Palladium-catalyzed amination and amidation of benzo-fused bromine-containing heterocycles

Article abstract of DOI:10.1007/s11178-005-0257-0

Amination and amidation of bromoindole, 6-bromo-1,2,3,4-tetrahydrocarbazol- 1-one, and 8-bromo-2,4,5,6-tetrahydro-1H-pyrazino[3,2,1-jk]carbazole derivatives was effected in the presence of palladium complexes. The use of the catalytic system Pd₂dba₃·CHCl₃-2-[di(tert-butyl) phosphino]biphenyl in the amination and of Pd₂dba₃· CHCl₃-Xantphos [or 3,5-(CF₃)₂Xantphos] in the amidation ensured moderate to high yields of the corresponding products.

Full text of DOI:10.1007/s11178-005-0257-0

Russian Journal of Organic Chemistry, Vol. 41, No. 6, 2005, pp. 860–874. Translated from Zhurnal Organicheskoi Khimii, Vol. 41, No. 6, 2005,
pp. 881–894.
Original Russian Text Copyright © 2005 by Sergeev, Artamkina, Velezheva, Fedorova, Beletskaya.
Palladium-Catalyzed Amination and Amidation of Benzo-Fused
Bromine-Containing Heterocycles
A. G. Sergeev1, G. A. Artamkina1, V. S. Velezheva2, I. N. Fedorova2, and I. P. Beletskaya1
1 Faculty of Chemistry, Lomonosov Moscow State University, Vorob’evy gory 1, Moscow, 119992 Russia
e-mail: gaa@elorg.chem.msu.ru
2 Nesmeyanov Institute of Organometallic Compounds, Russian Academy of Sciences, Moscow, Russia
Received October 4, 2004
Abstract—Amination and amidation of bromoindole, 6-bromo-1,2,3,4-tetrahydrocarbazol-1-one, and
8-bromo-2,4,5,6-tetrahydro-1H-pyrazino[3,2,1-jk]carbazole derivatives was effected in the presence of palla-
dium complexes. The use of the catalytic system Pd2dba3·CHCl3–2-[di(tert-butyl)phosphino]biphenyl in the
amination and of Pd2dba3·CHCl3–Xantphos [or 3,5-(CF3)2Xantphos] in the amidation ensured moderate to high
yields of the corresponding products.
Heterocycles containing a substituted or unsubsti-
tuted amino group are known to be structural frag-
ments of many medical agents. Taking into account
exceptional importance of natural and synthetic bio-
logically active derivatives of carbazole, benzofuran,
and especially indole, it seems to be reasonable to
search for new biologically active compounds and
drugs among benzo-fused heterocycles of the amino-
indole, aminobenzofuran, and aminocarbazole series.
Several drugs have been developed on the basis of
indole derivatives, e.g., antiphlogistic drug indometha-
cin and some its analogs, antiemetic agent tropisetron
and its analogs, β-adrenoblocker pindolol, sumatriptan
(used in the treatment of migraine), antiviral and im-
munomodulating agent arbidol, and antiallergic agent
dimebon [1, 2].
belong to the same class of compounds [2]. Taking into
account high efficiency of these antidepressants,
search for new synthetic approaches to their analogs is
now in progress both in Russia and abroad.
Synthetic and natural pterocarpans including a ben-
zofuran system as a structural fragment attract atten-
tion as potential antimicrobial, antitumor, antituber-
culous, and antiulcer agents, as well as inhibitors of
human immunodeficiency virus [11]. Polysubstituted
benzofurans having amino-, amido-, and ureido groups
were found to exhibit antiarrhythmic activity [12].
On the other hand, amino group is fairly rarely
encountered in the structure of indole-containing drugs
and their analogs. A few exceptions are antitumor
antibiotic mitomycin C and leucotriene biosynthesis
blocker zafirlukast (5-aminoindole derivative) [2].
There are data indicating that 3-piperidinoaminoin-
doles control serotonin and adrenaline functions of the
central nervous system and are used as antidepressants
and tranquilizers [13].
1-Alkylaminotetrahydrocarbazoles exhibit antiviral
[3], antifungal, and antibacterial activity [4, 5] and are
also active against Mycobacterium tuberculosis [5].
The parent compound of this series, 1-aminotetra-
hydrocarbazole was also found to be active against
Mycobacterium tuberculosis [6, 7], while 3-dimethyl-
amino-1,2,3,4-tetrahydrocarbazole showed antidepres-
sant activity [7]. Functional derivatives of 1-oxotetra-
hydrocarbazoles were the subjects of numerous bio-
logical studies [6, 8]; a broad spectrum of biological
properties was revealed in the series of polycyclic
1-oxotetrahydrocarbazole derivatives [9], specifically
in 1,10-trimethylenepyrazino[1,2-a]indoles (or 2,3,3a,-
4,5,6-hexahydro-1H-pyrazino[3,2,1-jk]carbazoles)
[10]. Antidepressants pyrazidol and tetrindole also
Extensive synthesis of new amino-substituted in-
doles, carbazoles, and benzofurans is restrained due to
the lack of general regioselective method for intro-
duction of amino group into these heterocycles. Such
procedures as reduction of nitro compounds (which is
widely used in the synthesis of aromatic amines) have
found limited application in the series of indole,
benzofuran, and carbazole. In the recent years, pal-
ladium-catalyzed arylation of amines (Buchwald–
Hartwig reaction) [14, 15] was successfully used for
1070-4280/05/4106-0860 © 2005 Pleiades Publishing, Inc.

PALLADIUM-CATALYZED AMINATION AND AMIDATION
861
I
CO2Et
OAc
CO2Et
AcO
Br
Br
Br
MeO
Br
Me
Me
N
O
N
N
O
SO2Ph
Ac
Me
I
II
III
IV
V
CO2Et
MeO
Br
Br
Br
Br
Me
O
N
N
N
N
N
N·HCl
Me
Me
VIIa–VIIe
VI
VIIIa
VIIIb
VII, R = H (a), Ac (b), Me (c), PhCH2 (d), Ph3C (e).
phenylsulfonyl protecting groups. Therefore, hetero-
cycles I–III, VIIa, and VIIb cannot be used as
substrates in the amination reaction under the given
conditions.
building up new CAr–N bonds. However, this reaction
still remains rare in the series of indole and its
derivatives. As far as we know, only Hooper et al. [16]
described palladium-catalyzed intermolecular amina-
tion of 2- and 3-bromoindoles [18], and two examples
were reported on intramolecular version of this reac-
tion [17]. He et al. [18] described intramolecular
amidation of 2-iodoindole.
The amination of compounds IV–VI and VIIc–
VIIe was initially performed using the system
Pd2dba3–BINAP–Cs2CO3 in toluene. This system was
widely used for the amination of aryl halides [15].
However, 5-bromo-1-methylindole (IV) failed to react
with piperidine under these conditions. We succeeded
in obtaining the target product in 83% yield when
BINAP was replaced by 2-(di-tert-butylphosphino)bi-
phenyl (t-Bu2BP-phos) and Cs2O3 was replaced by
a stronger base, sodium tert-butoxide (Scheme 1;
Table 1, run no. 1). In the presence of Cs2CO3, the
substrate conversion was as low as ~30%.
In the present work we examined the possibility of
applying the above approach to introduction of nitro-
gen-containing groups (amino, amido, and ureido) into
halogen-substituted indoles I, III, IV, and VI, benzo-
furans II and V, tetrahydrocarbazolones VIIa–VIIe,
and tetrahydropyrazinocarbazoles VIIIa and VIIIb. It
should be noted that bromoindoles having no substit-
uent on the nitrogen atom do not undergo palladium-
catalyzed arylation, as was demonstrated by the reac-
tion of compound VIIa with piperidine. This fact was
also noted in [16]. In addition, the reaction is accom-
panied by almost quantitative removal of acetyl and
The reaction with bromoindole VI was less smooth,
and the amount of palladium catalyst was increased to
4 mol % to attain a moderate yield of the amination
product. Moreover, the reaction was accompanied by
Scheme 1.
Pd2dba3 (1 mol %), (t-Bu)2BP-phos (3 mol %)
t-BuONa, toluene, 100°C, 5 h
Br
N
+
N
N
N
H
Me
Me
IV
83%
O
PPh2
PPh2
[(CF3)2C6H3]2P
P[C6H3(CF3)2]2
(t-Bu)2P
PPh2
PPh2
O
Me
Me
Me
Me
BINAP
(t-Bu)2P-phos
Xantphos
3,5-(CF3)2Xantphos
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 41 No. 6 2005

