Convenient synthesis of 3-unsubstituted oxindole-1-carboxamides

Article abstract of DOI:10.1016/j.tet.2011.12.027

The multiple reactivity of the mesomeric anion formed by N- or C(3)-deprotonation of 3-unsubstituted oxindoles hampers the selective introduction of substituents onto the nitrogen atom. A conveniently applicable reaction sequence has been elaborated for the synthesis of 3-unsubstituted oxindole-1-carboxamides starting from the easily available 1,3- bis(phenoxycarbonyl)oxindoles. Selective amidation of the N-phenoxycarbonyl moiety and subsequent removal of the C(3)-phenoxycarbonyl moiety furnished the title compounds, which are useful building blocks for further functionalization. Besides the novel methodologies, several new representatives of this valuable compound family and their intermediates are also described below.

Full text of DOI:10.1016/j.tet.2011.12.027

Tetrahedron 68 (2012) 1427e1435
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Convenient synthesis of 3-unsubstituted oxindole-1-carboxamides
a
,
a
b
a
*
ꢀ
ꢀ
ꢀ
Marta Porcs-Makkay , Balazs Volk , Eszter Kokai , Gyula Simig
a EGIS Pharmaceuticals Plc., Chemical Research Division, PO Box 100, H-1475 Budapest, Hungary
b Budapest University of Technology and Economics, Faculty of Chemical Engineering, PO Box 91, 1521 Budapest, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 July 2011
Received in revised form 22 November 2011
Accepted 12 December 2011
Available online 16 December 2011
The multiple reactivity of the mesomeric anion formed by N- or C(3)-deprotonation of 3-unsubstituted
oxindoles hampers the selective introduction of substituents onto the nitrogen atom. A conveniently
applicable reaction sequence has been elaborated for the synthesis of 3-unsubstituted oxindole-1-
carboxamides starting from the easily available 1,3-bis(phenoxycarbonyl)oxindoles. Selective amida-
tion of the N-phenoxycarbonyl moiety and subsequent removal of the C(3)-phenoxycarbonyl moiety
furnished the title compounds, which are useful building blocks for further functionalization. Besides the
novel methodologies, several new representatives of this valuable compound family and their in-
termediates are also described below.
ꢀ
Dedicated to the memory of Professor Istvan
Hermecz
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Oxindole
Amidation
Dephenoxycarbonylation
4-N,N-Dimethylaminopyridinum (DMAP)
salt
1. Introduction
introduced using isocyanates. Nevertheless, the use of isocyanates
for the introduction of the 1-carbamoyl group does not make the
The occurrence of 2-oxo-2,3-dihydroindole-1-carboxamides
(1,3-dihydro-2H-indol-2-one-1-carboxamides, oxindole-1-carbox-
amides, 1, Fig. 1) exhibiting various substituents at the 3-position is
scarce in scientific journals.1ꢀ7 On the contrary, the patent
literature of these compounds is rich due to the interest aroused by
the therapeutic efficacy of some members of this compound fam-
ily.8ꢀ12 An outstanding example of this type of oxindole derivatives
is (Z)-5-chloro-3-[1-hydroxy-1-(2-thienyl)methylene]-2-oxo-2,3-
dihydroindole-1-carboxamide (tenidap, 1a, Fig. 1)11,13,14 exhibiting
anxiolytic and antirheumatic activity, which was finally not
launched because of serious side-effects. The development of ilo-
nidap (1b, Fig. 1),6 a successor of tenidap, was also abandoned.
Earlier activity of our research group ranged from the synthesis of
3-acyloxindole-1-carboxamides(1, R3¼H, R4¼acyl)15ꢀ18 to oxindole-
1,3-dicarboxamides (2).19 Next, we aimed at elaborating a practical
synthesis of 3-unsubstituted oxindole-1-carboxamides (3), which
are appropriate building blocks for further functionalization.
According to the described procedures, the 1-carbamoyl moiety
of 3-unsubstituted (3),20ꢀ22 3-acyl (1, R3¼H, R4¼acyl)11,12,23 or 3,3-
dialkyl (1, R3,R4¼alkyl)24ꢀ26 substituted oxindoles can be
direct synthesis of N,N-disubstituted oxindole-1-carboxamides
possible. Moreover, the applicability of this method is further lim-
ited by the fact that relatively few organic isocyanates are com-
mercially available.14
3-Unsubstituted 1-alkoxy(aryloxy)carbonyl-oxindoles (4, Fig. 1)
seemed to be appropriate starting compounds for the
synthesis of 3-unsubstituted oxindole-1-carboxamides (3). How-
ever, our earlier experiments showed that treatment of 5-chloro-1-
phenoxycarbonyloxindole (4a) with ammonium carbonate
(1 equiv) in DMF at 25 ꢁC for 3 h resulted in a mixture of the desired
5-chlorooxindole-1-carboxamide (3a) and by-product 5-
chlorooxindole (5a) in a 2:1 ratio (Scheme 1),16 and the use of
various amines instead of ammonium carbonate also furnished
similar mixtures in a ratio depending on the character of the amine
applied.27
The use of the 1-(4-nitrophenoxy)carbonyl group seemed to
eliminate this problem (i.e., N-desaryloxycarbonylation), as de-
scribed in the only paper published in this field,28 and in a pat-
ent application29 for the transformation of 4b to the 1-carbamoyl
derivative 3b. The 1-(4-nitrophenoxy)carbonyl moiety has
also been applied to a similar reaction of 3,3-dialkylated oxin-
doles.24 Nevertheless, (4-nitrophenoxy)chloroformate is an ex-
pensive reagent and it has earlier been demonstrated that
preparation of the starting compound 4b via selective N(1)-
* Correspondingauthor. Fax:þ3612655613;e-mail address: porcs-makkay.marta@
egis.hu (M. Porcs-Makkay).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.12.027

1428
M. Porcs-Makkay et al. / Tetrahedron 68 (2012) 1427e1435
R3
R4
X
S
S
OH
OH
O
F
Cl
N
O
O
CONR1R2
1
N
N
Cl
R1, R2: H, alkyl
R3: H, alkyl, acyl
R4: alkyl, acyl
CONH2
CONH2
1a (tenidap)
1b (ilonidap)
CONR5R6
X
X
X
O
O
O
N
N
N
COOR7
CONR1R2
CONR1R2
2
3
4
R1, R2: H, alkyl
R5, R6: H, alkyl
R7: alkyl, aryl
R1, R2: H, alkyl
Fig. 1. Structure of various oxindole-1-carboxamides (1, 3), 1,3-dicarboxamides (2) and intermediates thereof (4).
Cl
Cl
Cl
(NH4)2CO3 (1 eq)
DMF, 25 °C, 3 h
O
O
O
+
N
N
N
H
COOPh
CONH2
4a
3a
5a
Cl
N
H2N
Cl
(1 eq)
O
O
N
CH2Cl2, 25 °C
N
N
NO2
O
O
4b
N
H
3b
O
S
S
OH
OH
Cl
Cl
R1R2NH (2 eq)
O
O
DMF, 25 °C, 2 h
N
N
CONR1R2
COOPh
8
COOPh
9
COOPh
HDMAP+
Cl
HDMAP+
Cl
R1R2NH (2 eq)
O
O
DMF, 25 °C, 2 h
N
N
CONR1R2
COOPh
7a
10
Scheme 1. Literature procedures for the preparation of oxindole-1-carboxamides.
aryloxycarbonylation could not be carried out due to the
thenoyloxindole (8, Scheme 1), which exists in the Z enol struc-
ture,16 and the 4-N,N-dimethylaminopyridinum (DMAP) salt of 5-
chloro-1,3-diphenoxycarbonyloxindole (7a)30 could easily be ami-
dated with various primary, secondary aliphatic and cyclic amines
to form the corresponding 1-carbamoyl derivatives 917 and 10,19
respectively, in good yields (Scheme 1).
facile formation of N(1),O- and N(1),C(3)-bis(aryloxycarbonyl)
derivatives (types
6
and 7, respectively, see Scheme 2)15,16
Thus, 4b did not seem an ideal starting material for our pur-
pose, either.
