The chemistry of homophthalic acid: a new synthetic strategy for construction of substituted isocoumarin and indole skeletons

Article abstract of DOI:10.1016/j.tet.2008.03.097

Homophthalic acid was reacted with thionylchloride/DMF and chloroethylformate/NEt₃ in the presence and absence of NaN₃. In all cases completely different isocoumarin derivatives were obtained. These unusual isocoumarin derivatives were isolated and characterized and their formation mechanisms are discussed. The homophthalic acid monomethyl ester was converted into the corresponding isocyanate. Reaction of the isocyanate with different amines produced the urea derivatives. Base-supported condensation reactions of these products gave first an indolinone derivative, which underwent further intermolecular condensation to give substituted indole derivatives. However, when the condensation reaction was carried out in the presence of acetic anhydride, the intermolecular reactions were suppressed. This methodology opens up a new way of synthesizing of various five-membered ring substituted indole derivatives.

Full text of DOI:10.1016/j.tet.2008.03.097

Tetrahedron 64 (2008) 5531–5540
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
The chemistry of homophthalic acid: a new synthetic strategy
for construction of substituted isocoumarin and indole skeletons
a
,
,
Sevil Ozcan b, Metin Balci a
*
¨
a Department of Chemistry, Middle East Technical University, 06531 Ankara, Turkey
b Department of Chemistry, Abant Izzet Baysal University, 14280 Bolu, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
Homophthalic acid was reacted with thionylchloride/DMF and chloroethylformate/NEt3 in the presence
and absence of NaN3. In all cases completely different isocoumarin derivatives were obtained. These
unusual isocoumarin derivatives were isolated and characterized and their formation mechanisms are
discussed. The homophthalic acid monomethyl ester was converted into the corresponding isocyanate.
Reaction of the isocyanate with different amines produced the urea derivatives. Base-supported
condensation reactions of these products gave first an indolinone derivative, which underwent further
intermolecular condensation to give substituted indole derivatives. However, when the condensation
reaction was carried out in the presence of acetic anhydride, the intermolecular reactions were
suppressed. This methodology opens up a new way of synthesizing of various five-membered ring
substituted indole derivatives.
Received 28 November 2007
Received in revised form 12 March 2008
Accepted 27 March 2008
Available online 3 April 2008
Keywords:
Isocoumarin
Indole
Benzochromenone
Curtius degradation
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
synthesis of the diazide 9 derived from homophthalic acid 8. A
preliminary communication of this work was published recently.10
Indole and its derivatives are found abundantly in nature and
are known to exhibit potent physiological properties.1,2 Numerous
methods for the preparation of indoles have been developed.3–7 In
some cases, specific substitution patterns have been difficult to
obtain by standard indole-forming reactions; thus, new method-
ologies have emerged. The quinazoline and quinazolinone moities,8
in particular, are found in a variety of biological active compounds
and several approved drugs. Therefore, we were interested in the
development of new synthetic methodologies, leading to the syn-
thesis of these class of compounds. The main idea of this work was
to synthesize the isocyanate 1 and 2, which then will be trapped
with alcohols or amines to produce the corresponding urethane
and urea derivatives, 3 and 4, which can undergo cyclization to
form the corresponding five-, six- and eventually seven-membered
ring compounds 6, 5, and 7, respectively (Scheme 1).
The reaction of the acid 8 with thionyl chloride always produced
the lactone 10.11
N,N-Dimethylchlorosulfitemethaniminium chloride formed
from thionyl chloride and dimethyl formamide has been shown as
an efficient reagent for the synthesis of acyl azides from carboxylic
acids.12 Therefore, homophthalic acid 8 was reacted with thionyl
COOR
O
C OR
H
N
N
O
NCO
NCO
ROH
NH
NCO
1
5
3
O
NHR
OR
N
H
2. Results and discussion
6
NHR
N
NCO
COOCH3
RNH2
O
Our plan for the construction of the desired heterocyclic ring
systems involved an intramolecular cyclization reaction of the di-
isocyanate, which can be generated by the Curtius reaction9 of the
corresponding diazide. Our investigation began with the attempted
H
O
NR
O
COOCH3
2
4
N
7
* Corresponding author. Tel.: þ90 312 2105140; fax: þ90 312 2103200.
E-mail address: mbalci@metu.edu.tr (M. Balci).
Scheme 1.
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.03.097

¨
5532
S. Ozcan, M. Balci / Tetrahedron 64 (2008) 5531–5540
O
O
O
O
COOH
COOH
CON3
CON3
O
O
O
O
+
O
O
8
10
9
Cl
O
O
O
(with NaN3)
Cl-COOEt
14 (34%)
15 (9.6%)
OEt
COOH
O
(with NaN3)
1. SOCl2, DMF
COOH
COOH
O
NEt3, THF, rt
NaN3, H2O
O
2. NaN3, Bu4NBr
Pyridine, CH2Cl2,
reflux, 41%
H
N
O
COOH
3
8
11
O
+
O
O
Cl-COOEt
O
NEt3, THF, rt
(without NaN3)
1. SOCl2, DMF
17 (10.8%)
16 (7.1%)
2. Bu4NBr, pyridine
CH2Cl2, reflux
69%
EtO
O
(without NaN3)
O
O
O
O
O
O
HCl, MeOH
reflux,
O
N
O
OCOOEt
O
18 (43%)
O
10 (26%)
CH3
O
H3CO
13
Scheme 3.
CH3
12
with the proposed structure. An HMBC experiment confirmed the
presence of a strong correlation between the carbonyl group of the
ketone, the double bond proton, and the aromatic proton. Finally, X-
ray diffraction analysis of 19 was carried out. The results of this study
confirmed unambiguously the proposed structure.10
Scheme 2.
chloride, DMF, and sodium azide in the presence of tetrabutyl-
ammonium bromide as a catalyst using CH2Cl2 as the solvent.
Unfortunately, the desired diazide 9 was not detected. 6H-Di-
benzo[c,h]chromen-6-one13,14 (11) was formed in 41% yield, which
was characterized by comparison of its spectral data with those
published in the literature (Scheme 2).
O
O
O
O
O
MeI, K2CO3
The azide anion was not incorporated in the product 11. To
determine the role of the azide anion in this reaction, the same
reaction was run in the absence of NaN3. Instead of the formation of
a dibenzochromen-6-one 11, an aminomethylene compound 12
was formed as the sole product in 69% yield (Scheme 2). The in-
termediate 12 was identified by comparison of the spectral data
with those reported in the literature, which was obtained under
Vilsmeier conditions (DMF/POCl3) starting from the homophthalic
acid 8.15,16 The intermediate 12 was further converted to the
isocoumarin derivative 1315–18 by the reaction with methanol
saturated with hydrogen chloride in 76% yield.
As an alternate method for the formation of acyl azide 9, homo-
phthalic acid 8 was treated with chloroethylformate in the presence
of triethylamine followed by addition of a solution of NaN3 in water.
Careful examination of the reaction mixture revealed the formation
of four compounds 14–17 (Scheme 3), with compound 14 pre-
cipitated fromthe reaction media. The other isomers wereseparated
on a silica gel column eluting with dichloromethane.
Next, homophthalic acid 8 was reacted with chloroethylformate
and triethylamine in the absence of NaN3. Surprisingly, none of the
products 14–17 were formed. Instead the isocoumarin derivative
1819 was formed, in 43% yield, as the major product along with
anhydride 10 in 26% yield (Scheme 3). The structure of 18 was
deduced by NMR spectral data.
COSY, HMQC, and HMBC experiments allowed for the assign-
ment of the structures 14–17. An HMBC experiment of 14 confirmed
this structure, especially by the correlation of the carbon atom
bearing the chlorine atom with the double bond proton located in
O
CH3CN, 60 °C
1 h, 70%
O
Cl
COOCH3
O
14
19
Scheme 4.
The HMBC experiment of 16 revealed a strong correlation (3JCH
between the carbon atom (CH) in the lactone ring with the double
bond proton as well as with the -proton of the second benzene ring.
)
a
We assume that compound 16 is a secondary product formed from
14 under the reaction conditions. Ring opening of 14 followed by
decarboxylation and substitution of the chlorine atom by a carboxy-
late anion would form the lactone 16. For the formation of 17 the
following mechanism is suggested. The initially formed acyl chloride
can react with azide to give the acyl azide 20, which then rearranges
to the corresponding isocyanate 21 followed by trapping of the
isocyanate functionality with the acid –OH group. Enolization of the
carbonyl group in 22 followed by trapping with chloroethylformate
ends up with the formation of compound 17 (Scheme 5).
H
N
O
N=C=O
COOH
CON3
COOH
intramolecular
cyclization
O
O
20
21
22
the isocoumarin ring and the a-proton of the other benzene ring.
H
N
H
N
O
O
Furthermore the presence of 14 carbon resonances and other
spectral data support the formation of an anhydride structure.
For further structural proof, the chlorine compound 14 was treated
with CH3I in the presence of K2CO3 in acetonitrile. The isocoumarin
derivative 19 was isolated as a single compound in 70% yield (Scheme
4). Again, COSY, HMQC, and HMBC experiments are in agreement
ClCOOEt
O
O
OCOOEt
OH
23
17
Scheme 5.

