Copper-catalyzed C-N cross-coupling reactions for the preparation of aryl diamines applying mild conditions

Article abstract of DOI:10.1016/j.tetlet.2013.02.048

In this work, aryl diamines were prepared by C-N cross-coupling reactions between aryl halides and ethylenediamine. These reactions were successfully catalyzed by low quantities of Cu₂O or CuO (1 mol %) employing low reflux temperature and low diamine excess. Products were afforded in good yields (up to 95%).

Full text of DOI:10.1016/j.tetlet.2013.02.048

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Tetrahedron Letters 54 (2013) 2332–2335
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Copper-catalyzed C–N cross-coupling reactions for the preparation of aryl
diamines applying mild conditions
⇑
⇑
Márcio V. Costa, Gil M. Viana, Thaís M. de Souza, Luiz Fernando B. Malta , Lúcia C. S. Aguiar
Instituto de Química, Universidade Federal do Rio de Janeiro, CT Bloco A Lab. 617/641, Rio de Janeiro 21949-909, RJ, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
In this work, aryl diamines were prepared by C–N cross-coupling reactions between aryl halides and eth-
ylenediamine. These reactions were successfully catalyzed by low quantities of Cu2O or CuO (1 mol %)
employing low reflux temperature and low diamine excess. Products were afforded in good yields (up
to 95%).
Received 11 December 2012
Revised 8 February 2013
Accepted 15 February 2013
Available online 24 February 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Aryl diamines
Copper oxide
Diamines
Cross-coupling reactions
Polyamines
Polyamines represent a class of compounds of great importance
both in coordination and biological chemistry, being involved with
cation complexation,1 cellular growth, and ribonucleic acid
transcription. Besides, their participation in protein synthesis and
regulation of immune responses2 are also described. In particular,
N-aryl substituted diamines are subject of interest from the
pharmaceutical industry, since they can regulate the growth of
cancerous cells.3 In this context, the development of N-arylation
methods of diamines/polyamines constitutes an important area
of research. The formation of the C–N bond has been a strategic
subject within organic synthesis field evidenced by the growing
number of manuscripts in the last years.4 Besides the use of
palladium based catalysts, the employment of copper in these
reactions has been re-evaluated due to its chemical stability under
air atmosphere as well as its low cost and toxicity.
Recently, Han and co-workers reported both the use of dia-
mines and aminoalcohols in the N-arylation of several aryl halides,
employing the ratio 1:3 equiv (halide:amine/aminoalcohol). These
reactions were catalyzed by 10 mol % of CuCl and the respective
products were obtained in moderate to good yields at 0–90 °C for
8 h in the absence of solvents.5
Motivated by the plethora of subjects surrounding the poly-
amines chemistry, we have been studying copper-catalyzed C–N
cross-coupling reactions aiming to develop a synthetic method to
obtain aryl diamines. Herein, we firstly report the use of Cu2O
and CuO nanoparticles (NPs) and CuO microparticles (MPs) as cat-
alysts in the model reaction between ethylenediamine and 4-iodo-
1-nitrobenzene (Scheme 1). For comparison, CuI was also evalu-
ated, since it is often applied as the catalyst in C–N cross-coupling
reactions.6 Moreover, several conditions were investigated such as
the ethylenediamine amount, the reaction time, and inert atmo-
sphere use in the reaction medium.
Initially, the ratio of 1:7.4 equiv between 4-iodo-1-nitroben-
zene and ethylenediamine was essayed. The results are summa-
rized in Table 1. Firstly, we verified that the non-employment of
a catalyst did not allow an appreciable yield, 26% (entry 1). With
this in mind, Cu2O catalyst was applied. Entries 2 and 3 (Table 1)
evidence that dropping the Cu2O amount from 10 to 1 mol % did
not influence significantly the reaction yield (94–95%). In contrast,
further diminishment of the catalyst amount to 0.5 mol % (entry 4)
was sufficient to slow the reaction (87% after 10 h).
Comparing Cu(I) catalysts, reactions employing CuI, entries 6
and 7, afforded less coupled product than those of entries 3 and
4, revealing the superior catalytic activity of copper oxide.
Furthermore, entries 2 and 8 allow comparing Cu2O and CuO
NPs performance. Here it is noticed that Cu2O NPs permitted en-
hanced catalytic activity (entry 2), signaling to the need of having
Cu(I) species in the reaction medium.7 However, the employment
of N2 atmosphere in CuO catalyzed reactions (entries 11 and 13)
afforded good to excellent yield (79–99%) even in low amounts
of catalyst (1 mol %). On the other hand, when this procedure
was applied to Cu2O (entry 5) it did not offer an appreciable yield
enhancement (compare entries 4 and 5). The deficient O2 atmo-
sphere possibly aids the creation of Cu(I) sites in the CuO lattice8
⇑
Corresponding authors. Tel.: +55 21 2562 7738; fax: +55 21 2562 7559.
E-mail addresses: lfbmalta@iq.ufrj.br (L.F.B. Malta), luciasequeira@yahoo.com.br
(L.C.S. Aguiar).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.02.048

