A recyclable Cu/Al-HT catalyst for amination of aryl chlorides

Article abstract of DOI:10.1016/j.tetlet.2007.03.136

A simple Cu/Al-HT catalyzed amination of aryl chlorides with primary and secondary aromatic amines has been developed. This ligand-free heterogeneous Cu/Al-HT catalyst, in conjunction with base, also efficiently works for the amination of aryl chlorides with cycloalkylamines. This method tolerates a variety of functional groups and does not require an expensive additive.

Full text of DOI:10.1016/j.tetlet.2007.03.136

Tetrahedron Letters 48 (2007) 3911–3914
A recyclable Cu/Al-HT catalyst for amination of aryl chlorides
Pravin R. Likhar,* R. Arundhathi and M. Lakshmi Kantam
Inorganic and Physical Chemistry Division, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 29 December 2006; revised 13 March 2007; accepted 21 March 2007
Available online 25 March 2007
Abstract—A simple Cu/Al-HT catalyzed amination of aryl chlorides with primary and secondary aromatic amines has been devel-
oped. This ligand-free heterogeneous Cu/Al-HT catalyst, in conjunction with base, also efficiently works for the amination of aryl
chlorides with cycloalkylamines. This method tolerates a variety of functional groups and does not require an expensive additive.
Ó 2007 Published by Elsevier Ltd.
N-Arylation of amines is an important reaction in chem-
ical synthesis because N-arylated compounds have wide
utility in pharmaceuticals and agrochemicals.1 Their
widespread importance has led to the development of
many synthetic methods for the formation of aryl-nitro-
gen bonds. Amongst them, the classical copper-mediated
Ullmann and recently developed palladium(0)-catalyzed
aryl coupling are commonly used methods.2 It has been
recognized that development of a clean N-arylation
method is an important challenge in green chemistry.
The most frequently used method for coupling reactions
is still the classical copper-mediated Ullmann type reac-
tion. The contributions of Buchwald and co-workers3
and Taillefer and co-workers4 in the development of cat-
alytic N-arylations with bromo- and iodo-arenes using
copper in the presence of ligands such as amino acids,5
diamines,6 diimines,7 diols8 and thiolate9 has generated
significant interest in industry. N-Arylation of hetero-
cycles with chloroarenes using copper oxide coated
copper nanoparticles and by palladium catalysis in the
presence of strong bases have also been reported.10 Solid
formula, ½MðIIÞ1ꢀxMðIIIÞxðOHÞ2ꢁ Anx=ꢀn ꢂyH2O, where
M(II) and M(III) are divalent and trivalent cations such
as Cu2+, Mg2+ and Al3+, respectively. The countera-
nions may be OHꢀ, Clꢀ, NO3ꢀ, CO32ꢀ, etc.13–15
Recently, we reported the preparation of recyclable
heterogeneous Cu-exchanged fluoroapatite and copper
exchanged tert-butoxyapatite catalysts, by incorporating
the basic species Fꢀ/t-BuOꢀ in apatite in situ by co-pre-
cipitation and subsequent exchange with Cu(II) for the
N-arylation of imidazoles and other heterocycles with
chloroarenes and fluoroarenes, with good to excellent
yields.16 In continuation of our work on N-arylation
reactions, we herein report Cu/Al-HT catalyzed amina-
tion of aryl chlorides with benzylamine, dibenzylamine
and cycloalkylamines at 100–160 °C in the presence of
base.
To identify the best system for the amination of para-
nitrochlorobenzene, 1a, with benzylamine, we employed
Cu/Al-HTA (Cu:Al, 3:1), Cu/Al-HTB (Cu:Al, 2.5:1),
Cu-HAP, and Cu-FAP as catalysts and it was found
that Cu/Al-HTB with K2CO3 (1.2 equiv) afforded a
good yield of N-arylated product (77%) at 160 °C. The
only by-product observed in this reaction was nitrobenz-
ene (5%). Several solvents were screened for the amina-
tion of 1a with benzylamine, and it was observed that
high boiling polar solvents such as DMSO and DMF
were found to be less effective. Although N-methylpyrr-
olidine (NMP) was found to be effective (60%), benzyl-
amine (benzylamine used as the reagent as well as
the solvent) was found to be more effective (77%) with
negligible amount of Cu leaching. A control reac-
tion conducted under identical conditions devoid of
Cu/Al-HTB gave no coupled product. Cu/Al-HTB
11
supports such as KF/Al2O3 and Cu–Fe-hydrotalcite
have been used for N-arylation in recent years.12
Heterogeneous catalysis is particularly attractive as it
allows the production and ready separation of large
quantities of products with the use of a small amount
of catalyst.
Hydrotalcites (HTs) are a class of layered materials
of current interest. They are represented by the general
Keywords: N-Arylation; Amination; Cu/Al-HT; Aryl chlorides.
*
Corresponding author. Tel.: +91 40 2719 3510; fax: +91 40 2716
0921; e-mail: plikhar@iict.res.in
0040-4039/$ - see front matter Ó 2007 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2007.03.136