¨
S. Ozcan, M. Balci / Tetrahedron 64 (2008) 5531–5540
5533
O
COH
O
O
N3
O
COCl
COOH
N3
O
O
OH
COOH
CON3
CON3
O
25
-HN3
-N3
–OOC
HOOC
O
O
-CO2
24
29
26
COOH
27
28
COOH
COOH
-H2O
O
O
O
COOH
COCl
O
O
O
ClCOOEt
32
EtOOCO
HO
O
30
15
31
Red.
-H2O
O
O
O
COOH
O
O
O
O
CON3
-H2O
-HN3
O
O
O
Cl
O
O
O
O
HOOC
HOOC
O
O
33
34
14
Scheme 6.
16
11
The results of these two attempted azidination reactions (Schemes
2 and 3) show that NaN3 plays an important role in the de-
termination of the mode of the reaction. During attempted
azidination reactions it was noticed that intermolecular conden-
sation products such as 11, 14, 15, and 16 were always formed.
However, when the reaction was run in the absence of NaN3, only
intramolecular cyclization products such as 12 and 18 were pro-
duced. In order to have more insight in to the formation mechanism
of 11, 14–16, the azidination reactions were carried out with the
anhydride 10 instead of homophthalic acid (8). We obtained similar
products with similar yields.
A tentative mechanism of the formation of 11, 14, 15, and 16 is
outlined inScheme6. Itisproposedthat thefirststepistheformation
of theanhydride10, whichcanbeopenedupbytheazideaniontothe
corresponding monoazide 24. Formation of the acyl azide 24 can
activate the methylene protons, which might easily undergo
intermolecular acylation reactions with 25 as well as with 32, to give
26 and 33, respectively. The formed anhydride 27 might undergo
again a ring-opening reaction by the attack of the azide anion to
produce 28, which will be in tautomeric equilibrium. Cyclization of
28 followed by decarboxylation then gives 29. Further cyclization of
29andreductionof thecarbonylgroup in30withNaN320 followedby
H2O elimination results in the formation of 11. Enolization of the
carbonyl group in 30 followed by trapping with ethylchloroformate
produces the compound 15. In addition, it is proposed that 34 is
formed from the intermediate 33 as shown in Scheme 6.
producing enol 39. Cyclization of 39 followed by decarbonylation (or
oxidation tothe carbocyclic acid followed by decarboxylation) forms
the 13C-incorporated isocoumarin derivative37. This experimentally
well established mechanism strongly supports our suggested
mechanism25 for the formation of the products 11, 14–16.
Our initial plan for the construction of quinazoline and quin-
azolinone moieties involved an intramolecular cyclization of di-
isocyanate 1, which could be derived from the diazide 9. However,
the attempted synthesis of diazide 9 failed. The homophthalic acid
8 preferred the cyclization reaction to produce the anhydride 10
from which the isolated products were derived. In order to block
the anhydride formation, we decided to synthesize the half ester 40
and generate the isocyanate 2. In this part, we describe the suc-
cessful implementation of this strategy.
The starting material, homophthalic acid 8, was reacted with
thionyl chloride to give an anhydride 10 by a ring-closing reaction,
which was then treated with methanol to produce the half ester 40
by a regiospecific ring-opening reaction.26 The half ester 40 was
then reacted with thionyl chloride, DMF, and sodium azide in the
O
O
O
C13
Cl
SnCl4
O
O
+
C13
PhNO2, 150 °C
NO2
NO2
35
36
37
Recently, Threadgill et al.21 have treated5-nitroisocoumarinwith
various aromatic acyl chlorides under Friedel–Crafts conditions22–24
to give 3-aryl-5-nitroisocoumarins rather than the expected 4-acyl-
5-nitroisocoumarins. In order to elucidate the mechanism of the
reaction, they designed an elegant reaction and reacted nitro-
isocoumarin 35 with [13C]-carbonyl benzoyl chloride (36) and
determined that the 13C is located at the C-3 position of the iso-
coumarin skeleton, indicating that the benzoyl carbon framework is
incorporated intact (Scheme 7). For this reaction they have sug-
gested a mechanism where 35 first undergoes an acylation reaction
at C-4 position followed by a ring-opening reaction by a nucleophile
-CO
or Oxid.
-CO2
Nu
O
O
Nu
cyclization
O
OH
C13
O2N
C13
O2N
C
O
O
H
38
39
Scheme 7.

¨
S. Ozcan, M. Balci / Tetrahedron 64 (2008) 5531–5540
5534
presence of tetrabutylammonium bromide as a catalyst using
CH2Cl2 as the solvent. Unfortunately, the desired monoazide 41 was
not detected. Instead, a mixture of three compounds 42, 43, and 44
was obtained in 12, 31, and 25% yields, respectively (Scheme 8). The
products 43 and 44 were characterized by NMR spectral data. The
high resolution mass spectrum of 43 clearly indicates the formation
of a dimeric product. The experimental value of Mþ¼356.1363 is
fully in agreement with the theoretical value, Mþ¼356.1372. The
3-methoxy-1H-isochromen-1-one (42) was characterized by
comparison of its spectral data with those published in the
literature.27,28
H3CO
O
O
C
H
N
H
N
H
N
O
K2CO3
CH3CN
60 °C
N
O
H3CO
O
OCH3
O
46
43
O
N
O
N
H
46a
O
COOH
CON3
COOCH3
COOH
COOCH3
H3CO
?
1. SOCl2, 98%
2. MeOH, 85%
O
40
COOH
OCH3
41
H3CO
8
1. SOCl2/DMF
HN
O
O
O
2. Bu4NBr, NaN3,
pyridine, CH2Cl2
reflux
O
HN
N
O
OH
H
N
O
N
+
H
N
O
O
C
O
O
N
H
N
H
N
HN
NHCl
O
O
49
OCH3
OCH3
+
+
COOCH3
O
OMe
47
48 (58%)
44
42
H3CO
O
43
OCH3
O
Scheme 10.
Scheme 8.
As an alternate method for the formation of acyl azide 41,
homophthalic acid ester 40 was treated with ethylchloroformate in
the presence of triethylamine followed by the addition of a solution
of NaN3 in water. In contrast to the previous experiment, this
azidination method was successful and provided acyl azide 41 in
68% yield (Scheme 9). The azide function provided a convenient
handle for the generation of the corresponding isocyanate 2. Thus,
acyl azide 41 was allowed to reflux in benzene under nitrogen
atmosphere to effect its quantitative transformation to the corre-
sponding isocyanate 2.29 Hydrolysis of this isocyanate 2 with water
formed amine 45.30 The reaction of amine 45 with isocyanate 2
gave the dimeric product 43 in excellent yield. On the basis of these
reactions, the mechanism of formation of 43 obtained from re-
action of 40 with DMF/SOCl2 and NaN3 (Scheme 8) was established.
product 48 was formed as the major product (58% yield) along with
the fragmentation product 49.31 The formation of a five-membered
ring was preferred over the seven-membered ring. Under the
reaction conditions, the product 46 undergoes a further conden-
sation reaction with the in situ formed carbanion 46a and forms the
intermediate 47, whose fragmentation results in the formation of
48 as shown in Scheme 10.
In order to force the system to undergo a regioselective ring-
closure reaction to generate a 1,3-benzodiazepine-2,4-dione 7
structure, we decided to increase the acidity of one of the NH
groups in 43. For that purpose, isocyanate 2 was reacted with
p-nitroaniline to give the urea derivative 50. The product 50 was
subjected to an intramolecular condensation reaction with K2CO3
to form 51. Unfortunately, the interference of the other intra-
molecular process (condensation with the NH-proton attached to
the benzene ring) gave the indole derivative 52 resulting from
intramolecular condensation followed by intermolecular conden-
sation (Scheme 11).
It became apparent that the urea derivatives 43 and 50 undergo
first an intramolecular condensation to form a five-membered ring
followed by an intermolecular condensation reaction as depicted in
Scheme 10. To prevent the intermolecular condensation reaction
and as a further support for the formation mechanism of 48 and 52,
we decided to trap the intermediate having the structure of the
type 46a.
To address this question, isocyanate 2 was reacted with aniline
to give the urethane 53 in high yield. The reaction of 53 with NaH in
the presence of acetic anhydride in THF gave two easily separable
products 54 and 55 in yields of 75 and 16%, respectively (Scheme
12). Careful examination of the reaction mixture did not reveal the
formation of any trace of the intermolecular condensation products
having the structure such as 48. The exclusive formation of 54 and
55 confirmed our original hypothesis that an intramolecular con-
densation takes place first. The indolinone derivative 55 undergoes
a proton abstraction to form a carbanion having the structure of the
type 46a, which is then trapped by acetic anhydride. On the other
hand, the reaction of 53 with K2CO3 in acetonitrile at 60 ꢀC resulted
in the formation of 49 and 56, as expected.
1. NEt3
2. ClCO2Et
N=C=O
COOH
CON3
Δ
3. NaN3
COOCH3
41 (68%)
COOCH3
2 (99%)
40
COOCH3
H2O
N=C=O
COOCH3
O
C
H
N
H
N
NH2
COOCH3
2
45 (89%)
H3CO
O
OCH3
O
43 (91%)
Scheme 9.
As a result of this, we redirected our efforts to the ring-closure
reaction of 43, already bearing the necessary functionalities as
shown in Scheme 1. The ring-closure reaction of urea derivative 43
was accomplished by treatment with K2CO3 in acetonitrile at 60 ꢀC
(Scheme 10).