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M. V. Costa et al. / Tetrahedron Letters 54 (2013) 2332–2335
2333
H
N
I
Copper catalyst
CH3CN (reflux)
NH2
NH2
H2N
O2N
O2N
3a
2a
1a
Scheme 1. N-arylation of ethylenediamine.
Table 1
Reaction yields regarding the catalyzed C–N cross-couplings between 4-iodo-1-nitrobenzene (1a) and ethylenediamine (2a) using a variable ratio 1a:2a in acetonitrile applying
different copper catalysts
Entry
Ratio 1a:2a
Catalyst amount (mol %)
Atmosphere
Reaction time (reflux) (h)
3a13 Yield %
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
1:7.4
1:7.4
1:7.4
1:7.4
1:7.4
1:7.4
1:7.4
1:7.4
1:7.4
1:7.4
1:7.4
1:7.4
1:7.4
1:4
1:4
1:4
1:4
1:4
1:4
1:2
1:2
1:2
—
—
—
—
—
N2
—
—
—
—
—
N2
—
N2
—
N2
—
N2
N2
N2
—
6
6
6
10
10
6
26a
95b
94b
87b
89b
90b
85a
85b
87b
30a
96b/99a
5a
NPs Cu2O-10
NPs Cu2O-1
NPs Cu2O-0.5
NPs Cu2O-0.5
CuI-1
CuI-0.5
6
NPs CuO-10
MPs CuO-10
MPs CuO-1
MPs CuO-1
NPs CuO-1
NPs CuO-1
NPs Cu2O-1
NPs Cu2O-1
NPs Cu2O-1
NPs Cu2O-1
MPs CuO-1
NPs CuO-1
NPs Cu2O-1
NPs Cu2O-1
MPs CuO-1
—
10
10
6
6
6
6
6
6
8
8
8
8
6
24
24
48
48
79a
61a
51a
87b/91a
57a
68a
56a
1a
—
83a
79a
18a
95b
N2
N2
N2
1:2
1:2
MPs CuO-1
a
Molar yield calculated by 1H NMR.
Isolated yield.
b
generating non-stoichiometric copper(II) oxide (CuO1Àx).9 In addi-
tion, it is noteworthy to say that CuO MPs (1 mol %) were surpris-
ingly more active than CuO NPs (1 mol %; compare entries 10 and
12; and entries 11 and 13).
er time (18%; entry 23). From these experiments, it became clear
that the employment of smaller proportions of aryl halide to dia-
mine is critical for the kinetics of the C–N cross-coupling reaction.
Therefore, it shows that the diamine amount is crucial to carry out
the reaction in significant velocity. Such conclusion is supported by
a nucleophilic substitution mechanism.
So far in our study, we evidenced that the employment of
1 mol % of Cu2O or CuO under N2 atmosphere afforded yields of
94–99% (results regarding the model reaction, Table 1). However,
a 7.4-fold molar excess of ethylenediamine was still being applied,
as described in the literature.10 The use of this excess is not desir-
able since a residual of the starting diamine still remains at the end
of the process, implying either in the discard of the reagent or in
extra costs to purify it for re-utilization hence impacting in the glo-
bal process cost. To search for the motivation to use such an excess,
in the next set of model reactions we managed to diminish the mo-
lar excess of diamine applying the ratios of 1:4 and 1:2 equiv keep-
ing the best reaction conditions described so far in Table 1.
Interestingly, the decrease of ethylenediamine amount in the reac-
tion medium led to lower yields of the coupled product 3a. This is
noticed for all the reactions (compare entry 3 with entries 14 and
20, Table 1), including those in which N2 atmosphere was applied
(compare entries 11 and 13 with entries 18 and 19 of Table 1).
However, the increase of the reaction time allowed obtaining 3a
in a higher yield (compare entries 14 and 16 and also 20 and 21 of
Table 1). In addition, it is noteworthy that even for a ratio of 1:2 the
model reaction catalyzed by CuO microparticles under nitrogen
atmosphere, provided 3a in significantly high yields. However, to
obtain this result longer reaction times (24–48 h) were employed
(entries 22 and 24). Once again, we verified that the non-employ-
ment of a catalyst did not allow a satisfactory yield, even in a long-
To better understand the mechanism of the C–N cross coupling
reaction we carried out reactions employing other substrates and
some of the conditions established for the model reaction in Table 1
(1 mol % Cu2O or CuO under N2 atmosphere applying reflux for 6–
48 h, besides of 2 or 7.4 equiv of the amine). Firstly, the results
were obtained upon variation of the aryl iodide employed (1a–d;
Table 2). A comparison between entries 1–4 discloses that 4-
iodo-1-nitrobenzene was more reactive than other aryl iodides,
having a major conversion into the product after 6 h (94%, entry
1; Table 2). Couplings with iodobenzene, 4-iodotoluene, and 4-
iodoanisole demanded longer reaction time, although not present-
ing such satisfactory results (Table 2, entries 2–4). These results
showed that the presence of electron withdrawing groups in the
aromatic ring favored the reaction kinetic, in conformity with the
oxidative addition and nucleophilic substitution mechanisms.
Still in search of mechanistic insights on the C–N cross-coupling
reaction, we essayed the reactivity of a series of aryl halides com-
posed of iodobenzene, bromobenzene, and chlorobenzene using
the same catalytic system (Table 2, entries 2, 5, and 6). It was ob-
served that the reaction between iodobenzene and ethylenedia-
mine provided
a superior yield in a reduced time when
compared to those employing other halides. In fact, the reaction
between chlorobenzene and ethylenediamine did not afford any