SERGEEV et al.
862
Table 1. Palladium-catalyzed amination of 5- and 6-bromoindoles and 6-bromo-1,2,3,4-tetrahydrocarbazol-1-onesa
Reaction
time, h
Yield,
%
Run no.
Substrate
Amine
Product
Br
01
05
83
N
N
N
N
H
Me
Me
IV
CO2Et
CO2Et
MeO
Br
MeO
Me
Me
02
03
"
"
10
04
53
N
N
N
Me
Me
VI
Br
N
74
O
N
N
Me
O
Me
VIIc
H
N
Me
Me
Me
04b
"
22
04
97
68
Me
NH2
O
N
Me
Br
N
05
O
N
N
H
N
O
Bzl
VIId
Bzl
O
O
N
06
"
"
"
"
"
03
04
02
04
20
91
91
90
95
83
O
N
H
N
Bzl
07c
08
"
Me
"
"
Me
N
N
N
O
N
N
H
Bzl
09c
10b
"
H
N
Me
Me
Me
NH2
Me
O
N
Bzl
a
The reactions were carried out under argon using 1 equiv of hetaryl bromide, 1.2 equiv of amine, 1.4 equiv of t-BuONa, 1–2 mol % of
Pd2dba3, and 3–6 mol % of t-Bu2BP-phos (toluene, 100°C).
At 80°C.
Without a solvent.
b
c
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 41 No. 6 2005

PALLADIUM-CATALYZED AMINATION AND AMIDATION
863
Scheme 2.
CO2Et
CO2Et
Pd2dba3 (2 mol %), (t-Bu)2BP-phos (6 mol %)
t-BuONa, toluene, 100°C, 10 h
MeO
Br
MeO
+
Me
Me
N
N
N
R
H
Me
Me
VI
R = piperidino (53%), H (30%)
Scheme 3.
I
I
Pd2dba3 (1 mol %), (t-Bu)2BP-phos (3 mol %)
t-BuONa, toluene, 100°C, 4 h
+
+
N
N
N
N
H
H
H
SO2Ph
I
50%
48%
Scheme 4.
R2
R3
N
Pd2dba3 (1 mol %), (t-Bu)2BP-phos (3 mol %)
t-BuONa, toluene, 80–100°C, 3–22 h
VIIc, VIId
+
R2R3NH
N
O
R1
68–97%
Scheme 5.
O
H
Br
N
Pd2dba3, ligand (ligand/Pd = 1.5)
Cs2CO3, solvent, 100°C
CONH2
+
Me
N
N
O
O
Bzl
VIId
Bzl
Me
formation of an appreciable amount (30%) of the
dehydrobromination product (Scheme 2; Table 1, run
no. 2). The contribution of the dehydrohalogenation
process was even larger in the reaction of 3-iodo-1-
phenylsulfonylindole (I) with piperidine (Scheme 3);
in this case, no amination product was detected.
Nevertheless, the system Pd2dba3–t-Bu2BP-phos–
t-BuONa–toluene ensured amination of compounds
VIIc and VIId in high yields (Scheme 4; Table 1,
run nos. 3–10).
We also performed palladium-catalyzed amidation
of compounds VI, VIIc, VIId, VIIIa, and VIIIb with
the goal of introducing amido and ureido groups into
functionally substituted heterocycles. The conditions
Table 2. Palladium-catalyzed reaction of 9-benzyl-6-bromo-
1,2,3,4-tetrahydrocarbazol-1-one (VIId) with 4-methyl-
benzamidea
Run [Pd],
no. mol %
Yield, %
(conversion, %)
Ligand
Base Solvent
These reactions can also be carried out in the
absence of a solvent: the product yields were either
comparable to or even greater than those obtained in
toluene (Table 1; cf. run nos. 6 and 7, 8 and 9). The
reaction with N-(triphenylmethyl)carbazole VIIe was
less successful: even in the presence of 3 mol % of
palladium, the conversion was only 36% in 22 h, and
palladium black was formed.
1
2
t-Bu2BP- t-BuONa Toluene
phos
– (16)
2
3
4
4
Xantphos t-BuONa Toluene
31 (100)
82 (100)
Xantphos Cs2CO3 Dioxane
a
The reactions were carried out under argon using 1 equiv of
hetaryl bromide, 1.2 equiv of 4-methylbenzamide, 1.4 equiv of
base, 1–2 mol % of Pd2dba3, and 3–6 mol % of ligand in toluene
or dioxane at 100°C.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 41 No. 6 2005

SERGEEV et al.
864
for catalytic amidation of bromine-containing hetero-
cyclic compounds were optimized using the reaction
of p-methylbenzamide with bromocarbazole VIId
(Scheme 5, Table 2).
of N-aryl and N-phenyl derivatives of the initial amide.
Reduction of the amount of catalyst to 1–2 mol % and
of the ligand to 1.5–3 mol % allowed us to minimize
the yield of N-phenylation products and increase
the yield of the target products to 68–84% (Table 3,
run nos. 6–10).
We found that the amidation of bromocarbazolone
VIId under the conditions optimal for amination
(Pd2dba3–t-Bu2BP-phos–toluene) was characterized by
a poor conversion (Table 2, run no. 1). We succeeded
in attaining the complete conversion of initial halogen
derivative VIId with the use of Xantphos as ligand
in toluene; however, the product yield was as low as
31% (Table 2, run no. 2). The yield increased to 82%
(Table 2, run no. 3) in the presence of a milder base,
Cs2CO3, in dioxane. These conditions were applied to
the amidation of brominated indole-containing hetero-
cycles with various amides and ureas. The results are
summarized in Table 3.
Bromocarbazolone VIId reacts with N,N'-ethylene-
urea (imidazolidin-2-one) more difficultly than with
amides. The reaction in the presence of 2 mol % of Pd
and 3 mol % of Xantphos gives an inseparable mixture
of the corresponding N,N'-dihetarylurea and N-hetaryl-
N'-phenylurea. We previously showed that a modified
analog of Xantphos, 3,5-(CF3)2Xantphos, containing
acceptor trifluoromethyl substituents in the phenyl
rings of the ligand is more effective in the arylation of
ureas with nonactivated aryl halides. In our case, the
use of 3,5-(CF3)2Xantphos also favored a smoother
reaction and formation of the target product in a good
yield (Scheme 6, Table 3, run no. 4).
The amidation of compound VIId in the presence
of 4 mol % of palladium catalyst gave 81–84% of the
corresponding amides (Table 3, run nos. 1–3). Interest-
ingly, the yields of the target products in the reactions
with N-methylcarbazole VIIc decreased to 57–58%
(Table 3, run nos. 5, 7, 9), and these reactions were
accompanied by formation of appreciable amounts of
N-phenyl derivatives of the initial amides. Phenylation
of amides at the nitrogen atom often occurs in palla-
dium-catalyzed amidation of nonactivated aryl halides
[19–21]. This process involves exchange of the aryl
group linked to palladium with phenyl group of the
phosphine ligand in the complex Pd(Xantphos)(Ar)Br
[22]. As a result, replacement of the bromine atom by
amide group and reductive elimination gives a mixture
However, we failed to attain complete conversion
of bromocarbazolone VIId and a satisfactory yield of
its ureido derivatives in the presence of both Xantphos
and 3,5-(CF3)2Xantphos (4 mol % of palladium).
Unlike amination, the amidation of 6-bromoindole
VI having a methoxy group in position 5 (in the ortho
position with respect to bromine), was characterized by
high yield of the products (1 mol % of Pd, Xantphos;
Table 3, run nos. 11,12). 6-Bromoindole VI turned out
to be more reactive than bromocarbazoles VIIc and
VIId (Table 3, run no. 14) in the reaction with urea.
The yield of the corresponding N,N'-dihetarylurea in
the presence of Xantphos was 69%, while in the
Scheme 6.
Br
Pd2dba3, 3,5-(CF3)2Xantphos
Cs2CO3, dioxane, 100°C
HN
NH
N
N
+
O
O
N
N
N
O
O
O
Bzl
Bzl
Bzl
VIId
71%
Scheme 7.
OMe
MeO
CO2Et
H
H
N
N
Pd2dba3, ligand, Cs2CO3
dioxane, 100°C
MeO
Br
H2N
NH2
EtOCO
CO2Et
+
Me
O
N
O
N
N
Me
Me
Me
Me
Me
VI
Ligand = Xantphos, 69%
Ligand = 3,5-(CF3)2Xantphos, 91%
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 41 No. 6 2005