Detailed examination of the NMR spectra, including COSY,
HMQC, and HMBC and HRMS indicated that the condensation

¨
S. Ozcan, M. Balci / Tetrahedron 64 (2008) 5531–5540
5535
H
N
monoazide 41 derived from homophthalic acid was successfully
synthesized. The conversion of the monoazide 41 into the corre-
sponding isocyanate 2, followed by trapping with different amine
bases gave the urea derivatives 43, 50, and 53. Base-supported
condensation reactions of these products gave first an indolinone
structure, which further undergoes intermolecular cyclization to
give substituted indole derivatives. However, when the condensa-
tion reaction is carried out in the presence of a trapping reagent, the
intermolecular reaction can be controlled.
O
N
NO2
O
51
K2CO3
CH3CN
60 °C
These methodologies open up new ways of synthesizing of
various isocoumarins and five-membered ring substituted indole
derivatives. Further application and extension of this methodology
is currently under investigation.
O
H
H
N
NCO
COOCH3
C N
p-Nitroaniline
CH2Cl2, 40 °C
90%
NO2
2
COOCH3
50
3. Experimental
3.1. General
K2CO3
CH3CN
60 °C
Melting points were determined on a Thomas-Hoover capillary
melting point apparatus. IR spectra were recorded on a Perkin–
Elmer 980 spectrometer. NMR spectra were recorded on a Bruker
instrument at 300 MHz for 1H and 75 MHz for 13C NMR. Apparent
splitting is given in all cases. Column chromatography was per-
formed on silica gel (60-mesh, Merck). TLC was carried out on
Merck 0.2 mm silica gel 60 F254 analytical aluminum plates. All
substances reported in this paper are in their racemic form.
HN
NO2
O
O
H
N
+
O
OH
N
49 25%
N
H
NO2
52 57%
3.2. Synthesis of 6H-dibenzo[c,h]chromen-6-one (11)
Scheme 11.
In a 25 mL dropping funnel, benzene (10 mL), dimethyl form-
amide (2 mL, 20.4 mmol), and thionyl chloride (1.6 mL, 22 mmol)
were consecutively added. After 3–5 min the two phases were
separated and the lower layer was added to a suspension of
In conclusion, the attempted synthesis of a diazide derived from
homophthalic acid failed. However, unusual coumarin derivatives
were produced instead. The isolated products were completely
different, depending on whether the reaction was carried out in the
presence or absence of NaN3; in spite of the fact that the Nꢁ3 anion
was not incorporated into the molecule. This method opens up
a new route for the synthesis of coumarin derivatives. The targeted
homophthalic acid
8 (1.8 g, 10 mmol), sodium azide (2.6 g,
40 mmol), tetrabutylammonium bromide (0.6 g, 2 mmol), and
pyridine (3.2 mL, 40 mmol) in dichloromethane (50 mL). The mix-
ture was then refluxed overnight and washed with saturated
sodium bicarbonate solution (3ꢂ50 mL) and water (2ꢂ25 mL). The
organic phase was dried over magnesium sulfate and concentrated
under reduced pressure. The residue was purified by column
chromatography (silica gel, 30 g, CHCl3) to give yellow crystals 11
(0.5 g; mp 182–183 ꢀC, lit. mp 179–180 ꢀC13) in 41% yield. The
product was crystallized from ethylacetate. 1H NMR (400 MHz,
O
O
NHPh
OH
NHPh
O
N
N
+
55, 16%
CDCl3)
d
8.60 (dd, J7,8¼7.9 Hz, J7,9¼1.2 Hz, 1H, H-7), 8.49 (dd,
Me
O
J4,3¼7.9 Hz, J4,2¼1.2 Hz, 1H, H-4), 8.21 (br d, J1,2¼8.1 Hz, 1H, H-1),
8.08 (d, J12,11¼8.8 Hz, 1H, H-12), 7.89 (ddd, J2,1¼8.1 Hz, J2,3¼7.3 Hz,
J2,4¼1.2 Hz, 1H, H-2), 7.87 (dd, J10,9¼8.1 Hz, J10,8¼1.4 Hz, 1H, H-10),
7.78 (d, J11,12¼8.8 Hz, 1H, H-11), 7.65 (ddd, J8,7¼7.9 Hz, J8,9¼6.9 Hz,
J10,8¼1.4 Hz, 1H, H-8), 7.63 (dd, J9,10¼8.1 Hz, J9,8¼6.9 Hz, 1H, H-9),
7.61 (dd, J3,4¼7.9 Hz, J3,2¼7.3 Hz, 1H, H-3); 13C NMR (100 MHz,
54 75%
NaH, 2 equiv.
Ac2O
THF
O
NHPh
NH C
NCO
COOCH3
Aniline
CDCl3) d 161.2 (s, carbonyl), 147.4 (s, C-4b), 135.5 (s, C-10a), 134.9 (d,
COOCH3
CH2Cl2, rt. 98%
C-9), 134.3 (s, C-12a), 130.7 (d, C-4), 128.6 (d, C-3), 127.9 (d, C-8),
127.7 (d, C-2), 127.2 (d, C-10), 124.5 (d, C-11), 123.9 (s, C-6a), 122.4
(d, C-7),122.1 (d, C-1),121.3 (s, C-10b),119.2 (d, C-12),113.1 (s, C-4a).
53
2
K2CO3
CH3CN
60 °C
3.3. Synthesis of (4Z)-4-[(dimethylamino)methylene]-1H-
isochromen-1,3(4H)-dione (12)
O
NHPh
In a 25 mL dropping funnel, benzene (10 mL), dimethyl form-
amide (2 mL, 20.4 mmol), and thionyl chloride (1.6 mL, 22 mmol)
were consecutively added. After 3–5 min the two phases were
separated and the lower layer was added to a suspension of
homophthalic acid (8) (1.8 g, 10 mmol), tetrabutylammonium bro-
mide (0.6 g, 2 mmol), and pyridine (3.2 mL, 40 mmol) in dichloro-
methane (50 mL). The mixture was then refluxed overnight and
washed with aqueous HCl solution (2ꢂ50 mL), water (2ꢂ50 mL),
H
N
N
+
OH
O
49, 34%
NHPh
O
56 60%
Scheme 12.

¨
S. Ozcan, M. Balci / Tetrahedron 64 (2008) 5531–5540
5536
and aqueous sodium bicarbonate solution (2ꢂ50 mL). The organic
phase was dried over magnesium sulfate and concentrated by
vacuum. The residue was chromatographed (silica gel, 40 g, ethyl
acetate) togive the product 12 as yellowsolid (1.5 g) in 69% yield (mp
156–157 ꢀC, lit. mp 144–145 ꢀC15). The product was crystallized from
ethylacetate/hexane (8:2). 1H NMR (400 MHz, DMSO-d6, 65 ꢀC)
(s, C-10), 163.6 (s, C-1), 160.6 (s, C-30), 156.6 (s, C-3), 143.6 (s, C-4a0),
140.4 (s, C-4a), 135.4 (d, C-6), 134.1 (d, C-60), 129.7 (d, C-80), 129.1 (d,
C-8),126.5 (d, C-7),125.8 (d, C-5),121.1 (d, C-50),118.8 (d, C-70),118.6
(s, C-8a), 113.5 (s, C-8a0), 103.8 (d, C-4), 80.2 (s, C-40); IR (KBr, cmꢁ1):
1723 (s), 1699 (s), 1628 (s), 1563 (w), 1079 (w). Anal. Calcd for
C18H9ClO5: C, 63.45; H, 2.66. Found: C, 62.73; H, 2.42.
d
8.34 (br s, 1H, H-1), 7.96 (br d, J5,6¼7.8 Hz, 1H, H-5), 7.59 (br dd,
J6,5¼7.8 Hz, J6,7¼7.4 Hz,1H, H-6), 7.53 (br d, J8,7¼8.2 Hz,1H, H-8), 7.18
3.5.2. 3-(3-Oxo-1,3-dihydro-2-benzofuran-1-yl)-1H-
isochromen-1-one (16)
(dd, J7,8¼8.2 Hz, J7,6¼7.4 Hz, 1H, H-7), 3.34 (s, 6H, –CH3); 13C NMR
(100 MHz, DMSO-d6)
d
163.5 (d, C-1),159.2 (s, C-1, carbonyl),157.9 (s,
Yellow-brown solid (550 mg, 7.1%), mp 256–257 ꢀC. 1H NMR
C-3, carbonyl), 140.5 (s, C-4a), 135 (d, C-6), 129.9 (d, C-8), 123.7 (d,
C-5), 120.7 (d, C-7), 116.4 (s, C-8a), 86.8 (s, C-4), 46.2 (q, –CH3).