Our earlier studies demonstrated, although for 3-substituted
congeners, that the 1-phenoxycarbonyl moiety took part in ami-
nolysis under mild conditions. 5-Chloro-1-phenoxycarbonyl-3-
Based on the above, and supposing that removal of the 3-
phenoxycarbonyl group is viable, we decided to investigate

M. Porcs-Makkay et al. / Tetrahedron 68 (2012) 1427e1435
1429
X
O
5, 6, 7
a
X
N
H
5-Cl
5
NR1R2
10, 3
X
b
c
d
e
f
6-Cl
H
2.2 eq Et3N, THF
2.2 eq ClCOOPh
25 °C, 30 min
a
b
5-Cl
5-Cl
NH2
5-NO2
5-F
N
N
X
6-F
OCOOPh
N
c
d
e
f
5-Cl
5-Cl
5-Cl
5-Cl
g
5-MeO
N
O
COOPh
6
N
N
DMAP, DMF
N
N
route A,B
0-2 °C, 10 min
HN
COOPh
X
HDMAP+
H
N
g
h
5-Cl
5-Cl
route B
O
N
1.) 2 eq HNR1R2
DMF
HN
route C
COOPh
7
25 °C, 2-4 h
i
5-Cl
6-Cl
H
N
N
1.) DMAP, DMF
25 °C, 2-4 h
HNR1R2
DMF
0-2 °C, 10 min
2.) aq. HCl
25 °C, 1-3 h
route A
j
N
N
N
2.) 2 eq HNR1R2
25 °C, 2-4 h
COOPh
k
X
3.) aq. HCl
HDMAP+
80 °C, 1-3 h
O
l
5-NO2
5-F
N
m
n
N
N
10 CONR1R2
aq. HCl
6-F
60-80 °C, 1-3 h route A
-CO2
N
o
5-MeO
X
O
N
CONR1R2
3
Scheme 2. New synthesis of oxindole-1-carboxamides.
a general synthesis of oxindole-1-carboxamides (3) starting from
the easily available30 1,3-bis(phenoxycarbonyl)oxindole DMAP salts
7 (Scheme 2).
compounds 10 with aqueous hydrochloric acid for 0.5e3 h at room
temperature or at 60e80 ꢁC resulted in the removal of the 3-
phenoxycarbonyl group via hydrolysis and decarboxylation, lead-
ing to 3-unsubstituted oxindole-1-carboxamides 3 (Scheme 2,
route A). Carrying out the amidation and the subsequent dephe-
noxycarbonylation in one-pot (route B) was also viable, as shown
by the transformation of diesters 7b and 7c to target compounds 3j
and 3k.
Considering the reaction conditions of the single synthetic steps
leading from diesters 6 to 3-unsubstituted amides 3, the opportu-
nity arose to carry out the transformations in one-pot (Scheme 2,
route C). Thus, compounds 3aeo were prepared in most cases in
good yields in one-pot, by treatment of the corresponding N,O-
bis(phenoxycarbonyl) derivatives 6 with DMAP in DMF, followed by
amidation of the resulting 1,3-diester salts 7, without isolation of
intermediates 10, and subsequent removal of the 3-
phenoxycarbonyl group on acidic treatment of the reaction
mixture.
2. Results and discussion
We describe here a convenient, widely applicable synthesis of 3-
unsubstituted oxindole-1-carboxamides (3). The synthetic route
applied is depicted in Scheme 2.
The synthesis of diester salts 7aed has been described in our
earlier publication30 by N,O-bis(phenoxycarbonylation) of oxin-
doles 5aed to 6aed and their subsequent rearrangement (Scheme
2). New derivatives 6eeg and 7eeg were now obtained by using the
same protocol.
Selective amidation of diester DMAP salt 7a to form 1-
carboxamido-3-phenoxycarbonyl compounds 10beg (Scheme 2)
has been described earlier.19 New compounds 10a and 10heo were
now prepared by an analogous procedure. Treatment of

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M. Porcs-Makkay et al. / Tetrahedron 68 (2012) 1427e1435
Table 1 summarizes the yields of transformations 6/3 carried
At the beginning, 5-chlorooxindole derivatives were used as
model compounds (see 3aei). Later on, we inquired whether this
methodology could be generalised by varying the character and the
position of the substituent on the aromatic nucleus. Thus, we in-
vestigated the analogous synthesis of 6-chloro (3j), 5-nitro (3l), 5-
methoxy (3o), 5-fluoro (3m), 6-fluoro (3n) and unsubstituted (3k)
oxindole derivatives, using piperidine as the amine reagent. It was
concluded that in each case the desired oxindole-1-carboxamides
(3) could be prepared using the one-pot procedure, in medium to
good yield.
out with isolation of intermediates 7 and 10 (route A), with iso-
lation of 10 alone (route B), and in one-pot (route C). In cases where
the total yield of the first two steps (6/7 and 7/10) was lower
than the yield of the one-pot reaction (6/3), acidic hydrolysis of
intermediates 10 to compounds 3 was not performed. The data
demonstrate that the one-pot procedure (route C) is in most cases
superior to routes A and B, in terms of yield and synthetic sim-
plicity. However, for a few derivatives (3a, 3iek), the stepwise
approach resulted in a higher overall yield.
Table 1
Comparison of the total yields of transformations 6/3 carried out with isolation of intermediates 7 and 10 (route A), with isolation of 10 alone (route B), and in one-pot
(route C)
6,7
X
10,3
NR1R2
Yield (%)
Yield (%)
Yield (%)
Total yield (%) of sequential
steps (route Aa)
Total yield (%)
via route
One-pot yield (%)
via route Ca
a
6/7
7/10
10/3
6/7/10/3
6/7/3
6/3
a
a
5-Cl
5-Cl
a
NH2
93b
93
95
82
49
b
93b
63c
71
86
N
a
a
a
5-Cl
5-Cl
5-Cl
c
93b
83c
N
d
e
93b
93b
77c
94c
65
67
47
59
51
68
N
O
N
N
N
N
a
a
5-Cl
5-Cl
f
93b
93b
80c
50c
99
40
74
19
97
34
HN
N
g
H3C
a
5-Cl
h
93b
43
67
99
27
79
93
HN
a
b
c
d
e
f
5-Cl
6-Cl
H
i
93b
97b
96b
94b
92
86
90
95
48
72
57
46
86
46
86
73
75
N
N
j
88
41
N
N
N
N
N
k
l
74
99
67
46
5-NO2
5-F
m
n
6-F
66
g
5-MeO
o
96
34
88
N
a
Yield of product 3 is calculated for 6 as the starting compound.
See Ref. 30.
See Ref. 19.
b
c

M. Porcs-Makkay et al. / Tetrahedron 68 (2012) 1427e1435
1431
3. Conclusions
cmꢀ1): 1784, 1757, 1613, 1497. 1H NMR (CDCl3, 400 MHz)
d
7.92 (1H,
dd, J¼10.2, 2.3 Hz), 7.51 (1H, d, J¼8.7 Hz), 7.30 (10H, m), 7.06 (1H,
Various procedures have been developed at our laboratory for
the practical synthesis of 3-unsubstituted oxindole-1-
carboxamides (3). The most convenient one-pot approach applies
the easily available N(1),O-bis(phenoxycarbonyl) derivatives (6) as
starting materials, and involves (i) O/C(3) migration of the phe-
noxycarbonyl moiety (6/7); (ii) amidation in position 1 (7/10);
and (iii) hydrolysis and decarboxylation of the 3-phenoxycarbonyl
group upon acidic treatment, furnishing oxindole-1-carboxamides
(3) in medium to high overall yields. The methodology described
above is applicable for oxindole derivatives with various sub-
stituents on the aromatic nucleus and offers a convenient approach
to a wide range of new oxindole-1-carboxamides, which are only
circuitously or, in the case of N,N-disubstituted carboxamides, not
at all available by other procedures.
dd, J¼8.8, 2.4 Hz), 6.48 (1H, s). 13C NMR (CDCl3, 100 MHz)
d 161.0 (d,
J¼241.2 Hz), 151.1, 150.8, 149.8, 148.3, 141.1 (d, J¼3.4 Hz), 133.0 (d,
J¼13.3 Hz), 129.8, 129.6, 126.9, 126.6, 122.7, 121.8 (d, J¼9.6 Hz),
121.4, 120.7, 112.2 (d, J¼24.0 Hz), 103.4 (d, J¼29.3 Hz), 98.0. Anal.
Calcd for C22H14FNO5 (391.36): C 67.52, H 3.61, N 3.58%. Found: C
67.09, H 3.69, N 3.55%.
4.2.3. Phenyl 5-methoxy-2-[(phenoxycarbonyl)oxy]-1H-indole-1-
carboxylate (6g). This compound was prepared according to the
general procedure I using 5-methoxyoxindole (5g) to give 6g
(14.0 g, 87%) as colourless crystals, mp 117e121 ꢁC (ethyl acetate).
IR (KBr, cmꢀ1): 1787, 1758, 1604, 1481. 1H NMR (CDCl3, 400 MHz)
d
8.05 (1H, d, J¼9.1 Hz), 7.40e7.09 (10H, m), 7.03 (1H, d, J¼2.3 Hz),
6.95 (1H, dd, J¼9.1, 2.3 Hz), 6.43 (1H, s), 3.85 (3H, s). 13C NMR
(CDCl3, 100 MHz)
d 156.7, 151.1, 150.9, 149.9, 148.4, 141.5, 129.7,
4. Experimental section
4.1. General
129.5, 127.5, 127.2, 126.7, 121.5, 120.7, 116.6, 113.3, 104.1, 98.4, 55.7.
Anal. Calcd for C23H17NO6 (403.40): C 68.48, H 4.25, N 3.47%. Found:
C 68.13, H 4.33, N 3.44%.