PALLADIUM-CATALYZED AMINATION AND AMIDATION
865
Table 3. Palladium-catalyzed amidation of 6-bromoindole, 6-bromobenzofuran, and 6-bromo-1,2,3,4-tetrahydrocarbazol-1-
one derivatives and 8-bromo-2,4,5,6-tetrahydro-1H-pyrazino[3,2,1-jk]carbazolea
Run
no.
[Pd],
mol %
Time,
h
Yield,
%
Substrate
Amide
Ligand
Product
Br
O
H
N
CONH2
01
02
4
4
Xantphos
03
07
82
84
N
O
N
Bzl
VIId
O
Me
Bzl
Me
O
H
N
Me
MeCONH2
"
Xantphos
Xantphos
N
O
Bzl
N
03
04
"
"
4
2
06
81
71
O
N
O
O
H
N
Bzl
HN
NH
3,5-(CF3)2-
Xantphos
N
N
0.07.5
O
O
N
N
O
O
Bzl
Bzl
Br
O
H
N
CONH2
05
4
Xantphos
08
58
N
O
N
Me
VIIc
O
Me
Me
Me
06
07
"
"
1
4
Xantphos
Xantphos
17
06
"
68
57
O
H
N
Me
"
MeCONH2
N
O
Me
08
09
10
"
"
"
"
2
4
1
Xantphos
Xantphos
Xantphos
11
04
16
"
74
57
84
N
O
N
O
O
N
H
Me
"
"
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 41 No. 6 2005

SERGEEV et al.
866
Table 3. (Contd.)
Run
no.
[Pd],
mol %
Time,
h
Yield,
%
Substrate
Amide
Ligand
Product
MeO
CONH2
CO2Et
MeO
Br
CO2Et
Me
HN
Me
11
1
1
Xantphos
10
85
96
Me
N
N
O
Me
VI
Me
Me
3,5-(CF3)2-
Xantphos
12
13
"
"
06
"
OMe
MeO
N
N
"
2
4
Xantphos
Xantphos
13 EtOCO
CO2Et 87
O
N
O
H
N
N
Me
Me
Me
OMe
Me
MeO
H
N
H
N
H2N
NH2
EtOCO
CO2Et
14
"
"
23
69
O
O
N
N
Me
Me
Me
Me
3,5-(CF3)2-
Xantphos
15
16
"
2
2
10
09
"
91
82
OMe
MeO
CO2Et
N
N
MeO
Br
HN
NH
Xantphos
Me
EtOCO
CO2Et
O
O
O
V
O
O
Me
Me
Me
CONH2
Br
H
N
17
18
3
4
Xantphos
Xantphos
13
04
68
70
N
N· HCl
O
N
N
VIIIb
Me
Br
HN
NH
O
N
N
N
N
N
N
N
N
O
VIIIa
a
The reactions were carried out under argon using 1 equiv of hetaryl bromide, 1.2 equiv of amide or 0.5 equiv of urea, 1.4 equiv of
Cs2CO3, 1–2 mol % of Pd2dba3, and 3–6 mol % of Xantphos or 3,5-(CF3)2Xantphos in dioxane at 100°C.
presence of 3,5-(CF3)2Xantphos it increased to 91%
(Scheme 7; Table 3, run no. 15). This result sharply
differs from the data obtained by us previously: the
reaction of urea with ortho-substituted aryl halides
under the same conditions (in the presence of
Xantphos) afforded the corresponding diarylamines
as the major products [20, 21]. Bromoindole VI and
its furan analog V fairly readily reacted with cyclic
urea to give dihetarylureas in high yields (Table 3,
run nos. 13, 16).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 41 No. 6 2005

