Copper-catalyzed N-arylation of amines/amides in poly(ethylene glycol) as recyclable solvent medium

Article abstract of DOI:10.1055/s-2006-926328

The Buchwald N-arylation of amines and amides is achieved efficiently in PEG (400 Daltons) as solvent medium. The solvent and catalyst recyclability is studied. Interestingly amides underwent N-arylation with better yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-926328

PAPER
839
Copper-Catalyzed N-Arylation of Amines/Amides in Poly(ethylene glycol) as
Recyclable Solvent Medium
N
S
-Arylation
o
r
f
A
mine
s
i
/Amid
v
es in Poly(eth
a
ylene glyc
r
ol) i Chandrasekhar,* S. Shameem Sultana, Srinivasa Rao Yaragorla, N. Ramakrishna Reddy
Organic division-1, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Fax +91(40)27160512; E-mail: srivaric@iict.res.in
Received 24 August 2005; revised 23 September 2005
Br
CuI (5 mol%), ligand (10 mol%)
K2CO3 (2 equiv), PEG-400
Abstract: The Buchwald N-arylation of amines and amides is
achieved efficiently in PEG (400 Daltons) as solvent medium. The
solvent and catalyst recyclability is studied. Interestingly amides
underwent N-arylation with better yields.
N
8
0 °C, 24 h
+
N
H
7
9%
OMe
Key words: N-arylation, copper iodide, poly(ethylene glycol), re-
usability
OMe
Scheme 1
The synthesis of nitrogen-containing heterocycles contin-
ues to attract medicinal and synthetic chemists due to the
bromoanisole was taken as arylating species to observe
the formation of 1-(4-methoxyphenyl)indole (2b) in 79%
yield (entry 2). In order to study the recycling of the cata-
lytic system and the solvent, this reaction (entry 2) was re-
peated six times using the same solvent medium
containing catalyst (after extracting the product with cold
diethyl ether) (Table 2). It was observed that the solvent
recovery was efficient, but due to loss of catalyst in small-
er quantities during every extraction, the yields of the
product declined gradually. To overcome this limitation,
after the third run, 2 mol% of catalyst is additionally add-
ed (Table 2).
1
excellent biological activity profiles they exhibit against
2
various targets. Also several natural products, especially
3
alkaloids, incorporate nitrogen heterocycles. These natu-
ral products have become drugs and drug candidates after
derivatization. Owing to this important feature, various
research groups have developed general methods for N-
4
,5
arylation of amines/amides. Most of these reports suffer
from limitations such as high reaction temperature and
poor substrate versatility. Recently, Buchwald and co-
workers reported a versatile method wherein copper-di-
amine complex has been used as a catalyst for N-arylation
of pyrroles, pyrazoles, imidazoles, indazoles and tri- For checking the generality of the protocol, other aryl ha-
6
azoles. Encouraged by these findings, we have initiated a lides, such as iodobenzene (Table 1, entry 3), o-iodo-
program to explore the possibility of developing a recy- aniline (entry 4), o-bromoaniline (entry 5), and 3,4-
clable system for both the copper catalyst and the solvent methylenedioxybromobenzene (entry 6), were subjected
medium used for the reaction.
to the reaction conditions. The yields of the products 3b,
b and 6b obtained were in the range of 60–86%. To
4
In our earlier efforts, we demonstrated efficiently the
check the compatibility of the amine partner, piperidine
was subjected to Buchwald arylation with 4-bromoanisole
(entry 7) and 1-bromonaphthalene (entry 8) to isolate the
products 7b and 8b in 69 and 60% yields respectively. In
a different series, benzamide was subjected to N-arylation
with iodobenzene (entry 10), 4-bromoanisole (entry 11)
and 1-bromonaphthalene (entry 12). In all the three cases
studied, the product was isolated in good yields (Table 1).
functional-group transformations in PEG as a solvent, viz.
7
8
9
Heck reaction, asymmetric dihydroxylation, aldol and
1
0
hydrogenation reactions, wherein both the catalyst and
solvent (PEG) were efficiently recycled for several runs.
This communication describes the first PEG (400 Dal-
tons) as solvent medium for Buchwald N-arylation of
amines/amides wherein both PEG and CuI are recycled
with equal ease (Scheme 1).
In summary, this paper describes an alternative and prac-
tically viable methodology for N-arylation of aromatic
and aliphatic amines/amides with equal ease. Extension of
this methodology to more functional amines including
supported ones is currently under progress.
In the first instance, indole was N-arylated with 1-bromo-
naphthalene by stirring the two substrates in the presence
of CuI, ethylenediamine ligand and potassium carbonate
in PEG (400 Daltons) at 80 °C. The reaction was complete
in 24 hours with isolation of the product 1b in over 92%
yield (Table 1, entry 1). In the next case electron-rich 4-
SYNTHESIS 2006, No. 5, pp 0839–0842
x
x
.
x
x
.2
0
0
6
Advanced online publication: 07.02.2006
DOI: 10.1055/s-2006-926328; Art ID: Z16205SS
Georg Thieme Verlag Stuttgart · New York
©

