N-Arylation of aliphatic, aromatic and heteroaromatic amines catalyzed by copper bis(2,2,6,6-tetramethyl-3,5-heptanedionate)

Article abstract of DOI:10.1016/j.tetlet.2007.07.009

Copper bis(2,2,6,6-tetramethyl-3,5-heptanedionate) was found to be an efficient catalyst for N-arylation of aliphatic, aromatic and heteroaromatic amines with aryl iodides/bromides under mild conditions. The system tolerated a variety of hindered and functionalized amines/aryl halides and the desired N-aryl amines were obtained in good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2007.07.009

Tetrahedron Letters 48 (2007) 6573–6576
N-Arylation of aliphatic, aromatic and heteroaromatic
amines catalyzed by copper bis(2,2,6,6-tetramethyl-
3
,5-heptanedionate)
Nitin S. Nandurkar, Mayur J. Bhanushali, Malhari D. Bhor
and Bhalchandra M. Bhanage*
Department of Chemistry, Institute of Chemical Technology, University of Mumbai, N.Parekh marg, Matunga, Mumbai 400019, India
Received 1 May 2007; revised 23 June 2007; accepted 5 July 2007
Available online 2 August 2007
Abstract—Copper bis(2,2,6,6-tetramethyl-3,5-heptanedionate) was found to be an efficient catalyst for N-arylation of aliphatic, aro-
matic and heteroaromatic amines with aryl iodides/bromides under mild conditions. The system tolerated a variety of hindered and
functionalized amines/aryl halides and the desired N-aryl amines were obtained in good to excellent yields.
Ó 2007 Elsevier Ltd. All rights reserved.
The synthesis of N-aryl amines and N-aryl heterocycles is
an active area in organic synthesis due to their occur-
rence in biologically important natural products,
pharmaceuticals and their applications in materials
Thus in continuation of our work on C–N coupling
1
2
reactions, we herein report a facile N-arylation of
aliphatic, aromatic and heteroaromatic amines cata-
lyzed by a well-defined and stable complex, viz. copper
bis (2,2,6,6-tetramethyl-3,5-heptanedionate) [Cu(II)-
TMHD] as the catalyst in an efficient manner. The ease
of preparation of the complex, its high solubility in
organic solvents, indefinite shelf life, stability towards
air and compatibility with various hindered and func-
tionalized amines/aryl halides makes it an ideal complex
for N-arylation of amines (Scheme 1).
1
research. Among the various strategies developed to
date, the copper-catalyzed Ullmann reaction has proven
to be the most convenient synthetic route for installing
2
3
an N-aryl functionality. In addition, Buchwald and
4
Hartwig have reported on Pd mediated C–N bond
formation. However, copper-mediated couplings are still
the reaction of choice for large and industrial scale
formation of C–N bonds. The reaction system mostly
employs an in situ generated catalyst from a copper
source and highly efficient N/P-containing ligands such
Initially, various copper based b-diketonate complexes
such as copper bis(2,2,6,6-tetramethyl-3,5-heptanedio-
5
6
7
8
as amino acids, diamines, diimines, pyridine, oxime-
nate) [A], copper bis(acetyl acetonate) [B] and copper
9
10
13
phosphine oxides and phosphoramidite. In spite of
the significant advances in this area, very few reports
employing a structurally well defined and stable copper
bis(methylacetoacetate) [C] were synthesized
and
investigated for the amination of diphenylamine with
iodobenzene in toluene at 120 °C (Table 1, entries 1–
3). However, of these Cu-b-diketonate catalysts, only
the Cu(II)TMHD complex was found to be effective
providing an excellent yield of 95% of the desired
1
1
complex as a catalyst have been reported. Another lim-
itation is that, no single method has been successful for
coupling aliphatic, aromatic and heteroaromatic amines
with aryl halides. Thus, there is a need to develop a chem-
ically well defined, stable solid metal complex, which
could replace N or P-containing ligands and could
directly catalyze the N-arylation of a wide range of
weakly basic amines.
R1
R1
Cu(II)TMHD
X
+
H
N
N
KO Bu, 120 oC
t
R2
R2
1
2
X= I, Br
HNR R = alkyl, aryl, heteroaryl
*
Corresponding author. Tel.: +91 22 24145616; fax: +91 22
4145614; e-mail: bhalchandra_bhanage@yahoo.com
Scheme 1. N-arylation of aliphatic, aromatic and heteroaromatic
amines with aryl halides.