(400 MHz, DMSO-d6)
d
8.13 (br d, J8,7¼8.1 Hz, 1H, H-8), 7.76 (br d,
0
0
J4 ,5 ¼7.7 Hz, 1H, H-4), 7.87 (dd, J6,5¼7.4 Hz, J6,7¼7.2 Hz, J6,8¼1.1 Hz,
0
0
0
0
0
0
0
1H, H-6), 7.83 (dd, J6 5 ¼7.6 Hz, J6 ,7 ¼7.1 Hz, J6 ,8 ¼1.1 Hz, 1H, H-6 ),
3.4. Methyl-1-oxo-1H-isochromene-4-carboxylate (13)15
7.73 (br d, J5,6¼7.4 Hz, 1H, H-5), 7.70 (br d, J5 ,4 ¼7.7 Hz, J5 ,6 ¼7.6 Hz,
0
0
0
0
1H, H-50), 7.68 (br d, J7 ,6 ¼7.1 Hz, 1H, H-7 ), 7.64 (dd, J7,8¼8.1 Hz,
0
0
0
The product 12 (0.7 g, 3 mmol) was dissolved in 20 mL methanol
and dry HCl gas, produced from sulfuric acid and sodium chloride,
was passed slowly through this solution. After saturation was
complete, it was refluxed for 2 h. The solvent was removed and
water was added to the residue, which was then extracted with
chloroform (3ꢂ10 mL). The combined extracts were dried over
magnesium sulfate and the solvent was removed at reduced pres-
sure yielding the product 13, as a white solid, which was then
crystallized from methanol (mp 97–98 ꢀC, lit. mp 97 ꢀC;15 0.5 g,
J7,6¼7.2 Hz, J7,5¼1.1 Hz, 1H, H-7), 7.14 (s, 1H, H-4), 6.63 (s, 1H, H-1);
13C NMR (100 MHz, DMSO-d6)
d 170.0 (s, C-3), 161.5 (s, C-1), 150.3
(s, C-3a), 146.6 (s, C-7a), 136.5 (s, C-4a), 135.8 (d, C-6), 131.0 (d, C-60),
130.4 (d, C-50), 129.7 (d, C-7), 127.6 (d, C-8), 126.0 (d, C-5), 125.8 (d,
C-4), 125.6 (s, C-3), 124.0 (d, C-70), 121.1 (s, C-8a), 107.7 (d, C-4), 79.0
(d, C-1); IR (KBr, cmꢁ1): 1770 (s), 1727 (s), 1661 (w), 1381 (w), 1219
(m), 1147 (w); MS: 70 eV, m/z 279 (MþHþ, 41%), 278 (100%), 249
(76%), 145 (60%), 117 (39%), 89 (74%); HRMS calcd for C17H10 O4:
278.0579; found: 278.0585. Anal. Calcd for C17H10O4: C, 73.38; H,
3.62. Found: C, 73.24; H, 3.67.
76%). 1H NMR (400 MHz, CDCl3)
d
8.66 (br d, J8,7¼8.0 Hz, 1H, H-8),
8.33 (br d, J5,6¼7.9 Hz, 1H, H-5), 8.20 (s, 1H, –CH), 7.82 (ddd,
J6,5¼7.9 Hz, J6,7¼7.5 Hz, J6,8¼1.2 Hz,1H, H-6), 7.59 (br dd, J7,8¼8.0 Hz,
J7,6¼7.5 Hz, 1H, H-7), 3.92 (s, 3H, –OCH3); 13C NMR (100 MHz,
3.5.3. Ethyl 6-oxo-6H-dibenzo[c,h]chromen-11-yl carbonate (15)
Yellow solid (880 mg, 9.6%), mp 174–175 ꢀC. 1H NMR (400 MHz,
CDCl3)
d
164.5 (s, ester carbonyl), 160.7 (s, lactone carbonyl), 152.6
CDCl3)
d
8.69 (dd, J7,8¼8.0 Hz, J7,9¼0.7 Hz, 1H, H-7), 8.5 (dd,
(d, C-3), 135.4 (d, C-6), 133.5 (s, C-4a), 130.0 (d, C-8), 129.0 (d, C-7),
125.4 (d, C-5), 120.5 (s, C-8a), 110.0 (s, C-4), 52.1 (q, –OCH3).
J10,9¼8.1 Hz, J10,8¼1.5 Hz, 1H, H-10), 7.98 (dd, J4,3¼8.2 Hz,
J4,2¼0.9 Hz, 1H, H-4), 7.89 (dd, J1,2¼7.0 Hz, J1,3¼1.5 Hz, 1H, H-1), 7.86
(ddd, J8,7¼8.0 Hz, J8,9¼7.8 Hz, J5,8¼1.5 Hz, 1H, H-8), 7.55 (s, 1H,
H-12), 7.64 (dt, J9,10¼J9,8¼8.1 Hz, J7,9¼1.1 Hz, 1H, H-9), 7.6 (dt,
J1,2¼J2,3¼7.0 Hz, J2,4¼1.5 Hz, 1H, H-2), 7.56 (ddd, J3,4¼8.2 Hz,
J3,2¼7.0 Hz, J3,1¼1,5 Hz, 1H, H-3), 4.38 (q, J¼7.0 Hz, 2H, H-1), 1.41 (t,
3.5. Reaction of homophthalic acid (8) with
ethylchloroformate and triethylamine in the presence of NaN3
To a solution of homophthalic acid 8 (10 g, 56 mmol) in 40 mL
THF at ꢁ5 ꢀC, a solution of triethylamine (12 mL, 87 mmol) in 25 mL
THF was added dropwise and the mixture was stirred for 30 min.
This was followed by slow addition of a cooled solution of ethyl-
chloroformate (12 mL, 130 mmol) in 25 mL THF and the reaction
mixture was stirred at the same temperature, for 30 min. A solution
of sodium azide (14 g, 215 mmol) in 50 mL water was then added
dropwise and the mixture was left to stir at room temperature
overnight. The product 14 (2.5 g), which was precipitated from the
reaction medium was separated by filtration and the filtrate was
extracted with two portions of ethyl acetate (50 mL). The organic
phase was then washed with saturated sodium bicarbonate solu-
tion (3ꢂ75 mL) and with water (2ꢂ50 mL), and dried over mag-
nesium sulfate. By removal of ethyl acetate, under reduced
pressure, a mixture of the products 15, 16, and 17 (2.95 g) was
obtained. When the mixture was dissolved in CHCl3, compound 16
precipitated and was filtered off. The filtrate was concentrated in
vacuum and the mixture was chromatographed over silica gel
(60 g) eluting with CH2Cl2. The first fraction was identified as the
dibenzochromen-6-one derivative 15. The compound 17 was
isolated as the second fraction.
J¼7.0 Hz, 3H, H-2); 13C NMR (100 MHz, CDCl3)
d 160.8 (s, C-6), 152.8
(s, C-13),148.7 (s, C-11),144.7 (s, C-4a),135.5 (d, C-8),133.7 (s, C-6a),
133.2 (s, C-12a), 131.3 (d, C-10), 129.6 (d, C-9), 128.5 (d, C-2), 127.6
(d, C-1), 126.8 (d, C-3),126.4 (d, C-7),125.2 (s, C-4a),122.5 (s, C-10a),
121.8 (d, C-4), 112.5 (d, C-12), 111.5 (s, C-10b), 66.2 (q, C-19), 14.6 (t,
C-20); IR (KBr, cmꢁ1): 1753 (s), 1633 (s), 1604 (w), 1464 (w), 1320
(m), 1233 (s); MS: 70 eV, m/z 334 (Mþ, 28%), 289 (25%), 262 (100%),
233 (76%), 204 (22%), 176 (27%). Anal. Calcd for C20H14O5: C, 71.85;
H, 4.59. Found: C, 71.48; H, 4.36.
3.5.4. Ethyl 2-oxo-1,2-dihydro-3,1-benzoxazepin-4-yl carbonate(17)
Viscous yellow liquid (750 mg,10.8%). 1H NMR (400 MHz, CDCl3)
d
8.43 (br s, 1H, –NH), 7.93 (br d, J6,7¼7.6 Hz, 1H, H-6), 7.89 (br d,
J9,8¼7.7 Hz, 1H, H-9), 7.76 (br dd, J8,9¼7.7 Hz, J8,7¼7.4 Hz, 1H, H-8),
7.63 (br dd, J7,6¼7.6 Hz, J7,8¼7.4 Hz, 1H, H-7), 5.93 (s, 1H, H-5), 4.26
(q, J¼7.1 Hz, 2H, –CH2–), 1.31 (t, J¼7.1 Hz, 3H, –CH3); 13C NMR
(100 MHz, CDCl3)
d 168.9 (s, C-2), 165.2 (s, C-4), 149.9 (s, ester
carbonyl),143.9 (s, C-9a),135.3 (d, C-8),130.5 (d, C-7),125.9 (d, C-6),
124 (s, C-5a), 123.9 (d, C-9), 77.9 (d, C-5), 62.9 (t, –OCH2), 14.1 (q,
–CH3); IR (KBr, cmꢁ1): 1780 (s), 1721 (s), 1466 (m), 1286 (s), 1185
(m); MS: 70 eV, m/z 249 (Mþ, 5%), 145 (6%), 133 (100%), 105 (45%),
89 (10%). Anal. Calcd for C12H11NO5: C, 52.83; H, 4.45; N, 5.62.
Found: C, 52.14; H, 4.39; N, 5.31.
3.5.1. 40-Chloro-1H,10H-3,40-biisochromen-1,10,30(40H)-trione (14)
Yellow-green solid (3.9 g, 34%), decomposition at 227–228 ꢀC.