PALLADIUM-CATALYZED AMINATION AND AMIDATION
867
Scheme 8.
Me
4-MeC6H4CONH2
H
N
O
N
N
Pd2dba3, Xantphos, Cs2CO3
dioxane, 100°C
Br
68%
N
N
HN
NH
VIIIa
O
N
N
N
N
N
N
O
70%
The amidation of heterocycles VIIIa and VIIIb
furan-3-carboxylate (V), mp 128–131°C (from
ethanol), published data [30]: mp 129–130°C (from
ethanol); 8-bromo-2,4,5,6-tetrahydro-1H-pyrazino-
[3,2,1-jk]carbazole (VIIIb), yield 69%, mp 284–288°C
(from alcohol), published data [31]: mp 298–300°C.
requires larger amounts of the catalyst, as compared
to reactions with compounds V, VI, VIIc, and VIId,
and the yields are somewhat lower (Scheme 8; Table 3,
run. no. 17, 18).
9-Acetyl-6-bromo-1,2,3,4-tetrahydrocarbazol-
1-one (VIIb). A mixture of 2.0 g (7.90 mmol) of
6-bromo-1,2,3,4-tetrahydrocarbazol-1-one (VIIa),
0.14 g (5.0 mmol) of fused sodium acetate, and
6.70 ml (71.0 mmol) of acetic anhydride was heated
for 6 h under reflux. The mixture was cooled, and the
precipitate was filtered off and washed with methanol
and water. Yield 1.93 g (83%), mp 157–158°C.
1H NMR spectrum (DMSO-d6), δ, ppm: 8.11–8.13 d
(1H, J = 8 Hz), 7.75 s (1H), 7.56–7.59 d (1H, J =
8 Hz), 2.96–2.99 m (2H, J = 6 Hz), 2.69–2.73 m (2H),
2.65 s (3H), 2.24–2.29 m (2H, J = 6 Hz). Found, %:
C 54.92; H 3.95; N 4.57. C14H12BrNO2. Calculated, %:
C 54.76; H 3.87; N 4.71.
EXPERIMENTAL
1
The H NMR spectra were recorded on a Varian
VXR 400 instrument (400 MHz); the chemical shifts
were measured relative to signals from residual pro-
tons in the deuterated solvent. The mass spectra (elec-
tron impact, 70 eV) were obtained on Kratos MS-30
and Kratos MS-890 instruments.
Dioxane and toluene were purified and dried by
standard procedures and were stored over potassium
diphenylketyl under reduced pressure. Cesium carbo-
nate and potassium phosphate were dried at 200°C
under reduced pressure. The palladium complexes and
ligands were prepared according to known procedures:
Pd2dba3·CHCl3 [23], Xantphos [24], 3,5-(CF3)2Xant-
phos [21]. The amines used were purified and dried by
standard procedures, and the amides were distilled or
recrystallized prior to use. Initial hetaryl halides II–VI
were synthesized by known methods: 3-acetoxy-1-
acetyl-5-bromoindole (III) [25], mp 120–122°C (from
2-propanol), published data [26]: mp 122–123°C (from
hexane–benzene, 5:1); 5-bromo-1-methylindole (IV),
bp 160–163°C (8 mm), published data [27]: bp 155°C
(6.5 mm); ethyl 6-bromo-5-methoxy-1,2-dimethyl-
indole-3-carboxylate (VI), mp 163–164°C (from
ethanol), published data [28]: mp 164–165°C (from
CCl4)]; ethyl 5-acetoxy-6-bromo-2-methylbenzo-
furan-3-carboxylate (II), mp 120–121°C (from 2-pro-
panol); published data [29]: mp 120–121°C (from
methanol); ethyl 6-bromo-5-methoxy-2-methylbenzo-
9-Benzyl-6-bromo-1,2,3,4-tetrahydrocarbazol-
1-one (VIId). A solution of 2.64 g (10.0 mmol) of
6-bromo-1,2,3,4-tetrahydrocarbazol-1-one (VIIa) in
20 ml of DMF was cooled to 0–5°C, and 0.24 g
(10.0 mmol) of 100% sodium hydride was added in
portions under stirring and cooling. The mixture was
stirred for 30 min, and 1.15 ml (10.0 mmol) of benzyl
chloride was slowly added. The mixture was heated for
30 min at 70°C, cooled, and poured into water. The
aqueous phase was extracted with ethyl acetate, and
the extract was dried over MgSO4 and evaporated.
Yield 2.69 g (76%), mp 101–102°C (from heptane).
1H NMR spectrum (DMSO-d6), δ, ppm: 7.82 s (1H),
7.40–7.72 d (1H, J = 7 Hz), 7.21–7.27 m (4H), 7.08–
7.10 d (2H, J = 7 Hz), 5.81 s (2H), 3.00–3.02 m
(2H, J = 6 Hz), 2.64–2.68 m (2H), 2.23–2.26 m
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SERGEEV et al.
868
argon and charged with 0.4–0.5 mmol of hetaryl
bromide IV, VI, VIIc, or VIId, 0.48–0.6 mmol of the
corresponding amine, 0.56–0.7 mmol of base, 1 mol %
of Pd2dba3 · CHCl3 (2 mol % of Pd), 3 mol % of
t-Bu2BP-phos or BINAP, and 3 ml of toluene saturated
with argon. The mixture was degassed by triple freeze–
thaw cycles, and the reactor was filled with argon. The
mixture was then stirred at 100°C until the initial aryl
halide disappeared (TLC), diluted with 30 ml of ethyl
acetate, and filtered, silica gel was added to the filtrate,
and the solvent was distilled off. The residue was
subjected to chromatography on Merck 60 silica gel
(40–63 μm).
(2H, J = 6 Hz). Found, %: C 64.42; H 4.55; N 3.95.
C14H12BrNO2. Calculated, %: C 64.42; H 4.75; N 3.81.
6-Bromo-9-methyl-1,2,3,4-tetrahydrocarbazol-
1-one (VIIc) was synthesized as described above for
compound VIId from 3.0 g (11.4 mmol) of 6-bromo-
1,2,3,4-tetrahydrocarbazol-1-one and 0.7 ml
(11.4 mmol) of methyl iodide. Yield 2.68 g (85%),
1
mp 121–123°C (from 2-propanol). H NMR spectrum
(DMSO-d6), δ, ppm: 7.93 s (1H), 7.53 d (1H, J =
10 Hz), 7.47 d (1H, J = 10 Hz), 3.98 s (3H), 2.93 m
(2H, J = 6 Hz), 2.57–2.59 m (2H), 2.11 m (2H, J =
6 Hz). Found, %: C 56.14; H 4.35; N5.04. C13H12BrNO.
Calculated, %: C 56.19; H 4.21; N 4.94.
Amination of 9-benzyl-6-bromo-1,2,3,4-tetra-
hydrocarbazol-1-one (VIId) in the absence of
a solvent. The reaction was performed in a spherical
reactor (30 mm in diameter) with a steel Teflon-lined
screw-top. The reactor was charged with appropriate
reactants, 5 steel balls (d = 4 mm), and 100–150 mg of
Carbopack C (specific surface 10 m2/g). The reactor
was evacuated using an analogous steel Teflon-lined
screw-top with a welded steel tube (d = 4 mm). The
mixture was degassed, the reactor was filled with
argon, and the reactor was shaken with a frequency
of 25 Hz and an amplitude of 1.5 cm on heating
with an electric oven (a glass cylinder wound with
a nichrome wire).
Reaction of 9-acetyl-6-bromo-1,2,3,4-tetrahydro-
carbazol-1-one (VIIb) with piperidine in the pres-
ence of K3PO4. The reaction was performed with 59 μl
(51 mg, 0.6 mmol) of piperidine, 157 mg (0.74 mmol)
of K3PO4, 5.23 mg (5.1 × 10–3 mmol) of Pd2dba3 ·
CHCl3, 5.5 mg (16.9×10–3 mmol) of t-Bu2BP-phos,
and 3 ml of toluene saturated with argon. The product
was isolated using ethyl acetate–petroleum ether (1:6)
as eluent. Yield of 6-bromo-1,2,3,4-tetrahydrocarba-
zol-1-one (VIIa) 129 mg (97%), light beige solid
substance, mp 229–231°C.
Reaction of 9-acetyl-6-bromo-1,2,3,4-tetrahydro-
carbazol-1-one (VIIb) with piperidine in the pres-
ence of t-BuONa. The reaction was performed with
153 mg of compound VIIb, 59 μl (51 mg, 0.6 mmol)
of piperidine, 66 mg (0.686 mmol) of t-BuONa,
5.17 mg (5.0×10–3 mmol) of Pd2dba3·CHCl3, 5.03 mg
(16.9 × 10–3 mmol) of t-Bu2BP-phos, and 3 ml of
toluene. The product was isolated using ethyl acetate–
petroleum ether (1:6) as eluent. Yield of 6-bromo-
1,2,3,4-tetrahydrocarbazol-1-one (VIIa) 121 mg
(92%), light beige solid substance.
6-Bromo-9-triphenylmethyl-1,2,3,4-tetrahydro-
carbazol-1-one (VIIe).) Sodium hydride, 0.086 g
(3.6 mmol), was slowly added under stirring to 0.95 g
(3.6 mmol) of 6-bromo-1,2,3,4-tetrahydrocarbazol-1-
one in 10 ml of anhydrous DMF on cooling to 0–5°C.
The mixture was stirred for 1.5 h at that temperature,
1.0 g (3.6 mmol) of chlorotriphenylmethane was
added, and the mixture was heated at 70°C until the
initial compound disappeared (TLC), cooled, and
poured into water. The precipitate was filtered off and
washed with water to pH 7. We thus isolated 1.78 g
(98%) of crude product VIIe which was recrystallized
several times from 2-propanol (TLC) and was then
subjected to chromatography on silica gel using
1
benzene as eluent. mp 205–207°C. H NMR spectrum
(DMSO-d6), δ, ppm: 7.94 s (1H), 7.18–7.31 m (15H),
7.05 d (1H, J = 9 Hz), 5.98 d (1H, J = 9 Hz), 2.99 m
(2H, J = 5.6 Hz), 2.28–2.29 m (2H), 2.05 m (2H,
J = 5.6 Hz). Found, %: C 73.52; H 4.78; N 2.77.
C31H24BrNO. Calculated, %: C 73.26; H 4.74; N 2.77.
8-Bromo-2,4,5,6-tetrahydro-1H-pyrazino-
[3,2,1-jk]carbazole (VIIIa). Aqueous ammonia (25%),
was added under stirring to a suspension of 0.26 g
(8.0 mmol) of 8-bromo-2,4,5,6-tetrahydro-1H-pyra-
zino[3,2,1-jk]carbazole (VIIIb) in 20 ml of methylene
chloride until pH 8–9, and the mixture was stirred until
the precipitate completely dissolved. The organic
phase was washed with water until neutral (pH 7),
dried over MgSO4, and evaporated. Yield 0.20 g
1
(85%), white substance, mp 114–115°C. H NMR
spectrum (DMSO-d6), δ, ppm: 7.74 s (1H), 7.38 d (1H,
J = 9 Hz), 7.20 d (1H, J = 9 Hz), 3.99–4.07 m (4H),
2.85 m (2H, J = 6 Hz), 2.67 m (2H, J = 6 Hz), 2.17 m
(2H, J = 6 Hz). Found, %: C 57.92; H 5.15; N 9.57.
C14H15BrN2. Calculated, %: C 57.75; H 5.19; N 9.62.
General procedure for amination of compounds
Reaction of 3-iodo-1-phenylsulfonylindole (I)
IV, VI, VIIc, and VIId. A reactor was filled with
with piperidine. The reaction was performed with
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 41 No. 6 2005

