A ligand-free and base-free copper catalyzed reaction: Arylation of ammonia and primary amines as their acetate salts

Article abstract of DOI:10.1016/j.tetlet.2012.07.048

A ligand-free, base-free copper catalyzed arylation of ammonia and primary amines as their corresponding acetate salts are established. The Carboxylate group is believed to be catalyzing the arylation of ammonia. This reaction is specific for primary amines.

Full text of DOI:10.1016/j.tetlet.2012.07.048

Tetrahedron Letters 53 (2012) 5219–5222
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Tetrahedron Letters
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A ligand-free and base-free copper catalyzed reaction: arylation
of ammonia and primary amines as their acetate salts
Maravanahalli S. Siddegowda a, Hemmige S. Yathirajan b, Ramesha A. Ramakrishna a,
⇑
a R L Fine Chem, No. 15, KHB Industrial Area, Yelahanka New Town, Bangalore 560106, India
b Department of studies in Chemistry, University of Mysore, Manasagangotri, Mysore 570006, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A ligand-free, base-free copper catalyzed arylation of ammonia and primary amines as their correspond-
ing acetate salts are established. The Carboxylate group is believed to be catalyzing the arylation of
ammonia. This reaction is specific for primary amines.
Received 10 April 2012
Revised 10 July 2012
Accepted 11 July 2012
Available online 20 July 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Ammonium acetate
Copper
Amines
Arylation
Primary amines
Metal catalyzed reactions of amines are very well documented
in the literature1 which are part of industrially and academically
important strategies. Ammonia, a primary source of nitrogen is
an abundant and inexpensive source of nitrogen.2 Substituted
ammonia has great importance in pharmaceutical industry and
other branches of industry.3 Hence, there is great interest in using
ammonia as a reagent for transformations leading to alkyl/aryl
amines. Generally, reactions that use ammonia employ high pres-
sures for successful completion of the reaction. Recently, several
catalysts have been designed to overcome this problem.4 Though,
copper and palladium catalyzed amination are very well docu-
mented in the literature, their utility in arylation of ammonia is
reported recently.5 Due to the continued importance of arylation
of ammonia, several modifications and improvisations in the cop-
per and palladium catalyzed arylation of amines have been pub-
lished over a period of several decades. In copper catalyzed
reactions, generally copper or copper salts like CuI,6 Cu(OAc)2,-
CuBr/Cu/Cu2O7,8 have been used as catalyst in the presence of inor-
ganic bases such as potassium phosphate,6a potassium carbonate,9
or cesium carbonate.5b Normally, ligands such as aminoacids,6a
diamines,7,8 or thio ligands9b have been used as catalyst. However,
palladium catalyzed reactions have been carried out in the
presence of phosphine ligands5c and bases such as sodium tert-
butoxide, potassium carbonate, potassium phosphate etc. In these
transformations solvents such as DMF,5b DMSO,6a water, alcohols10
etc. have been used. Although these reactions work very well for
organic amines, they are not successful for the arylation of ammo-
nia. Recently, Taillefer and coworkers documented the utility of
aqueous ammonia,5b which provides a new direction for the
copper catalyzed arylation of ammonia.5b In this CuI catalyzed
reaction, diketones are used as the ligand in the presence of cesium
carbonate and is selective for aromatic bromides and iodides to
furnish the corresponding anilines in moderate yield. Another re-
cent paper by Stradiotto5c presents an interesting improvisation
of arylation of ammonia using palladium catalyst. Unlike copper
catalyzed reactions, palladium catalyzed reactions work well for
many aromatic chloro compounds. Further, Wan11 and coworkers
reported an interesting reaction, wherein copper oxide and
N2,N2-diisopropyloxalohydrazide have been successfully used for
the arylation of ammonia. Apart from these literature precedence,
the use of ammonia as a reagent has also been reviewed recently.12
There are several attempts to directly convert aromatic halides
to anilines using many reagents. For example, trifluoroacetamide,13
sodium hexamethyldisilazane, and14 TMSN3-CuF2
have been
15
used as a source of ammonia for the direct arylation of aromatic
halides. Despite the success of these initial reports, there are a
number of limitations concerning the scope and utility of
this metal catalyzed cross coupling of aryl halides with
ammonia.