3912
P. R. Likhar et al. / Tetrahedron Letters 48 (2007) 3911–3914
Table 1. Cu/Al-HTB catalyzed amination of aryl chlorides with benzylaminesa
Entry
1
Aryl chloride
Production
Time (h)
16
Yieldb (%)
77, 77c
O2N
Cl
O2N
NH CH2Ph
2a
NO2
NO2
Cl
2
3
8
16
12
16
8
80, 60d
NH CH2Ph
2b
HOOC
NH
CH2Ph
Cl
68
OHC
2c
NH CH2Ph
Cl
4
69
Cl
CHO
OHC
Cl
2d
HOOC
NH
CH2Ph
2e
5
46
HOOC
Cl
CN
CN
Cl
6
52
NH CH2Ph
2f
NH
CN
CH2Ph
2g
7
16
14
16
16
45
NC
Cl
NO2
NO2
Cl
CH2Ph
CH2Ph
8e
9
76
N
3b
—
—
—
Cl
10
—
MeO
Cl
a Reaction conditions: 20 wt % catalyst, 3.60 mmol (ꢃ1.1 equiv) K2CO3, 3.17 mmol aryl chloride, 1.5 ml amine, temperature 160 °C.
b Isolated yield. All the products were characterized by 1H NMR and mass spectroscopy and compared with the literature data (Ref. 19).
c Recycled catalyst used (isolated yields %: 77, 77, 76, 76).
d Using NMP as solvent.
e Using dibenzylamine.
was recovered quantitatively by simple filtration and re-
Z
Z
Y
H2N
+
Y
used, and gave consistent activity even after the fourth
cycle (Table 1, entry 1). Moreover, the absence of cop-
per in the filtrate was confirmed by ICP-MS, which reit-
erated that no leaching of copper had occurred during
the reaction and provided evidence for heterogeneity
throughout the reaction.
Cu-HTB/K2CO3
160 oC/16 h
X
Cl
X
NH
2a-g
1a-g
a:X-NO2, Y-H, Z-H; b: X-H, Y-H, Z-NO2; c:X-CHO, Y-H, Z-H
d:X-CHO, Y-Cl, Z-H; e:X-COOH, Y-H, Z-H; f:X-H, Y-H, Z-CN
g:X-CN, Y-H, Z-H.
NO2
NO2
We chose a variety of substituted chloroarenes possess-
ing a wide range of functional groups for our study
(Scheme 1) to demonstrate the scope and the generality
of the Cu/Al-HTB catalyzed amination of chloroarenes
with K2CO3 as base, and the results are summarized in
Table 1. Chlorobenzenes with electron-withdrawing
groups, such as 4-nitro-chlorobenzene, 4-chlorobenzal-
dehyde and 4-cyano-chlorobenzene provided moderate
to good yields (Table 1, entries 1, 3 and 7). Interestingly,
ortho-substituted electron-withdrawing groups on the
aryl chloride provided good yields in shorter times (Ta-
ble 1, entries 2, 4, 6 and 8) compared with 4-substituted
chlorobenzenes. When chlorobenzene and 4-chloroani-
sole were employed in the reaction, no product forma-
tion was observed (Table 1, entries 9 and 10). In the
case of 2,4-dichlorobenzaldehyde, the chloro group at
the ortho position was N-arylated (entry 4). The ortho
Cu-HTB/K2CO3
160 oC/16 h
+
Cl
HN
N
1b
3
3b
Scheme 1.
Z
Z
Y
X
Y
Cu-HTB/K2CO3
Cl
H2N
R
+
X
NH R
100 oC/8 h
1a-f
4a-f, 5b
a:X-NO2, Y-H, Z-H; b:X-H, Y-H, Z-NO2; c:X-CHO, Y-H, Z-H
d:X-CHO, Y-Cl, Z-H; e:X-COOH, Y-H, Z-H; f:X-H, Y-H, Z-CN
4: R-Cyclohexyl; 5:R-Cyclopentyl
Scheme 2.