PALLADIUM-CATALYZED AMINATION AND AMIDATION
869
148 mg (0.386 mmol) of compound I, 48 μl (42 mmol)
of piperidine, 57 mg (0.59 mmol) of t-BuONa,
4.09 mg (3.95×10–3 mmol) of Pd2dba3·CHCl3, 4.08 mg
(13.68×10–3 mmol) of t-Bu2BP-phos, and 2.5 ml of
toluene. By chromatography using ethyl acetate–pe-
troleum ether (1:10) as eluent we isolated 23 mg
(50%) of indole and 36 mg (48%) of 3-iodoindole.
1H NMR spectrum of indole (CDCl3), δ, ppm: 8.13 br.s
(1H), 7.67 d (1H, J = 8 Hz), 7.41 d (1H, J = 8 Hz),
7.18–7.24 m (2H), 7.13 t (1H, J = 7.5 Hz), 6.55–
3.81 s (3H), 3.65 s (3H), 3.18 s (3H), 2.92–2.98 m
(4H), 2.66 s (3H), 1.64–1.72 m (4H), 1.49–1.58 m
(2H), 1.36 t (3H, J = 7 Hz). Found, %: C 68.96;
H 83.5; N 8.19. C19H29N2O3. Calculated, %: C 69.09;
H 7.93; N 8.48. Ethyl 5-methoxy-1,2-dimethylindole-
3-carboxylate, 37 mg (30%), was also isolated as
by-product (using CHCl3 as eluent). mp 118–120°C.
1H NMR spectrum (acetone-d6), δ, ppm: 7.62 d (1H,
J = 2.5 Hz), 7.30 d (1H, J = 9 Hz), 6.82 d.d (1H, J =
2.5, 9 Hz), 4.32 q (2H, J = 7 Hz), 3.82 s (3H), 3.71 s
(3H), 2.71 s (3H), 1.40 t (3H, J = 7 Hz).
1
6.59 m (1H). H NMR spectrum of 3-iodoindole
(CDCl3), δ, ppm: 8.09 br.s (1H), 7.38 d (1H, J =
7.5 Hz), 7.21 d (1H, J = 8 Hz), 7.08–7.18 m (3H).
9-Methyl-6-piperidino-1,2,3,4-tetrahydrocarba-
zol-1-one was obtained from 139 mg (0.5 mmol) of
6-bromo-9-methyl-1,2,3,4-tetrahydrocarbazol-1-one
(VIIc), 52 mg (0.614 mmol) of piperidine, 71 mg
(0.74 mmol) of t-BuONa, 5.19 mg (5.01×10–3 mmol)
of Pd2dba3·CHCl3, 4.63 mg (15.53×10–3 mmol) of
t-Bu2BP-phos, and 2.5 ml of toluene. The product was
isolated using ethyl acetate–petroleum ether (1:2) as
eluent. Yield 104 mg (74%), yellow solid substance,
Reaction of ethyl 5-acetoxy-6-bromo-2-methyl-
benzofuran-3-carboxylate (II) with morpholine. The
reaction was performed with 86 mg (0.253 mmol) of
compound II, 26 μl (26 mg, 0.298 mmol) of mor-
pholine, 135 mg (0.414 mmol) of Cs2CO3, 5.20 mg
(5.02 × 10–3 mmol) of Pd2dba3 · CHCl3, 9.42 mg
(15.12×10–3 mmol) of BINAP, and 2 ml of toluene.
The product was isolated using ethyl acetate–petro-
leum ether (1:3) and ethyl acetate as eluents. Yield of
ethyl 5-bromo-4-hydroxy-2-methylbenzofuran-2-car-
boxylate 73 mg (96%). White solid. 1H NMR spectrum
(acetone-d6), δ, ppm: 7.69 s (1H), 7.58 s (1H), 4.36 t
(2H, J = 7 Hz), 2.70 s (2H), 1.40 t (3H, J = 7 Hz).
1
mp 147–148°C. H NMR spectrum (CDCl3), δ, ppm:
7.20–7.27 m (2H), 7.05 d (1H, J = 1.5 Hz), 4.03 s
(3H), 3.07–3.12 m (2H), 2.94–2.99 m (2H), 2.59–
2.64 m (2H), 2.15–2.24 m (2H), 1.73–1.82 m (4H),
1.54–1.62 m (2H). Found, %: C 76.55; H 8.02; N 8.82.
C24H26N2O. Calculated, %: C 76.56; H 7.85; N 9.92.
1-Methyl-5-piperidinoindole was obtained from
133 mg (0.632 mmol) of 5-bromo-1-methylindole
(IV), 63 mg of piperidine, 90 mg (0.936 mmol) of
t-BuONa, 6.21 mg (6×10–3 mmol) of Pd2dba3·CHCl3,
5.36 mg (18×10–3 mmol) of t-Bu2BP-phos, and 3 ml of
toluene. The product was isolated using ethyl acetate–
petroleum ether (1:4) as eluent. Yield 112 mg (83%),
6-Isopropylamino-9-methyl-1,2,3,4-tetrahydro-
carbazol-1-one was obtained from 140 mg
(0.503 mmol) of compound VIIc, 50 μl (35 mg,
0.592 mmol) of isopropylamine, 67 mg (0.697 mmol)
of t-BuONa, 5.23 mg (5.05 × 10–3 mmol) of
Pd2dba3 · CHCl3, 4.80 mg (16.1×10–3 mmol) of
t-Bu2BP-phos, and 2.5 ml of toluene. Yield 126 mg
1
1
light beige solid substance, mp 85–87°C. H NMR
(97%), yellow solid substance, mp 63–65°C. H NMR
spectrum (CDCl3), δ, ppm: 7.23 s (1H, J = 9 Hz),
7.18 d (1H, J = 2 Hz), 7.03 d.d (1H, J = 2, 9 Hz),
6.99 d (1H, J = 3 Hz), 6.38 d (1H, J = 3 Hz), 3.75 s
(3H), 3.05–3.11 m (4H), 1.72–1.83 m (4H), 1.52–
1.62 m (2H). Found, %: C 76.55; H 8.02; N 9.82.
C18H22N2O. Calculated, %: C 76.56; H 7.85; N 9.92.
spectrum (CDCl3), δ, ppm: 7.16 d (1H, J = 9 Hz),
6.82 d (1H, J = 9 Hz), 6.72 s (1H), 4.00 s (2H), 3.66 m
(1H, J = 6 Hz), 2.89–2.97 m (2H), 2.56–2.65 m (2H),
2.12–2.23 m (2H), 1.23 d (6H). Found, %: C 75.04;
H 8.00; N 10.80. C16H20N2O. Calculated, %: C 74.97;
H 7.86; N 10.93.
Ethyl 5-methoxy-1,2-dimethyl-6-piperidinoin-
dole-3-carboxylate was obtained from 163.67 mg
(0.501 mmol) of ethyl 6-bromo-5-methoxy-1,2-di-
methylindol-3-carboxylate (VI), 52 mg (0.611 mmol)
of piperidine, 59 mg (0.613 mmol) of t-BuONa,
5.15 mg (4.98×10–3 mmol) of Pd2dba3·CHCl3, 4.64 mg
(15.56×10–3 mmol) of t-Bu2BP-phos, and 2.5 ml of
toluene. Yield 92 mg (55%), pale yellow substance,
9-Benzyl-6-piperidino-1,2,3,4-tetrahydrocarba-
zol-1-one was obtained from 177 mg (0.5 mmol) of
9-benzyl-6-bromo-1,2,3,4-tetrahydrocarbazol-1-one
(VIId), 59 μl (51 mg, 0.6 mmol) of piperidine, 67 mg
(0.697 mmol) of t-BuONa, 5.23 mg (5.05×10–3 mmol)
of Pd2dba3·CHCl3, 4.58 mg (15.36×10–3 mmol) of
t-Bu2BP-phos, and 3 ml of toluene. The product was
isolated using ethyl acetate–petroleum ether (1:6) as
eluent. Yield 122 mg (68%), yellow solid substance,
1
mp 174–175°C. H NMR spectrum (DMSO-d6), δ,
ppm: 7.47 s (1H), 6.96 s (1H), 4.27 q (2H, J = 7 Hz),
1
mp 117–118°C. H NMR spectrum (CDCl3), δ, ppm:
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 41 No. 6 2005