Copper catalyzed reaction of aniline with 2-halobenzoic acid
under reflux condition was first reported by Ullmann almost a
⇑
Corresponding author. Tel.: +91 80 3272 0351; fax: +91 80 2856 6630.
E-mail address: ramesha63@hotmail.com (R.A. Ramakrishna).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.07.048

5220
M. S. Siddegowda et al. / Tetrahedron Letters 53 (2012) 5219–5222
Table 1
yield of aniline (Table 1, entry 5). Further, it was noticed that
Alkylation of ammonium salts in the absence of base
methyl ammonium acetate reacted smoothly with bromobenzene
to give N-methyl aniline in moderate yield (55%, Table 1, entry
6). However, secondary amine salts such as dimethylamine acetate
or N-methyl piperazenium acetate (Scheme 1, Table 1, entries 7–8)
did not react with bromobenzene under the reaction conditions.
Interestingly, in these experiments neither external base nor exter-
nal ligand has been used for the reaction. Reaction of iodobenzene
with ammonium acetate, ammonium benzoate, and methyl
ammonium acetate gave comparable results (Table 1, entries 11–
13). Under the similar condition chlorobenzene almost did not re-
act (Table 1, entry 15). To find out whether the reaction is cata-
lyzed by carboxyl moiety, the reaction was carried with
bromobenzene, diammonium phosphate, and ammonium chloride
(Table 1, entries 9, 10). As expected, there was no reaction under
identical reaction conditions. These results clearly indicate that
the carboxylic acid group is catalyzing the arylation of amines.
To study the scope of the reaction, a variety of aromatic ha-
lides17 were reacted with ammonium acetate/methyl ammonium
acetate to furnish the corresponding aniline or N-methylaniline
(Table 2, entries 1–5) in good to moderate yields. 4-Bromo chloro-
benzene (Table 2, entry 1) reacted with ammonium acetate, to fur-
nish 4-chloro aniline in moderate yield (Table 2, entry 1). 4-Nitro
bromobenzene gave a mixture of 4-nitro aniline and corresponding
N,N-diacetate (Table 2, entry 2). 2-Chloro methyl benzoate fur-
nished methyl anthranilate in moderate yield (Table 2, entry 3).
4-Nitro bromobenzene reacted with methyl ammonium acetate
to give 4-nitro-N-methyl aniline in good yield. Similarly 3-bromo
doxepinone and 4-bromo-2,2-dimethyl phenyl acetic acid methyl
ester furnished the corresponding N-methyl anilines in moderate
yield (Table 2, entries 5–6). However, piperidine acetate failed to
react under the present reaction condition (Table 2, entry 7). Fur-
ther, for substrates having internal carboxyl group, corresponding
amine salts were prepared in situ and reacted with copper in
DMF. Thus, 2-halo benzoic acid is converted to their methylamine
salt and then reacted with copper in DMF to afford N-methyl
anthranilic acid in good yield (Table 2, entries 8–9). In the entries
8–9, no external carboxylate was used. As a control, these sub-
strates were also reacted with 2 equiv of external ammonium/
methyl ammonium acetate to see whether it has any effect on
yield. However, we obtained comparable yields in these
experiments too (see the yield in the bracket). Further, this
strategy has been extended for other primary amines such as
aniline (Table 2, entry 10), amino ethanol (Table 2, entry 11), and
phenyl ethylamine(Table 2, entry 12). When aniline is reacted with
2-chloro benzoic acid, a moderate yield of N-phenyl anthranilic
acid is obtained (Table 2, entry 10). When 2-amino ethanol acetate
was reacted with bromobenzene under similar condition,
N-phenylamino ethanol is obtained as a major product (Table 2,
entry 11). Similarly, phenyl ethyl ammonium acetate furnished
N-phenyl phenyl ethylamine in moderate yield (Table 2, entry
12). From these experiments we have shown that it is possible to
carry out ligand-free, base-free copper catalyzed arylation of
ammonia and primary amines as their corresponding carboxylic
acid salts.