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M. V. Costa et al. / Tetrahedron Letters 54 (2013) 2332–2335
Table 2
Reaction yields regarding the copper-catalyzed C–N cross-couplings between 1 equiv of aryl halides and 2 or 7.4 equiv of amines in acetonitrile
X
NR2
n
R
NR2
n
HN
HN
H2N
copper catalyst
(1mol%)
+
or
R
or
H2N
Y
CH3CN(reflux)
Y
Y
1
2
3
4
3a (n=1; R=H; Y=NO2)
3b (n=1; R=H; Y=H)
1a (X=I; Y=NO2)
1b (X=I; Y=H)
1c (X=I; Y=CH3)
1d (X=I; Y=OCH3)
1e (X=Br; Y=H)
1f (X=Cl; Y=H)
4a (R=(CH2)2OH; Y=NO2)
4b (R=(CH2)3CH3; Y=NO2)
4c (R=(CH2)2OH; Y=H)
3c (n=1; R=H; Y=CH3)
3d (n=1; R=H; Y=OCH3)
3e (n=1; R=Et; Y=NO2)
3f (n=2; R=H; Y=NO2)
3g (n=2; R=CH3; Y=NO2)
3h (n=5; R=H; Y=NO2)
3i (n=2; R=H; Y=H)
3j (n=2; R=H; Y=CH3)
Entry
Aryl halide (1)
Amine (2)
Ratio 1:2
Catalyst (atmosphere) 1 mol %
Reaction time (reflux) (h)
Productlit.,c (%)a,b,
3a13 (94)b
3b5 (78)b
3c14 (68)b
3d14 (67)b
3b5 (24)b
—
NH2
NH2
NH2
NH2
NH2
NH2
1
2
3
4
5
6
4-Iodo-1-nitrobenzene (1a)
Iodobenzene (1b)
1:7.4
1:7.4
1:7.4
1:7.4
1:7.4
1:7.4
NPs Cu2O
NPs Cu2O
NPs Cu2O
NPs Cu2O
NPs Cu2O
NPs Cu2O
6
10
10
9
H2N
H2N
H2N
H2N
H2N
H2N
4-Iodotoluene (1c)
4-Iodoanisole (1d)
Bromobenzene (1e)
Chlorobenzene (1f)
12
12
7
4-Iodo-1-nitrobenzene (1a)
1:7.4
NPs Cu2O
6
3e (11)a
N
H2N
H2N
H2N
8
9
4-Iodo-1-nitrobenzene (1a)
4-Iodo-1-nitrobenzene (1a)
NH2
N
1:7.4
1:7.4
NPs Cu2O
NPs Cu2O
6
6
3f16(83)b
3g15 (14)a
NH2
5
H2N
10
11
4-Iodo-1-nitrobenzene (1a)
4-Iodo-1-nitrobenzene (1a)
1:7.4
1:7.4
NPs Cu2O
NPs Cu2O
6
6
3h16 (16)a
4a16 (94)b
OH
H2N
H2N
H2N
12
13
4-Iodo-1-nitrobenzene (1a)
4-Iodo-1-nitrobenzene (1a)
1:7.4
1:2
NPs Cu2O
6
4b5 (6)a
NH2
NH2
MPs CuO (N2)
48
3f16 (52)b
14
15
16
Iodobenzene (1b)
Iodobenzene (1b)
Iodobenzene (1b)
1:2
1:2
1:2
MPs CuO (N2)
MPs CuO (N2)
MPs CuO (N2)
48
48
48
3b5 (80)b
3i5 (36)b
H2N
H2N
NH2
OH
4c5 (<10%)b
H2N
NH2
17
18
19
4-Iodotoluene (1c)
4-Iodotoluene (1c)
4-Iodoanisole (1d)
1:2
1:2
1:2
MPs CuO (N2)
MPs CuO (N2)
MPs CuO (N2)
48
48
48
3c14 (40)b
3j5 (47)b
H2N
H2N
NH2
NH2
3d14 (49)b
H2N
a
b
c
Molar yield calculated by 1H NMR.
Isolated yield.
All the products are known compounds and were characterized by comparison of their spectral data with those reported in the literature.
product. According to the literature, aryl iodides are usually more
reactive than their bromides and chlorides analogues5 being this
order of reactivity suggestive of an oxidative addition mechanism.
As another part of our efforts to determine the scope of our
method, we decided to investigate the synthesis of several aryl dia-
mines employing different aliphatic amines. In this comparative
study, the reactivities of these amines were firstly evaluated for
the reaction with 4-iodo-1-nitrobenzene. Also the ratio of
1:7.4 equiv, 1 mol % of Cu2O, and a 6 h-time of reaction were cho-
sen as the conditions to perform the experiments. The results are
summarized in Table 2, entries 7–12. We verified that replacing
ethylenediamine by propane-1,3-diamine allowed an appreciable
yield (83%; entry 8), although less than that of the model reaction
(94%, entry 1). Along with this result, entry 10 evidenced that hex-
ane-1,6-diamine has low reactivity (16%). The data discussed until
now permit inferring that increasing the methylenic chain of the
diamines resulted in decreasing the yield of aryl diamines. In the
literature, it is described that copper(I)-catalyzed nucleophilic sub-
stitution reactions between amines and arenes has one mechanis-
tic step related to the formation of a chelate ring between the