The product darkens at room temperature. 1H NMR (400 MHz,
3.6. Synthesis of methyl 2-[(1-oxo-1H-isochromen-3-
0
0
DMSO-d6)
d
8.03 (br d, J8,7¼7.7 Hz, 1H, H-8), 7.76 (dd, J8 ,7 ¼7.8 Hz,
yl)carbonyl]benzoate (19)
0
0
0
J8 6 ¼1.1 Hz, 1H, H-8 ), 7.70 (dt, J6,7¼J6,5¼8.0 Hz, J6,8¼1.1 Hz, 1H, H-
0
0
0
6), 7.48 (br d, J5,6¼8.0 Hz, 1H, H-5), 7.41 (br d, J5 ,6 ¼8.2 Hz,1H, H-5 ),
To a suspension of compound 14 (0.48 g, 1.4 mmol) in acetoni-
trile (15 mL), potassium carbonate (1 g, 7.2 mmol) and methyl
iodide (0.2 g, 1.4 mmol) were added. The suspension was stirred at
60 ꢀC and the reaction was complete in 1 h (determined by TLC).
0
0
7.36 (br dd, J7,6¼8.0 Hz, J7,8¼7.7 Hz, 1H, H-7), 7.29 (ddd, J6 ,5 ¼8.2 Hz,
0
0
0
0
0
J6 ,7 ¼7.8 Hz, J6 ,8 ¼1.2 Hz, 1H, H-6 ), 6.89 (br s, 1H, H-4), 6.73 (br t,
J7 ,6 ¼J7 ,8 ¼7.8 Hz, 1H, H-7 ); 13C NMR (100 MHz, DMSO-d6)
d
165.5
0
0
0
0
0

¨
S. Ozcan, M. Balci / Tetrahedron 64 (2008) 5531–5540
5537
The residue was filtered off to remove the excess potassium
carbonate. The filtrate was concentrated by vacuum to give the
product 19 (0.3 g, 70%). Yellow crystals from methanol/chloroform
(1:1), mp 140–141 ꢀC. 1H NMR (400 MHz, CDCl3) d0 8.33 (br d,
(br s, 1H, –OH), 8.17 (dd, J6,5¼7.8 Hz, J6,4¼1.3 Hz, 1H, H-6), 7.56 (dt,
J4,5¼J4,3¼7.6 Hz, J4,6¼1.3 Hz, 1H, H-4), 7.43 (dt, J5,6¼7.8 Hz,
J5,4¼7.6 Hz, J5,3¼0.9 Hz, 1H, H-5), 7.30 (d, J3,4¼7.6 Hz, 1H, H-3); 13C
NMR (100 MHz, CDCl3)
d 172.3 (s, ester carbonyl), 171.9 (s, acid
0
0
J8,7¼7.8 Hz, 1H, H-8), 8.08 (br d, J6 ,5 ¼7.7 Hz, 1H, H-6 ), 7.79 (br0t,
carbonyl), 136.8 (s, C-2), 133.3 (d, C-6), 132.4 (d, C-4), 131.9 (d, C-3),
128.6 (s, C-1), 127.6 (d, C-5), 51.9 (t, –OCH3), 40.6 (t, –CH2).
0
0
0
0
J6,7¼J6,5¼7.8 Hz, 1H, H-6), 7.68 (br t, J4 ,3 ¼J4 ,5 ¼7.4 Hz, 1H, H-4 ),
7.66 (br dd, J5 ,6 ¼7.7 Hz, J5 ,4 ¼7.4 Hz, 1H, H-50), 7.62 (br t,
0
0
0
0
J7,8¼J7,6¼7.8 Hz, 1H, H-7), 7.61 (br d, J5,6¼7.8 Hz, 1H, H-5), 7.47 (br d,
3.10. Reaction of 40 with SOCl2/DMF and NaN3
J3 ,4 ¼7.4 Hz, 1H, H-3 ), 7.34 (s, 1H, H-4), 3.80 (s, 3H, –OCH3); 13C
0
0
0
NMR (100 MHz, CDCl3)
d
189.3 (s, ketone carbonyl), 166.4 (s, ester
In a 25 mL dropping funnel, benzene (6 mL), dimethyl form-
amide (1.18 mL, 11.8 mmol), and thionyl chloride (0.86 mL,
22 mmol), were consecutively added. After 3–5 min two phases
were separated and the lower layer was added to a suspension of
the half ester 40 (2.3 g,11.8 mmol), sodium azide (1.5 g, 23.6 mmol),
tetrabutylammonium bromide (0.35 g, 1.18 mmol), and pyridine
(1.89 mL, 23.6 mmol) in dichloromethane (50 mL). The mixture was
then refluxed overnight and washed with saturated sodium
bicarbonate solution (3ꢂ50 mL) and water (2ꢂ25 mL). The organic
phase was dried over magnesium sulfate and concentrated under
reduced pressure to give 1.5 g of mixture of 42, 43, and 44. The
compounds were separated on a silica gel column (40 g) eluting
with chloroform/hexane (95:5). The first compound was identified
as 42 (0.24 g, 11.5%), the second was the viscous liquid 44 (0.6 g,
25.4%), and the last was 43 (0.65 g, 31.0%).
carbonyl), 160.5 (s, lactone carbonyl), 149.7 (s, C-8a), 139.5 (s, C-20),
135.2 (s, C-10), 135.1 (d, C-6), 132.8 (d, C-40), 130.7 (C-50), 130.5 (d,
C-7), 130.06 (d, C-60), 130.04 (d, C-8), 129.5 (s, C-3), 128.1 (d, C-30),
127.9 (d, C-5), 122.8 (s, C-4a), 110.9 (d, C-4), 52.6 (q, –OCH3); IR (KBr,
cmꢁ1): 3075 (w), 1733 (s), 1681 (w), 1453 (w), 1308 (s), 1284 (s),
1141 (m). Anal. Calcd for C18H12O5: C, 70.13; H, 3.92. Found: C,
69.88; H, 3.96.
3.7. Reaction of homophthalic acid (8) with ethylchloro-
formate and triethylamine in the absence of NaN3
To a solution of homophthalic acid 8 (2.5 g, 14 mmol) in 10 mL
THF at ꢁ5 ꢀC, triethylamine (3 mL, 22 mmol) in 6 mL THF was added
dropwise and the mixture was stirred for 30 min. This was followed
by slow addition of a cooled solution of ethylchloroformate (3 mL,
32 mmol) in 6 mL THF and the reaction mixture was stirred at the
same temperature for 30 min. The mixture was extracted with two
portions of ethyl acetate (15 mL) and the organic phase was then
washed with saturated sodium bicarbonate (3ꢂ40 mL) and with
water (2ꢂ25 mL), and dried over magnesium sulfate. Removal of the
solvent under vacuum gave a mixture of the compounds 18 and 10
(2.2 g, 3:2), which were separated on silica gel (40 g) column
chromatography using ethyl acetate/n-hexane (7:3). From the first
fraction 18 was isolated (1.40 g, 43%, white crystals from CHCl3, mp
93–94 ꢀC). The second fraction was identified as the anhydride 10
(585 mg, 26%).
3.10.1. 3-Methoxy-1H-isochromen-1-one (42)
White crystals, mp 67–68 ꢀC, lit. mp 70–71 ꢀC.27 1H NMR
(400 MHz, CDCl3)
d
8.16 (d, J8,7¼8.2 Hz, 1H, H-8), 7.60 (br dd,
J6,5¼8.1 Hz, J6,7¼7.2 Hz, 1H, H-6), 7.30 (d, J5,6¼8.1 Hz, 1H, H-5), 7.29
(br dd, J7,8¼8.2 Hz, J7,6¼7.2 Hz,1H, H-7), 5.58 (s,1H, H-4), 3.91 (s, 3H,
–OCH3); 13C NMR (100 MHz, CDCl3)
d 161.1 (s, C-1), 159.8 (s, C-3),
139.9 (s, C-4a), 135.1 (d, C-6), 129.9 (d, C-8), 125.5 (d, C-5), 124.6 (d,
C-7), 117.9 (s, C-8a), 79.1 (d, C-4), 56.0 (q, –OCH3).
3.10.2. Methyl 2-[2-({[2-(2-methoxy-2-oxoethyl)anilino]carbonyl}-
amino)phenyl]acetate (43)
White solids from ethyl acetate/n-hexane (7:3), mp 177–178 ꢀC.