SERGEEV et al.
870
7.13–7.26 m (5H), 7.04–7.12 m (2H), 5.77 s (2H),
3.05–3.12 m (4H), 3.00 t (2H, J = 6 Hz), 2.59–2.65 m
(2H), 2.17–2.25 m (2H), 1.71–1.81 m (4H), 1.53–
1.61 m (2H). Found, %: C 80.27; H 7.33; N 8.03.
C24H26N2O. Calculated, %: C 80.41; H 7.31; N 7.81.
9-Benzyl-6-isopropylamino-1,2,3,4-tetrahydro-
carbazol-1-one was obtained from 141 mg
(0.398 mmol) of compound VIId, 68 μl (43 mg,
0.901 mmol) of isopropylamine, 68 mg (0.695 mmol)
of t-BuONa, 4.22 mg (4.07×10–3 mmol) of Pd2dba3·
CHCl3, 3.57 mg (11.97×10–3 mmol) of t-Bu2BP-phos,
and 2.5 ml of toluene (the reaction was carried out at
80°C in a closed vessel). The product was isolated by
chromatography using ethyl acetate–petroleum ether
(1:4 to 1:3) as eluent. Yield 110 mg (83%), yellow
9-Benzyl-6-morpholino-1,2,3,4-tetrahydrocarba-
zol-1-one. a. (Table 1, run no. 6). The reaction of
178 mg (0.501 mmol) of compound VIId with 53 μl
(53 mg, 0.608 mmol) of morpholine, 68 mg
(0.707 mmol) of t-BuONa, 5.12 mg (4.94×10–3 mmol)
of Pd2dba3·CHCl3, and 4.48 mg (15.02×10–3 mmol) of
t-Bu2BP-phos in 3 ml of toluene, followed by chroma-
tography using ethyl acetate–petroleum ether (3:4) as
eluent, gave 165 mg (91%) of the product as a yellow
1
solid substance, mp 108–109°C. H NMR spectrum
(CDCl3), δ, ppm: 7.03–7.32 m (7H), 6.72 s (1H),
5.75 s (2H), 3.64 m (1H, J = 6.0 Hz), 2.91–3.05 m
(2H), 2.54–2.62 m (2H), 2.13–2.27 m (2H), 1.23 d
(2H, J = 6.0 Hz). Found, %: C 79.73; H 7.02; N 8.26.
C22H24N2O. Calculated, %: C 79.48; H 7.28; N 8.43.
1
solid substance with mp 118–120°C. H NMR spec-
trum (CDCl3), δ, ppm: 7.00–7.34 m (8H), 5.78 s (2H),
3.86–3.94 m (4H), 3.10–3.11 m (4H), 2.97–3.05 m
(2H), 2.59–2.68 m (2H), 2.16–2.28 m (2H). Found, %:
C 76.78; H 6.54; N 7.59. C23H24N2O2. Calculated, %:
C 76.64; H 6.71; N 7.77.
Reaction of compound VIId with 4-methylbenz-
amide. a. (Table 2, run no. 1). The reaction was
performed with 124 mg (0.35 mmol) of compound
VIId, 48 mg (0.350 mmol) of 4-methylbenzamide,
56 mg (0.582 mmol) of t-BuONa, 7.24 mg (7.0×
10–3 mmol) of Pd2dba3 · CHCl3, 6.25 mg (20.96 ×
10–3 mmol) of t-Bu2BP-phos, and 3 ml of toluene. The
mixture was heated for 18 h at 100°C, and 104 mg
(84%) of initial compound VIId was recovered by
chromatography using ethyl acetate–petroleum ether
(1:8) as eluent (conversion 16%).
b. (Table 1, run no. 7). The reaction of 177 mg
(0.5 mmol) of compound VIId with 54 μl (54 mg,
0.620 mmol) of morpholine, 68 mg (0.707 mmol) of
t-BuONa, 5.6 mg (5.41×10–3 mmol) of Pd2dba3 ·
CHCl3, 5.2 mg (17.44×10–3 mmol) of t-Bu2BP-phos,
and 112 mg of Carbopack C gave 164 mg (91%) of the
product as a yellow solid substance.
b. (Table 2, run no. 2). The reaction was performed
with 177 mg (0.5 mmol) of compound VIId, 67 mg
(0.498 mmol) of 4-methylbenzamide, 67 mg
(0.697 mmol) of t-BuONa, 10.38 mg (10.0 ×
10–3 mmol) of Pd2dba3 ·CHCl3, 17.66 mg (30.52×
10–3 mmol) of Xantphos, and 3 ml of toluene. The
product was isolated by chromatography using ethyl
acetate–petroleum ether (1:5 to 1:2) as eluent.Yield
64 mg (31%), light beige solid substance, mp 212–
9-Benzyl-6-(4-methyl-1-piperazinyl)-1,2,3,4-
tetrahydrocarbazol-1-one. a. (Table 1, run no. 8).
The reaction of 177 mg (0.5 mmol) of 9-benzyl-6-
bromo-1,2,3,4-tetrahydrocarbazol-1-one (VIId) with
67 μl (60 mg, 0.598 mmol) of 1-methylpiperazine,
67 mg (0.697 mmol) of t-BuONa, 5.34 mg (5.16×10–3
mmol) of Pd2dba3·CHCl3, and 4.41 mg (14.79×10–3
mmol) of t-Bu2BP-phos in 3 ml of toluene, followed
by chromatography using ethyl acetate–methanol (2:1)
as eluent, gave 169 mg (90%) of the product as a light
1
213°C. H NMR spectrum (DMSO-d6), δ, ppm:
1
brown solid substance with mp 147–148°C. H NMR
10.17 br.s (1H), 8.21 s (1H), 7.91 d (2H, J = 8 Hz),
7.66 d (2H, J = 9 Hz), 7.51 d (2H, J = 9 Hz), 7.33 d
(2H, J = 9 Hz), 7.22–7.28 m (2H), 7.16–7.21 m (1H),
7.09 d (2H, J = 9 Hz), 5.80 s (2H), 2.95–3.01 m (2H),
2.56–2.62 m (2H), 2.38 s (3H), 2.11–2.19 m (2H).
Found, %: C 79.32; H 5.93; N 6.91. C27H24N2O2. Cal-
culated, %: C 79.39; H 5.92; N 6.86.
spectrum (CDCl3), δ, ppm: 7.01–7.30 m (8H), 5.77 s
(2H), 3.14–3.21 m (2H), 2.96–3.03 m (2H), 2.57–
2.67 m (2H), 2.36 s (3H), 2.14–2.27 m (2H). Found,
%: C 77.40; H 7.25; N 11.15. C24H26N2O. Calculated,
%: C 77.18; H 7.29; N 11.25.
b. (Table 1, run no. 9). The reaction of 178 mg
(0.501 mmol) of compound VIId with 67 μl (60 mg,
0.598 mmol) of 1-metylpiperazine, 72 mg (0.75 mmol)
of t-BuONa, 5.20 mg (5.02×10–3 mmol) of Pd2dba3·
CHCl3, 5 mg (16.77×10–3 mmol) of t-Bu2BP-phos,
and 160 mg of Carbopack C gave 177 mg (95%) of the
product as a light brown solid substance.
c. (Table 2, run no. 3; Table 3, run no. 1). The
reaction was performed with 142 mg (0.401 mmol) of
compound VIId, 55 mg (0.406 mmol) of 4-methyl-
benzamide, 185 mg (0.568 mmol) of Cs2CO3, 8.36 mg
(8.07 × 10–3 mmol) of Pd2dba3 · CHCl3, 14.19 mg
(24.52×10–3 mmol) of Xantphos, and 2.5 ml of di-
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PALLADIUM-CATALYZED AMINATION AND AMIDATION
871
oxane. The product was isolated by chromatography
using ethyl acetate–petroleum ether (1:4 to 1:2) as
eluent. Yield 117 mg (82%), white solid substance.
1,3-Bis(9-benzyl-1-oxo-1,2,3,4-tetrahydrocar-
bazol-6-yl)imidazolidin-2-one was obtained from
178 mg (0.401 mmol) of compound VIId, 22 mg
(0.253 mmol) of imidazolidin-2-one, 250 mg
(0.760 mmol) of Cs2CO3, 2.68 mg (2.59×10–3 mmol)
of Pd2dba3·CHCl3, 8.66 mg (7.71×10–3 mmol) of
3,5-(CF3)2-Xantphos, and 3 ml of dioxane. The product
was isolated by chromatography using ethyl acetate–
petroleum ether (1:2 to 1:1) as eluent. Yield 112 mg
(71%), light beige solid substance, mp >250°C.
1H NMR spectrum (CDCl3), δ, ppm: 7.71 s (1H),
7.68 d (1H, J = 9 Hz), 7.32 d (1H, J = 9 Hz), 7.15–
7.29 m (4H), 7.10 d (2H, J = 7.5 Hz), 5.81 s (6H),
3.98 s (3H), 2.98–3.05 m (2H), 2.59–2.66 m (2H),
2.15–2.26 m (2H). Found, %: C 77.76; H 5.41; N 8.59.
C41H36N4O3. Calculated, %: C 77.83; H 5.73; N 8.85.
General procedure for amidation of bromine-
containing heterocycles V, VI, and VIIa–VIId.
A reactor was filled with argon and charged with 0.4–
0.5 mmol of compound V, VI, or VIIa–VIId, 0.48–
0.6 mmol of the corresponding amide, 0.56–0.7 mmol
of base, 0.5–2 mol % of Pd2dba3·CHCl3 (4 mol % of
Pd), 6 mol % of Xantphos or 3,5-(CF3)2Xantphos, and
3 ml of dioxane saturated with argon. The mixture was
degassed by three freeze–thaw cycles, the reactor was
filled with argon, and the mixture was stirred at 100°C
until the initial halogen derivative disappeared (TLC).
The mixture was diluted with 30 ml CHCl3 and
filtered, and the filtrate was evaporated with addition
of silica gel. The residue was subjected to chromatog-
raphy on Merck 60 silica gel (40–63 μm).
N-(9-Methyl-1-oxo-1,2,3,4-tetrahydrocarbazol-6-
yl)-4-methylbenzamide. a. (Table 3, run no. 5). The
reaction of 140 mg (0.502 mmol) of 6-bromo-9-
methyl-1,2,3,4-tetrahydrocarbazol-1-one (VIIc) with
82 mg (0.606 mmol) of 4-methylbenzamide, 230 mg
(0.706 mmol) of Cs2CO3, 10.40 mg (10.04×10–3 mmol)
of Pd2dba3·CHCl3, and 17.30 mg (29.90×10–3 mmol)
of Xantphos in 3 ml of dioxane, followed by chroma-
tography using ethyl acetate–petroleum ether (1:3 to
1:2) as eluent, gave 97 mg (58%) of the product as
a white solid substance, mp 200–202°C. Found, %:
C 75.75; H 6.12; N 8.23. C21H20N2O2. Calculated, %:
C 75.88; H 6.06; N 8.43.
N-(9-Benzyl-1-oxo-1,2,3,4-tetrahydrocarbazol-6-
yl)acetamide was obtained from 142 mg (0.4 mmol)
of compound VIId, 27 mg (0.463 mmol) of acetamide,
200 mg (0.613 mmol) of Cs2CO3, 8.25 mg (7.97×
10–3 mmol) of Pd2dba3·CHCl3, 13.56 mg (23.43×
10–3 mmol) of Xantphos, and 3 ml of dioxane. The
product was isolated by chromatography using ethyl
acetate–petroleum ether (1:1 to 2:1) as eluent. Yield
112 mg (84%), light beige solid substance, mp 213–
1
215°C. H NMR spectrum (DMSO-d6), δ, ppm: 9.94
br.s (1H), 8.04 s (1H), 7.45 d (1H, J = 9 Hz), 7.38 d
(1H, J = 9 Hz), 7.14–7.30 m (3H), 7.06 d (2H, J =
7.5 Hz), 5.76 s (2H), 2.90–2.98 m (2H), 2.53–2.63 m
(2H), 2.07–2.18 m (2H), 2.03 s (3H). Found, %:
C 75.64; H 6.28; N 8.12. C21H20N2O2. Calculated, %:
C 75.88; H 6.06; N 8.43.
b. (Table 3, run no. 6). The reaction of 140 mg
(0.502 mmol) of compound VIIc with 82 mg
(0.606 mmol) of 4-methylbenzamide, 230 mg
(0.706 mmol) of Cs2CO3, 2.62 mg (2.53×10–3 mmol)
of Pd2dba3·CHCl3, and 4.46 mg (7.71×10–3 mmol) of
Xantphos in 3 ml of dioxane, followed by chromatog-
raphy using ethyl acetate–petroleum ether (1:3 to 1:2)
as eluent, gave 114 mg (68%) of the product as a white
1-(9-Benzyl-1-oxo-1,2,3,4-tetrahydrocarbazol-6-
yl)pyrrolidin-2-one was obtained from 142 mg
(0.401 mmol) of compound VIId, 37 μl (0.48 mmol)
of 2-pyrrolidinone, 200 mg (0.613 mmol) of Cs2CO3,
8.39 mg (7.97×10–3 mmol) of Pd2dba3·CHCl3, 14.07 mg
(24.31×10–3 mmol) of Xantphos, and 3 ml of dioxane.
The product was isolated by chromatography using
ethyl acetate–petroleum ether (1:4 to 1:2) as eluent.
Yield 109 mg (81%), light beige solid substance,
1
solid substance. H NMR spectrum (acetone-d6), δ,
ppm: 9.48 br.s (1H), 8.27 d (1H, J = 2 Hz), 7.94 d (2H,
J = 8 Hz), 7.73 d.d (1H, J = 2, 9 Hz), 7.44 d (1H, J =
9 Hz), 7.32 d (2H, J = 8 Hz), 4.04 s (3H), 2.96–3.02 m
(2H), 2.53–2.61 m (2H), 2.4 s (3H), 2.16–2.24 m (2H).
N-(9-Methyl-1-oxo-1,2,3,4-tetrahydrocarbazol-6-
yl)acetamide. a. (Table 3, run no. 7). The reaction was
performed with 139 mg (0.499 mmol) of compound
VIIc, 36 mg (0.609 mmol) of acetamide, 250 mg
(0.767 mmol) of Cs2CO3, 10.42 mg (10.06 ×
10–3 mmol) of Pd2dba3·CHCl3, 17.82 mg (30.79×
10–3 mmol) of Xantphos, and 3 ml of dioxane. By
chromatography using ethyl acetate–petroleum ether
(1:1 to 2:1) as eluent we isolated 73 mg (57%) of
1
mp 195–196°C. H NMR spectrum (DMSO-d6), δ,
ppm: 7.80 d (1H, J = 2 Hz), 7.70 d.d (1H, J = 2,
9 Hz), 7.53 d (1H, J = 9 Hz), 7.15–7.28 m (3H), 7.06 d
(2H, J = 7.5 Hz), 5.79 s (2H), 3.86 t (2H, J = 7 Hz),
2.98 m (2H), 2.59 m (2H), 2.45–2.50 m (2H), 2.13 m
(2H), 2.01–2.10 m (2H). Found, %: C 77.02; H 6.06;
N 8.01. C23H22N2O2. Calculated, %: C 77.07; H 6.19;
N 7.82.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 41 No. 6 2005

