Versatile synthesis of oxindole-1,3-dicarboxamides

Article abstract of DOI:10.1016/j.tet.2010.06.017

A new, high-yielding synthesis of oxindole-1,3-dicarboxamides was elaborated starting from 1-phenoxycarbonyl-3-ethoxycarbonyl-2-oxindole and 1,3-diphenoxycarbonyl-2-oxindole. This method permits also the preparation of N,N,N′-tri- and N,N,N′,N′-tetrasubstituted oxidole-1,3-dicarboxamides, families of compounds that are unknown in the literature. The scope and limitations of the methodology have also been investigated, and a remarkable selectivity has been observed among the amines used in the amidation steps.

Full text of DOI:10.1016/j.tet.2010.06.017

Tetrahedron 66 (2010) 7017e7027
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Versatile synthesis of oxindole-1,3-dicarboxamides
,
a
b
a
Márta Porcs-Makkaya , Balázs Volk , Zoltán Mucsi , Gyula Simig
*
a EGIS Pharmaceuticals Plc., Chemical Research Division, PO Box 100, H-1475 Budapest, Hungary
b University of Szeged, Faculty of Education, Boldogasszony Str. 6, H-6725 Szeged, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
A new, high-yielding synthesis of oxindole-1,3-dicarboxamides was elaborated starting from 1-phe-
noxycarbonyl-3-ethoxycarbonyl-2-oxindole and 1,3-diphenoxycarbonyl-2-oxindole. This method per-
mits also the preparation of N,N,N0-tri- and N,N,N0,N0-tetrasubstituted oxidole-1,3-dicarboxamides,
families of compounds that are unknown in the literature. The scope and limitations of the methodology
have also been investigated, and a remarkable selectivity has been observed among the amines used in
the amidation steps.
Received 2 February 2010
Received in revised form 17 May 2010
Accepted 7 June 2010
Available online 12 June 2010
Dedicated to Professor Károly Lempert on
the occasion of his 85th birthday
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Oxindole
Amidation
Regioselectivity
Keto/enol equilibrium
Aminolysis
1. Introduction
not launched because of serious side-effects.23 The development of
ilonidap (2),24 a successor of tenidap or its corresponding lysine salt,25
The occurrence of 3-unsubstituted 2-oxo-2,3-dihydroindole
(oxindole) 1-carboxamides,1,2 oxindole-1,3-dicarboxamides,2 1-acyl-
oxindole-3-carboxamides,3 1-alkyloxindole-3-carboxamides,4e7 and
1-aryloxindole-3-carboxamides8 is very scarce in the scientific liter-
ature. In the patent literature, there is somewhat more published
information on these families of compounds, nonetheless the chem-
istry of these derivatives is still far from being completely revealed.
Several 2-oxo-2,3-dihydroindole (oxindole) 1-carboxamides,9
1,3-dicarboxamides,10 1-acyl-3-carboxamides,11 and 1-alkyl-3-car-
boxamides12 were published by researchers at Pfizer as potential an-
algesic, anti-inflammatory, and antiarthritic agents. All these
compounds contained N-monoalkylated carboxamide moieties.
According to the literature, 3-substituted oxindole-1-carboxamides
can act as inhibitors of interleukin-1 biosynthesis,13 and they are ef-
fective in the treatment of autoimmune disorders14 or in the pre-
vention of virus infections.15 An outstanding example of this type of
oxindole derivatives was (Z)-5-chloro-3-[1-hydroxy-1-(2-thienyl)
methylene]-2-oxo-2,3-dihydroindole-1-carboxamide (tenidap, 1,
Fig. 1).16e18 The sodium salt of 119,20 exhibiting anxiolytic and anti-
rheumatic activity, was granted regulatory approval in several coun-
tries.21 In spite of the very high market expectations,22 it was finally
with the aim of eliminating the undesired side-effects, was aban-
doned, as well.
S
S
OH
O
OH
O
Cl
F
N
N
Cl
NH2
NH2
O
O
1 (tenidap)
2 (ilonidap)
Figure 1. Structure of tenidap (1) and ilonidap (2).
According to the described procedures for the preparation of
oxindole-1,3-dicarboxamides,9,10 the two carbamoyl moieties were
introduced successively into the oxindole molecule using alkyl, aryl or
acyl isocyanates (Scheme 1). First, the 1-carbamoyl function was
formed by refluxing the starting oxindole derivative 3 with the
appropriate isocyanate in an aprotic solvent, preferably in toluene at
reflux temperature,9,18 butthisstepwasalsodescribedindiethylether,
* Corresponding author. Fax: þ36 1 2655613; e-mail address: porcs-makkay.
marta@egis.hu (M. Porcs-Makkay).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.06.017

7018
M. Porcs-Makkay et al. / Tetrahedron 66 (2010) 7017e7027
CONHR''
O
R''NCO
R'NCO
O
X
X
O
X
toluene
reflux
polar solvent
base
0-25 °C
N
N
N
H
CONHR'
CONHR'
5
3
4
Scheme 1. Literature procedures for the preparation of oxindole-1-carboxamides and oxindole-1,3-dicarboxamides.
THF or acetonitrile at room temperature.18 In the second step, the
oxindole-1-carboxamide 4 thus obtained was converted into 1,3-
dicarboxamide 5 by treatment with a further isocyanate in a polar
solvent (DMF, diethylformamide or DMSO, preferably DMF) at
0e25 ꢀC, in the presenceof a base(TEA or NaH). The use of isocyanates
for the introduction of the carbamoyl moieties has three major dis-
advantages: (i) relatively few organic isocyanates are commercially
available,20 (ii) 1-unsubstituted oxindole-3-carboxamides can not be
prepared by this method, (iii) N,N-disubstituted oxindole-1-carbox-
amides, N,N,N0-tri- and N,N,N0,N0-tetrasubstituted oxindole-1,3-dicar-
boxamides can not be synthesized, either.
COOR3
COOR3
O
R1
OH
COOR2
R1
N
N
COOR2
7
R1 = H, 5-Cl, 6-Cl, 5-NO2
R2, R3 = Me, Et, Ph, Bn
Earlier several papers have dealt with the reactions of 3-
substituted-2-oxindole derivatives and alkylchloroformates under
various conditions, encountering the formation of product mixtures
and a low yield of the required regioisomer.26e30 In the most
instructive paper in this field, Beccalli et al. described the reactions of
3-aroylmethyl-2-oxo-2,3-dihydroindoles with ethyl chloroformate31
and the OeC(3) acyl migrations were carried out in the presence of
a catalytic amount of 4-dimethylaminopyridine (DMAP). As a part of
our research program on the novel synthesis of tenidap (1),32 we have
elaborated two protocols for the synthesis of 1,3-di[alkoxy(aryloxy)
carbonyl]-oxindoles (oxindole-1,3-dicarboxylates) with identical or
different acyl groups in the two positions.33 These compounds could
be easily isolated as 4-dimethylaminopyridinium (DMAP) salts of the
enolates (6, Fig. 2). On treatment of salts 6 (R2¼R3) with aqueous acid,
3-aryl- and 3-benzyloxycarbonyl groups underwent hydrolysis and
decarboxylation. However, compounds 7 containing an alkox-
ycarbonyl moiety in position 3 were isolated in good yield. The 1H
NMR spectra of compounds 7 indicated an equilibrium between the
keto and enol forms in solution (Scheme 2), while single crystal X-ray
analysis of compound 7 (R1¼H, R2¼R3¼Et) exhibited the presence of
the enol form in crystalline state.33 In a subsequent paper it was
demonstrated that 3-(thiophen-2-ylcarbonyl) derivatives bearing
a phenoxycarbonyl moiety inposition 1 could be reacted with various
primary and secondary amines.34
Scheme 2. Keto/enol equilibrium of oxindole-1,3-dicarboxylates.
1-carboxamido compounds 12 (Scheme 3, route A, Table 1). The pri-
marily formed diester enolate salts 11, the formation of which has
already been demonstrated in our earlier studies,32e34 underwent
a selective amidation at the 1-position and after acidic work-up
compounds 12 were obtained. An equilibrium between the keto and
enol forms of compounds 12 in solution has been indicated by the 1H
NMR spectra. The simultaneous presence of the keto and the enol form
induced the duplication of several signals in the 13C spectra, the signal
for C(3) appeared at d w85 ppm for the enolic form and at d w52 ppm
for the keto form.
Surprisingly, amide-ester 12a (NR4R5: 1-pyrrolidinyl) failed to
react with piperidine, when refluxed in toluene for 11 h. Con-
versely, the reaction of amide-esters 12a,c with a primary aromatic
amine, 2-aminothiazole in refluxing toluene afforded diamide
enolate salts 13a,b in good yield (Scheme 3, route A, Table 2). This
seemingly inconsistent behavior of the 3-ethoxycarbonyl group of
12a toward the two amines will be discussed later. Treatment of the
salts 13a,b with diluted aqueous hydrochloric acid solution resulted
in compounds 8a,b (Scheme 3, route A, Table 5). In dimethyl sulf-
oxide-d6 solution of compounds 8a,b, exclusively the signals of the
enol form were detected by 1H NMR. The absence of the keto tau-
tomer was also shown by 13C NMR technique, which did not exhibit
any sp3 signal for the oxindole skeleton.
COOR3
The above mentioned studies carried out starting from ‘mixed’
diester 9 have shown that the two ester groups can be selectively
amidated. Because of the different character of the two ester groups
(phenylcarbamate vs ethyl acetoacetate), the selective amidation in
position 1 can not be explained simply with the higher reactivity of
the phenyl ester. The formation of enolate salts 11 in the course of
the amidation reactions decreases much more the reactivity of the
ester group at the 3-position due to delocalization of the negative
charge than at the 1-position.