P. R. Likhar et al. / Tetrahedron Letters 48 (2007) 3911–3914
Table 2. Cu/Al-HTB catalyzed amination of aryl chlorides with cycloalkylaminesa
3913
Entry
Aryl chloride
Production
Time (h)
9
Yieldb (%)
O2N
NH
4a
1
71
Cl
O2N
NO2
NO2
Cl
2
3
4
5
6
7
8
8
8
8
9
6
91, 91c
NH
4b
HOOC
NH
4c
89
56
88
59
93
Cl
OHC
NH
Cl
Cl
CHO
Cl
CHO
4d
HOOC
CN
NH
HOOC
Cl
4e
CN
NH
4f
Cl
NO2
NO2
Cl
NH
5b
a Reaction conditions: 20 wt % catalyst, 3.6 mmol (ꢃ1.1 equiv), K2CO3, 3.17 mmol aryl chloride, 2 ml amine, temperature 100 °C.
b Isolated yield. All the products were characterized by 1H NMR and mass spectroscopy and compared with the literature data (Ref. 18).
c Recycled catalyst used (isolated yields %: 91, 91, 90, 90).
effect of the chloro group can be visualized when com-
pared with para-chlorobenzaldehyde. The C–N coupling
product bearing an aldehyde group is oxidized to an
acid while in the case of 2,4-dichlorobenzaldehyde, no
oxidation of the aldehyde group occurred (Table 1, en-
try 3 vs 4). In the case of the secondary amine, dibenzyl-
amine, the reaction proceeded in a similar manner
without the formation of nitrobenzene (entry 8). Benzyl-
amines with electron-donating and electron-withdraw-
ing moieties were found to be inactive in this reaction.
Acknowledgement
We wish to thank the CSIR for financial support under
the Task Force Project CMM-0005.
References and notes
1. (a) Negwer, M. In Organic-Chemical Drugs and their
Synonyms: (An International Survey), 7th ed.; Akademie:
Berlin, 1994; (b) Southon, I. W.; Buckingham, J. In
Dictionary of Alkaloids; Saxton, J. E., Ed.; Chapman and
Hall: London, 1989.
2. (a) Lindley, J. Tetrahedron 1984, 40, 1433; (b) Hartwig, J.
F. Pure Appl. Chem. 1999, 71, 1417; (c) Driver, M. S.;
Hartwig, J. F. J. Am. Chem. Soc. 1997, 119, 8232; (d)
Hartwig, J. F. Synlett 1996, 329; (e) Wolfe, J. P.; Tomori,
H.; Sadighi, J. P.; Yin, J. J.; Buchwald, S. L. J. Org. Chem
2000, 65, 1158; (f) Djakovitch, L.; Wagner, M.; Kohler, K.
J. Organomet. Chem. 1999, 592, 225.
3. (a) Antilla, J. C.; Baskin, J. M.; Barder, T. E.; Buchwald,
S. L. J. Org. Chem. 2004, 69, 5578; (b) Antilla, J. C.;
Klapars, A.; Buchwald, S. L. J. Am.Chem. Soc. 2002, 124,
11684; (c) Klapars, A.; Antilla, J. C.; Huang, X.; Buch-
wald, S. L. J. Am. Chem. Soc. 2001, 123, 7727; (d)
Kiyomori, A.; Marcoux, J. F.; Buchwald, S. L. Tetra-
hedron Lett. 1999, 40, 2657.
4. (a) Cristau, H. J.; Cellier, P. P.; Spindler, J. F.; Taillefer, M.
Eur. J. Org. Chem. 2004, 695; (b) Cristau, H. J.; Cellier, P.
P.; Spindler, J. F.; Tailefer, M. Chem. Eur. J. 2004, 10, 5607.
5. (a) Ma, D.; Xia, C.; Jiang, J.; Zhang, J.; Tang, W. J. Org.
Chem. 2003, 68, 442; (b) Clement, J.-B.; Hayes, J. F.;
Sheldrake, H. M.; Sheldrake, P. W.; Wells, A. S. Synlett
2001, 1423.
In order to expand the scope of this methodology, the
Cu/Al-HTB catalyzed amination protocol was extended
to aliphatic amines and cycloalkylamines17 (Scheme 2).
Cycloalkylamines were found to react at relatively low
temperature and in short periods of time. A variety of
substituted chloroarenes possessing a wide range of
functional groups were successfully coupled with cyclo-
alkylamines (cyclohexylamine and cylopentylamine) to
give the corresponding N-arylated products in excellent
yields and the results are summarized in Table 2. The re-
sults on the amination of various aryl chlorides with
cycloalkylamines are impressive and reported for the
first time.18
In conclusion, we have developed a simple and efficient
method for the amination of aryl chlorides using Cu/Al-
HTB as a heterogeneous catalyst. Various aryl chlorides
were coupled with benzylamine, dibenzylamine and
cycloalkylamines to yield the corresponding N-arylated
products in good to excellent yields (45–93%). The cata-
lyst can be readily recovered and reused.