SERGEEV et al.
872
1
the product as a white solid substance with mp 205–
207°C. H NMR spectrum (DMSO-d6), δ, ppm:
193°C. H NMR spectrum (CDCl3–DMSO-d6, 2:1), δ,
1
ppm: 8.82 br.s (1H), 8.41 s (1H), 7.75 d (2H, J =
8.0 Hz), 7.57 s (1H), 7.25 d (2H, J = 8.0 Hz), 4.28 q
(2H, J = 7.0 Hz), 3.93 s (3H), 3.65 s (3H), 2.67 s (3H),
2.37 s (3H), 1.37 t (3H, J = 7.0 Hz). Found, %:
C 69.40; H 6.27; N 7.30. C26H26N2O4. Calculated, %:
C 69.46; H 63.36; N 7.36.
9.93 br.s (1H), 8.01 s (1H), 7.40–7.41 m (2H), 3.94 s
(3H), 2.85–2.92 m (2H), 2.51–2.58 m (2H), 2.06–
2.15 m (2H), 2.04 s (3H). Found, %: C 70.19; H 6.41;
N 10.70. S15H16N2O2. Calculated, %: C 70.29; H 6.29;
N 10.93.
b. (Table 3, run no. 8). The reaction of 140 mg
(0.5 mmol) of compound VIIc with 36 mg
(0.609 mmol) of acetamide, 230 mg (0.706 mmol) of
Cs2CO3, 5.25 mg (5.07 × 10–3 mmol) of Pd2dba3 ·
CHCl3, and 8.84 mg (15.27×10–3 mmol) of Xantphos
in 3 ml of dioxane, followed by chromatography using
ethyl acetate–petroleum ether (1:1 to 2:1) as eluent,
gave 96 mg (74%) of the product as a white solid
substance.
b. (Table 3, run no. 12). From 131 mg (0.4 mmol)
of compound VI, 65 mg (0.480 mmol) of 4-methyl-
benzamide, 190 mg (0.583 mmol) of Cs2CO3, 2.10 mg
(2.03×10–3 mmol) of Pd2dba3 ·CHCl3, and 6.72 mg
(5.98×10–3 mmol) of 3,5-(CF3)2Xantphos in 3 ml of
dioxane (eluent ethyl acetate–petroleum ether, 1:2 to
1:1) we isolated 147 mg (96%) of the product as
a white solid substance.
1,3-Bis(3-ethoxycarbonyl-5-methoxy-1,2-dimeth-
ylindol-6-il)imidazolidin-2-one was obtained from
164 mg (0.502 mmol) of compound VI, 21.9 mg
(0.254 mmol) of imidazolidin-2-one, 230 mg
(0.706 mmol) of Cs2CO3, 5.16 mg (4.98×10–3 mmol)
of Pd2dba3·CHCl3, and 8.9 mg (15.38×10–3 mmol) of
Xantphos in 3 ml of dioxane. The product was isolated
by chromatography using ethyl acetate–petroleum
ether (1:2 to 1:1) and then ethyl acetate as eluent.
Yield 126 mg (87%), white solid substance, mp >250°C.
1H NMR spectrum (CDCl3), δ, ppm: 7.25 s (1H),
7.46 s (1H), 4.39 q (2H, J = 7 Hz), 3.99 s (2H), 3.96 s
(3H), 3.64 s (3H), 2.73 s (3H), 1.45 t (3H, J = 7 Hz).
Found, %: C 64.61; H 6.21; N 9.84. C31H36N4O7. Cal-
culated, %: C 64.57; H 6.29; N 9.72.
1-(9-Methyl-1-oxo-1,2,3,4-tetrahydrocarbazol-6-
yl)pyrrolidin-2-one. a (Table 3, run no. 9). The reac-
tion was performed with 140 mg (0.502 mmol) of
compound VIIc, 46 μl (52 mg, 0.610 mmol) of
2-pyrrolidinone, 230 mg (0.706 mmol) of Cs2CO3,
10.49 mg (10.13×10–3 mmol) of Pd2dba3·CHCl3,
17.66 mg (30.52×10–3 mmol) of Xantphos, and 3 ml of
dioxane. By chromatography using ethyl acetate–
petroleum ether (1:1) and then ethyl acetate as eluent
we isolated 82 mg (57%) of the product as a white
1
solid substance with mp 200–202°C. H NMR spec-
trum (DMSO-d6), δ, ppm: 7.64 s (1H), 7.63 d (1H, J =
9 Hz), 7.33 d (1H, J = 9 Hz), 3.94 s (3H), 3.80–3.89 m
(2H), 2.83–2.84 m (2H), 2.44–2.56 m (2H), 2.01–
2.18 m (4H). Found, %: C 72.04; H 6.33; N 9.62.
C17H18N2O2. Calculated, %: C 72.32; H 6.43; N 9.92.
b. (Table 3, run no. 10). From 140 mg (0.502 mmol)
of compound VIIc, 38 μl (43 mg, 0.505 mmol) of
2-pyrrolidinone, 240 mg (0.736 mmol) of Cs2CO3,
2.62 mg (2.53×10–3 mmol) of Pd2dba3 ·CHCl3, and
4.58 mg (7.91×10–3 mmol) of Xantphos in 3 ml of
dioxane (eluent ethyl acetate–petroleum ether, 1:1, and
then ethyl acetate) we isolated 120 mg (84%) of the
product as a white solid substance.
N,N'-Bis(3-ethoxycarbonyl-5-methoxy-1,2-di-
methylindol-6-yl)urea. a. (Table 3, run no. 14). The
reaction was performed with 164 mg (0.503 mmol) of
compound VI, 18 mg (0.305 mmol) of urea, 230 mg
(0.706 mmol) of Cs2CO3, 10.74 mg (10.37 ×
10–3 mmol) of Pd2dba3·CHCl3, 17.57 mg (30.36×
10–3 mmol) of Xantphos, and 3 ml of dioxane. By
chromatography using ethyl acetate–petroleum ether
(1:2 to 1:1) and then ethyl acetate as eluent we
isolated 96 mg (69%) of the product as a light beige
Ethyl 5-methoxy-1,2-dimethyl-6-(4-methylben-
zamido)indole-3-carboxylate. a. (Table 3, run no. 11).
The reaction was performed with 131 mg (0.4 mmol)
of ethyl 6-bromo-5-methoxy-1,2-dimethylindole-3-car-
boxylate (VI), 65 mg (0.480 mmol) of 4-methyl-
benzamide, 180 mg (0.552 mmol) of Cs2CO3, 2.03 mg
(1.96×10–3 mmol) of Pd2dba3·CHCl3, 4.27 mg (7.38×
10–3 mmol) of Xantphos, and 3 ml of dioxane. By
chromatography using ethyl acetate–petroleum ether
(1:2 to 1:1) as eluent we isolated 130 mg (85%) of
the product as a white solid substance with mp 192–
1
solid substance with mp >250°C. H NMR spectrum
(CDCl3), δ, ppm: 8.23 s (1H), 7.65 s (1H), 7.43 br.s
(1H), 4.39 q (2H, J = 7.0 Hz), 3.95 s (3H), 3.68 s (3H),
2.73 s (3H), 1.44 t (3H, J = 7.0 Hz).
b. (Table 3, run no. 15). The reaction of 163 mg
(0.5 mmol) of compound VI with 37 mg (0.616 mmol)
of urea, 230 mg (0.705 mmol) of Cs2CO3, 2.57 mg
(2.48×10–3 mmol) of Pd2dba3 ·CHCl3, and 8.71 mg
(7.76×10–3 mmol) of 3,5-(CF3)2Xantphos in 3 ml of
dioxane, followed by chromatography using ethyl
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 41 No. 6 2005