R1
HDMAP+
O
N
R1 = H, 5-Cl, 6-Cl, 5-NO2
R2, R3 = Me, Et, Ph, Bn
COOR2
6
Figure 2. 4-Dimethylaminopyridinium (DMAP) salts of oxindole-1,3-dicarboxylates.
With knowledge of the above results, it seemed to be reasonable
to test also the DMAP salt of 1,3-diphenoxycarbonyl derivative (10)
as the starting compound of the amidation reactions, since this
compound is easier to prepare than the derivatives bearing differ-
ent alkoxy or aryloxy moieties in the two positions.32 In line with
the above observed regioselectivity, the reactions of enolate salt 10
with an equivalent amount of various primary and secondary ali-
phatic amines in DMF at ambient temperature resulted in selective
amidation at the 1-position, affording DMAP salts 14aeg (Scheme
3, Table 3). However, primary aromatic amines (e.g., aniline, 3-
aminopyridine) failed to react with 10 under the same conditions.
2. Results and discussion
Now we describe the synthesis of a wide variety of new oxin-
dole-1,3-dicarboxamides 8 by reacting dicarboxylates 9 or 10 suc-
cessively with various amines (Scheme 3). The new methodology,
in contrast to the literature procedures, also allows the synthesis of
N,N-disubstituted diamides.
Treatment of 3-ethoxycarbonyl-1-phenoxycarbonyl derivative 9
with 2 equiv of secondary aliphatic amines (pyrrolidine, piperidine,
and morpholine) in DMF at ambient temperature afforded

M. Porcs-Makkay et al. / Tetrahedron 66 (2010) 7017e7027
7019
COOEt
O
Cl
N
N
R4R5NH =
N
NH
NH
(CH3)2N(CH2)2NH2
NH
NH
O
N
COOPh
9
PhCH2NH(CH3)
CH3(CH2)2NH2
R4R5NH (1 eq)
route A
R6R7NH =
COOPh
COOEt
N
N N
N
+
HDMAP+
Cl
Cl
H2NR4R5
NH2
NH2
NH2
NH2
S
S
N
O
N
H
O
N
N
COOPh
COOPh
N
NH2
NH2
10
11
1. R4R5NH (1 eq)
DMF, 25 oC, 2 h
2. aq. HCl
R4R5NH (1 eq)
DMF, 25 oC, 2 h
PhCH2NH2
PhCH2NH(CH3)
50-94 %
72-86 %
COOPh
COOEt
HDMAP+
Cl
Cl
route C
O
enol
O
N
N
CONR4R5
CONR4R5
14
12
R6R7NH (2 eq)
toluene
reflux, 1 h
R6R7NH (1.1 eq)
toluene
reflux, 1 h
route B
1. R6R7NH (1.1 eq)
toluene
reflux, 1 h
87-88 %
48-81 %
2. aq. HCl
rt, 3 h
CONR6R7
CONR6R7
+
HDMAP+
Cl
Cl
H2NR6R7
60-97 %
O
O
N
N
CONR4R5
CONR4R5
13
15
aq. HCl
rt, 3 h
aq. HCl
rt, 3 h
46-81 %
73 %
CONR6R7
O
CONR6R7
OH
Cl
Cl
N
N
CONR4R5
CONR4R5
8
Scheme 3. Synthesis of new oxindole-1,3-dicarboxamides from oxindole-1,3-dicarboxylates.
Table 1
Compounds 12
Table 2
Compounds 13
NR4R5
Yield (%)
NR4R5
NR6R7
N
Yield (%)
a
79
N
a
87
N
HN
S
b
86
N
N
c
72
b
88
N
O
N
O
HN
S

7020
M. Porcs-Makkay et al. / Tetrahedron 66 (2010) 7017e7027
Table 3
Table 5
Compounds 14
Compounds 8
NR4R5
Yield (%)
63
NR4R5
NR6R7
Yielda,b (%)
Route
73
(31)
81
N
A
B
a
b
c
d
e
f
N
a
N
HN
S
(41)
N
73
(46)
83
77
94
94
50
N
b
A
C
N
O
O
HN
HN
S
N
76
(59)
N
O
c
N
N
N
N
N
N
73
(61)
79
C
d
D
HN
HN
(62)
N
N
HN
61
(31)
e
f
B
C
N
N
S
N
N
84
(70)
HN
HN
N
g
80
HN
67
(37)
g
B
N
N
N
H
Amidation of the 3-phenoxycarbonyl group of 14a,b,d,g with an
equivalent amount of primary aromatic amines was carried out in
refluxing toluene to give the DMAP salts of diamides 15aee
(Scheme 3, route B, Table 4). Cyclic secondary amines (piperidine,
morpholine) resisted again to react not only under these condi-
N N
S
67
(56)
h
i
C
B
C
HN
HN
N
N
46
(21)
N
N
N
N
N
N
S
N
N
N
Table 4
Compounds 15
60
(56)
NR4R5
NR6R7
Yield (%)
81
j
N
N
HN
N
a
b
c
N
HN
HN
S
64
(60)
k
l
C
C
C
C
N
N
63
67
N
HN
HN
97
(91)
S
N
HN
HN
N
N
N
71
(67)
N
H
m
n
N
N
N
HN
HN
N
N
N
d
e
48
65
N
N
87
(82)
HN
HN
S
HN
99
(65)
HN
o
B
HN
HN
a
Yields are calculated for compounds 12 (route A), 15 (route B), 14 (route C) or 17
tions, but even when the reaction was carried out in DMF at 110 ꢀC.
Compounds 15aee were then transformed to the corresponding
diamides 8a,e,g,i,o (Scheme 3, route B, Table 5) by treatment with
aqueous hydrochloric acid. The second amidation reaction of
derivative 14 could be performed in good yield also without the
isolation of intermediate 15, by subsequent treatment with a pri-
mary or secondary aliphatic or primary aromatic amine and
(route D).
b
Yields in parenthesis are overall yields, calculated for compounds 9 (route A) or
10 (routes B, C or D).
aqueous hydrochloric acid solution, as demonstrated by the syn-
thesis of diamides 8c,d,f,h,jen (Scheme 3, route C, Table 5).
We were looking for an explanation of the anomalous reactivity of
primaryaromatic amines inposition 1 and cyclic secondaryamines in

M. Porcs-Makkay et al. / Tetrahedron 66 (2010) 7017e7027
7021
N
COOPh
COOPh
O
COOPh
O
N
Cl
Cl
Cl
+
OH
COOPh
+
H3NAr
N
N
N
toluene
reflux
N+
H
N
COOPh
COOPh
16
10
ArNH2 (1 eq)
toluene
reflux, 5 h
78-80 %
N
CONHAr
O
ArNH =
2
Cl
N
N N
S
NH2
NH2
S
NH2
N
N+
H
COOPh
17
Scheme 4. Explanation of the selective 3-amidation with aromatic amines.
position 3. Surprisingly, the reaction of diester salt 10 with various
primary aromatic amines in refluxing toluene resulted in amide salts
17, i.e., in products selectively amidated at the 3-position (Scheme 4,
Table 6). Itisreasonabletoassumethatenolatesalts (10,14)cannotbe
the substrates of the 3-amidation reactions, because of the decreased
reactivity of the 3-alkoxy(aryloxy)carbonyl group toward
nucleophiles. We have to suppose that in the presence of a weak base
(primary aromatic amine) enolate salt 10 is in equilibrium with its
components, i.e., with the corresponding diester (16) and DMAP.
Diester 16 is the substrate of the amidation reaction with primary
aromatic amines. The 3-phenoxycarbonyl group of compound 16 is
more reactive than the same moiety at the 1-position, as demon-
strated also by the partial hydrolysis and decarboxylation of salt 10 in
position 3 on treatment with aqueous acid.32 Amidation of 16 occurs
selectively at the 3-position indicating the particularly sluggish re-
activity of the 1-phenoxycarbonyl group toward primary aromatic
amines. Similar behavior of the 1-phenoxycarbonyl group of a related
3-acyl derivative has also been described.34 Itis presumable, of course
that the equilibrium shown in Scheme 4 exists also in DMFat ambient
temperature. However, no amidation with primary aromatic amines
takes place under these mild conditions at all.
The failure of the 3-amidation reaction of amide-ester enolate
salt 14aed with cyclic secondary amines might be explained on
a similar basis (Scheme 5). The lack of reaction suggests the
absence of ‘free’ amide-ester 18 in the reaction mixture, as
a consequence of the salt formation with the two strongly basic
amines (DMAP, piperidine). A similar formation of enolate salt
19 (Fig. 3) can explain the failure of 3-amidation in the reaction
of amide-ester 12a with piperidine.
Table 6
Compounds 17
NHAr
Yield (%)
78
a
HN
HN
N
b
80
78
S
N N
S
c
HN
N
COOPh
OH
COOPh
COOPh
O
N
N
Cl
Cl
Cl
H
H
N+
+
O
toluene
reflux
N
N
N
N
H
+
CONR4R5
CONR4R5
CONR4R5
14a-d
18
HN
CON
Cl
OH
CONR4R5
N
Scheme 5. Explanation for the failure of 3-amidation with cyclic secondary amines.