€
All melting points were determined on a Buchi 535 capillary
4.3. General procedure II for the synthesis of 1,3-diacylated
oxindole DMAP salts 730
melting point apparatus. IR spectra were obtained on a Bruker IFS-
113v FT spectrometer in KBr pellets. 1H NMR spectra were recorded
on a Varian Gemini 200 (200 MHz), Bruker Avance III (400 MHz) or
a Varian Unity Inova 500 (500 MHz) spectrometer. CDCl3 or DMSO-
d6 was used as solvent and tetramethylsilane (TMS) as internal
To a solution of 6 (10 mmol) in DMF (10 mL) was added a so-
lution of DMAP (10 mmol) in DMF (10 mL) at 0e2 ꢁC. The mixture
was stirred for 10 min and ice-water (40 g) was added. The crude
product was filtered and washed with water to give compounds 7.
An analytical sample was recrystallized from the solvent
indicated.
standard. Chemical shifts (d) and coupling constants (J) are given in
parts per million and in hertz, respectively. Elemental analyses
were performed on a PerkineElmer 2400 analyzer. The reactions
were followed by analytical thin layer chromatography on silica gel
60 F254. All unspecified reagents were purchased from commercial
sources. Compounds 6aed,30 7aed30 and 10beg19 were described
in our earlier papers. New intermediates and final products are
described below in detail.
4.3.1. 4-(Dimethylamino)pyridinium
5-fluoro-1,3-bis(phenoxycarbo
nyl)-1H-indol-2-olate(7e). This compound was prepared according to
the general procedure II using 6e (3.91 g, 10 mmol) to give 7e (4.70 g,
92%) as colourless crystals, mp 184e186 ꢁC (acetonitrile). IR (KBr,
cmꢀ1): 2795, 1715, 1628, 1570. 1H NMR (DMSO-d6, 400 MHz)
d 13.18
4.2. General procedure I for the synthesis of N,O-diacylated
(1H, s), 8.20 (2H, d, J¼7.7 Hz), 7.60 (1H, d, J¼9.0 Hz), 7.48e7.08 (10H,
oxindoles 630
m), 7.32 (1H, d, J¼2.4 Hz), 6.96 (2H, d, J¼7.7 Hz), 6.49 (1H, d, J¼9.6,
2.8 Hz), 3.17 (6H, s). 13C NMR (DMSO-d6, 100 MHz)
d 163.3, 161.5 (d,
To a solution of the corresponding substituted oxindole (5,
40 mmol) and triethylamine (88 mmol) in THF (140 mL) was added
phenyl chloroformate (13.76 g, 11.0 mL, 88 mmol) dropwise. The
temperature was kept below 30 ꢁC during the addition. After stir-
ring for 30 min at room temperature, the solvent was evaporated.
Water (40 mL) was added to the residue and the mixture was
stirred for 2 h at 0e5 ꢁC. The crystalline product was filtered and
recrystallized from ethyl acetate to give compounds 6.
J¼248.0 Hz), 158.3, 157.5, 157.1, 152.2, 150.7 (d, J¼9.3 Hz), 139.4, 129.7
(d, J¼22.8 Hz), 129.5, 129.0, 126.4, 125.8, 124.0, 122.5, 122.0, 121.4,
115.4, 113.2 (d, J¼9.3 Hz), 107.0, 103.4 (d, J¼23.4 Hz), 102.9 (d,
J¼25.4 Hz), 80.4, 24.1. Anal. Calcd for C29H24FN3O5 (513.53): C 67.83, H
4.71, N 8.18%. Found: C 67.53, H 4.75, N 8.09%.
4.3.2. 4-(Dimethylamino)pyridinium 6-fluoro-1,3-bis(phenoxycarbo
nyl)-1H-indol-2-olate (7f). This compound was prepared according
to the general procedure II using 6f (3.93 g, 10 mmol) to give 7f
(3.41 g, 66%) as colourless crystals, mp 210e214 ꢁC (ethanol). IR
(KBr, cmꢀ1): 2776, 1732, 1672, 1621. 1H NMR (DMSO-d6, 400 MHz)
4.2.1. Phenyl 5-fluoro-2-[(phenoxycarbonyl)oxy]-1H-indole-1-
carboxylate (6e). This compound was prepared according to the
general procedure I using 5-fluorooxindole (5e) to give 6e (5.90 g,
38%) as colourless crystals, mp 95e98 ꢁC (ethyl acetate). IR (KBr,
d
13.19 (1H, s), 8.19 (2H, d, J¼7.7 Hz), 7.53 (1H, td, J¼6.0, 2.4 Hz), 7.40
(10H, m), 7.08 (1H, d, J¼8.6 Hz), 6.97 (2H, d, J¼7.7 Hz), 6.77 (1H, td,
cmꢀ1): 1785, 1749, 1615, 1475. 1H NMR (CDCl3, 400 MHz)
d
8.13
J¼8.5, 2.6 Hz), 3.17 (6H, s). 13C NMR (DMSO-d6, 100 MHz)
d 163.2,
(1H, dd, J¼9.1, 4.5 Hz), 7.47 (2H, m), 7.37e7.23 (6H, m), 7.31 (1H, d,
162.8, 157.0, 156.8 (d, J¼230.0 Hz), 152.4, 150.7 (d, J¼10.3 Hz), 139.3,
130.3 (d, J¼11.7 Hz), 129.6, 129.0, 125.8, 123.8, 122.5, 122.0, 116.5,
108.7 (d, J¼21.0 Hz), 107.1, 100.7 (d, J¼28.8 Hz), 78.8. Anal. Calcd for
C29H24FN3O5 (513.53): C 67.83, H 4.71, N 8.18%. Found: C 67.56, H
4.69, N 8.39%.
J¼8.2 Hz), 7.09 (2H, m), 7.07 (1H, dd, J¼7.8, 2.6 Hz), 6.48 (1H, s).
13C NMR (CDCl3, 100 MHz)
d
159.8 (d, J¼241.3 Hz), 151.0, 150.8,
149.8, 148.3, 142.1, 129.8, 129.6, 129.1 (d, J¼1.3 Hz), 127.6 (d,
J¼10.2 Hz), 126.8, 126.6, 121.5, 120.7, 117.0 (d, J¼9.1 Hz), 112.9 (d,
J¼24.9 Hz), 106.6 (d, J¼24.4 Hz), 98.3 (d, J¼3.7 Hz). Anal. Calcd for
C22H14FNO5 (391.36): C 67.52, H 3.61, N 3.58%. Found: C 67.40, H
3.63, N 3.58%.
4.3.3. 4-(Dimethylamino)pyridinium 5-methoxy-1,3-bis(phenoxycar
bonyl)-1H-indol-2-olate (7g). This compound was prepared
according to the general procedure II using 6g (4.03 g, 10 mmol) to
give 7g (5.05 g, 96%) as colourless crystals, mp 189e190 ꢁC (tolu-
ene). IR (KBr, cmꢀ1): 2814, 1715, 1674, 1622, 1584. 1H NMR (DMSO-
4.2.2. Phenyl 6-fluoro-2-[(phenoxycarbonyl)oxy]-1H-indole-1-
carboxylate (6f). This compound was prepared according to the
general procedure I using 6-fluorooxindole (5f) to give 6f (11.3 g,
73%) as colourless crystals, mp 125e128 ꢁC (ethyl acetate). IR (KBr,
d6, 400 MHz)
d
13.18 (1H, s), 8.18 (2H, d, J¼7.5 Hz), 7.54 (1H, d,
J¼8.6 Hz), 7.31 (10H, m), 7.24 (1H, d, J¼2.6 Hz), 6.92 (2H, d,

1432
M. Porcs-Makkay et al. / Tetrahedron 68 (2012) 1427e1435
J¼7.4 Hz), 6.32 (1H, dd, J¼8.6, 2.7 Hz), 3.76 (3H, s), 3.14 (6H, s). 13
C
Calcd for C33H32ClN5O4 (598,11): C 66.27, H 5.39, Cl 5.93, N 11.71%.
Found: C 66.10, H 5.57, Cl 6.19, N 11.48%.
NMR (DMSO-d6, 100 MHz)
d 163.4, 156.9, 155.9, 152.4, 150.9, 150.6,
139.9, 132.6, 129.8, 129.6, 129.5, 129.0, 125.6, 124.4, 123.8, 122.5,
122.1, 121.8, 115.5, 113.0, 107.0, 103.6, 102.6, 80.2, 55.0. Anal. Calcd
for C30H27N3O6 (525.57): C 68.56, H 5.18, N 8.00%. Found: C 68.70, H
5.23, N 8.06%.