3.7.1. Ethyl 1-oxo-1H-isochromen-3-yl carbonate (18)19
1H NMR (400 MHz, CDCl3)
d
7.71 (dd, J3,4¼7.9 Hz, J3,5¼1.2 Hz, 1H,
1H NMR (400 MHz, CDCl3)
d
8.27 (br d, J8,7¼8.3 Hz,1H, H-8), 7.72
H-3), 7.40 (br s, 1H, –NH), 7.31 (ddd, J4,3¼7.9 Hz, J4,5¼7.5 Hz,
J4,6¼1.5 Hz, 1H, H-4), 7.22 (dd, J6,5¼7.4 Hz, J6,4¼1.5 Hz, 1H, H-6), 7.13
(ddd, J5,4¼7.5 Hz, J5,6¼7.4 Hz, J5,3¼1.2 Hz,1H, H-5), 3.58 (s, 2H, –CH2),
(ddd, J6,5¼7.9 Hz, J6,7¼7.6 Hz, J6,8¼0.8 Hz, 1H, H-6), 7.49 (br dd,
J7,8¼8.3 Hz, J7,6¼7.6 Hz, 1H, H-7), 7.44 (br d, J5,6¼7.9 Hz, 1H, H-5),
6.27 (s, 1H, –CH), 4.37 (t, J¼7.1 Hz, 2H, –OCH2), 1.41 (q, J¼7.1 Hz, 3H,
3.54 (s, 3H, –OCH3); 13C NMR (100 MHz, CDCl3)
d 172.5 (s, ester
–CH3); 13C NMR (100 MHz, CDCl3)
d
160.6 (s, C-3), 151.0 (s, lactone
carbonyl), 154.4 (s, amide carbonyl), 137.1 (s, C-2), 131.2 (d, C-6),
128.8 (d, C-4), 127.9 (s, C-1), 126.1 (d, C-5), 125.7 (d, C-3), 52.6 (q,
–OCH3), 38.5 (t, –CH2); IR (KBr, cmꢁ1): 3332 (s), 3268 (s), 1740 (s),
1638 (s), 1599 (m), 1432 (m), 1168 (s); HRMS calcd for C19H20N2O5:
356.1363; found: 356.1372. Anal. Calcd for C19H20N2O5: C, 64.04; H,
5.66; N, 7.86. Found: C, 64.31; H, 5.52; N, 6.84.
carbonyl), 150.4 (s, ester carbonyl), 137.4 (s, C-4a), 135.3 (d, C-6),
130.0 (d, C-8), 127.9 (d, C-5), 126.0 (d, C-7), 119.5 (s, C-8a), 93.0 (d,
C-4), 66.2 (t, –OCH2), 14.0 (q, –CH3).
3.8. Synthesis of 1H-isochromen-1,3-(4H)-dione (10)
A mixture of homophthalic acid (8) (9.3 g, 50 mmol) and thionyl
chloride (14.5 mL, 200 mmol) in 150 mL of methylene chloride was
refluxed overnight and the solvent and excess thionyl chloride were
evaporated under vacuum to give 10 as a yellow solid (8.4 g) in 98%
yield, mp 143–144 ꢀC, lit. mp 144–145 ꢀC.11 1H NMR (400 MHz,
3.10.3. Methyl 2-[2-(chloroamino)phenyl]acetate (44)
Viscous oil (not stable at room temperature). 1H NMR (400 MHz,
CDCl3)
d
8.45 (br s, –NH), 7.85 (br d, J6,5¼7.6 Hz,1H, H-6), 7.33 (br dd,
J4,5¼8.0 Hz, J4,3¼7.3 Hz, 1H, H-4), 7.20 (br d, J3,4¼7.3 Hz, 1H, H-3),
7.13 (br dd, J5,4¼8.0 Hz, J5,6¼7.6 Hz, 1H, H-5), 3.73 (s, 3H, –CH3), 3.63
CDCl3)
d
8.22 (br d, J8,7¼7.8 Hz, 1H, H-8), 7.70 (br dd, J7,8¼7.8 Hz,
(s, 2H, –CH2); 13C NMR (100 MHz, CDCl3)
d 172.9 (s, ester carbonyl),
J7,6¼7.6 Hz, 1H, H-7), 7.52 (br t, J6,7¼J6,5¼7.6 Hz, 1H, H-6), 7.35 (br d,
154.8 (s, C-2), 136 (s, C-1), 130.9 (d, C-6), 128.7 (d, C-4), 125.6 (d,
C-5), 123.8 (d, C-3), 52.7 (t, CH2), 38.5 (q, –OCH3).
J5,6¼7.6 Hz, 1H, H-5), 4.14 (s, 2H, –CH2); 13C NMR (100 MHz, CDCl3)
d
165.0 (s, C-3), 161.3 (s, C-1), 135.9 (d, C-6), 134.7 (s, C-4a), 131.3 (d,
C-8), 129.1 (d, C-7), 127.9 (d, C-5), 121.9 (s, C-8a), 34.7 (t, –CH2).
3.11. Methyl 2-[2-(azidocarbonyl)phenyl]acetate (41)
3.9. 2-(2-Methoxy-2-oxoethyl)benzoic acid (40)
To a solution of half ester 40 (2.4 g, 12 mmol) in 10 mL of THF at
ꢁ5 ꢀC was added a solution of triethylamine (1.7 mL, 12 mmol) in
6 mL of THF dropwise and the mixture was stirred for 30 min. This
was followed by slow addition of a cooled solution of ethyl-
chloroformate (1.6 mL, 14.4 mmol) in 6 mL of THF and the reaction
mixture was stirred at the same temperature for 30 min. Then
Homophthalic anhydride (10) (6 g, 37 mmol) was refluxed in
methanol (50 mL) for 2 h. The solvent was concentrated in vacuum
to give the pure 40 (pale yellow crystalline compound 6.1 g, 85%;
mp 99–101 ꢀC, lit. mp 98 ꢀC).26 1H NMR (400 MHz, CDCl3)
d 11.0

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S. Ozcan, M. Balci / Tetrahedron 64 (2008) 5531–5540
5538
sodium azide (1.6 g, 25 mmol) in 10 mL of water was added drop-
wise at 0 ꢀC and the mixture was let to stir overnight. The mixture
was extracted with two portions of ethyl acetate (15 mL) and the
organic phase was washed with saturated sodium bicarbonate
(3ꢂ40 mL) and with water (2ꢂ25 mL), and dried over magnesium
sulfate. After the concentration,1.8 g (68%) of azide 41 (yellow solid,
mp 71–73 ꢀC, unstable at room temperature) was obtained. 1H NMR
3.14.1. 2-Hydroxy-N,N0-methylphenylacetato-1H-indole-1,3-
dicarboxamide (48)
1H NMR (400 MHz, acetone-d6)
d 12.48 (br s, –NH), 10.59 (br s,
–NH), 8.38 (dd, J6c,5c¼7.9 Hz, J6c,4c¼1.1 Hz, 1H, H-6c), 8.08 (br d,
J7,6¼7.7 Hz, 1H, H-7), 8.04 (br d, J6b,5b¼8.0 Hz, 1H, H-6b), 7.88 (dd,
J4,5¼7.7 Hz, J4,6¼1.1 Hz,1H, H-4), 7.30(dd, J3b,4b¼8.4 Hz, J3b,5b¼1.5 Hz,
1H, H-3a), 7.29 (dd, J5a,6a¼8.1 Hz, J5a,4a¼7.7 Hz, 1H, H-5a), 7.20 (dd,
J3c,4c¼7.3 Hz, J3c,5c¼1.5 Hz, 1H, H-3b), 7.18 (ddd, J5c,4c¼8.4 Hz,
J5c,6c¼7.7 Hz, J5c,3c¼1.5 Hz, 1H, H-5b), 7.07 (ddd, J4b,3b¼8.4 Hz,
J4b,5b¼7.7 Hz, J4b,6b¼1.1 Hz), 6.96 (dt, J5,4¼J5,6¼7.7 Hz, J5,7¼1.1 Hz,1H,
H-5), 6.90 (ddd, J4c,5c¼8.4 Hz, J4c,3c¼7.3 Hz, J4c,6c¼1.1 Hz, 1H, H-4c),
6.79 (dt, J6,5¼J6,7¼7.7 Hz, J6,4¼1.1 Hz,1H, H-6), 3.84 (s, 2H, –CH2), 3.81
(s, 2H, –CH2), 3.59 (s, 3H, –OCH3), 3.58 (s, 3H, –OCH3); 13C NMR
(400 MHz, CDCl3)
d
8.02 (br d, J6,5¼7.9 Hz, 1H, H-6), 7.55 (br dd,
J4,3¼7.6 Hz, J4,5¼7.5 Hz, 1H, H-4), 7.37 (br dd, J5,6¼7.9 Hz, J5,4¼7.5 Hz,
1H, H-5), 7.27 (br d, J3,4¼7.6 Hz, 1H, H-3), 4.05 (s, 2H, –OCH2), 3.71
(s, 3H, –OCH3); 13C NMR (100 MHz, CDCl3)
d 173.2 (s, azide
carbonyl), 171.6 (s, ester carbonyl), 136.8 (s, C-2), 133.7 (d, C-4),
132.7 (d, C-6), 131.3 (d, C-5), 129.6 (s, C-1), 127.6 (d, C-3), 51.9 (q,
–OCH3), 40.3 (t, –CH2); IR (KBr, cmꢁ1): 2280 (s), 2138 (s), 1740 (s),
1691 (s), 1490 (m), 1238 (s), 1169 (s).
(100 MHz, acetone-d6)
d 171.8 (s, ester carbonyl), 171.7 (s, ester car-
bonyl), 165.4 (s, carbonyl carbon), 165.1 (s, C-2), 140.1 (s, C-1b), 138.1
(s, C-1c),131.5 (d, C-3b),131.1 (d, C-3c),130.6 (s, C-7a),130.1 (s, C-3a),
128.3 (d, C-5b),127.9 (d, C-5c),126.5 (s, C-2b),124.1 (d, C-4b),123.7 (s,
C-2c), 123.0 (d, C-4b), 122.7 (d, C-5), 121.8 (d, C-4c), 121.1 (d, C-6c),
118.9 (d, C-6),117.5 (d, C-4),114.1 (d, C-7), 86.1 (s, C-3); IR (KBr, cmꢁ1):
3321 (m), 1723 (s), 1699 (s), 1563 (s), 1403 (s), 1283 (m), 1133 (s);
HRMS calcd for C28H25N3O7: 515.1693, found: 515.1690.