2
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.07.009

6574
N. S. Nandurkar et al. / Tetrahedron Letters 48 (2007) 6573–6576
a
Table 1. Effect of catalyst on the N-arylation of diphenylamine with
iodobenzene in toluene
Table 2. N-arylation of secondary amines catalyzed by Cu(II)TMHD
a
R1
R1
b
2
0 mol % Cu(II)TMHD
Entry
Complex
Base
Yield (%)
I
+
H
N
t
N
KO Bu, toluene,
12 h,120 oC
t
R2
1
R2
1
2
3
4
5
6
A
B
C
A
A
A
KO Bu
95
35
—
10
—
5
t
R
R
KO Bu
t
2
KO Bu
R= Me, OMe, NO2 HNR R = alkyl, aryl
NaOMe
CO
KOH
c
Entry Secondary amine Aryl halide
Yield (%)
K
2
3
a
1
2
3
4
5
I
95
Reaction conditions: diphenylamine (2 mmol); iodobenzene
N
H
t
(4 mmol); catalyst (20 mol %); KO Bu (4 mmol); toluene (10 ml);
temperature 120 °C; reaction time 12 h.
Isolated yield.
b
I
90
90
83
81
N
H
product. The reactivity trend could result from the fact
that a better balance exists between the electronic and
steric effects in the Cu(II)TMHD complex.
O N
I
2
N
H
The influence of bases on the yield of triphenylamine
(
was also investigated (Table 1, entries 1 and 4–6). It
was found that KO Bu was the most effective base, while
the use of other bases such as NaOMe, K CO and
KOH resulted in much lower or no yields. The probable
reason for this may be due to the higher solubility of
MeO
I
I
N
H
TPA) in the presence of Cu(II)TMHD as a catalyst
t
b
I
2
3
N
H
a
Reaction conditions: diaryl amine (2 mmol); aryl iodide (4 mmol);
Cu(II)TMHD (20 mol %); KO Bu (4 mmol); toluene (10 ml); tem-
t
t
KO Bu in organic solvents.
perature 120 °C; reaction time 12 h.
Mole ratio of amine to halide 2.5:1.
Isolated yield.
t
b
c
Thus, using Cu(II)TMHD as a catalyst, KO Bu as a
base and toluene as solvent, various aliphatic, aromatic
and heteroaromatic amines were coupled with aryl
halides under mild conditions. Initially, the activity of
Cu(II)TMHD was tested for the coupling of a secondary
amine with iodobenzene leading to excellent yields of the
desired products (Table 2, entries 1–5). The protocol
was successfully applied to couple electron rich aryl
halides with diarylamine in high yields. The coupling
of 4-iodonitrobenzene which is a difficult substrate
a
Table 3. N-arylation of primary amines catalyzed by Cu(II)TMHD
R
R
1
4
20 mol % Cu(II)TMHD
I
+ H2 NR1
t
KO Bu, toluene,
o
40 h,120
C
N
R
1
R1
R= H, Me, OMe
H NR = alkyl, aryl
2
(
since it is dehalogenated easily to the corresponding
b
Entry
1
Primary amine
Aryl halide
Yield (%)
arene) also proceeded smoothly under the present condi-
tions (entry 3). Encouraged by the above results, double
amination of diiodobiphenyl with diarylamine was also
carried out and was found to proceed smoothly (entry
NH2
NH2
NH2
NH2
I
94
5
). Thus, considerable rate enhancement along with an
2
3
4
I
72
70
73
increased yield was observed for the N-arylation of sec-
ondary amines.
MeO
MeO
I
I
The scope of this methodology was further extended for
coupling of primary amines with aryl iodides (Table 3,
1
5
entries 1–6). Substrates with varying degrees of substi-
tution on both the reagents were examined and were
found to provide triarylamines in good to excellent
yields. Usually, primary amines give a mixture of sec-
ondary and tertiary amines, however, in the present case
the coupling of anline with iodobenzene gave triphenyl-
amine selectively in 94% yield (entry 1). A variety of
functional groups including methyl, methoxy and triflu-
oromethyl were well tolerated. Also, no significant elec-
tronic and steric effects were observed for meta and para
substituted substrates. The aliphatic amine benzylamine
was also found to react smoothly under the present con-
ditions (entry 6).
MeO
F3C
5
6
I
I
82
89
NH2
NH2
a
Reaction conditions: primary amine (2 mmol); aryl iodide (8 mmol);
Cu(II)TMHD (20 mol %); KO Bu (6 mmol); toluene (10 ml); tem-
t
perature 120 °C; reaction time 40 h.