4.4.4. 4-(Dimethylamino)pyridinium 6-chloro-3-(phenoxycarbonyl)-
1-(piperidin-1-ylcarbonyl)-1H-indol-2-olate (10j). This compound
was prepared according to the general procedure III using 7b and
piperidine to give 10j (1.88 g, 90%) as colourless crystals, mp
183e185 ꢁC (acetonitrile). IR (KBr, cmꢀ1): 3066, 2942,1700,1493. 1H
4.4. General procedure III for the synthesis of compounds
1019
NMR (DMSO-d6, 200 MHz)
d
13.21 (1H, br s), 8.19 (2H, d, J¼7.3 Hz),
7.48 (1H, d, J¼7.9 Hz), 7.36 (2H, t, J¼7.8 Hz), 7.15 (1H, t, J¼7.3 Hz), 7.07
(2H, d, J¼7.8Hz), 6.98 (2H, d, J¼7.3 Hz), 6.69 (2H, d, J¼8.4 Hz), 3.55
(2H, br s), 3.29 (2H, br s), 3.15 (6H, s),1.59 (6H, br s).13C NMR (DMSO-
A solution of the DMAP salt of the 1,3-bis(phenoxycarbonyl)-
1H-indol-2-olate (7, 4.0 mmol) and the corresponding amine
(8.0 mmol) in DMF (10 mL) was stirred at room temperature for
2e4 h. The reaction mixture was poured onto ice-water (20 g) and
stirred for 1 h. The crystalline product was filtered and washed
with water to give compound compounds 10. The compounds
obtained could be used in the next step without further purifica-
tion. An analytical sample was recrystallized from the solvent
indicated.
d6, 100 MHz)
d 157.0, 154.0, 140.0, 128.9, 123.7, 122.5, 119.8, 115.3,
108.5, 107.1, 24.0. Anal. Calcd for C28H29ClN4O4 (521.03): C 64.55, H
5.61, Cl 6.81, N 10.75%. Found: C 64.29, H 5.61, Cl 6.89, N 10.42%.
4.4.5. 4-(Dimethylamino)pyridinium 3-(phenoxycarbonyl)-1-(piper-
idin-1-ylcarbonyl)-1H-indol-2-olate (10k). This compound was
prepared according to the general procedure III using 7c and pi-
peridine to give 10k (1.85 g, 95%) as colourless crystals, mp
174e176 ꢁC (acetonitrile). IR (KBr, cmꢀ1): 2931, 1696, 1646, 1546. 1H
4.4.1. 4-(Dimethylamino)pyridinium 1-carbamoyl-5-chloro-3-(phe-
noxycarbonyl)-1H-indol-2-olate (10a). A solution of the DMAP salt
of the 1,3-bis(phenoxycarbonyl)-1H-indol-2-olate 7a (2.12 g,
4.0 mmol) and ammonium carbonate (1.36 g, NH3 content 10%,
8.0 mmol) in DMF (10 mL) was stirred at 45 ꢁC for 2 h. The reaction
mixture was poured onto ice-water (20 g) and stirred for 1 h. The
crystalline product was filtered and washed with water to give 10a
(1.69 g, 93%) as colourless crystals, mp 186e187 ꢁC (acetonitrile).
IR (KBr, cmꢀ1): 3316, 1704, 1557, 1436. 1H NMR (DMSO-d6,
NMR (DMSO-d6, 200 MHz)
d
13.33 (1H, br s), 8.18 (2H, d, J¼7.2 Hz),
7.48 (1H, d, J¼7.6 Hz), 7.34 (2H, t, J¼7.7 Hz), 7.12 (1H, m), 7.07 (2H, d,
J¼7.6 Hz), 6.92 (2H, d, J¼7.2 Hz), 6.76 (2H, m), 6.67 (1H, t, J¼7.6Hz),
3.70 (2H, br s), 3.40 (2H, br s), 3.15 (6H, s), 1.61 (6H, m). 13C NMR
(DMSO-d6, 100 MHz)
d 157.4, 154.0, 142.0, 141.0, 129.5, 128.9, 127.6,
123.6, 122.5, 120.2, 118.9, 117.6, 115.3, 108.5, 107.0, 44.4, 26.1, 25.4,
24.1. Anal. Calcd for C28H30N4O4 (486.58): C 69.12, H 6.21, N 11.51%.
Found: C 69.13, H 6.42, N 11.14%.
500 MHz)
d
13.18 (1H, br s), 9.44 (1H, br s), 8.18 (2H, d, J¼7.6 Hz),
7.99 (1H, d, J¼8.5 Hz), 7.53 (1H, d, J¼2.2 Hz), 7.37 (2H, m), 7.15 (1H,
m), 7.09 (2H, d, J¼7.6 Hz), 6.98 (1H, s), 6.96 (2H, J¼7.6 Hz), 6.71 (1H,
dd, J¼8.5, 2.2 Hz), 3.16 (6H, s). 13C NMR (DMSO-d6, 100 MHz)
4.4.6. 4-(Dimethylamino)pyridinium 5-nitro-3-(phenoxycarbonyl)-
1-(piperidin-1-ylcarbonyl)-1H-indol-2-olate (10l). This compound
was prepared in a one-pot procedure starting from 6d (1.67 g,
4.0 mmol), treated in a solution of DMF (10 mL) with DMAP (0.49 g,
4.0 mmol) at 0e2 ꢁC. The mixture was stirred for 10 min, then pi-
peridine (0.68 g, 0.79 mL, 8.0 mmol) was added and stirred for 1 h
at room temperature. It was poured onto a mixture of ice and water
(20 g) and stirred for 1 h. The crystalline product was filtered and
washed with water to give 10l (1.02 g, 48%) as yellow crystals, mp
205e206 ꢁC (acetonitrile). IR (KBr, cmꢀ1): 3058, 2946,1691,1515. 1H
d
165.7, 163.1, 157.1, 154.9, 152.1, 139.3, 131.5, 129.6, 129.0, 126.1,
124.1, 122.6, 117.4, 115.6, 114.3, 80.8. Anal. Calcd for C23H21N4O4
(452.90): C 61.00, H 4.67, Cl 7.83, N 12.37%. Found: C 60.92, H 4.66,
Cl 7.81, N 12.44%.
4.4.2. 4-(Dimethylamino)pyridinium 1-(benzylcarbamoyl)-5-chloro-
3-(phenoxycarbonyl)-1H-indol-2-olate (10h). This compound was
prepared according to the general procedure III using 7a and ben-
zylamine to give 10h (0.90 g, 43%) as colourless crystals, mp
202e205 ꢁC (acetonitrile). IR (KBr, cmꢀ1): 3058, 1701, 1647, 1538,
NMR (DMSO-d6, 200 MHz)
d
8.34 (1H, d, J¼2.4 Hz), 8.18 (2H, d,
J¼7.6 Hz), 7.66 (1H, dd, J¼8.4, 2.4 Hz), 7.41 (2H, m), 7.16 (3H, m),
6.94 (3H, d, J¼8.6 Hz), 3.70 (2H, br s), 3.40 (2H, br s), 3.15 (6H, s),
1398. 1H NMR (CDCl3, 400 MHz)
d
10.21 (1H, t, J¼5.4 Hz), 8.24 (1H,
1.90e1.30 (6H, m). 13C NMR (DMSO-d6, 100 MHz)
d 164.3, 163.1,
d, J¼8.8 Hz), 7.87 (2H, d, J¼7.5 Hz), 7.73 (1H, d, J¼2.2 Hz), 7.31 (11H,
157.0, 152.1, 151.6, 141.7, 139.3, 136.7, 130.3, 129.1, 124.2, 122.6, 114.6,
111.1, 107.7, 107.1, 79.7, 47.8, 44.4, 26.3, 25.5, 24.0. Anal. Calcd for
C28H29N5O6 (531.55): C 63.23, H 5.50, N 13.18%. Found: C 63.07, H
5.52, N 13.16%.
m), 6.94 (1H, dd, J¼8.7, 2.4 Hz), 6.39 (2H, d, J¼7.6 Hz), 4.60 (2H, d,
J¼5.4 Hz), 3.05 (6H, s). 13C NMR (CDCl3, 100 MHz)
d 165.8, 163.0,
157.0, 154.5, 152.1, 139.7, 139.6, 131.4, 129.5, 129.1, 128.6, 127.4, 127.3,
127.0, 126.2, 124.1, 122.5, 117.5, 115.7, 114.2, 107.1, 80.9, 42.6. Anal.
Calcd for C30H27ClN4O4 (543.03): C 66.36, H 5.01, Cl 6.53, N 10.32%.
Found: C 66.08, H 5.13, Cl 6.51, N 10.48%.