3914
P. R. Likhar et al. / Tetrahedron Letters 48 (2007) 3911–3914
6. Wang, X.; Porco, J. A., Jr. J. Am. Chem. Soc. 2003, 125,
17. Typical procedure for the amination of aryl chloride with
cyclohexylamine (Table 2, entry 2, 4b): Cu/Al-HTB
(100 mg, 20 wt %) and, K2CO3 (0.5 g, 3.62 mmol) were
added to a mixture of ortho-nitrochlorobenzene (0.5 g,
3.17 mmol) in freshly distilled cyclohexylamine (2 ml) and
the mixture was stirred in an oil bath (preheated to the
given reaction temperature) for the required time. After
completion of the reaction as monitored by TLC, the
reaction mixture was cooled to room temperature, centri-
fuged and the solid catalyst was separated. The organic
layer was treated with water, washed with brine and dried
(Na2SO4). The resultant organic layer was concentrated to
give crude N-(2-nitrophenyl) cyclohexylamine and unre-
acted ortho-nitrochlorobenzene. Column chromatography
was performed using silica gel (60–200 mesh, eluent-
hexane) to afford the pure product. Yield 91%, Orange
6040; Padwa, A.; Crawford, K. R.; Rashatasakhon, P.;
Rose, M. J. Org. Chem. 2003, 68, 2609.
7. Kuil, M.; Bekedam, E. K.; Visser, G. M.; van den
Hoogenband, A.; Terpastra, J. W.; Kamer, P. C. J.; van
Leeuwen, P. W. N. M.; van Strijdonck, G. P. F.
Tetrahedron Lett. 2005, 46, 2405.
8. (a) Enguehard, C.; Allouchi, H.; Gueiffier, A.; Buchwald,
S. L. J .Org. Chem. 2003, 68, 4367; (b) Buchwald, S. L.;
Klapars, A.; Antilla, J. C.; Job, G. E.; Wolter, M.; Kwong,
F. Y.; Nordmann, G. Hennessy, E. J. Patent WO 02/
085838 A1, 2002, CA2445159 (A1).
9. Jerphagnon, T.; Van Klink, G. P. M.; De Vries, J. G.; Van
Koten, G. Org. Lett. 2005, 7, 5241.
10. (a) Son, S. U.; Park, I. K.; Park, J.; Hyeon, T. Chem.
Commun. 2004, 778; (b) Amrani, R. O.; Schneider, R.;
Fort, Y. Synthesis 2004, 15, 2527.
11. Smith, W. J.; Sawyer, J. S. Tetrahedron Lett. 1996, 37, 299.
12. Jadhav, V. H.; Dunbre, D. K.; Phapale, V. B.; Borate, H.
B.; Wakharkar, R. D. Catal. Commun. 2007, 8, 65.
13. Velu, S.; Swamy, C. S. Appl. Catal. 1994, 119, 241.
14. Cavani, F.; Trifiro, F.; Vaccari, A. Catal. Today 1991, 11,
173.
15. Trifiro, F.; Vaccari, A. In Comprehensive Supramolecular
Chemistry; Atwood, J. L., MacNicol, D. D., Davies, J. E.
D., Vogle, F., Eds.; Pergamon Press: Oxford, 1995; Vol. 7,
Chapter 10.
1
solid, mp ꢀ108 °C; H NMR (300 MHz, CDCl3): d 8.35
(1H, d, J = 8.3 Hz), 8.24 (1H, NH), 7.49 (1H, t,
J = 7.4 Hz), 6.85 (1H, d, J = 8.3 Hz), 6.61 (1H, t,
J = 8.3 Hz), 3.49 (1H, s), 2.21–1.35 (10H, m); 13C NMR
(75 MHz, CDCl3): d 136.9, 127.8, 115.5, 114.5, 51.9, 33.0,
26.1, 25.1. MS (ESI): m/z = 220. CHN Anal. Calcd for
C12H16N2O2: C, 65.4; H, 7.2; N, 12.7. Found: C, 65.6; H,
6.9; N,12.6.
18. (a) Wolf, C.; Liu, S.; Mei, X.; August, A. T.; Casimir, M.
D. J .Org. Chem. 2006, 71, 3270; (b) Lei, X.; Zhu, Di; Wu,
F.; Wang, R.; Wan, B. Tetrahedron 2005, 61, 6553.
19. Kwong, F. Y.; Klapars, A.; Buchwald, S. L. Org. Lett.
2002, 4, 581.
16. Choudary, B. M.; Sridhar, C.; Kantam, M. L.; Venkanna,
G. T.; Sreedhar, B. J. Am. Chem. Soc. 2005, 127, 9948.