NH4OAc, DMF,
Cu (0.5 eq)
H
N
NH2
+
X
reflux, no base
1a
1b
0-74%
X: Br/I/Cl
Entrya
Amine sourceb
Product/s
Yieldc
1
2
3
4
5
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OBz
1a:1b(2:1)
1a:1b(1:2)
1a:1b(1.6:1)
1a:1b(1:8)
1a:1b (1.3:1)
74
57d
70e
54f
35
H
N
6
CH3NH3OAc
55
1c
No reaction
7
8
(CH3)2NH2OAc
0
0
No reaction
N
NH2OAc
9
10
11
12
NH2HPO4
NH4Cl
NH4OAc
NH4OBz
No reaction
No reaction
1a:1b (2.2:1)
1a:1b (0.8:1)
0
0
58
45
H
N
13
CH3NH3OAc
60
1c
No reaction
14
15
(CH3) 2NH2OAc
NH4OAc
0
NH2
1a
Trace
a
Entries 1–10 with bromobenzene, entries 11–14 with lodobenzene, entry 15
with chlorobenzene.
b
Along with amine source, 0.5 at equiv of copper, DMF used as solvent. Ratio of
substrate/ammonium acetate (1:2).
c
Yield refers to isolated yield.
C6H5Br/NH4OAc (1:1).
C6H5Br/NH4OAc (1:5).
C6H5Br/NH4OAc (5:1).
d
e
f
century ago.1b This reaction requires harsh conditions and is usu-
ally catalyzed by copper or its salts in the presence of inorganic
bases. Several ligands have been found to accelerate this reac-
tion.6–8 A recent report on the mild Ullmann reaction by Pellon16
attracted our attention, wherein 2-chlorobenzoic acid is reacted
with aqueous methylamine in the presence of copper catalyst
and K2CO3 to furnish N-methlyanthranilic acid in good yield. This
facile copper catalyzed amination of 2-chlorobenzoic acid cannot
be explained by the electron withdrawing effect of the carboxylic
acid group alone. This prompted us to think whether the carboxylic
group present in the molecule is catalyzing the reaction. If this is
true, such reaction should also be catalyzed by external carboxyl-
ates such as acetates/benzoates. To test this hypothesis, we
decided to use the ammonium salt of carboxylic acid, wherein
the carboxylic group acts as ligand and the amine counterpart as
amine source. The results are presented in Table 1. When bromo-
benzene (1 equiv) is reacted with ammonium acetate (2 equiv),
copper (0.5 at equiv), and DMF, the reaction proceeded smoothly
to afford aniline as the major product and diphenylamine as the
minor product (Table 1, entry 1). Varying the ratio of substrate to
ammonium acetate did not give exclusive aniline/diphenylamine
(Table 1, entries 2–4). However, with an excess of bromobenzene
(5 equiv) diphenylamine is obtained as the major product (Table
1, entry 4) and with an excess of ammonium acetate (5 equiv), ani-
line is obtained as the major product. Similarly, the reaction of bro-
mobenzene with ammonium benzoate also furnished moderate
In a nutshell, we have shown that ammonia and primary
amines can be arylated by converting them into their acetate salts
in the presence of copper as catalyst. To the best of our knowl-
edge, this is the first example of arylation of ammonia using cop-
per catalyst under ligand-free and base-free conditions. In these
reactions, carboxyl anion is believed to be acting as ligand and
also as a base for the reaction. This reaction is specific for primary
amines. Secondary amines fail to react under the reaction condi-
tion. Efforts are underway to explore the mechanism of the
reaction.