4.4.7. 4-(Dimethylamino)pyridinium 5-fluoro-3-(phenoxycarbonyl)-
1-(piperidin-1-ylcarbonyl)-1H-indol-2-olate (10m). This compound
was prepared according to the general procedure III using 7e and
piperidine to give 10m (1.45 g, 72%) as colourless crystals, mp
179e180 ꢁC (acetonitrile). IR (KBr, cmꢀ1): 2937, 1698, 1648, 1558,
4.4.3. 4-(Dimethylamino)pyridinium 1-[(4-phenylpiperazin-1-yl)car
bonyl]-5-chloro-3-(phenoxycarbonyl)-1H-indol-2-olate (10i). This
compound was prepared according to the general procedure III
using 7a and 1-phenylpiperazine to give 10i (2.06 g, 86%) as col-
ourless crystals, mp 160e163 ꢁC (acetonitrile). IR (KBr, cmꢀ1): 3064,
1398. 1H NMR (DMSO-d6, 500 MHz)
d 13.33 (1H, br s), 8.19 (2H, d,
J¼7.6 Hz), 7.34 (2H, t, J¼7.7 Hz), 7.19 (1H, dd, J¼10.7, 2.6 Hz), 7.14
(1H, t, J¼7.7 Hz), 7.08 (2H, d, J¼7.6 Hz), 6.96 (2H, d, J¼7.6 Hz), 6.76
(1H, dd, J¼8.2, 5.0 Hz), 6.41 (1H, td, J¼8.3, 2.7 Hz), 3.52 (4H, br s),
1733,1647, 1558, 1394. 1H NMR (DMSO-d6, 500 MHz)
d 13.27 (1H, br
s), 8.19 (2H, d, J¼7.3 Hz), 7.45 (1H, d, J¼1.5 Hz), 7.36 (2H, t, J¼7.8 Hz),
7.22 (2H, t, J¼7.8 Hz), 7.14 (1H, m), 7.08 (2H, d, J¼7.8 Hz), 6.95 (2H,
d J¼7.3 Hz), 6.94 (2H, d, J¼7.1 Hz), 6.84 (1H, d, J¼8.2 Hz), 6.79 (1H,
m), 6.66 (1H, dd, J¼8.2, 2.1 Hz), 3.79 (2H, br s), 3.56 (2H, br s), 3.27
3.17 (6H, s), 1.55 (6H, br s). 13C NMR (DMSO-d6, 100 MHz)
d 163.3,
158.3 (d, J¼230.3 Hz), 156.8, 152.4 (d, J¼22.6 Hz), 140.1, 129.0, 128.0,
123.9, 122.5, 108.8, 107.1, 103.2 (d, J¼24.0 Hz), 24.0. Anal. Calcd for
C28H29FN4O4 (504.57): C 66.65, H 5.79, N 11.10%. Found: C 66.40, H
5.58, N 10.84%.
(4H, m), 3.16 (6H, s). 13C NMR (DMSO-d6, 100 MHz)
d 172.7, 157.4,
152.5, 152.3, 151.0, 149.6, 140.7, 139.8, 130.3, 129.5, 129.1, 129.0,
128.9, 127.5, 127.4, 127.3, 125.0, 124.7, 123.8, 122.6, 119.6, 119.4,116.7,
116.1, 116.0, 115.8, 115.3, 113.3, 113.2, 110.0, 107.1, 79.5, 35.9. Anal.
4.4.8. 4-(Dimethylamino)pyridinium 6-fluoro-3-(phenoxycarbonyl)-
1-(piperidin-1-ylcarbonyl)-1H-indol-2-olate (10n). This compound

M. Porcs-Makkay et al. / Tetrahedron 68 (2012) 1427e1435
1433
was prepared according to the general procedure III using 7f
(DMSO-d6, 100 MHz)
d
176.6, 152.0, 140.5, 128.0, 127.4, 126.8, 124.3,
(2.06 g, 4.0 mmol) and piperidine (0.68 g, 0.8 mL, 8.0 mmol) to give
10n (1.15 g, 57%) as colourless crystals, mp 173e176 ꢁC (acetoni-
trile). IR (KBr, cmꢀ1): 2945, 1707, 1655, 1632, 1481. 1H NMR (DMSO-
116.8, 36.6. Anal. Calcd for C9H7ClN2O2 (210.62): C 51.32, H 3.35, Cl
16.83, N 13.30%. Found: C 51.29, H 3.37, Cl 16.69, N 13.37%. Method 2.
This compound was also prepared according to the general pro-
cedure IV/A using 10a (0.91 g, 2 mmol), and stirred with aqueous
HCl at 55e60 ꢁC for 3 h to give 3a (0.40 g, 95%) as colourless crys-
tals, identical with compound obtained by Method 1.
d6, 400 MHz)
d
13.34 (1H, s), 8.19 (2H, d, J¼7.6 Hz), 7.40 (1H, dd,
J¼8.8, 6.0 Hz), 7.34 (2H, m), 7.10 (3H, m), 6.96 (2H, d, J¼7.6 Hz), 6.58
(2H, m), 3.39 (4H, br s), 3.17 (6H, s), 1.59 (6H, br s). 13C NMR (DMSO-
d6, 100 MHz)
d
156.9, 156.7 (d, J¼230.2 Hz), 155.6, 152.4 (d,
J¼16.3 Hz), 139.9, 129.5, 128.9, 123.6, 122.5, 107.1, 106.1 (d,
J¼21.0 Hz), 96.5 (d, J¼27.0 Hz), 78.6, 58.0, 34.0, 24.1. Anal. Calcd for
C28H29FN4O4 (504.57): C 66.65, H 5.79, N 11.10%. Found: C 66.55, H
5.59, N 10.98%.
4.5.2. 5-Chloro-1-(pyrrolidin-1-ylcarbonyl)-1,3-dihydro-2H-indol-2-
one (3b). This compound was prepared according to the general
procedure IV/C using 6a (4.08 g, 10 mmol) and pyrrolidine (1.44 g,
1.7 mL, 20 mmol), and stirred with aqueous HCl at room tempera-
ture for 1 h to give 3b (1.88 g, 71%) as colourless crystals, mp
159e162 ꢁC (ethyl acetate/hexane). IR (KBr, cmꢀ1): 2942, 1736,
4.4.9. 4-(Dimethylamino)pyridinium
5-methoxy-3-(phenoxycarbo
nyl)-1-(piperidin-1-ylcarbonyl)-1H-indol-2-olate (10o). This com-
pound was prepared according to the general procedure III using 7g
and piperidine to give 10o (0.70 g, 34%) as colourless crystals, mp
136e138 ꢁC (ethyl acetate). IR (KBr, cmꢀ1): 2939, 1693, 1644, 1561,
1688, 1588. 1H NMR (DMSO-d6, 500 MHz)
d
7.27 (1H, d, J¼2.1 Hz),
7.18 (2H, m), 3.65 (2H, t, J¼6.4 Hz), 3.61 (2H, s), 3.53 (2H, t,
J¼6.4 Hz),1.97 (4H, m). 13C NMR (DMSO-d6,100 MHz)
d 172.0,149.5,
140.3, 128.9, 128.0, 125.6, 124.6, 113.7, 47.7, 47.2, 36.0, 25.8, 24.5.
Anal. Calcd for C13H13ClN2O2 (264.72): C 58.98, H 4.93, Cl 13.39, N
10.58%. Found: C 58.65, H 4.93, Cl 13.30, N 10.54%.
1398. 1H NMR (DMSO-d6, 400 MHz)
d 13.30 (1H, br s), 8.19 (2H, d,
J¼7.6 Hz), 7.36 (2H, m), 7.11 (4H, m), 6.96 (2H, d, J¼7.6 Hz), 6.67 (1H,
d, J¼8.3 Hz), 6.25 (1H, dd, J¼8.3, 2.6 Hz), 3.65 (3H, s), 3.39 (4H, br s),
3.17 (6H, s), 1.59 (6H, br s). 13C NMR (DMSO-d6, 100 MHz)
d
163.2,
4.5.3. 5-Chloro-1-(piperidin-1-ylcarbonyl)-1,3-dihydro-2H-indol-2-
one (3c). This compound was prepared according to the general
procedure IV/C using 6a (4.08 g, 10 mmol) and piperidine (1.70 g,
2.0 mL, 20 mmol), and stirred with aqueous HCl at room temper-
ature for 1 h to give 3c (2.40 g, 86%) as colourless crystals, mp
112e114 ꢁC (ethyl acetate). IR (KBr, cmꢀ1): 2949, 1744, 1684, 1608.
157.5, 156.8, 154.5, 152.9, 152.6, 140.2, 129.5, 128.9, 126.4, 123.6,
122.5, 118.9, 115.4, 80.1, 59.9, 55.2, 25.9, 24.1, 23.8, 20.9, 14.2. Anal.
Calcd for C29H32N4O5 (516.6): C 67.43, H 6.24, N 10.85%. Found: C
67.38, H 6.34, N 10.53%.
4.5. General procedures IV/AeIV/C for the synthesis of
compounds 3
1H NMR (DMSO-d6, 500 MHz)
3.67 (2H, s), 3.61 (2H, s), 3.38 (2H, s), 1.69 (6H, s). 13C NMR (DMSO-
d6, 100 MHz) 172.1, 150.0, 140.6, 128.5, 127.8, 125.6, 124.5, 113.2,
d
7.25 (2H, m), 7.05 (1H, d, J¼8.1 Hz),
d
General procedure IV/A (route A). A suspension of compound 10
in a mixture of water (2 mL/mmol 10) and concentrated HCl (82 mL/
48.2, 45.0, 35.8, 26.2, 25.3, 24.0. Anal. Calcd for C14H15ClN2O2
(278.75): C 60.32, H 5.42, Cl 12.72, N 10.05%. Found: C 60.13, H 5.39,
Cl 12.65, N 9.93%.
mmol 10) was stirred for 0.5e3 h at room temperature or at
60e80 ꢁC. The crystalline product was filtered and washed with
water to give compound 3. An analytical sample was recrystallized
from the solvent indicated.
