methoxy-1,3-dihydro-2H-indol-2-one (25b),
2-Hydroxy-6-methoxy-N-phenyl-1H-indole-3-carboxamide
(26b), and 1,3-Diphenylurea (27)
Following the typical procedure for 24a and 25a using 23b (3.0 g,
9.55 mmol) with K2CO3 (5.0 g, 36 mmol). The major product 24b
was precipitated from CHCl3 (1.06 g, 56%). The residue was sub-
mitted to column chromatography (silica gel, EtOAc–CH2Cl2, 4:6).
The compounds were isolated in the following order: 25b (0.4 g,
26%), 26b (0.07 g, 2.6%), and 27 (0.06 g, 0.28 mmol, 2.9%).
1,1¢-(2-Hydroxy-6-methoxy-1H-indole-1,3-diyl)diethanone (31)
Purple solid; mp 158–160 °C (EtOAc).
IR (KBr): 3019, 1711, 1623, 1214, 711 cm–1.
2-Hydroxy-6-methoxy-N1,N3-diphenyl-1H-indole-1,3-dicarbox-
amide (24b)
Purple solid; mp 199–201 °C.
Synthesis 2011, No. 22, 3697–3705 © Thieme Stuttgart · New York

PAPER
Synthesis of Indolin-2-one and Isoindolin-1-one Skeletons
3705
1H NMR (400 MHz, CDCl3): d = 13.00 (br s, 1 H, OH), 7.93 (d,
J5,7 = 2.4 Hz, 1 H, H7), 7.18 (br d, J4,5 = 8.8 Hz, 1 H, H4), 7.56 (dd,
J4,5 = 8.8 Hz, J5,7 = 2.4 Hz, 1 H, H5), 3.77 (s, 3 H, OCH3), 2.68 (s,
3 H, CH3), 2.38 (s, 3 H, CH3).
13C NMR (100 MHz, CDCl3): d = 173.0, 172.4, 170.8, 158.4, 136.4,
119.8, 115.5, 111.1, 103.0, 101.5, 55.7, 26.9, 20.7.
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HRMS: m/z [M]+ calcd for C13H13NO4: 248.0922; found: 248.0917.
Methyl {4-Methoxy-2-[N-(anilinocarbonyl)acetamido]phe-
nyl}acetate (32)
Brown solid; mp 107–109 °C (EtOAc).
IR (KBr): 3341, 3019, 2953, 1713, 1660, 1447, 1372, 1305, 1215
cm–1.
(15) Norman, M. H.; Minick, D. J.; Ringdon, G. C. J. Med. Chem.
1996, 39, 149.
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1H NMR (400 MHz, CDCl3): d = 7.80 (d, J2,6 = 2.4 Hz, 1 H, H2),
7.30 (br d, J = 7.6 Hz, 2 H, Harom), 7.22 (br t, J = 7.6 Hz, 2 H, Harom),
7.05 (br d, J = 8.4 Hz, 1 H, H5), 6.98 (br t, J = 7.6 Hz, 1 H, Harom),
6.65–6.63 (m, 2 H, NH, H6), 3.74 (s, 3 H, OCH3), 3.69 (s, 3 H,
OCH3), 3.55 (s, 2 H, CH2), 2.58 (s, 3 H, CH3).
13C NMR (100 MHz, CDCl3): d = 176.0, 171.0, 159.7, 154.0, 137.9,
129.0, 124.4, 123.4, 118.7, 115.1, 110.8, 102.5, 110.7, 55.6, 52.3,
36.1, 26.7.
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2010, (ii), 148. (b) Billamboz, M.; Fabrice, B.; Barreca, M.
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Anal. Calcd for C19H20N2O5; C, 64.04; H, 5.66; N, 7.86. Found: C,
63.69; H, 5.43; N, 7.98.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
Acknowledgment
The authors are indebted to the Scientific and Technological Re-
search Council of Turkey (TUBITAK, Grants 108-M-168 and 110-
R-001), the Department of Chemistry at Middle East Technical
University and the Turkish Academy of Sciences (TUBA) for their
financial support of this work.
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Synthesis 2011, No. 22, 3697–3705 © Thieme Stuttgart · New York