M. S. Siddegowda et al. / Tetrahedron Letters 53 (2012) 5219–5222
5221
Table 2
Alkylation of ammonium salts in the absence of base
Entry
1
Substrates
Amine sourcea
NH4OAc
Products
Yieldb
40
Br
NH2
4
4a
Cl
Cl
Br
5
NH2
N(COCH3)2
+
73 (6:4)
5a:b
2
3
4
NH4OAc
5b
O2N
O2N
O2N
5a
CO2CH3
CO2CH3
NH4OAc
42
78
6
6a
7a
Cl
NH2
Br
7
H
N
CH3NH3OAc
O2N
O2N
O
O
O
O
5
6
CH3NH3OAc
24
55
Br
Br
N
H
8a
8
CO2CH3
CO2CH3
CH3NH3OAc
N
H
9a
9
Br
NH2OAc
7
8
No reaction
—
1
CO2H
CO2H
74(65)c
10a
11a
12a
CH3NH2
CH3NH2
C6H5NH2
10
Cl
N
H
CO2H
CO2H
79(74)c
11
9
I
N
H
CO2H
CO2H
60(56)c
46
12
10
11
Ph
N
Cl
Br
H
NH3OAc
H
N
HO
1
1
OH
13a
Br
NH3OAc
H
N
12
35
14
14a
a
b
c
Along with amine source, 0.5 at equiv of copper, DMF used as solvent.
Yield refers to isolated yield.
Substrate ammonium salts were made before the reaction. Yield in the bracket with 2 equiv of external ammonium acetate for entry 8 and 9 and aniline acetate for entry
10.
Zoi Rapport, Ed.; John Willey, 2007. 1–81; (d) Ullmann, F.; Illgen, K. Ber. Datsch.
Chem. Ges. 1914, 47, 380–383.
Acknowledgement
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The authors thank the director of R L Fine Chem., Mr. Anjan K
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Supplementary data
Supplementary data (spectral data and 1H and 13C NMR of
amines and corresponding products) associated with this article
can be found, in the online version, at http://dx.doi.org/10.1016/
j.tetlet.2012.07.048.
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bottom flask for 9 h. The reaction mixture was cooled to rt, dichloromethane
(200 mL) was added and then, filtered to remove Cu powder. The filtrate was
washed with water (200 mL) and dried over sodium sulphate and concentrated
under reduced pressure. Crude sample thus obtained was purified by column
chromatography (silica gel, ethyl acetate/petroleum ether, 2:98) to give aniline
and diphenylamine (58%, 1a:1b, 2.2:1). General procedure for aryl amines – with
methylamine acetate: A mixture of bromobenzene (10 g, 63.6 mmol), acetic acid
(5.76 g, 96 mmol), methylamine (3.0 g-100% basis, 95.5 mmol) of 40% solution,
and Cu powder (2.01 g) followed by DMF (20 mL) was heated at reflux in a
100 mL round bottom flask for 9 h. The mixture was cooled to rt,
dichloromethane (200 mL) was added and then filtered to remove Cu
powder. The filtrate was washed with water (200 mL) and dried over sodium
sulphate and concentrated under reduced pressure. Crude sample thus
obtained was purified by column chromatography (silica gel, ethyl acetate/
petroleum ether, 5:95) to give N-methyl aniline (3.74 g, 55%, 1c). Procedure for
N-methyl anthranillic acid:
A mixture of o-chloro benzoic acid (5.0 g,
31.9 mmol), methylamine (1.98 g, 64 mmol, calculated to 100%) of 40%
15. Maejima, T.; Shimoda, Y.; Nozaki, K.; Mori, S.; Sawama, Y.; Monguchi, Y.; Sajiki,
H. Tetrahedron 2012, 68(6), 1712–1722.
solution and Cu powder (1.01 g) followed by DMF (15 mL) was heated to
reflux in
a 100 mL round bottom flask for 9 h. Cooled to RT, added
16. Docompo, M. L.; Pellon, R. F.; Braun, A. E.; Ravelo, A. G. Eur. J. Org. Chem. 2007,
4111–4115.
17. General procedure for Aryl amines – with ammonium acetate: A mixture of
iodobenzene (5 g, 24.5 mmol), ammonium acetate (3.778 g, 49 mmol), Cu
powder (0.778 g), and DMF (15 mL) was heated at reflux in a 100 mL round
dichloromethane (200 mL), filtered to remove Cu powder. Filtrate was
washed with water (200 mL) and dried over sodium sulphate and
concentrated under reduced pressure. Crude sample thus obtained was
purified by column chromatography (silica gel, ethyl acetate/petroleum
ether, 5:95) to give the product N-methyl anthranillic acid (3.62 g, 74%, 10a).