General procedure IV/B (route B). To a solution of 4-(dimethyla-
mino)pyridinium 1,3-bis(phenoxycarbonyl)-1H-indol-2-olate (7) in
DMF (2 mL/mmol 7) the corresponding amine (2.0 equiv) was
added and the solution thus obtained was stirred at room tem-
perature for 2e4 h. It was poured onto a mixture of ice-water (2 g/
4.5.4. 5-Chloro-1-(morpholin-4-ylcarbonyl)-1,3-dihydro-2H-indol-
2-one (3d). Method 1. This compound was prepared according to
the general procedure IV/C using 6a (4.08 g, 10 mmol) and mor-
pholine (1.74 g, 1.70 mL, 20 mmol), and stirred with aqueous HCl at
room temperature for 1 h to give 3d (1.43 g, 51%) as colourless
crystals, mp 149e150 ꢁC (ethyl acetate). IR (KBr, cmꢀ1): 2930, 1733,
1681, 1613. 1H NMR (DMSO-d6, 500 MHz)
7.26 (1H, m), 7.14 (1H, d, J¼8.2 Hz), 3.78 (4H, s), 3.63 (2H, s), 3.50
(4H, s). 13C NMR (DMSO-d6, 100 MHz)
172.3, 150.1, 140.4, 129.2,
d
7.29 (1H, d, J¼2.1 Hz),
mmol 7) and concentrated HCl (82 mL/mmol 7), and stirred for 2 h
at room temperature. The crystalline product was filtered and
washed with water to give compound 3. An analytical sample was
recrystallized from the solvent indicated.
d
128.2, 125.6, 124.7, 113.9, 66.6, 36.0. Anal. Calcd for C13H13ClN2O3
(280.72): C 55.62, H 4.67, Cl 12.63, N 9.98%. Found: C 55.31, H 4.70,
Cl 12.41, N 9.71%. Method 2. This compound was also prepared
according to the general procedure IV/A using 10d (3.14 g, 6 mmol),
and stirred with aqueous HCl at room temperature for 1 h to give
3d (1.10 g, 65%) as colourless crystals, identical with compound
obtained by Method 1.
General procedure IV/C (route C). To
a solution of 1-
phenoxycarbonyl-2-(phenoxycarbonyloxy)indole (6) in DMF
(1 mL/mmol 6) was added a solution of DMAP (1.0 equiv) in DMF
(1 mL/mmol 6) at 0e2 ꢁC. The mixture was stirred for 10 min, the
corresponding amine (2.0 equiv) was added and the solution thus
obtained was stirred at room temperature for 2e4 h. It was poured
onto a mixture of ice-water (200 g) and concentrated HCl (82
m
L/
4.5.5. 5-Chloro-1-[(4-pyrimidin-2-ylpiperazin-1-yl)carbonyl]-1,3-
dihydro-2H-indol-2-one (3e). Method 1. This compound was pre-
pared according to the general procedure IV/C using 6a (4.08 g,
10 mmol) and 1-(pyrimidin-2-yl)piperazine (3.28 g, 20 mmol), and
stirred with aqueous HCl at 70e80 ꢁC for 2 h to give 3e (2.43 g, 68%)
as colourless crystals, mp 180e181 ꢁC (ethyl acetate). IR (KBr,
cmꢀ1): 2917, 1745, 1691, 1589, 1545. 1H NMR (DMSO-d6, 500 MHz)
mmol 6), and stirred for 1e3 h at room temperature or at
50e100 ꢁC. The crystalline product was filtered and washed with
water to give compound 3. An analytical sample was recrystallized
from the solvent indicated.
4.5.1. 5-Chloro-2-oxo-2,3-dihydro-1H-indole-1-carboxamide
(3a). Method 1. This compound was prepared according to the
general procedure IV/C using 6a (4.08 g, 10 mmol) and ammonium
carbonate (3.40 g, NH3 content 10%, 20 mmol), and stirred with
aqueous HCl at 60 ꢁC for 3 h to give 3a (1.03 g, 49%) as colourless
crystals, mp 206e209 ꢁC (acetonitrile) (lit.12 mp 211 ꢁC). IR (KBr,
cmꢀ1): 3368, 1740, 1716, 1584, 1470, 1375. 1H NMR (DMSO-d6,
d
8.33 (2H, d, J¼4.8 Hz), 7.28 (1H, d, J¼1.8 Hz), 7.26 (1H, m), 7.13 (1H,
d, J¼8.8 Hz), 6.55 (1H, t, J¼4.8 Hz), 3.96 (4H, s), 3.80 (2H, s), 3.65
(2H, s), 3.55 (2H, s). 13C NMR (DMSO-d6, 100 MHz)
190.4, 172.3,
d
161.4, 157.7, 150.2, 140.4, 129.0, 128.1, 125.7, 124.6, 113.9, 110.5, 43.5,
36.0. Anal. Calcd for C17H16ClN5O2 (357.80): C 57.07, H 4.51, Cl 9.91,
N 19.57%. Found: C 57.17, H 4.53, Cl 9.67, N 19.21%. Method 2. This
compound was also prepared according to the general procedure
IV/A using 10e (0.90 g, 1.5 mmol), and stirred with aqueous HCl at
500 MHz)
d
8.03 (1H, d, J¼8.7 Hz), 7.97 (1H, br s), 7.77 (1H, br s),
7.39 (1H, s), 7.34 (1H, dd, J¼8.7, 2.2 Hz), 3.85 (2H, s). 13C NMR

1434
M. Porcs-Makkay et al. / Tetrahedron 68 (2012) 1427e1435
70e80 ꢁC for 2 h to give 3e (0.36 g, 67%) as colourless crystals,
identical with compound obtained by Method 1.
according to the general procedure IV/A using 10i (0.60 g, 1 mmol),
and stirred with aqueous HCl at 70e80 ꢁC for 2 h to give 3i (0.35 g,
99%) as colourless crystals, identical with compound obtained by
Method 1.
4.5.6. 5-Chloro-2-oxo-N-propyl-2,3-dihydro-1H-indole-1-carboxamide
(3f). Method 1. This compound was prepared according to the general
procedure IV/A using 10f (1.24 g, 2.5 mmol), and stirred with aqueous
HCl at 80 ꢁC for 2 h to give 3f (0.63 g, 99%) as colourless crystals, mp
104e105 ꢁC (ethanol). IR (KBr, cmꢀ1): 3314, 2967, 1750, 1703, 1534. 1H
4.5.10. 6-Chloro-1-(piperidin-1-ylcarbonyl)-1,3-dihydro-2H-indol-2-
one (3j). Method 1. This compound was prepared according to the
general procedure IV/B using 7b (0.79 g, 1.5 mmol) and piperi-
dine (0.26 g, 0.30 mL, 3.0 mmol), and stirred with aqueous HCl at
room temperature for 2 h to give 3j (0.38 g, 91%) as colourless
crystals, mp 121e122 ꢁC (ethanol). IR (KBr, cmꢀ1): 2941, 1741,
NMR (DMSO-d6, 500 MHz)
d
8.51 (1H, t, J¼5.5 Hz), 8.01 (1H, d,
J¼8.7 Hz), 7.39 (1H, d, J¼2.3 Hz), 7.34 (1H, dd, J¼8.8, 2.3 Hz), 3.85 (2H,
s), 3.25 (2H, q, J¼6.9 Hz), 1.55 (2H, sext, J¼7.3 Hz), 0.90 (3H, t,
J¼7.3 Hz). 13C NMR (DMSO-d6, 100 MHz)
d
176.7, 151.5, 140.5, 128.0,
1685, 1610, 1437. 1H NMR (DMSO-d6, 200 MHz)
d 7.32 (1H, d,
127.3, 126.8, 124.3, 116.6, 41.1, 36.6, 22.4, 11.3. Anal. Calcd for
C12H13ClN2O2 (252.70): C 57.04, H 5.19, Cl 14.03, N 11.09%. Found: C
56.83, H 5.04, Cl 14.16, N 11.00%. Method 2. This compound was also
prepared according to the general procedure IV/C using 6a (4.08 g,
10 mmol) and propylamine (1.65 mL, 1.18 g, 20 mmol), and stirred
with aqueous HCl at 80 ꢁC for 2 h to give 3f (2.5 g, 97%) as colourless
crystals, identical with compound obtained by Method 1.