7022
M. Porcs-Makkay et al. / Tetrahedron 66 (2010) 7017e7027
4. Experimental section
COOEt
Cl
4.1. General
O
N+
N
All melting points were determined on a Büchi 535 capillary
H
H
melting point apparatus. IR spectra were obtained on a Bruker IFS-
113v FT spectrometer in KBr pellets. 1H NMR and 13C NMR spectra
were recorded on a Varian Gemini 200 (200 and 50 MHz for 1H and
13C NMR spectra, respectively), Bruker Avance III (400 and 100 MHz
for 1H and 13C NMR spectra, respectively) or a Varian Unity Inova
500 spectrometer (500 and 125 MHz for 1H and 13C NMR spectra,
respectively). CDCl3 or DMSO-d6 was used as solvent and tetra-
N
O
19
Figure 3. Enolate salt formed with piperidine.
methylsilane (TMS) as an internal standard. Chemical shifts (d) and
The peculiar reactivity of primary aromatic and cyclic secondary
aliphatic amines in the amidation reaction of diester enolate salt 10
is summarized in Scheme 6 (routes C and D), showing the two
synthetic approaches to diamide 8d.
coupling constants (J) are given in parts per million and in hertz,
respectively. Elemental analyses were performed on a Perkin/Elmer
2400 analyzer. The reactions were followed by analytical thin layer
chromatography on silica gel 60 F254. All unspecified reagents were
purchased from commercial sources.
COOPh
Cl
HDMAP+
H2N
O
N
1. toluene, 110 °C, 1 h
2. HCl
CON
HN
DMF, 25 °C, 2 h
73 %
14b
COOPh
O
83 %
CONHPh
OH
Cl
Cl
route C
HDMAP+
N
N
COOPh
route D
N
CO
toluene, 110 °C, 5 h
78 %
10
8d
HN
H2N
1. DMF, 25 °C, 2 h
2. HCl
CONHPh
O
Cl
79 %
HDMAP+
N
COOPh
17a
Scheme 6. Peculiar selective reactivity of oxindole-1,3-dicarboxylates with various amines.
3. Conclusion
4.2. General procedure I for the synthesis of compounds 12
In the present paper, a new, versatile method has been de-
scribed for the preparation of oxindole-1,3-dicarboxamides start-
ing from the corresponding 1,3-dicarboxylates. Amidation could
be performed with a wide variety of primary and secondary ali-
phatic amines in position 1, and with aromatic and primary and
secondary aliphatic amines in position 3. In the course of the
systematic studies on the scope and limitations of the amidation
reactions, we have revealed a plausible explanation for the unique
reactivity of different types of amines. The methodology described
above offers a convenient approach to a wide range of new
oxindole-1,3-dicarboxamides, which are only circuitously or, in the
case of N,N-disubstituted carboxamides, not at all available by
other procedures. By benefiting from the complete regioselectivity
of the amidation step, 1-carboxamido-oxindole-3-carboxylates
and 3-carboxamido-oxindole-1-carboxylates, as useful synthetic
building blocks, can also be synthesized using this novel
procedure.
To a solution of 3-ethyl 1-phenyl 5-chloro-2-oxo-2,3-dihydro-
1H-indole-1,3-dicarboxylate (9, 7.20 g, 0.02 mol) in DMF (50 mL)
was added the corresponding amine (0.04 mol) drop wise, under
vigorous stirring, at room temperature. The solution thus obtained
was stirred for additional 2 h, then water (50 mL) and concd HCl
(5 mL) were added. The precipitate was filtered off and recrystal-
lized to give compound 12.
4.2.1. Ethyl 5-chloro-2-oxo-1-(pyrrolidin-1-ylcarbonyl)-2,3-dihydro-
1H-indole-3-carboxylate (12a). This compound was prepared
according to the general procedure I using pyrrolidine (2.3 mL,
2.84 g, 0.04 mol) to give 5.32 g (79%) 12a as colorless crystals, mp
98e100 ꢀC (EtOAc/hexane). IR (KBr, cmꢁ1) 2985, 1762, 1726, 1684.
1H NMR (CDCl3, 400 MHz) enol/keto¼1:2,
d enol: 7.67 (1H, d,
J¼1.8 Hz), 7.32 (1H, d, J¼8.8 Hz), 7.15 (1H, dd, J¼8.8, 2.0 Hz), 4.44
(2H, q, J¼7.1 Hz), 3.60 (4H, m), 1.99 (4H, m), 1.46 (3H, t, J¼7.1 Hz),
d
keto: 7.35 (1H, d, J¼2.0 Hz), 7.34 (1H, dd, J¼8.8, 2.0 Hz), 7.30 (1H, d,

M. Porcs-Makkay et al. / Tetrahedron 66 (2010) 7017e7027
7023
J¼8.6 Hz), 4.48 (1H, s), 4.26 (2H, q, J¼7.1 Hz), 3.60 (4H, m), 1.99 (4H,
8.65 (2H, s), 7.63 (1H, d, J¼2.2 Hz), 7.37 (1H, d, J¼3.7 Hz), 7.21 (1H, d,
J¼4.2 Hz), 7.02 (1H, d, J¼3.7 Hz), 6.94 (1H, d, J¼8.2 Hz), 6.84 (1H, d,
J¼4.2 Hz), 6.75 (1H, dd, J¼8.4, 2.2 Hz), 3.66 (8H, s). 13C NMR (DMSO-
m), 1.30 (3H, t, J¼7.1 Hz). 13C NMR (CDCl3, 100 MHz)
d 168.8, 165.9,
148.8, 139.8, 129.4, 129.3, 124.7, 124.5, 122.4, 119.2, 114.0, 113.0, 85.7,
62.6, 60.9, 52.8, 47.7, 47.3, 25.8, 25.2, 24.5, 14.0. Anal. Calcd for
C16H17ClN2O4 (336.78): C 57.06, H 5.09, Cl 10.53, N 8.32%. Found: C
56.61, H 5.13, Cl 10.38, N 8.14%.
d6, 125 MHz)
d 170.1, 165.1, 161.6, 159.6, 151.9, 135.1, 130.6, 128.4,
125.6,117.4,115.5,111.8,110.9,108.1, 82.4, 66.4, 47.7, 44.1. Anal. Calcd
for C20H19ClN6O4S2 (507.01): C 47.38, H 3.78, Cl 6.99, N 16.58, S
12.65%. Found: C 47.50, H 3.81, Cl 7.02, N 16.15, S 12.66%.
4.2.2. Ethyl 5-chloro-2-oxo-1-(piperidin-1-ylcarbonyl)-2,3-dihydro-
1H-indole-3-carboxylate (12b). This compound was prepared
according to the general procedure I using piperidine (4.0 mL,
3.40 g, 0.04 mol) to give 6.04 g (86%) 12b as colorless crystals, mp
96e97 ꢀC (EtOH). IR (KBr, cmꢁ1) 2945, 2857, 1701, 1656. 1H NMR
4.4. General procedure III for the synthesis of compounds 14
A solution of 4-(dimethylamino)pyridinium 5-chloro-1,3-bis
(phenoxycarbonyl)-1H-indol-2-olate (10, 21.20 g, 0.04 mol) and the
corresponding amine (0.08 mol) in DMF (100 mL) was stirred at
room temperature for 4 h. It was poured onto a mixture of
ice-water (200 g) and stirred for 1 h. The crystalline product was
filtered, washed with water to give compound 14. Compounds were
of high purity without recrystallization, as indicated by elemental
analyses and 1H NMR spectra.
(CDCl3, 200 MHz) enol/keto¼1.0:1.1,
7.32 (1H, d, J¼8.8 Hz), 7.15 (1H, dd, J¼8.8, 2.0 Hz), 4.44 (2H, q,
keto: 7.35
d
enol: 7.68 (1H, d, J¼1.8 Hz),
J¼7.1 Hz), 3.51 (4H, m), 1.46 (6H, s), 1.46 (3H, t, J¼7.1 Hz),
d
(1H, d, J¼2.0 Hz), 7.30 (1H, d, J¼8.8 Hz), 7.15 (1H, dd, J¼8.8, 2.0 Hz),
4.48 (1H, s), 4.26 (2H, q, J¼7.1 Hz), 3.82e3.35 (4H, m), 1.46 (6H, s),
1.30 (3H, t, J¼7.1 Hz). 13C NMR (CDCl3, 50 MHz)
d 168.6, 167.9, 159.1,
149.0,148.4, 140.1, 129.1, 128.9, 128.6, 124.7, 124.5, 122.1, 119.0,113.6,
113.6, 112.6, 85.5, 62.4, 60.6, 52.5, 56.9, 25.6, 23.9, 13.8. Anal. Calcd
for C17H19ClN2O4 (350.81): C 58.20, H 5.46, Cl 10.11, N 7.99%. Found:
C 58.26, H 5.52, Cl 10.01, N 8.01%.
4.4.1. 4-(Dimethylamino)pyridinium 5-chloro-3-(phenoxycarbonyl)-
1-(pyrrolidin-1-ylcarbonyl)-1H-indol-2-olate (14a). This compound
was prepared according to the general procedure III using pyrro-
lidine (6.70 mL, 5.77 g, 0.08 mol) to give 12.80 g (63%) 14a as
colorless crystals, mp 182e186 ꢀC. IR (KBr, cmꢁ1) 2876, 1702, 1646,
4.2.3. Ethyl
5-chloro-1-(morpholin-4-ylcarbonyl)-2-oxo-2,3-dihy-
dro-1H-indole-3-carboxylate (12c). This compound was prepared
according to the general procedure I using morpholine (3.50 mL,
3.50 g, 0.04 mol) to give 5.08 g (72%) 12c as colorless crystals, mp
96e99 ꢀC (EtOH). IR (KBr, cmꢁ1) 2973, 1763, 1730, 1682. 1H NMR
1562. 1H NMR (DMSO-d6, 200 MHz)
d
8.18 (2H, d, J¼7.5 Hz), 7.41
(1H, d, J¼2.0 Hz), 7.38 (2H, m), 7.14 (3H, m), 6.95 (2H, d, J¼7.5 Hz),
6.85 (1H, d, J¼8.2 Hz), 6.68 (1H, dd, J¼8.2, 2.0 Hz), 3.46 (4H, m),
3.15 (6H, s), 1.83 (4H, s). 13C NMR (DMSO-d6, 50 MHz)
d 163.8,
(CDCl3, 400 MHz) enol/keto¼1:2,
(1H, d, J¼8.8 Hz), 7.15 (1H, dd, J¼8.8, 2.0 Hz), 4.44 (2H, q, J¼7.1 Hz),
keto: 7.35 (1H, d,
d
enol: 7.67 (1H, d, J¼2.0 Hz), 7.32
157.1, 152.3, 152.05, 139.9, 139.7, 129.9, 129.4, 129.2, 125.2, 124.3,
122.8, 117.2, 116.4, 116.1, 110.1, 107.2, 107.1, 80.3, 47.4, 46.7, 25.4,
24.5. Anal. Calcd for C27H27ClN4O4 (507.00): C 63.96, H 5.37, Cl
7.00, N 11.05%. Found: C 63.70, H 5.25, Cl 7.32, N 10.57%.