Isolated yield.
b

N. S. Nandurkar et al. / Tetrahedron Letters 48 (2007) 6573–6576
6575
azole and triazole (Table 4, entries 1–14).16 The
arylations of indole, imidazole, benzimidazole and tri-
azole required the use of a more polar solvent (DMF),
most likely because of the poor solubility of these sub-
strates in toluene. All the heteroaromatic compounds
were effectively N-arylated with various aryl iodides in
good to excellent yields. Successful coupling of these
heterocyclic compounds with the less reactive aryl bro-
mide was also carried out and afforded good yields of
the desired products (entries 2, 4, 8 and 11). ortho, meta
or para substituents on the aryl iodide were also toler-
ated. A variety of functional groups including methyl,
methoxy and nitro on the aryl halide were viable part-
ners under the present conditions.
Table 4. N-arylation of heteroaromatic amines catalyzed by
Cu(II)TMHD
a
2
0 mol% Cu(II)TMHD
X + HN-Het
N-Het
t
KO Bu, DMF,
o
2
4 h,120 C
R
R
X = I, Br, R= Me, OMe, NO2 HN-Het = pyrrole, indole, imidazole,
benzimidazole, triazole
d
Entry
Heterocycle
Aryl halide
Yield (%)
b
1
NH
I
94
b
2
NH
Br
88
92
88
86
87
92
90
74
90
70
74
51
46
c
In summary, the first example of the N-arylation of ali-
phatic, aromatic and heteroaromatic amines catalyzed
by the Cu(II)TMHD-complex is described. This cata-
lytic system is capable of coupling hindered substrates
and tolerates a wide range of functional groups. Further
work is in progress to broaden the scope of this catalytic
system especially for aryl chlorides and to understand
the reaction mechanism.
3
I
Br
N
H
c
4
N
H
c
5
MeO
I
N
H
c
6
O N
2
I
N
H
Acknowledgement
N
Financial assistance from the University Grants Com-
mission, India for a major research project (Project
No. 32-273/2006 (SR)) is acknowledged.
7
8
9
NH
I
N
NH
Br
I
References and notes
N
NH
1
2
3
. For a selected review, see: (a) Shirota, Y. J. Mater. Chem.
000, 10, 1–25; For selected references, see: (b) Porres, L.;
Mongin, O.; Katan, C.; Charlot, M.; Pons, T.; Mertz, J.;
Blanchard-Desce, M. Org. Lett. 2004, 6, 47–50; (c) Antilla,
J. C.; Baskin, J. M.; Barder, T. E.; Buchwald, S. L. J. Org.
Chem. 2004, 69, 5578–5587.
. (a) Ullmann, F. Ber. Dtsch. Chem. Ges 1903, 36, 2382; For
selected reviews, see: (b) Beletskaya, I. P.; Cherprakov, A.
V. Coord. Chem. Rev. 2004, 248, 2337–2364; (c) Ley, S. V.;
Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400–
5449; (d) Kunz, K.; Scholz, U.; Ganzetr, D. Synlett 2003,
2
N
1
1
1
1
1
0
1
2
3
4
I
NH
N
Br
NH
N
O N
2
I
NH
2
428–2439.
. (a) Wolfe, J. P.; Wagaw, S.; Buchwald, S. L. J. Am. Chem.
Soc. 1996, 118, 7215–7216; (b) Wolfe, J. P.; Wagaw, S.;
Marcoux, J. F.; Buchwald, S. L. Acc. Chem. Res. 1998, 31,
N
NH
I
N
8
05–818.
. (a) Driver, M. S.; Hartwig, J. F. J. Am. Chem. Soc. 1996,
18, 7217–7218; (b) Hartwig, J. F. Synlett 1997, 329–340.
. (a) Ma, D.; Xia, C.; Jiang, J.; Zhang, J.; Tang, W. J. Org.
Chem. 2003, 68, 442–451; (b) Clement, J. B.; Hayes, J. F.;
Sheldrake, H. M.; Sheldrake, P. W.; Wells, A. S. Synlett
4
5
N
NH
MeO
I
1
N
a
Reaction conditions: heteroaromatic (2 mmol); aryl halide (3 mmol);
Cu(II)TMHD (20 mol %); KO Bu (4 mmol); DMF (10 ml); temper-
t
ature 120 °C; reaction time 24 h.
Toluene (10 ml) used as solvent.
Aryl halide (4 mmol) was used.