8
40
S. Chandrasekhar et al.
PAPER
Table 1 Copper-Catalyzed N-Arylation of Amines/Amides in PEG
Entry
1
Amines/Amides
R–X
Producta
Time (h)
24
Yield (%)b
Br
N
92
79
N
H
1a
1
b
Br
N
2
1a
24
OMe
OMe
N
2
3
4
4
b
b
b
b
I
3
4
5
1a
1a
1a
12
18
24
86
84
79
I
N
N
N
NH2
NH2
NH2
NH2
Br
Br
6
7
1a
24
24
60
69
O
O
O
O
6
b
Br
N
N
H
OMe
Br
OMe
7
8
b
N
8
9
24
24
60
58
N
H
b
NH2
Br
HN
9
b
Synthesis 2006, No. 5, 839–842 © Thieme Stuttgart · New York

PAPER
N-Arylation of Amines/Amides in Poly(ethylene glycol)
841
Table 1 Copper-Catalyzed N-Arylation of Amines/Amides in PEG (continued)
Entry
Amines/Amides
R–X
Producta
Time (h)
8
Yield (%)b
75
O
O
I
1
1
0
1
N
H
NH2
1
1
0b
1b
Br
O
O
O
N
H
OMe
8
8
70
73
NH2
OMe
O
Br
N
H
1
2
NH2
1
2b
a
1
All products were characterized by H NMR and mass spectral data.
Isolated yields after column chromatography.
b
Table 2 Recycling Studies of Copper-Catalyzed N-Arylation of Indole with 4-Bromoanisole
Run
1
2
3
4
5
6
Isolated Yield
79
–
75
–
71
–
68
76
63
75
60
75
Isolated Yielda
a
After addition of 2 mol% extra catalyst.
1
All solvents and reagents were purified by standard techniques.
Crude products were purified by column chromatography on silica
gel of 60–120 mesh. IR spectra were recorded on Perkin-Elmer 683
H NMR (300 MHz, CDCl ): d = 7.92 (d, J = 7.5 Hz, 2 H), 7.83–
3
7.75 (m, 1 H), 7.67 (d, J = 7.5 Hz, 1 H), 7.59–7.36 (m, 4 H), 7.30
(d, J = 3.0 Hz, 1 H), 7.15–6.95 (m, 3 H), 6.71 (d, J = 3.0 Hz, 1 H).
1
13
spectrometer. H and C NMR spectra were recorded in CDCl sol-
+
+
3
EI-MS: m/z = 243 (M ), 242 (M – 1), 215, 154, 127.
vent on a Varian Gemini 200, Bruker 300 or Varian Unity 400 NMR
spectrometers. Chemical shifts were reported in ppm with respect to
internal TMS. Coupling constants (J) are quoted in Hz. Mass spec-
tra were obtained on a Finnegan MAT 1020B or a Micromass VG
1
-Phenylindole (3b)
Yellow oil.
1
H NMR (300 MHz, CDCl ): d = 7.61 (d, J = 7.5 Hz, 1 H), 7.54–
7
0-70H spectrometer operating at 70 eV using direct inlet system.
3
7
.43 (m, 6 H), 7.34–7.26 (m, 2 H), 7.13 (t, J = 8.3 Hz, 1 H), 6.62 (d,
J = 2.26 Hz, 1 H).
Copper-Catalyzed N-Arylation of Amines/Amides in PEG-400;
-(4-Methoxyphenyl)indole (2b); Typical Procedure
A mixture of indole (0.117 g, 1.0 mmol), 4-bromoanisole (0.224 g,