3.90e3.30 (8H, m), 1.46 (3H, t, J¼7.1 Hz),
d
J¼2.0 Hz), 7.34 (1H, dd, J¼8.8, 2.0 Hz), 7.30 (1H, d, J¼8.8 Hz), 4.48
(1H, s), 4.26 (2H, q, J¼7.1 Hz), 3.90e3.30 (8H, m), 1.30 (3H, t,
J¼7.1 Hz). 13C NMR (CDCl3, 100 MHz)
d 168.3, 159.2, 149.5, 139.9,
4.4.2. 4-(Dimethylamino)pyridinium 5-chloro-3-(phenoxycarbonyl)-
1-(piperidin-1-ylcarbonyl)-1H-indol-2-olate (14b). This compound
was prepared according to the general procedure III using piperi-
dine (8.0 mL, 6.80 g, 0.08 mol) to give 17.30 g (83%) 14b as colorless
crystals, mp 165e167 ꢀC. IR (KBr, cmꢁ1) 2944, 1695, 1647, 1596,
129.6, 129.5, 129.3, 124.7, 124.5, 123.1, 122.6, 119.3, 115.9, 114.3, 113.1,
86.0, 66.6, 62.8, 61.0, 52.8, 37.0, 14.5, 14.0. Anal. Calcd for
C16H17ClN2O5 (352.78): C 54.47, H 4.86, Cl 10.05, N 7.94%. Found: C
54.16, H 4.81, Cl 10.42, N 8.08%.
1561. 1H NMR (DMSO-d6, 200 MHz)
d
8.12 (2H, d, J¼7.5 Hz), 7.69
4.3. General procedure II for the synthesis of compounds 13
(1H, d, J¼2.0 Hz), 7.36 (2H, m), 7.22 (3H, m), 6.95 (1H, d, J¼8.3 Hz),
6.85 (1H, dd, J¼8.2 Hz, J¼2.0 Hz), 6.49 (2H, d, J¼6.8 Hz), 3.50 (4H, br
A mixture of compound 12 (0.015 mol) and the corresponding
amine (0.030 mol) in toluene (80 mL) was refluxed for 1 h. The
precipitate was filtered off to give compound 13. Compounds were
of high purity without recrystallization, as indicated by elemental
analyses and 1H NMR spectra.
s), 3.05 (6H, s), 1.63 (6H, s). 13C NMR (DMSO-d6, 50 MHz)
d 164.4,
163.1, 152.2, 131.5, 130.3, 129.4, 128.9, 124.8, 123.8, 122.5, 118.8,
116.7, 115.9, 115.3, 109.4, 107.0, 79.7, 43.9, 25.8, 24.0, 22.2, 21.8. Anal.
Calcd for C28H29ClN4O4 (521.03): C 64.55, H 5.61, Cl 6.81, N 10.75%.
Found: C 64.60, H 5.73, Cl 6.73, N 10.40%.
4.3.1. 1,3-Thiazol-2-aminium 5-chloro-1-(pyrrolidin-1-ylcarbonyl)-
3-(1,3-thiazol-2-ylcarbamoyl)-1H-indol-2-olate (13a). This com-
pound was prepared according to the general procedure II using
12a (5.05 g, 0.015 mol) and 2-aminothiazole (3.00 g, 0.03 mol) to
give 6.41 g (87%) 13a as colorless crystals, mp 258e260 ꢀC. IR (KBr,
4.4.3. 4-(Dimethylamino)pyridinium
5-chloro-1-(morpholin-4-yl-
carbonyl)-3-(phenoxycarbonyl)-1H-indol-2-olate (14c). This com-
pound was prepared according to the general procedure III using
morpholine (6.97 g, 0.08 mol) to give 16.20 g (77%) 14c as colorless
crystals, mp 158e160 ꢀC. IR (KBr, cmꢁ1) 3243, 2857, 1698, 1648,
cmꢁ1) 2976, 1670, 1599, 1524. 1H NMR (DMSO-d6, 200 MHz)
d 12.10
1594. 1554. 1H NMR (DMSO-d6, 200 MHz)
d
8.20 (2H, d, J¼7.3 Hz),
(1H, s), 8.65 (2H, s), 7.62 (1H, d, J¼2.2 Hz), 7.38 (1H, d, J¼3.6 Hz),
7.21 (1H, d, J¼4.4 Hz), 7.02 (1H, d, J¼3.6 Hz), 6.94 (1H, d, J¼8.3 Hz),
6.86 (1H, d, J¼4.4 Hz), 6.74 (1H, dd, J¼8.4, 2.2 Hz), 3.51 (4H, s), 1.86
(4H, s). Anal. Calcd for C20H19ClN6O3S2 (491.01): C 48.92, H 3.90, Cl
7.22, N 17.12, S 13.06%. Found: C 48.82, H 3.87, Cl 7.09, N 16.82, S
12.90%.
7.43 (1H, d, J¼2.0 Hz), 7.35 (1H, m), 7.18 (3H, m), 6.96 (2H, d,
J¼7.3 Hz), 6.84 (1H, d, J¼8.2 Hz), 6.74 (1H, m), 6.66 (1H, dd,
J¼8.2 Hz, J¼2.0 Hz), 3.67 (4H, s), 3.33 (4H, s), 3.17 (6H, s). 13C NMR
(DMSO-d6, 50 MHz)
d 157.6, 152.8, 152.5, 139.8, 130.4, 129.6, 129.1,
125.1, 123.9, 122.8, 119.0, 116.8, 115.8, 115.4, 110.2, 107.2, 79.5, 56.2,
18.6. Anal. Calcd for C27H27ClN4O5 (523.00): C 62.01, H 5.20, Cl 6.78,
N 10.71%. Found: C 62.57, H 5.14, Cl 6.46, N 10.22%.
4.3.2. 1,3-Thiazol-2-aminium 5-chloro-1-(morpholin-4-ylcarbonyl)-
3-(1,3-thiazol-2-ylcarbamoyl)-1H-indol-2-olate (13b). This com-
pound was prepared according to the general procedure II using 12c
(5.29 g, 0.015 mol) and 2-aminothiazole (3.00 g, 0.03 mol) to gꢁiv1e
4.4.4. 4-(Dimethylamino)pyridinium 5-chloro-3-(phenoxycarbonyl)-
1-[(4-pyrimidin-2-ylpiperazin-1-yl)carbonyl]-1H-indol-2-olate
(14d). This compound was prepared according to the general pro-
cedure III using 1-(pyrimidin-2-yl)piperazine (13.12 g, 0.08 mol) to
6.70 g (88%) 13b as colorless crystals, mp 254e255 ꢀC. IR (KBr, cm
)
3088,1667,1596,1522. 1H NMR (DMSO-d6, 200 MHz)
d 12.10 (1H, s),

7024
M. Porcs-Makkay et al. / Tetrahedron 66 (2010) 7017e7027
give 22.60 g (94%) 14d as colorless crystals, mp 145e150 ꢀC. IR (KBr,
cmꢁ1) 3058, 1690, 1647, 1588, 1551. 1H NMR (DMSO-d6, 200 MHz)
0.017 mol) to give 6.21 g (81%) 15a as colorless crystals, mp
204e205 ꢀC. IR (KBr, cmꢁ1) 2965, 1641, 1564, 1521. 1H NMR (DMSO-
d
8.39 (2H, t, J¼4.7 Hz), 8.18 (2H, d, J¼7.5 Hz), 7.46 (1H, d, J¼2.2 Hz),
d6, 200 MHz)
d
11.93 (1H, s), 8.19 (2H, d, J¼7.7 Hz), 7.62 (1H, d,
7.36 (2H, m), 7.14 (3H, m), 6.92 (2H, d, J¼7.5 Hz), 6.89 (1H, d,
J¼8.2 Hz), 6.70 (1H, dd, J¼8.2, 2.2 Hz), 6.66 (1H, d, J¼4.7 Hz), 3.83
J¼2.3 Hz), 7.32 (1H, d, J¼3.5 Hz), 6.95 (1H, d, J¼3.5 Hz), 6.94 (2H, d,
J¼7.6 Hz), 6.92 (1H, d, J¼8.2 Hz), 6.70 (1H, dd, J¼8.2, 2.3 Hz), 3.50
(4H, m), 3.17 (6H, s), 1.89 (4H, s). 13C NMR (DMSO-d6, 125 MHz)
(4H, s), 3.66 (4H, s), 3.15 (6H, s).13C NMR (DMSO-d6, 50 MHz)
d 165.3,
162.3, 159.3, 151.9, 137.4, 130.8, 130.0, 125.3, 117.2, 115.5, 115.4, 111.3,
110.3, 82.4, 57.6, 24.0. Anal. Calcd for C31H30ClN7O4 (600.09): C 62.05,
H 5.04, Cl 5.91, N 16.34%. Found: C 62.04, H 5.08, Cl 5.80, N 15.84%.
d 165.0, 162.1, 159.1, 157.0, 151.5, 139.2, 137.3, 130.6, 129.4, 125.2,
116.9, 115.3, 111.3, 110.4, 107.0, 82.5, 47.4, 46.7, 25.4, 24.4. Anal. Calcd
for C24H25ClN6O3S (513.04): C 56.19, H 4.91, Cl 6.91, N 16.38, S 6.25%.