Isolated yield.
2
001, 1423–1427.
. Wang, X.; Porco, J. A., Jr. J. Am. Chem. Soc. 2003, 125,
040–6041.
b
c
6
7
6
d
. Kuil, M.; Bekedam, E. K.; Visser, G. M.; van den
Hoogenband, A.; Terpstra, J. W.; Kamer, P. C. J.; van
Leeuwen, P. W. N. M.; van Strijdonck, G. P. F.
Tetrahedron Lett. 2005, 46, 2405–2409.
8. Patil, N. M.; Kelkar, A. A.; Chaudhari, R. V. J. Mol.
Catal. A: Chem. 2004, 223, 45–50.
We next investigated this Cu(II)TMHD catalytic system
and its tolerance to a wide range of heterocyclic com-
pounds such as pyrrole, indole, imidazole, benzimid-

6576
N. S. Nandurkar et al. / Tetrahedron Letters 48 (2007) 6573–6576
9
. Xu, L.; Zhu, D.; Wu, F.; Wang, R.; Wan, B. Tetrahedron
005, 61, 6553–6560.
obtained was purified by column chromatography (silica
gel, 60–120 mesh) using petroleum ether (60/80) as eluent
to afford the pure product.
2
1
1
0. Zhang, Z.; Mao, J.; Zhu, D.; Wu, F.; Chen, H.; Wan, B.
Tetrahedron 2006, 62, 4435–4443.
1. (a) Gujadhur, R. K.; Bates, C. J.; Venkatraman, D. Org.
Lett. 2001, 3, 4315–4317; (b) Pu, Y. M.; Ku, Y. Y.;
Grieme, T.; Henry, R.; Bhatia, A. V. Tetrahedron Lett.
15. General procedure for the Cu(II)TMHD catalyzed N-
arylation of primary amines with aryl iodides: Under a
nitrogen atmosphere, primary amine (2 mmol), iodobenz-
ene (8 mmol), Cu(II)TMHD (20 mol %) with respect to
t
2006, 47, 149–153.
amine and KO Bu (6 mmol) in toluene (10 ml) were stirred
1
2. Bhanushali, M. J.; Nandurkar, N. S.; Bhor, M. D.;
Bhanage, B. M. J. Mol. Catal. A: Chem. 2006, 259, 46–50.
3. Typical procedure for the preparation of Cu(II)TMHD:
NaOH (22 mmol) was dissolved in methanol (20 ml) with
stirring and the resulting solution was cooled to room
temperature followed by the addition of 2,2,6,6-
tetramethyl-3,5-heptanedione (20 mmol). To the mixture,
at room temperature. The reaction mixture was then
heated in an oil bath at 120 °C for 40 h. The reaction
mixture was cooled to room temperature and the solvent
was removed under reduced pressure. The residue
obtained was purified by column chromatography (silica
gel, 60–120 mesh) using petroleum ether (60/80) as eluent
to afford the pure product.
1
a
(
3
solution obtained by dissolving Cu(NO
10 mmol) in 20 ml methanol was added over a period of
0 min. The reaction mixture was stirred for 6 h and the
3
)
2
Æ6H
2
O
16. General procedure for the Cu(II)TMHD catalyzed N-
arylation of heteroaromatic amines with aryl iodides/
bromides: Under a nitrogen atmosphere, heteroaromatic
amine (2 mmol), aryl halide (3 mmol), Cu(II)TMHD
resulting precipitate was filtered and dried. mp 196–198 °C.
4. General procedure for the Cu(II)TMHD catalyzed N-
arylation of secondary amines with aryl iodides: Under a
nitrogen atmosphere, secondary amine (2 mmol), iodo-
benzene (4 mmol), Cu(II)TMHD (20 mol %) with respect
t
1
(20 mol %) with respect to amine and KO Bu (4 mmol)
in DMF (10 ml) were stirred at room temperature. The
reaction mixture was then heated in an oil bath at 120 °C
for 24 h. The reaction mixture was cooled to room
temperature and the solvent was removed under reduced
pressure. The residue obtained was purified by column
chromatography (silica gel, 60–120 mesh) using petroleum
ether (60/80)/ethyl acetate as eluent to afford the pure
product.
t
to amine and KO Bu (4 mmol) in toluene (10 ml) were
stirred at room temperature. The reaction mixture was
heated in an oil bath at 120 °C for 12 h. The reaction
mixture was cooled to room temperature and the solvent
was removed under reduced pressure. The residue