PALLADIUM-CATALYZED AMINATION AND AMIDATION
873
acetate–petroleum ether (1:2 to 1:1) and then ethyl
acetate as eluent, gave 126 mg (91%) of the product as
a white solid substance.
10–3 mmol) of Xantphos in 2.5 ml of dioxane. The
product was isolated by chromatography using chloro-
form–methanol (20:2 to 10:1) as eluent. Yield 87 mg
1
(70%), beige solid substance, mp >250°C. H NMR
1,3-Bis(3-ethoxycarbonyl-5-methoxy-2-methyl-
benzofuran-6-yl)imidazolidin-2-one was obtained
from 156 mg (0.498 mmol) of ethyl 6-bromo-5-
methoxy-2-methylfuran-3-carboxylate (V), 21.6 mg
(0.251 mol) of imidazolidin-2-one, 230 mg
(0.706 mmol) of Cs2CO3, 5.20 mg (5.02×10–3 mmol)
of Pd2dba3·CHCl3, and 8.73 mg (15.08×10–3 mmol) of
Xantphos in 3 ml of dioxane. The product was isolated
by chromatography using ethyl acetate–petroleum
ether (1:2 to 1:1) as eluent. Yield 113 mg (82%),
spectrum (CDCl3), δ, ppm: 7.68 s (1H), 7.67 d (1H),
7.31 d (1H), 3.92–4.13 m (6H), 2.80–2.95 m (2H)
2.56–2.73 m (2H), 2.07–2.24 m (2H). Mass spectrum,
m/z (Irel, %): 503 (100) [M]+. Found, %: C 71.13;
H 6.17; N 6.85. C31H30N6O. Calculated, %: C 71.08;
H 6.02; N 16.72.
This study was performed under financial support
by the Russian Foundation for Basic Research (project
no. 01-03-32518).
1
white solid substance, mp 230–231°C. H NMR spec-
trum (CDCl3), δ, ppm: 7.55 s (1H), 7.53 s (1H), 4.41 q
(2H, J = 7.0 Hz), 3.96 s (2H), 3.95 s (3H), 2.74 s (3H),
1.44 t (3H, J = 7.0 Hz). Found, %: C 63.32; H 6.71;
N 5.17. C29H30N2O9. Calculated, %: C 63.27; H 5.49;
N 5.09.
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