J¼8.1 Hz), 7.13 (1H, dd, J¼8.1, 1.8 Hz), 7.03 (1H, d, J¼1.8 Hz), 3.73
(2H, br s), 3.57 (2H, br s), 3.36 (2H, br s), 1.65e1.40 (6H, m). 13C
NMR (DMSO-d6, 100 MHz)
d 172.9, 149.3, 143.2, 131.9, 126.0,
124.2, 122.7, 111.7, 47.7, 44.5, 35.9, 26.2, 25.3, 23.7. Anal. Calcd for
C14H15ClN2O2 (278.74): C 60.33, H 5.42, Cl 12.72, N 10.05%. Found:
C 60.06, H 5.50, Cl 12.75, N 10.03%. Method 2. This compound was
also prepared according to the general procedure IV/C using 6b
(4.08 g, 10 mmol) and piperidine (1.70 g, 2.0 mL, 20 mmol), and
stirred with aqueous HCl at room temperature for 2 h to give 3j
(2.40 g, 86%) as colourless crystals, identical with compound
obtained by Method 1.
4.5.7. N-Benzyl-5-chloro-N-methyl-2-oxo-2,3-dihydro-1H-indole-1-
carboxamide (3g). Method 1. This compound was prepared
according to the general procedure IV/C using 6a (0.82 g, 2.0 mmol)
and N-benzylmethylamine (0.48 g, 0.51 mL, 4.0 mmol), and stirred
with aqueous HCl at 80e100 ꢁC for 2 h to give 3g (0.13 g, 34%) as
yellow crystals, mp 130e132 ꢁC (acetonitrile). IR (KBr, cmꢀ1): 2941,
4.5.11. 1-(Piperidin-1-ylcarbonyl)-1,3-dihydro-2H-indol-2-one
(3k). Method 1. This compound was prepared according to the
general procedure IV/B using 7c (1.0 g, 2.0 mmol) and piperidine
(0.34 g, 0.4 mL, 4.0 mmol), and stirred with aqueous HCl at room
temperature for 2 h to give 3k (0.21 g, 43%) as colourless crystals,
mp 117e122 ꢁC (ethanol). IR (KBr, cmꢀ1): 2944, 1732, 1675, 1610,
1735, 1693, 1476. 1H NMR (DMSO-d6, 500 MHz)
d 7.44e7.18 (7H, m),
7.05 (1H, d, J¼8.2 Hz), 4.70 (2H, br s), 3.81 (2H, br s), 2.94 (3H, s). 13C
NMR (DMSO-d6, 100 MHz)
d 172.7, 151.6, 140.6, 136.5, 128.7, 127.5,
127.4, 127.3, 124.8, 113.1, 53.8, 51.8, 35.9. Anal. Calcd for
C17H15ClN2O2 (314.77): C 64.87, H 4.80, Cl 11.26, N 8.90%. Found: C
64.53, H 4.94, Cl 11.16, N 8.97%. Method 2. This compound was also
prepared according to the general procedure IV/A using 10g (2.23 g,
4 mmol), and stirred with aqueous HCl at 70e80 ꢁC for 2 h to give
3g (0.50 g, 40%) as colourless crystals, identical with compound
obtained by Method 1.
1437. 1H NMR (DMSO-d6, 200 MHz)
d
7.30 (1H, d, J¼7.0 Hz), 7.26
(1H, t, J¼7.9 Hz), 7.07 (1H, t, J¼7.5 Hz), 6.97 (1H, d, J¼7.9 Hz),
3.80e3.50 (4H, m), 3.36 (2H, br s), 1.65e1.40 (6H, m). 13C NMR
(DMSO-d6, 100 MHz) d 173.0, 149.7, 142.0, 127.6, 125.1, 124.6, 123.0,
111.3, 47.6, 44.4, 35.7, 26.3, 25.3, 23.8. Anal. Calcd for C14H16N2O2
(244.30): C 68.83, H 6.60, N 11.47%. Found: C 68.65, H 6.68, N
11.50%. Method 2. This compound was also prepared according to
the general procedure IV/C using 6c (1.87 g, 5 mmol) and piperi-
dine (0.85 g, 1.0 mL, 10 mmol), and stirred with aqueous HCl at
room temperature for 2 h to give 3k (0.56 g, 46%) as colourless
crystals, identical with compound obtained by Method 1. Method
3. This compound was also prepared according to the general
procedure IV/A using 10k (0.49 g, 1 mmol), and stirred with
aqueous HCl at room temperature for 2 h to give 3k (0.18 g, 74%)
as colourless crystals, identical with compound obtained by
Method 1.
4.5.8. N-Benzyl-5-chloro-2-oxo-2,3-dihydro-1H-indole-1-carboxamide
(3h). Method 1. This compound was prepared according to the gen-
eral procedure IV/A using 10h (0.50 g, 0.9 mmol), and stirred with
aqueous HCl at 60e80 ꢁC for 2 h to give 3h (0.18 g, 67%) as colourless
crystals, mp 141e142 ꢁC (acetonitrile). IR (KBr, cmꢀ1): 2944, 1742,
1730, 1689, 1472. 1H NMR (DMSO-d6, 500 MHz)
d
8.9 (1H, br s), 8.21
(1H, d, J¼8.8 Hz), 7.37 (4H, m), 7.32e7.27 (2H, m), 7.24 (1H, m), 4.58
(2H, s), 3.71 (2H, s).13C NMR (DMSO-d6,100 MHz)
176.5,151.9,140.2,
d
137.8, 129.9, 128.7, 128.4, 127.6, 127.5, 124.6, 124.1, 117.6, 43.8, 36.7.
Anal. Calcd for C16H13ClN2O2 (300.75): C 63.90, H 4.36, Cl 11.79, N
9.31%. Found: C 63.65, H 4.41, Cl 11.86, N 9.34%. Method 2. This
compound was also prepared according to the general procedure IV/C
using 6a (4.08 g, 10 mmol) and benzylamine (2.14 g, 2.2 mL,
20 mmol), and stirred with aqueous HCl at 70e80 ꢁC for 2 h to give
3h (2.80 g, 93%) as colourless crystals, identical with compound ob-
tained by Method 1.
4.5.12. 5-Nitro-1-(piperidin-1-ylcarbonyl)-1,3-dihydro-2H-indol-2-
one (3l). Method 1. This compound was prepared according to the
general procedure IV/C using 6d (8.37 g, 20 mmol) and piperidine
(3.40 g, 4.0 mL, 40 mmol), and stirred with aqueous HCl at
50e55 ꢁC for 1 h to give 3l (5.0 g, 86%) as pale brown crystals, mp
160e162 ꢁC (ethanol). IR (KBr, cmꢀ1): 2948, 1762, 1693. 1H NMR
(CDCl3, 200 MHz)
(1H, d, J¼8.8 Hz), 3.74 (4H, br s), 3.40 (2H, br s), 1.95e1.40 (6H, m).
13C NMR (CDCl3, 100 MHz)
172.1, 149.1, 147.6, 143.8, 125.0, 124.8,
120.1, 112.2, 48.4, 45.3, 35.6, 26.3, 25.3, 24.0. Anal. Calcd for
C14H15N3O4 (289.30): C 58.12, H 5.23, N 14.53%. Found: C 58.23, H
5.39, N 14.15%. Method 2. This compound was also prepared
according to the general procedure IV/A using 10l (11.15 g,
21 mmol), and stirred with aqueous HCl at 65 ꢁC for 0.5 h to give 3l
(6.0 g, 99%) as yellow crystals, identical with compound obtained
by Method 1.
d
8.22 (1H, dd, J¼8.8, 2.2 Hz), 8.16 (1H, br s), 7.25
4.5.9. 5-Chloro-1-[(4-phenylpiperazin-1-yl)carbonyl]-1,3-dihydro-
2H-indol-2-one (3i). This compound was prepared according to the
general procedure IV/C using 6a (4.08 g, 10 mmol) and 1-
phenylpiperazine (3.24 g, 3.0 mL, 20 mmol), and stirred with
aqueous HCl at 70e80 ꢁC for 2 h to give 3i (1.64 g, 46%) as colourless
crystals, mp 189e190 ꢁC (ethyl acetate). IR (KBr, cmꢀ1): 2922, 2825,
d
1736, 1677, 1598. 1H NMR (DMSO-d6, 500 MHz)
(1H, d, J¼8.3 Hz), 6.92 (3H, m), 3.89 (4H, s), 3.65 (2H, s), 3.28 (4H, s).
13C NMR (DMSO-d6, 100 MHz)
172.5, 150.1, 140.5, 129.4, 129.2,
d 7.26 (4H, m), 7.10
d
128.3, 125.7, 124.8, 117.0, 114.0, 36.0. Anal. Calcd for C19H18ClN3O2
(355.81): C 64.13, H 5.10, Cl 9.96, N 11.81%. Found: C 64.45, H 5.25, Cl
9.59, N 11.60%. Method 2. This compound was also prepared
4.5.13. 5-Fluoro-1-(piperidin-1-ylcarbonyl)-1,3-dihydro-2H-indol-2-
one (3m). This compound was prepared according to the general

M. Porcs-Makkay et al. / Tetrahedron 68 (2012) 1427e1435
1435
procedure IV/C using 6e (1.17 g, 3.0 mmol) and piperidine (0.51 g,
0.60 mL, 6.0 mmol), and stirred with aqueous HCl at room tem-
perature for 2 h to give 3m (0.58 g, 73%) as colourless crystals, mp
114e117 ꢁC (obtained by chromatography on silica gel, eluent:
hexane/ethyl acetate 7:3). IR (KBr, cmꢀ1): 2950, 1736, 1681, 1483,
26.6, 25.7, 24.4. Anal. Calcd for C15H18N2O3 (274.32): C 65.68, H 6.61,
N 10.21%. Found: C 65.45, H 6.59, N 10.24%.