3.12. Methyl 2-(2-isocyanatophenyl)acetate (2)
The azide 41 (2.0 g, 9 mmol) was refluxed in benzene (25 mL)
for 1.5 h and the solvent was evaporated under vacuum to give the
isocyanate 2 (1.64 g, 99%), which was not stable at room tempera-
ture. 1H NMR (400 MHz, CDCl3)
d
7.23 (br d, J3,4¼7.5 Hz, 1H, H-3),
3.14.2. 1,3-Dihydro-2H-indol-2-one (49)
7.22 (br dd, J4,3¼7.5 Hz, J4,5¼6.7 Hz, 1H, H-4), 7.14 (br d, J6,5¼7.6 Hz,
1H, H-6), 7.12 (br dd, J5,6¼7.6 Hz, J5,4¼6.7 Hz, 1H, H-5), 3.69 (s, 3H,
White solid, mp 118–120 ꢀC, lit. mp 124 ꢀC.31 1H NMR (400 MHz,
–OCH3), 3.66 (s, 2H, –CH2); 13C NMR (100 MHz, CDCl3)
d 170.9 (s,
CDCl3)
d
9.10 (s, 1H, H-1), 7.25 (d, J7,6¼7.2 Hz, 1H, H-7), 7.20 (dd,
J6,5¼7.5 Hz, J6,7¼7.2 Hz, 1H, H-6), 7.0 (t, J5,6¼7.5 Hz, J5,4¼7.8 Hz, 1H,
ester carbonyl), 132.9 (s, C-1), 131.0 (d, C-3), 128.9 (s, C-2), 128.4 (d,
C-6), 125.9 (d, C-5), 125.8 (s, C-4), 125.0, 52.0 (q, –OCH3), 37.4 (t,
–CH2); IR (KBr, cmꢁ1): 2280 (s), 2145 (w), 1737 (s), 1591 (m), 1455
(w), 1341 (s), 1223 (s).
H-5), 6.9 (d, J4,5¼7.8 Hz, 1H, H-4), 3.5 (s, 2H, H-3); 13C NMR
(100 MHz, CDCl3) d 178.3 (s, C-2),142.6 (s, C-7a),129.5 (d, C-6),127.9
(s, C-3a), 125.3 (d, C-4), 122.4 (d, C-5), 109.9 (d, C-7), 36.34 (t, C-3).
3.15. Methyl [2-({[(4-nitrophenyl)amino]carbonyl}amino)-
phenyl]acetate (50)
3.13. Methyl (2-aminophenyl)acetate (45)
To a solution of isocyanate 2 (1.3 g, 6.8 mmol) in dichloro-
methane (30 mL), water (0.12 g, 6.8 mmol) was added slowly at
room temperature and the mixture was stirred at the same tem-
perature for 30 min. After concentration of the solvent, the com-
pound 45 was purified over a short silica gel column eluting with
ethylacetate/hexane (3:1) (0.98 g, 89% yield). The spectroscopic
data of 45 was in agreement with those reported in the literature.30
To a solution of isocyanate 2 (0.48 g, 2.5 mmol) in dichloro-
methane (25 mL), 4-nitroaniline (0.35 g, 2.5 mmol) was added and
themixturewas stirred at35 ꢀC for3 h. Thesolventwas removed and
the urethane was purified by recrystallization from ethyl acetate
(yellow solid, mp 175–176 ꢀC; 0.74 g, 90%).1H NMR (400 MHz, CDCl3)
d
8.14 (br d, J3a,2a¼J5a,6a¼8.3 Hz, 2H, H-3a and H-5a), 7.67 (br s, –NH),
7.60 (br d, J3,4¼8.0 Hz,1H, H-3), 7.56 (br d, J6a,5a¼J2a,3a¼8.3 Hz, 2H, H-
2a and H6a), 7.37 (br s,1H, –NH), 7.34 (br dd, J6,5¼8.0 Hz, J6,4¼1.6 Hz,
1H, H-6), 7.27–7.21 (m, 2H, H-5 and H-6), 3.71 (s, 2H, –OCH2), 3.69 (s,
3.13.1. Methyl 2-[2-({[2-(2-methoxy-2-oxoethyl)anilino]-
carbonyl}amino)phenyl]acetate (43)
3H, –OCH3); 13C NMR (100 MHz, CDCl3)
d 173.3 (s, ester carbonyl),
To a solution of isocyanate 2 (1.16 g, 6.05 mmol) in dichloro-
methane (30 mL) the aniline derivative 45 (1.0 g, 6.05 mmol) was
added slowly at room temperature and the mixture was stirred at
the same temperature for 1 h. The solvent was concentrated under
vacuo and the residue was crystallized from ethyl acetate to give 43
(1.96 g, 91%). The spectral data of the isolated compound was same
as previously isolated (Section 3.10).
152.9 (s, amide carbonyl),145.0 (s, C-1a),142.6 (s, C-4a),136.0 (s, C-2),
131.3 (d, C-6), 128.9 (d, C-4), 128.5 (s, C-1), 126.6 (d, C-3), 126.4 (d, C-
5),125.0 (d, C-3a and C-5a),118.3 (d, C-2a and C-6a), 52.6 (q, –OCH3),
38.0 (t, –CH2); IR (KBr, cmꢁ1): 3352 (m), 1735 (s), 1659 (s), 1590 (s),
1563 (s), 1332 (s), 1179 (m). Anal. Calcd for C16H9N3O3: C, 58.36; H,
4.59; N, 12.76. Found: C, 58.75; H, 4.61; N, 12.56.
3.16. Reaction of 50 with K2CO3
3.14. Reaction of 43 with K2CO3 in acetonitrile
The urea derivative 50 (0.3 g, 0.9 mmol) was suspended in ace-
tonitrile (10 mL). The mixture was heated to 58–60 ꢀC and at that
temperature excess potassium carbonate (1 g, 7.2 mmol) was added.
The reaction was completed in 1 h. Excess potassium carbonate was
filtered and the solution was concentrated under reduced pressure.
The residue was treated with chloroform. 1,3-Dihydro-2H-indol-2-
one (49) was separated as described above (0.03 g, 25%). The major
product 52 was recrystallized from methanol/chloroform (3:1) (red-
brown solid, mp 266–267 ꢀC; 0.12 g, 57%).
The urea derivative 43 (0.6 g, 1.7 mmol) was suspended in
acetonitrile (20 mL). The suspension was heated to 58–60 ꢀC and at
that temperature excess potassium carbonate (1.0 g, 7.2 mmol) was
added. After stirring for 1 h, excess potassium carbonate was
filtered and the solution was concentrated under reduced pressure.
The formed products 48 and 49 were separated by treatment of the
mixture with chloroform. The condensation product 48 was
insoluble in chloroform whereas 49 was soluble. Evaporation of the
solvent followed by column chromatography over silica gel (25 g)
eluting with ethyl acetate/n-hexane (7:1) provided 1,3-dihydro-2H-
indol-2-one (49) in 35% yield (0.08 g). The major product 48
crystallized with methanol/chloroform (3:1). Yellow crystals, mp
205–206 ꢀC (0.25 g, 58%).
3.16.1. 2-Hydroxy-N,N0-bis(4-nitrophenyl)-1H-indole-1,3-
dicarboxamide (52)
1H NMR (400 MHz, acetone-d6)
d
13.76 (br s, –NH), 11.49 (br s,
–NH), 8.30 (br d, J3b,2b¼J5b,6b¼8.3 Hz, 2H, H-3b and H-5b), 8.25 (br

¨
S. Ozcan, M. Balci / Tetrahedron 64 (2008) 5531–5540
5539
d, J7,6¼8.0 Hz, 1H, H-7), 8.20 (br d, J3c,2c¼J5c,6c¼8.3 Hz, 1H, H-3c and
(100 MHz, CDCl3)
d
177.7 (s, C-2), 149.5 (s, carbonyl), 141.6 (s, C-7a),
H-5c), 8.1 (br d, J4,5¼7.1 Hz, 1H, H-5), 7.99 (m, 4H, H-4b, H-6b, H-4c,
and H-6c), 7.05 (br dd, J5,6¼7.6 Hz, J5,4¼7.1 Hz, 1H, H-5), 6.99 (br dd,
J6,5¼7.6 Hz, J6,7¼8.0 Hz, 1H, H-5b); 13C NMR (100 MHz, acetone-d6)
137.1 (s, 1b), 129.1 (d, C-3b and C-5b), 128.5 (d, C-4), 124.7 (d, C-5),
124.5 (d, C-6), 123.9 (d, C-7), 122.9 (s, C-3a), 120.6 (d, C-2b and
C-6b), 116.8 (d, C-4b), 37.1 (t, –CH2).
d
166.4 (s, carbonyl), 165.5 (s, double bond), 152.7 (s, amide
carbonyl), 148.9 (s, C-4c), 146.8 (s, C-1c), 143.3 (s, C-4b), 141.6 (s,
C-1b), 131.6 (s, C-6), 130.6 (s, C-7a), 126.9 (s, C-3a), 125.9 (d, C-3c
and C-5c), 123.5 (d, C-2c and C-6c), 119.9 (d, C-5), 119.8 (d, C-3b and
C-5b), 118.5 (d, C-4), 118.3 (d, C-2b and C-6b), 114.8 (d, C-7), 87.3 (s,
C-3); IR (KBr, cmꢁ1): 3326 (m), 2909, 1681 (s), 1595 (s), 1504 (s),
1470 (s), 1406 (s), 1328 (m), 1133 (m). Anal. Calcd for C22H15N5O7: C,
57.27; H, 3.28; N, 15.18. Found: C, 57.45; H, 3.20; N, 14.96.