Found: C 55.90, H 4.86, Cl 7.16, N 15.91, S 6.12%.
4.4.5. 4-(Dimethylamino)pyridinium 5-chloro-1-{[2-(dimethylamino)
ethyl]carbamoyl}-3-(phenoxycarbonyl)-1H-indol-2-olate (14e). This
compound was prepared according to the general procedure III using
(2-dimethylamino)ethylamine (8.7 mL, 7.05 g, 0.08 mol) to gꢁiv1e
4.5.2. 4-(Dimethylamino)pyridinium 5-chloro-1-(piperidin-1-ylcar-
bonyl)-3-(1,3-thiazol-2-ylcarbamoyl)-1H-indol-2-olate (15b). This
compound was prepared according to the general procedure IV
using 14b (7.81 g, 0.015 mol) and 2-aminothiazole (1.70 g,
0.017 mol) to give 5.00 g (63%) 15b as colorless crystals, mp
210e212 ꢀC. IR (KBr, cmꢁ1) 2932, 1642, 1608, 1564, 1519. 1H NMR
19.70 g (94%) 14e as colorless crystals, mp 184e185 ꢀC. IR (KBr, cm
)
3056, 2939,1710,1644,1618,1596.1511.1HNMR (DMSO-d6, 400 MHz)
d
10.19 (1H, s), 8.14 (2H, dd, J¼5.7, 1.5 Hz), 8.01 (1H, d, J¼8.4 Hz), 7.52
(DMSO-d6, 200 MHz)
d
11.95 (1H, s), 7.97 (2H, d, J¼7.3 Hz), 7.95 (1H,
(1H, d, J¼2.2 Hz), 7.38 (2H, m), 7.14 (3H, m), 6.77 (2H, dd, J¼5.7, 1.5 Hz),
6.75 (1H, dd, J¼8.5, 2.2 Hz), 3.50 (2H, q, J¼5.8 Hz), 3.05 (6H, s), 2.81
s), 7.38 (1H, d, J¼3.7 Hz), 6.88 (1H, d, J¼8.3 Hz), 6.85 (1H, d,
J¼2.0 Hz), 6.83 (1H, dd, J¼8.3, 2.0 Hz), 6.55 (2H, d, J¼7.3 Hz),
3.82e3.35 (4H, m), 3.11 (6H, s), 1.63 (6H, s). Anal. Calcd for
C25H27ClN6O3S (527.06): C 56.97, H 5.16, Cl 6.73, N 15.95, S 6.08%.
Found: C 56.63, H 5.13, Cl 6.53, N 15.63, S 6.10%.
(2H, q, J¼5.8 Hz), 2.49 (6H, s). 13C NMR (DMSO-d6, 100 MHz)
d 167.0,
163.3, 155.6, 154.7, 152.2, 145.0, 144.9, 131.5, 129.6, 129.2, 126.3, 124.3,
122.7, 117.6, 115.9, 114.4, 107.0, 81.0, 57.9, 44.4, 44.3, 35.9. Anal. Calcd
for C27H30ClN5O4 (524.02): C 61.89, H 5.77, Cl 6.77, N 13.36%. Found: C
61.70, H 5.83, Cl 6.67, N 13.13%.
4.5.3. 4-(Dimethylamino)pyridinium 5-chloro-3-(1H-imidazol-2-yl-
carbamoyl)-1-(piperidin-1-ylcarbonyl)-1H-indol-2-olate (15c). This
compound was prepared according to the general procedure IV
using 14b (7.81 g, 0.015 mol) and 2-aminoimidazole (1.62 g,
0.017 mol) to give 5.15 g (67%) 15c as colorless crystals, mp
221e225 ꢀC. IR (KBr, cmꢁ1) 2935, 1648, 1571, 1511. 1H NMR (DMSO-
4.4.6. 4-(Dimethylamino)pyridinium 1-[benzyl(methyl)carbamoyl]-
5-chloro-3-(phenoxycarbonyl)-1H-indol-2-olate (14f). This com-
pound was prepared according to the general procedure III using
N-benzylmethylamine (10.28 mL, 9.68 g, 0.08 mol) to give 11.20 g
(50%) 14f as colorless crystals, mp 156e159 ꢀC. IR (KBr, cmꢁ1) 3062,
2684, 1691, 1618, 1564. 1H NMR (DMSO-d6, 200 MHz)
d 13.10 (1H, br
d6, 200 MHz)
d
11.36 (1H, s), 8.52 (2H, d, J¼4.7 Hz), 8.18 (2H, dd,
J¼6.2, 1.2 Hz), 7.68 (1H, d, J¼2.2 Hz), 6.94 (1H, t, J¼4.7 Hz), 6.91 (2H,
dd, J¼6.2 Hz, J¼1.2 Hz), 6.83 (1H, d, J¼8.3 Hz), 6.66 (1H, dd, J¼8.2,
2.2 Hz), 3.35 (4H, s), 3.14 (6H, s), 1.59 (6H, s). Anal. Calcd for
C25H28ClN7O3 (510.01): C 58.88, H 5.53, Cl 6.95, N 19.23%. Found: C
58.55, H 5.37, Cl 6.69, N 18.80%.
s), 8.20 (2H, d, J¼7.6 Hz), 7.40 (6H, m), 7.15 (5H, m), 6.95 (2H, d,
J¼7.6 Hz), 6.82 (1H, d, J¼8.2 Hz), 6.70 (1H, dd, J¼8.2, 2.2 Hz), 4.68
(2H, s), 3.17 (6H, s), 2.91 (3H, s).13C NMR (DMSO-d6, 50 MHz)
d 164.4,
163.1,156.9,154.3,152.2,139.6,137.2,132.0,130.2,129.4,129.0,128.6,
127.2, 125.0, 126.9, 122.5, 118.8, 116.8, 115.9, 115.3, 109.6, 107.0, 79.8,
51.6, 36.1. Anal. Calcd for C31H29ClN4O4 (557.06): C 66.84, H 5.25, Cl
6.36, N 10.06%. Found: C 66.64, H 5.22, Cl 6.28, N 9.99%.
4.5.4. 4-(Dimethylamino)pyridinium 5-chloro-1-[(4-pyrimidin-2-yl-
piperazin-1-yl)carbonyl]-3-(1,3-thiazol-2-ylcarbamoyl)-1H-indol-2-
olate monohydrate (15d). This compound was prepared according to
the general procedure IV using 14d (9.00 g, 0.015 mol) and 2-ami-
nothiazole (1.70 g, 0.017 mol) to give 4.50 g (48%) 15d as colorless
crystals, mp 231e233 ꢀC. IR (KBr, cmꢁ1) 2911, 1676, 1647, 1587. 1H
4.4.7. 4-(Dimethylamino)pyridinium 5-chloro-3-(phenoxycarbonyl)-
1-(propylcarbamoyl)-1H-indol-2-olate monohydrate (14g). This
compound was prepared according to the general procedure III
using propylamine (6.58 mL, 4.73 g, 0.08 mol) to give 16.40 g (80%)
14g as colorless crystals, mp 209e211 ꢀC. IR (KBr, cmꢁ1) 3057, 2961,
NMR (DMSO-d6, 200 MHz)
d
11.87 (1H, s), 8.39 (2H, d, J¼4.7 Hz), 8.20
1712, 1647, 1618, 1564. 1H NMR (DMSO-d6, 500 MHz)
d 13.10 (1H, br
(2H, d, J¼7.8 Hz), 7.65 (1H, d, J¼2.2 Hz), 7.31 (1H, d, J¼3.5 Hz), 6.95
(4H, d, J¼8.4 Hz), 6.70 (2H, m), 3.83 (4H, s), 3.66 (4H, s), 3.15 (6H, s).
Anal. Calcd for C28H28ClN9O3S$H2O (624.14): C 53.88, H 4.85, Cl 5.68,
N 20.20, S 5.13%. Found: C 54.07, H 4.59, Cl 5.63, N 19.89, S 5.10%.
s), 10.11 (1H, s), 8.20 (2H, d, J¼7.6 Hz), 8.00 (1H, d, J¼8.6 Hz), 7.53
(1H, d J¼2.2 Hz), 7.37 (2H, m), 7.15 (3H, m), 6.95 (2H, d, J¼7.6 Hz),
6.73 (1H, dd, J¼8.6, 2.2 Hz), 3.34 (2H, q, J¼7.2 Hz), 3.17 (6H, s), 1.54
(2H, q, J¼7.2 Hz), 0.93 (3H, t, J¼7.2 Hz). 13C NMR (DMSO-d6,
4.5.5. 4-(Dimethylamino)pyridinium 5-chloro-3-(phenylcarbamoyl)-
1-(propylcarbamoyl)-1H-indol-2-olate monohydrate (15e). This
compound was prepared according to the general procedure IV using
14g (7.69 g, 0.015 mol) and aniline (1.37 mL,1.40 g, 0.017 mol) to gꢁiv1e
125 MHz)
d 157.8, 154.4, 152.1, 139.3, 129.6, 126.0, 124.0, 123.3,
122.5, 117.4, 115.6, 114.1, 107.1, 40.5, 40.2, 22.8, 11.6. Anal. Calcd for
C26H27ClN4O4$H2O (512.98): C 60.87, H 5.70, Cl 6.91, N 10.92%.