References and notes
1430, 1167. 1H NMR (CDCl3, 400 MHz)
d
7.07 (1H, m), 6.98 (2H, m),
3.69 (2H, m), 3.61 (2H, s), 3.40 (2H, br s), 1.69 (6H, br s). 13C NMR
(CDCl3, 100 MHz)
1. Andreani, A.; Rambaldi, M. J. Heterocycl. Chem. 1988, 25, 1519.
2. Oezcan, S.; Balci, M. Tetrahedron 2008, 64, 5531.
3. Blizzard, A. T.; Margiatto, G.; Mrozik, H.; Schaeffer, J. M.; Fisher, M. H. Tetra-
hedron Lett. 1991, 32, 2441.
4. Fulton, J. B.; Warkentin, J. Can. J. Chem. 1987, 65, 1177.
5. Becker, D. P.; Flynn, D. L.; Moormann, A. E.; Nosal, R.; Villamil, C. I.; Loeffler, R.;
Gullikson, G. W.; Moummi, Ch.; Yang, D.-C. J. Med. Chem. 2006, 49, 1125.
6. Robinson, R. P.; Reiter, L. A.; Barth, W. E.; Campeta, A. M.; Cooper, K.; Cronin, B.
J.; Destito, R.; Donahue, K. M.; Falkner, F. C.; Fiese, E. F.; Johnson, D. L.; Kuper-
man, A. V.; Liston, T. E.; Malloy, D.; Martin, J. J.; Mitchell, D. Y.; Rusek, F. W.;
Shamblin, S. L.; Wright, C. F. J. Med. Chem. 1996, 39, 10.
d
172.4, 159.3 (d, J¼241.6 Hz), 150.2, 138.1 (d,
J¼2.5 Hz), 125.6 (d, J¼8.8 Hz), 114.5 (d, J¼23.4 Hz), 113.3 (d,
J¼8.3 Hz), 111.9 (d, J¼24.8 Hz), 48.3, 45.1, 36.3 (d, J¼1.5 Hz), 26.3,
25.4, 24.1. Anal. Calcd for C14H15FN2O2 (262.29): C 64.11, H 5.76, N
10.68%. Found: C 63.75, H 5.78, N 10.65%.
4.5.14. 6-Fluoro-1-(piperidin-1-ylcarbonyl)-1,3-dihydro-2H-indol-2-
one (3n). This compound was prepared according to the general
procedure IV/C using 6f (1.61 g, 4.0 mmol) and piperidine (0.68 g,
0.80 mL, 8.0 mmol), and stirred with aqueous HCl at room tem-
perature for 2 h to give 3n (0.78 g, 75%) as colourless crystals, mp
139e142 ꢁC (ethyl acetate/hexane). IR (KBr, cmꢀ1): 2927,1737, 1679,
7. Sun, L.; Tran, N.; Tang, F.; App, H.; Hirth, P.; McMahon, G.; Tang, C. J. Med. Chem.
1998, 41, 2588.
8. Kadin, S. B. EP 208510, 1986; Chem. Abstr. 1987, 106, 138254.
9. Kadin, S. B. U.S. Patent 4,725,616, 1987; Chem. Abstr. 1989, 110, 23728.
10. Kadin, S. B. U.S. Patent 4,730,004, 1988; Chem. Abstr. 1989, 110, 23729.
11. Kadin, S. B. EP 153818, 1985; Chem. Abstr. 1986, 104, 88427u.
12. Crawford, Th. Ch. EP 155828, 1985; Chem. Abstr. 1986, 104, 109466y.
13. (a) Robinson, C. Drugs Future 1990, 15, 898; (b) Drugs Future 1993, 18, 875.
14. Robinson, R. P.; Donahue, K. M. J. Heterocycl. Chem. 1994, 31, 1541.
1434. 1H NMR (CDCl3, 400 MHz)
d
7.18 (1H, dd, J¼8.2, 5.4 Hz), 6.90
(1H, dd, J¼9.2, 2.4 Hz), 6.78 (1H, td, J¼9.4, 2.4 Hz), 3.70 (2H, m), 3.58
ꢀ
ꢀ
ꢀ ꢀ
15. Blasko, G.; Lukacs, Gy.; Reiter, J.; Florian, E.; Porcs-Makkay, M.; Mezei, T.; Simig,
Gy. WO 9736895, 1997; Chem. Abstr. 1997, 127, 318879.
(2H, s), 3.40 (2H, br s), 1.69 (6H, br s). 13C NMR (CDCl3, 100 MHz)
d
173.0, 162.6 (d, J¼245.1 Hz), 149.8, 143.3 (d, J¼12.1 Hz), 125.2 (d,
16. Porcs-Makkay, M.; Simig, Gy Org. Process Res. Dev. 2000, 4, 10.
17. Porcs-Makkay, M.; Simig, Gy J. Heterocycl. Chem. 2001, 38, 451.
J¼9.3 Hz), 119.3 (d, J¼3.4 Hz), 109.9 (d, J¼22.5 Hz), 101.0 (d,
J¼28.3 Hz), 48.4, 45.2, 35.5, 26.4, 25.4, 24.1. Anal. Calcd for
C14H15FN2O2 (262.29): C 64.11, H 5.76, N 10.68%. Found: C 63.83, H
5.86, N 10.74%.
€
18. Porcs-Makkay, M.; Volk, B.; Kapiller-Dezsofi, R.; Mezei, T.; Simig, Gy Monatsh.
Chem. 2004, 135, 697.
19. Porcs-Makkay, M.; Volk, B.; Mucsi, Z.; Simig, Gy Tetrahedron 2010, 66, 7017.
20. Kadin, S. B. EP 156603, 1985; Chem. Abstr. 1986, 104, 109468a.
21. Kelly, S. E. U.S. Patent 4,952,703, 1989; Chem. Abstr. 1991, 114, 42571q.
22. Gruber, J. M. WO 9520574, 1994; Chem. Abstr. 1995, 123, 339735g.
23. DeMello, K. L.; Bronk, B. S.; Crosson, R. M. U.S. Patent 2003/0207897, 2003;
Chem. Abstr. 2003, 139, 350756.
24. McConnel, D.; Steurer, S.; Krist, B.; Weyer-Czernilofsky, U.; Impagnatiello, M.;
Treu, M.; Kauffmann-Hefner, I.; Garin-Chesa, P.; Schnapp, A. EP 1598353, 2005;
Chem. Abstr. 2005, 144, 6787.
25. Nadler, G.; Martin, M.; Zimmermann, R. EP381374,1990; Chem. Abstr.1991,114, 62126.
26. Martin, M.; Nadler, G.; Zimmermann, R. EP303418,1989; Chem. Abstr.1989,111, 97293.
27. Porcs-Makkay, M.; Volk, B.; Simig, Gy.; unpublished results.
28. Giraud, I.; Rapp, M.; Dupuy, J.-M.; Maurizis, J.-C.; Madelmont, J.-C. J. Labelled
Compd. Radiopharm. 2000, 43, 297.
4.5.15. 5-Methoxy-1-(piperidin-1-ylcarbonyl)-1,3-dihydro-2H-indol-
2-one (3o). This compound was prepared according to the general
procedure IV/C using 6g (1.57 g, 4.0 mmol) and piperidine (0.68 g,
0.80 mL, 8.0 mmol), and stirred with aqueous HCl at room tem-
perature for 2 h to give 3o (0.98 g, 88%) as colourless crystals, mp
81e84 ꢁC (obtained by chromatography on silica gel, eluent: hex-
ane/ethyl acetate 7:3). IR (KBr, cmꢀ1): 2941, 1736, 1718, 1700, 1487,
1425. 1H NMR (CDCl3, 400 MHz)
d
7.05 (1H, d, J¼8.6 Hz), 6.85 (1H, d,
29. No yield given in: Madelmont, J. -C.; Giraud, I.; Nicolas, C.; Maurizis, J. -C.; Rapp,
M.; Ollier, M.; Renard, P.; Caignard, D. -H. WO 2001000621, 2001; Chem. Abstr.
2001, 134, 71584.
J¼2.2 Hz), 6.81 (1H, dd, J¼8.6, 2.2 Hz), 3.79 (3H, s), 3.68 (2H, m),
3.59 (2H, s), 3.40 (2H, br s), 1.68 (6H, m). 13C NMR (CDCl3, 100 MHz)
ꢀ ꢀ
30. Porcs-Makkay, M.; Kalman, A.; Argay, Gy.; Simig, Gy Tetrahedron 2000, 56, 5893.
d
173.8, 157.3, 151.3, 136.5, 126.1, 113.6, 111.8, 56.1, 48.6, 45.4, 36.8,