.2 mmol), PEG-400 (1.0 g), CuI (0.0095 g, 5 mol%), ethylenedi-
1
+
EI-MS: m/z = 193 (M ), 116, 77.
1
1
-(2-Aminophenyl)indole (4b)
amine (66 mL, 10 mol%) and K CO (0.196 g, 2 mmol) was placed
2
3
Light yellow oil.
in a 10 mL round bottomed flask and heated at 80 °C for 24 h. After
completion of the reaction (monitored by TLC), the mixture was
–
1
IR (neat): 3380, 1600, 1582, 1464, 1332, 1212, 780, 740 cm .
1H NMR (400 MHz, CDCl
): d = 7.69 (m, 1 H), 7.18 (m, 6 H), 6.82
(m, 2 H), 6.67 (d, J = 6 Hz, 1 H), 3.52 (s, 2 H).
13C NMR (100 MHz, CDCl
): d = 143.1, 136.3, 129.1, 128.6, 128.5,
124.8, 122.2, 120.9, 120.1, 118.5, 116.2, 110.7, 103.2, 102.0.
cooled and extracted with cold Et O (3 × 10 mL) and purified by
3
2
column chromatography; yield: 79% (Table 1, entry 2).
Colorless oil.
3
1
H NMR (300 MHz, CDCl ): d = 7.85 (m, 2 H), 7.5 (m, 2 H), 7.1–
3
+
+
7
.4 (m, 4 H), 6.70 (d, J = 5.2 Hz, 2 H), 3.9 (s, 3 H).
EI-MS: m/z = 208 (M ), 207 (M – 1), 181, 142, 104, 89.
+
+
EI-MS: m/z = 223 (M ), 208 (M – 15), 181, 153.
1
-(4-Methoxyphenyl)piperidine (7b)
Analytical and spectral data for some selected compounds are given
below (Table 1).
Colorless oil.
1
H NMR (400 MHz, CDCl ): d = 6.85 (d, J = 8.9 Hz, 2 H), 6.75 (d,
3
J = 8.9 Hz, 2 H), 3.75 (s, 3 H), 3.01 (t, J = 5.2 Hz, 4 H), 1.69–1.80
1
-Naphthylindole (1b)
(m, 4 H), 1.51–1.59 (m, 2 H).
Colorless oil.
+
+
EI-MS: m/z = 191 (M ), 190 (M – 1), 176, 41.
Synthesis 2006, No. 5, 839–842 © Thieme Stuttgart · New York

8
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S. Chandrasekhar et al.
PAPER
N-Phenylbenzamide (10b)
Viscous liquid.
(4) Yang, B. H.; Buchwald, S. L. J. Organomet. Chem. 1999,
576, 125; and references cited therein.
1
(5) (a) Harbert, C. A.; Plattner, J. J.; Welch, W. M.; Weissman,
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3
s, 1 H), 7.61 (d, J = 7.5 Hz, 2 H), 7.56–7.42 (m, 3 H), 7.34 (t,
J = 7.55 Hz, 2 H), 7.11 (t, J = 7.5 Hz, 1 H).
+
EI-MS: m/z = 197 (M ), 141, 105, 77.
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(
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2
(
(
(
(
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Synthesis 2006, No. 5, 839–842 © Thieme Stuttgart · New York