Found: C 60.57, H 5.39, Cl 7.20, N 10.75%.
5.00 g (65%) 15e as colorless crystals, mp 209e211 ꢀC. IR (KBr, cm
)
3066, 2963, 1693, 1646, 1538. 1H NMR (DMSO-d6, 400 MHz)
d 13.12
4.5. General procedure IV for the synthesis of compounds 15
(1H, br s), 10.53 (1H, br s), 9.84 (1H, br s), 8.20 (2H, d, J¼6.6 Hz), 7.95
(1H, d, J¼8.3 Hz), 7.79 (1H, s), 7.59 (2H, d, J¼7.6 Hz), 7.22 (2H, m), 6.94
(2H, d, J¼6.6 Hz), 6.87 (1H, m), 6.69 (1H, d, J¼7.8 Hz), 3.24 (2H, q,
J¼7.2 Hz), 3.15 (6H, s), 1.54 (2H, q, J¼7.2 Hz), 0.91 (3H, t, J¼7.2 Hz).
Anal. Calcd for C26H28ClN5O3$H2O (512.01): C 60.99, H 5.91, Cl 6.91, N
13.68%. Found: C 60.87, H 5.90, Cl 7.04, N 13.56%.
A mixture of compound 14 (0.015 mol) and the corresponding
amine (0.017 mol) in toluene (80 mL) was refluxed for 1 h. The
precipitate was filtered off to give compound 15. Compounds were
of high purity without recrystallization, as indicated by elemental
analyses and 1H NMR spectra.
4.5.1. 4-(Dimethylamino)pyridinium 5-chloro-1-(pyrrolidin-1-ylcar-
bonyl)-3-(1,3-thiazol-2-ylcarbamoyl)-1H-indol-2-olate (15a). This
compound was prepared according to the general procedure IV
using 14a (7.60 g, 0.015 mol) and 2-aminothiazole (1.70 g,
4.6. General procedure V for the synthesis of compounds 17
A mixture of compound 10 (5.30 g, 0.01 mol) and the corre-
sponding aromatic amine (0.0112 mol) in toluene (50 mL) was

M. Porcs-Makkay et al. / Tetrahedron 66 (2010) 7017e7027
7025
refluxed for 5 h. The precipitate was filtered off to give compound
17. Compounds were of high purity without recrystallization, as
indicated by elemental analyses and 1H NMR spectra.
added and the mixture was stirred for 2 h at room temperature,
then filtered off to give compound 8.
4.7.1. 5-Chloro-2-hydroxy-1-(pyrrolidin-1-ylcarbonyl)-N-1,3-thia-
4.6.1. 4-(Dimethylamino)pyridinium 5-chloro-1-(phenoxycarbonyl)-
3-(phenylcarbamoyl)-1H-indol-2-olate (17a). This compound was
prepared according to the general procedure V using aniline (1.04 g,
1.02 mL, 0.0112 mol) to give 4.12 g (78%) 17a as colorless crystals,
mp 196e197 ꢀC. IR (KBr, cmꢁ1): 3051, 2996, 1758, 1648, 1592, 1561,
zol-2-yl-1H-indole-3-carboxamide hemihydrate (8a).
(a) This compound was prepared according to Route A using 12a
(5.05 g, 0.015 mol) and 2-aminothiazole (3.00 g, 0.03 mol) to
give 4.28 g (73%) 8a as colorless crystals, mp >260 ꢀC. IR (KBr,
cmꢁ1): 3094, 2881, 1681, 1594. 1H NMR (DMSO-d6, 200 MHz)
1525. 1H NMR (DMSO-d6, 200 MHz)
d 13.15 (1H, s), 10.78 (1H, s),
8.20 (2H, d, J¼7.6 Hz), 7.83 (1H, d, J¼2.4 Hz), 7.63 (3H, d, J¼8.2 Hz),
7.48 (2H, t, J¼7.6 Hz), 7.26 (5H, m), 6.96 (2H, d, J¼7.6 Hz), 6.90 (1H, t,
J¼7.6 Hz), 6.74 (1H, dd, J¼8.2, 2.4 Hz), 3.17 (6H, s). Anal. Calcd for
C29H25ClN4O4 (529.01): C 65.84, H 4.76, Cl 6.70, N 10.59%. Found: C
65.25, H 4.70, Cl 6.66, N 10.54%.
d
12.93 (1H, s), 7.64 (1H, d, J¼4.0 Hz), 7.59 (1H, d, J¼1.5 Hz), 7.26
(1H, d, J¼4.0 Hz), 6.98 (1H, d, J¼8.2 Hz), 6.82 (1H, dd, J¼8.2,
1.5 Hz), 3.51 (4H, s), 1.87 (4H, s). 13C NMR (DMSO-d6, 125 MHz)
d
165.6, 161.4, 160.0, 150.9, 130.1, 129.5, 127.5, 125.7, 118.6, 115.9,
113.2, 111.1, 83.0, 47.3, 46.8, 25.4, 24.5. Anal. Calcd for
C17H15ClN4O3S$½H2O (399.87): C 51.06, H 4.03, Cl 8.86, N 14.01,
S 8.03%. Found: C 50.92, H 3.91, Cl 8.84, N 13.87, S 8.06%.
4.6.2. 4-(Dimethylamino)pyridinium 5-chloro-1-(phenoxycarbonyl)-
3-(1,3-thiazol-2–ylcarbamoyl)-1H-indol-2-olate (17b). This com-
pound was prepared according to the general procedure V using
2-aminothiazole (1.12 g, 0.0112 mol) to give 4.29 g (80%) 17b a col-
orless crystals, mp 225e230 ꢀC. IR (KBr, cmꢁ1) 3085, 2969, 1718,
(b) This compound was prepared according to the Route B using 14a
(7.60 g, 0.015 mol) and 2-aminothiazole (1.70 g, 0.017 mol) to give
4.85 g (81%)8a identical with the compound obtained viaRoute A.
1646, 1594, 1562. 1H NMR (DMSO-d6, 400 MHz)
d 13.00 (1H, br s),
11.91 (1H, s), 8.98 (1H, s), 8.20 (2H, d, J¼7.7 Hz), 7.77 (1H, d,
J¼2.2 Hz), 7.62 (1H, d, J¼8.4 Hz), 7.48 (2H, m), 7.34 (1H, d, J¼3.7 Hz),
7.32 (3H, m), 7.00 (1H, d, J¼3.7 Hz), 6.97 (2H, d, J¼7.7 Hz), 6.84 (1H,
dd, J¼8.4, 2.2 Hz), 3.17 (6H, s). Anal. Calcd for C26H22ClN5O4S
(536.01): C 58.26, H 4.14, Cl 6.61, N 13.07, S 5.98%. Found: C 58.36, H
4.04, Cl 7.09, N 13.21, S 6.25%.
4.7.2. 5-Chloro-2-hydroxy-1-(morpholin-4-ylcarbonyl)-N-1,3-thia-
zol-2-yl-1H-indole-3-carboxamide hemihydrate (8b). This com-
pound was prepared according to Route A using 12c (5.29 g,
0.015 mol) and 2-aminothiazole (3.00 g, 0.03 mol) to give 4.55 g
(73%) 8b as colorless crystals, mp >260 ꢀC. IR (KBr, cmꢁ1): 3101,
2858, 1665, 1594. 1H NMR (DMSO-d6, 200 MHz)
d 7.64 (1H, d,
J¼4.2 Hz), 7.61 (1H, d, J¼2.0 Hz), 7.26 (1H, d, J¼4.2 Hz), 6.99 (1H, d,
4.6.3. 4-(Dimethylamino)pyridinium 5-chloro-1-(phenoxycarbonyl)-
3-(1,3,4-thiadiazol-2-yl-carbamoyl)-1H-indol-2-olate monohydrate
(17c). This compound was prepared according to the general pro-
cedureV using 2-amino-1,3,4-thiadiazole (1.13 g, 0.0112 mol) to gꢁiv1e
J¼8.4 Hz), 6.84 (1H, dd, J¼8.4, 2.2 Hz), 3.66 (8H, s). 13C NMR (DMSO-
d6, 125 MHz)
d 165.6, 161.4, 160.0, 151.5, 130.5, 130.5, 129.7, 127.6,
125.9, 118.7, 115.9, 113.3, 111.4, 82.6, 66.4, 47.7, 44.2. Anal. Calcd for
C17H15ClN4O4S$½H2O (415.86): C 49.10, H 3.88, Cl 8.53, N 13.47, S
7.71%. Found: C 49.02, H 3.92, Cl 8.66, N 13.35, S 7.56%.
4.33 g (78%) 17c as colorless crystals, mp 190e195 ꢀC. IR (KBr, cm
)
3069, 2936, 1755, 1646, 1562. 1H NMR (DMSO-d6, 400 MHz)
d 13.14
(1H, br s),12.20 (1H, s), 8.98 (1H, s), 8.20 (2H, d, J¼7.7 Hz), 7.74 (1H, d,
J¼2.4 Hz), 7.68 (1H, d, J¼8.4 Hz), 7.48 (2H, m), 7.33 (3H, m), 6.97 (2H,
d, J¼7.7 Hz), 6.84 (1H, dd, J¼8.4, 2.2 Hz), 3.17 (6H, s). 13C NMR
4.7.3. 5-Chloro-2-hydroxy-1-(morpholin-4-ylcarbonyl)-N-pyridin-3-
yl-1H-indole-3-carboxamide dihydrate (8c). This compound was
prepared according to Route C using 14c (7.85 g, 0.015 mol) and 3-
aminopyridine (1.60 g, 0.017 mol) to give 5.00 g (76%) 8c as color-
less crystals, mp 194e196 ꢀC. IR (KBr, cmꢁ1): 3451, 2935, 1671, 1600,
(DMSO-d6, 125 MHz)
d 165.0, 161.4, 158.7, 150.5, 150.2, 147.2, 139.3,
131.7, 129.7, 128.6, 127.7, 126.1, 122.0, 118.3, 115.6, 114.2, 107.1, 82.9,
40.2. Anal. Calcd for C25H21ClN6O4S$H2O (555.00): C 54.10, H 4.17, Cl
6.39, N 15.14, S 5.78%. Found: C 54.06, H 4.19, Cl 6.48, N 15.11, S 5.74%.