3.20. Reaction of 53 with K2CO3 in acetonitrile
The urea derivative 53 (2.47 g, 8.7 mmol) was suspended in
acetonitrile (20 mL). The suspension was heated to 58–60 ꢀC and at
that temperature excess potassium carbonate (4 g, 29 mmol) was
added. The reaction was complete in 1 h. Excess potassium
carbonate was filtered and the solution was concentrated under
reduced pressure. The residue was treated with chloroform to
separate the soluble compound 49. The major compound 56 was
recrystallized from methanol/chloroform (3:1).
3.17. Methyl {2-[(anilinocarbonyl)amino]phenyl}acetate (53)
To a solution of isocyanate 2 (0.76 g, 4 mmol) in dichloro-
methane (25 mL), aniline (0.37 g, 4 mmol) was added and the
mixture was stirred at room temperature for 2 h. The solvent was
removed and the urethane was purified by recrystallization from
ethyl acetate (white solid, mp157–158 ꢀC; 1.13 g, 98%). 1H NMR
3.20.1. 2-Hydroxy-N,N0-diphenyl-1H-indole-1,3-dicarboxamide (56)
Purple solid, mp 245–247 ꢀC; 0.98 g, 60%. 1H NMR (400 MHz,
acetone-d6)
d 12.94 (br s, 1H, –NH), 10.93 (br s, 1H, –NH), 8.28
(br d, J7,6¼8.0 Hz, 1H, H-7), 8.09 (br d, J4,5¼7.6 Hz, 1H, H-4), 7.79
(br d, J6c,5c¼J2c,3c¼8.0 Hz, 2H, H-6c and H-2c), 7.74 (br d,
J6b,5b¼J2b,3b¼8.0 Hz, 2H, H-6b and H-2b), 7.36 (br dd,
J5c,6c¼J3c,2c¼8.0 Hz, J5c,4c¼J3c,4c¼7.7 Hz, 2H, H-5c and H-3c), 7.25 (br
dd, J5b,6b¼J3b,2b¼8.0 Hz, J5b,4b¼J3b4b¼7.7 Hz, 2H, H-5b and H-3b),
7.05 (br t, J4c,5c¼J4c,3c¼7.4 Hz, 1H, H-4c), 6.96 (br t, J5,4¼J5,6¼7.5 Hz,
1H, H-5), 6.89 (br dd, J4b,5b¼7.7 Hz, J4b,3b¼7.7 Hz, 1H, H-4b), 6.88 (br
dd, J6,7¼8.0 Hz, J6,5¼7.6 Hz, 1H, H-6); 13C NMR (100 MHz, acetone-
(400 MHz, CDCl3)
d
7.64 (br d, J3,4¼7.9 Hz, 1H, H-3), 7.4 (br s, 1H,
–NH), 7.25–7.38 (m, 6H, arom.), 7.16 (br dd, J4,3¼7.9 Hz, J4,5¼7.5 Hz,
1H, H-4), 7.1 (br t, J5,4¼J5,6¼7.3 Hz,1H, H-5), 6.78 (br s,1H, –NH), 3.67
(s, 2H, –CH2), 3.63 (s, 3H, –OCH3); 13C NMR (100 MHz, CDCl3)
d 172.7
(s, ester carbonyl),153.9 (s, amide carbonyl), 138.3 (s, C-1a),136.7 (s,
C-2), 131.0 (d, C-6), 129.1 (d, C-3a and C-5a), 128.7 (d, C-3), 128.2 (s,
C-1), 126.2 (d, C-4), 125.9 (d, C-5), 123.8 (d, C-2a and C-6a), 120.6 (d,
C-4a), 52.4 (q, –OCH3), 38.1 (t, –CH2); IR (KBr, cmꢁ1): 3319 (m), 1736
(s), 1647 (s), 1455 (m), 965 (m). Anal. Calcd for C16H16N2O3: C, 67.59;
H, 5.67; N, 9.85. Found: C, 67.06; H, 5.70; N, 9.72.
d6) d 165.4 (s, C-2), 165.2 (s, double bond), 152.3 (s, amide carbonyl),
141.9 (s, C-1b), 139.8 (s, C-1c), 130.7 (s, C-7a), 130.3 (s, C-3a), 128.7
(d, C-3b and C-5b), 128.4 (d, C-3c and C-5c), 122.3 (d, C-6), 121.8 (d,
C-5), 120.5 (d, C-4b), 119.4 (d, C-4c), 118.3 (d, C-6b and C-2b), 117.9
(d, C-2c and C-6c), 117.2 (d, C-4), 113.6 (d, C-7), 85.9 (s, C-3). IR (KBr,
cmꢁ1): 3335 (w), 1691 (s), 1595 (s), 1469 (m), 1437 (s), 1353 (m),
1244 (m), 1134 (m). Anal. Calcd for C22H17N3O3: C, 71.15; H, 4.61; N,
11.31. Found: C, 71.41; H, 4.33; N, 11.12.
3.18. Reaction of 53 with NaH in the presence of Ac2O
To a solution of urethane 53 (0.5 g, 1.8 mmol) in freshly distilled
THF (15 mL) at 0 ꢀC, sodium hydride (0.086 g, 3.6 mmol) was added
and the resulting mixture was stirred at the same temperature for
30 min. Then acetic anhydride (0.26 g, 2.5 mmol) was added to this
solution and stirred at room temperature overnight. The product 54
precipitated from the reaction medium. The precipitate was filtered
off and purified by washing with chloroform (0.4 g, 75.5%). The
filtrate was concentrated under vacuum to give the crude 55, which
was recrystallized from ethylacetate/hexane (5:2) (0.07 g, 16.0%).
Acknowledgements
The authors are indebted to TUBITAK (Scientific and Techno-
logical Research Council of Turkey), Department of Chemistry
(Middle East Technical University), and TUBA (Turkish Academy of
Sciences) for financial support of this work.
3.19. Synthesis of 3-acetyl-2-hydroxy-N-phenyl-1H-indole-1-
carboxamide (54)
Supplementary data
1H and 13C NMR spectra for all new compounds (74 pages) are
provided. Supplementary data associated with this article can be
found in the online version, at doi:10.1016/j.tet.2008.03.097.
White solid, mp 168–169 ꢀC.1H NMR (400 MHz, DMSO-d6)
d 11.30
(s, 1H, NH), 8.12 (dd, J4,5¼8.0 Hz, J4,6¼1.5 Hz, 1H, H-4), 7.83 (br d,
J6,7¼6.6 Hz, 1H, H-7), 7.59 (d, J10,11¼J14,13¼7.3 Hz, 2H, H-10 and H-14),
7.35 (br t, J10,11¼J11,12¼7.3 Hz, 2H, H-11 and H-14), 7.17 (dt,
J6,7¼J5,6¼7.3 Hz, J4,6¼1.5 Hz, 1H, H-6), 7.15 (dt, J4,5¼J5,6¼7.3 Hz,
J5,7¼1.4 Hz,1H, H-5), 7.10 (t, J6,7¼7.3 Hz,1H, H-12), 2.65 (s, 3H, –CH3);
References and notes
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d 176.3 (s, C-15),170.6 (s, C-2),150.6 (s,
C-8),138.3(s, C-9),135.0 (s, 7a),129.7(d, C-11 andC-13),125.8(d, C-6),
124.5 (d, C-12), 124.4 (d, C-5), 124.3 (d, C-6), 122.3 (s, 3a), 120.5 (C-10
and C-14), 115.1 (d, H-4), 101.6 (s, C-3), 20.4 (q, C-16); IR (KBr, cmꢁ1):
3202 (m), 3144 (m),1720 (s),1662 (s),1589 (s),1560 (s),1461 (s),1375
(m), 1294 (s), 1227 (s); MS: 70 eV, m/z 294 (Mþ, 15%), 175 (100%), 157
(49%), 133 (24%), 119 (38%), 91 (25%), 77 (26%). Anal. Calcd for
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3.19.1. 2-Oxo-N-phenylindoline-1-carboxamide (55)
1H NMR (400 MHz, CDCl3)
10.59 (br s, 1H, H–NH), 8.24 (br d,
J7,6¼8.2 Hz, 1H, H-7), 7.51 (br d, J2b,3b¼J6b,5b¼8.1 Hz, 2H, H-2b and
H-6b), 7.28 (m, 3H, H-5, H-3b, and H-5b), 7.22 (br d, J4,5¼8.1 Hz, 1H,
H-4), 7.18 (m, 2H, H-6 and H-4b), 3.7 (s, 2H, –CH2); 13C NMR
d
11. (a) Tabor, D. C.; Evans, S. A., Jr.; Kenan, W. R., Jr. Synth. Commun. 1982, 12, 855;
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5540
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20. Recently, we discovered that NaN3 can reduce the carbonyl groups in quinones
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about the synthesis and physical data of this compound: Niki, T.; Mizukoshi, T.;
Takahashi, H.; Satow, J.; Ogura, T.; Yamagishi, K.; Suzuki, H.; Hayasaka, F. PCT
Int. Appl. EP 1243580 A1, 2001; 350 pp.
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