1554, 1526. 1H NMR (DMSO-d6, 200 MHz)
d 11.30 (1H, s), 9.46 (1H,
s), 8.44 (1H, d, J¼7.5 Hz), 8.37 (1H, d, J¼5.5 Hz), 7.87 (1H, d,
J¼5.5 Hz), 7.66 (1H, d, J¼2.2 Hz), 6.94 (1H, J¼8.4 Hz), 6.74 (1H, dd,
J¼8.4, 2.0 Hz), 3.65 (4H, s), 3.38 (4H, s). Anal. Calcd for
C19H21ClN4O6$2H2O (436.87): C 52.23, H 4.84, Cl 8.11, N 12.82%.
Found: C 52.17, H 4.44, Cl 8.15, N 12.80%.
4.7. General procedures for the synthesis of compounds 8
Route A: A mixture of compound 12 (0.015 mol) and the corre-
sponding amine (0.030 mol) in toluene (80 mL) was refluxed for
30 min. The precipitate was filtered off to give compound 13. A
mixture of 13 thus obtained, water (50 mL) and concd HCl (1.0 mL)
was stirred for 3 h at room temperature, then the precipitate was
filtered off to give compound 8.
Route B: A mixture of compound 14 (0.015 mol) and the corre-
sponding amine (0.017 mol) in toluene (80 mL) was refluxed for
1 h. The precipitate was filtered off to give compound 15. A mixture
of 15 thus obtained, water (50 mL) and concd HCl (1.0 mL) was
stirred for 3 h at room temperature, then the precipitate was fil-
tered off to give compound 8.
4.7.4. 5-Chloro-2-hydroxy-N-phenyl-1-(piperidin-1-ylcarbonyl)-1H-
indole-3-carboxamide (8d).
(a) This compound was prepared according to Route C using 14b
(7.81 g, 0.015 mol) and aniline (1.37 mL, 1.40 g, 0.017 mol) to
give 4.36 g (73%) 8d as colorless crystals, mp 181e183 ꢀC. IR
(KBr, cmꢁ1): 3290, 2945, 1744, 1684, 1664, 1600. 1H NMR
(DMSO-d6, 200 MHz)
d 10.70 (1H, br s), 7.62 (3H, m), 7.33 (3H,
m), 7.07 (2H, m), 3.51 (4H, s), 1.87 (6H, s). Anal. Calcd for
C21H20ClN3O3 (397.87): C 63.40, H 5.07, Cl 8.91, N 10.56%.
Found: C 63.32, H 5.21, Cl 9.01, N 10.32%.
(b) This compound was prepared according to Route D using 17a
(1.32 g, 2.5 mmol) and piperidine (0.49 mL, 0.43 g, 5.0 mmol) to
give 0.79 g (79%) 8d identical with the compound obtained via
Route C.
Route C: A mixture of compound 14 (0.015 mol) and the corre-
sponding amine (0.017 mol) in toluene (80 mL) was refluxed for
1 h. After cooling to room temperature, water (50 mL) and concd
HCl (1.0 mL) were added and the mixture was stirred for 3 h at
room temperature, then filtered off to give compound 8.
Route D: A mixture of compound 17 (2.5 mmol) and the corre-
sponding amine (5.0 mmol) in DMF (6 mL) was stirred at ambient
temperature for 2 h, water (6 mL) and concd HCl (0.6 mL) were
4.7.5. 5-Chloro-2-hydroxy-1-(piperidin-1-ylcarbonyl)-N-1,3-thiazol-
2-yl-1H-indole-3-carboxamide (8e). This compound was prepared

7026
M. Porcs-Makkay et al. / Tetrahedron 66 (2010) 7017e7027
according to Route B using 14b (7.81 g, 0.015 mol) and 2-amino-
thiazole (1.70 g, 0.017 mol) to give 3.70 g (61%) 8e as colorless
crystals, mp >260 ꢀC. IR (KBr, cmꢁ1): 2938, 1658, 1599, 1511. 1H
(4H, s), 3.66 (4H, s). Anal. Calcd for C23H20ClN7O3 (477.93): C 57.80,
H 4.22, Cl 7.42, N 20.52%. Found: C 57.77, H 4.24, Cl 7.29, N 19.96%.
NMR (DMSO-d6, 200 MHz)
d
12.90 (1H, s), 7.63 (1H, d, J¼4.3 Hz),
4.7.11. N-Benzyl-5-chloro-2-hydroxy-1-[(4-pyrimidin-2-ylpiperazin-
1-yl)carbonyl]-1H-indole-3-carboxamide (8k). This compound was
prepared according to Route C using 14d (9.00 g, 0.015 mol) and
benzylamine (1.86 mL, 1.82 g, 0.017 mol) to give 4.71 g (64%) 8k as
colorless crystals, mp 205e206 ꢀC. IR (KBr, cmꢁ1): 3307, 1745, 1691,
7.59 (1H, d, J¼2.0 Hz), 7.27 (1H, d, J¼4.3 Hz), 6.96 (1H, J¼8.2 Hz),
6.83 (1H, dd, J¼8.2, 2.0 Hz), 3.44 (4H, s), 1.63 (6H, s). Anal. Calcd for
C18H17ClN4O3S (404.89): C 53.40, H 4.23, Cl 8.76, N 13.84, S 7.92%.
Found: C 52.90, H 4.16, Cl 8.52, N 13.65, S 7.77%.
1663, 1588, 1552. 1H NMR (DMSO-d6, 200 MHz)
d 9.12 (1H, s), 8.40
4.7.6. 5-Chloro-2-hydroxy-1-(piperidin-1-ylcarbonyl)-N-pyridin-3-
yl-1H-indole-3-carboxamide monohydrate (8f). This compound was
prepared according to Route C using 14b (7.81 g, 0.015 mol) and 3-
aminopyridine (1.60 g, 0.017 mol) to give 5.25 g, (84%) 8f as color-
less crystals, mp 257e258 ꢀC. IR (KBr, cmꢁ1): 2935, 2855, 1685,
(2H, d, J¼4.7 Hz), 7.33 (7H, m), 7.14 (1H, d, J¼8.8 Hz), 6.69 (1H, t,
J¼4.7 Hz), 4.80 (1H, s), 4.39 (2H, s), 3.69 (8H, m).13C NMR (DMSO-d6,
50 MHz)
d 165.4, 161.1, 158.1, 128.9, 128.4, 127.7, 127.3, 127.1, 125.0,
113.0,110.7, 54.0, 43.3, 42.8. Anal. Calcd for C25H23ClN6O3 (490.96): C
61.16, H 4.72 Cl 7.22, N 17.12%. Found: C 61.32, H 4.69, Cl 7.17, N 17.00%.
1543. 1H NMR (DMSO-d6, 200 MHz)
d 11.38 (1H, s), 9.48 (1H, s), 8.44
(1H, d, J¼8.8 Hz), 8.37 (1H, d, J¼5.3 Hz), 7.86 (1H, dd, J¼8.7, 5.5 Hz),
7.65 (1H, d, J¼2.2 Hz), 6.85 (1H, J¼8.2 Hz), 6.72 (1H, dd, J¼8.2,
2.0 Hz), 3.82e3.35 (4H, s), 1.60 (6H, s). Anal. Calcd for
C20H19ClN4O3$H2O (416.88): C 57.62, H 5.08, Cl 8.51, N 13.44%.
Found: C 57.25, H 4.76, Cl 8.78, N 13.38%.
4.7.12. 5-Chloro-N1-[2-(dimethylamino)ethyl]-2-hydroxy-N3-pyr-
idin-2-yl-1H-indole-1,3-dicarboxamide (8l). This compound was
prepared according to Route C using 14e (7.86 g, 0.015 mol) and 2-
aminopyridine (1.60 g, 0.017 mol) to give 5.85 g (97%) 8l as colorless
crystals, mp 188e190 ꢀC. IR (KBr, cmꢁ1): 3026, 1687, 1594, 1543. 1H
NMR (DMSO-d6, 200 MHz)
d
11.03 (1H, s), 10.04 (1H, t, J¼5.5 Hz),
4.7.7. 5-Chloro-2-hydroxy-N-1H-imidazol-2-yl-1-(piperidin-1-ylcar-
bonyl)-1H-indole-3-carboxamide (8g). Thiscompound wasprepared
according to Route B using 14b (7.81 g, 0.015 mol) and 2-amino-
imidazole (1.62 g, 0.017 mol) to give 3.90 g (67%) 8g as colorless
crystals, mp 234e236 ꢀC. IR (KBr, cmꢁ1): 2941, 2857, 1669, 1578. 1H
8.30 (1H, J¼8.6 Hz), 8.19 (1H, m), 8.02 (1H, d, J¼8.5 Hz), 7.84 (1H, d,
J¼2.4 Hz), 7.68 (1H, td, J¼8.6, 1.8 Hz), 6.92 (1H, m), 6.78 (1H, dd,
J¼8.5, 2.4 Hz), 3.65 (2H, q, J¼5.5 Hz), 3.12 (2H, t, J¼5.5 Hz), 2.72 (6H,
s). Anal. Calcd for C19H20ClN5O3 (401.87): C 56.79, H 5.02, Cl 8.82, N
17.43%. Found: C 56.48, H 4.88, Cl 8.50, N 17.49%.
NMR (DMSO-d6, 200 MHz)
d
12.53 (1H, s), 8.86 (2H, d, J¼5.2 Hz), 7.63
(1H, d, J¼2.2 Hz), 7.40 (1H, t, J¼5.2 Hz), 6.91 (2H, m), 3.35 (4H, s),1.59
(6H, s). Anal. Calcd for C18H18ClN5O3 (387.84): C 55.74, H 4.68, Cl 9.14,
N 18.06%. Found: C 55.42, H 4.57, Cl 9.06, N 17.85%.
4.7.13. N3-Benzyl-5-chloro-N1-[2-(dimethylamino)ethyl]-2-hydroxy-
N3-methyl-1H-indole-1,3-dicarboxamide (8m). This compound was
prepared according to Route C using 14e (7.86 g, 0.015 mol) and N-
benzylmethylamine (2.2 mL, 2.06 g, 0.017 mol) to give 4.57 g (71%)
8m as colorless crystals, mp 191e192 ꢀC. IR (KBr, cmꢁ1): 3012, 1688,
4.7.8. 5-Chloro-2-hydroxy-1-(piperidin-1-ylcarbonyl)-N-1,3,4-thia-
diazol-2-yl-1H-indole-3-carboxamide (8h). This compound was
prepared according to Route C using 14b (7.81 g, 0.015 mol) and 2-
amino-1,3,4-thiadiazole (1.72 g, 0.017 mol) to give 4.10 g (67%) 8h
as colorless crystals, mp 235e243 ꢀC. IR (KBr, cmꢁ1): 2939, 1746,
1619, 1589, 1567, 1526. 1H NMR (DMSO-d6, 200 MHz)
d 10.58 (1H, t,
J¼5.5 Hz), 7.93 (1H, d, J¼8.4 Hz), 7.35 (1H, d, J¼2.2 Hz), 7.28 (5H, m),
6.59 (1H, dd, J¼8.4, 2.2 Hz), 4.67 (2H, s), 3.65 (2H, q, J¼6.0 Hz), 3.25
(2H, q, J¼6.0 Hz), 2.89 (3H, s), 2.81 (6H, s). 13C NMR (DMSO-d6,
1658, 15,925, 1531. 1H NMR (DMSO-d6, 200 MHz)
d
12.70 (1H, s),
50 MHz) d 168.5, 161.6, 155.6, 139.6, 134.1, 128.8, 124.4, 127.4, 126.7,
9.08 (1H, s), 7.60 (1H, d, J¼2.1 Hz), 7.00 (1H, s), 6.91 (1H, J¼8.2 Hz),
6.81 (1H, dd, J¼8.2, 2.0 Hz), 3.45 (4H, s), 1.59 (6H, s). Anal. Calcd for
C17H16ClN5O3S (405.88): C 50.30, H 3.97, Cl 8.74, N 17.25, S 7.90%.
Found: C 50.50, H 3.59, Cl 8.52, N 16.88, S 7.96%.
125.7, 115.5, 114.9, 84.6, 57.1, 51.7, 43.0, 35.3, 29.9, 27.0. Anal. Calcd
for C22H25ClN4O3 (428.93): C 61.60, H 5.87, Cl 8.27, N 13.06%. Found:
C 61.40, H 5.86, Cl 8.17, N 12.74%.
4.7.14. 5-Chloro-N1-[2-(dimethylamino)ethyl]-2-hydroxy-N3-phe-
nyl-1H-indole-1,3-dicarboxamide (8n). This compound was pre-
pared according to Route C using 14e (7.86 g, 0.015 mol) and aniline
(1.37 mL, 1.40 g, 0.017 mol) to give 5.25 g (87%) 8n as colorless
crystals, mp 228e229 ꢀC. IR (KBr, cmꢁ1): 3191, 2401, 1693, 1612,
4.7.9. 5-Chloro-2-hydroxy-1-[(4-pyrimidin-2-ylpiperazin-1-yl)car-
bonyl]-N-1,3-thiazol-2-yl-1H-indole-3-carboxamide
monohydrate
(8i). This compound was prepared according to Route B using
14d (9.00 g, 0.015 mol) and 2-aminothiazole (1.70 g, 0.017 mol)
to give 3.46 g (46%) 8i as colorless crystals, mp 200e202 ꢀC. IR
(KBr, cmꢁ1): 3455, 1648, 1589, 1550, 1502. 1H NMR (DMSO-d6,
1594, 1538. 1H NMR (DMSO-d6, 200 MHz)
d 10.59 (1H, s), 10.05 (1H,
t, J¼5.8 Hz), 9.28(1H, br s), 8.00 (1H, d, J¼8.5 Hz), 7.84 (1H, d,
J¼2.5 Hz), 7.60 (2H, m), 7.26 (2H, m), 6.91 (1H, m), 6.75 (1H, dd,
J¼8.5, 2.5 Hz), 3.68 (2H, m), 3.33 (2H, m), 2.85 (6H, s). 13C NMR
200 MHz)
d
12.89 (1H, s), 8.39 (2H, d, J¼4.5 Hz), 7.66 (1H, d,
J¼4.3 Hz), 7.62 (1H, d, J¼2.2 Hz), 7.28 (1H, d, J¼4.3 Hz), 7.01 (1H,
d, J¼8.5 Hz), 6.87 (1H, dd, J¼8.3, 2.2 Hz), 6.68 (1H, d, J¼4.6 Hz),
3.87 (4H, s), 3.63 (4H, s). Anal. Calcd for C21H18ClN7O3S$H2O
(501.97): C 50.25, H 4.02, Cl 7.06, N 19.53, S 6.39%. Found: C
50.38, H 3.98, Cl 6.82, N 18.87, S 6.15%.
(DMSO-d6, 125 MHz)
d 165.0, 164.4, 154.7, 140.9, 131.4, 128.9, 128.6,
126.4, 121.2, 118.1, 117.2, 115.7, 114.3, 85.0, 56.9, 42.9, 34.4. Anal.
Calcd for C20H21ClN4O3 (400.88): C 59.93, H 5.28, Cl 8.84, N 13.98%.
Found: C 59.78, H 5.32, Cl 8.77, N 14.02%.
4.7.15. 5-Chloro-2-hydroxy-N3-phenyl-N1-propyl-1H-indole-1,3-di-
carboxamide monohydrate (8o). This compound was prepared
according to Route B using 14g (7.69 g, 0.015 mol) and aniline
(1.37 mL, 1.40 g, 0.017 mol) to give 5.79 g (99%) 8o as colorless
crystals, mp 208e210 ꢀC. IR (KBr, cmꢁ1): 3347, 3301, 2965, 1736,
4.7.10. 5-Chloro-2-hydroxy-N-pyridin-3-yl-1-[(4-pyrimidin-2-ylpi-
perazin-1-yl)carbonyl]-1H-indole-3-carboxamide (8j). This com-
pound was prepared according to Route C using 14d (9.00 g,
0.015 mol) and 3-aminopyridine (1.60 g, 0.017 mol) to give 4.30 g
(60%) 8j as colorless crystals, mp 235e243 ꢀC. IR (KBr, cmꢁ1): 2854,
1680, 1586, 1549. 1H NMR (DMSO-d6, 200 MHz)
d
11.36 (1H, s), 9.50
1696, 1669, 1541. 1H NMR (DMSO-d6, 200 MHz)
d 10.57 (1H, br s),
(1H, s), 8.46 (1H, dd, J¼8.4, 1.8 Hz), 8.39 (2H, d, J¼4.8 Hz), 7.88 (1H,
dd, J¼8.4, 5.2 Hz), 7.69 (1H, d, J¼2.1 Hz), 7.19 (1H, m), 6.91 (1H, d,
J¼8.2 Hz), 6.76 (1H, dd, J¼8.4, 2.1 Hz), 6.68 (1H, t, J¼4.8 Hz), 3.83
9.85 (1H, br s), 8.00 (1H, d, J¼8.4 Hz), 7.80 (1H, br s), 7.62 (2H, dd,
J¼8.6, 1.1 Hz), 7.25 (2H, t, J¼8.6 Hz), 6.93 (1H, m), 6.76 (1H, br s),
3.26 (2H, br s), 1.55 (2H, q, J¼7.2 Hz), 0.94 (3H, t, J¼7.2 Hz). Anal.

M. Porcs-Makkay et al. / Tetrahedron 66 (2010) 7017e7027
7027
13. Otterness, I. G. U.S. 4,861,794, 1988; Chem. Abstr. 1990, 112, 70013.
Calcd for C19H18ClN3O3$H2O (389.83): C 58.54, H 5.17, Cl 9.10, N
10.78%. Found: C 58.14, H 5.38, Cl 9.10, N 10.66%.
14. Showell, H. J. U.S. 4,853,409, 1988; Chem. Abstr. 1989, 111, 225312.
15. Silbermann, S. C.A. 2,156,120, 1994; Chem. Abstr. 1996, 124, 333055.
16. Kadin, S. B. E.P. 153,818, 1985; Chem. Abstr. 1986, 104, 88427.
17. Crawford, T. C. E.P. 155,828, 1985; Chem. Abstr. 1986, 104, 109466.
18. Kadin, S. B. E.P. 156,603, 1985; Chem. Abstr. 1986, 104, 109468.
Supplementary data
19. (a) Robinson, C. Drugs Future 1990, 15, 898; (b) Drugs Future 1993, 18, 875.
20. Robinson, R. P.; Donahue, K. M. J. Heterocycl. Chem. 1994, 31, 1541.
21. Drugs Future 1995, 20, 972.
Supplementary data associated with this article can be found in
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