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M. V. Costa et al. / Tetrahedron Letters 54 (2013) 2332–2335
2335
ligand and the metal center.11 Bearing this in mind, one hypothesis
to explain our results is based on the chelate ring formation be-
tween the diamine and Cu(I). This process implies in a diminish-
ment of the system entropy hence not favoring the chelate ring
formation. This is more dramatic when the diamine methylenic
chain is long, hence giving a greater conformational flexibility to
the ligand and not affording significant chelate formation.12
Interestingly, entries 7 and 9 reveal that the aryl diamines 3e
and 3g, generated respectively from N,N-diethyl-ethylenediamine
and N,N-dimethylpropane-1,3-diamine, were obtained in lower
yields than those generated from their non-substituted analogues
whose results are in entries 1 and 8, respectively. This reduced
reactivity can be assigned to the steric effects of ethyl and methyl
groups attached to the nitrogen atom.
Furthermore, the effect of exchanging amine and hydroxyl
groups was also verified. Thus, monoethanolamine was as reactive
as ethylenediamine leading to the formation of the respective aryl
aminoalcohol in 94% (entry 11). According to the literature, amino-
alcohols can also act as Cu(I) ligands4c,5 which is in conformity
with this result. Supporting this hypothesis, the use of an alkyl
monoamine shows that almost no product was formed (6%: entry
12) in contrast to its diamine analogue (83%, entry 8). This result
reinforces the mechanistic insights of copper(I)-mediated nucleo-
philic substitution reaction between amines and arenes, as de-
scribed before herein, since butylamine presents no possibility of
forming a chelate ring.
General procedure for C–N cross-coupling reactions: In a 10 mL
flask were placed aryl halide (0.5 mmol), diamine (1.0; 2.0 or
3.7 mmol), copper catalyst (0.5; 1.0 or 10 mol %), and acetonitrile
(2–3 mL). The reaction was then kept under stirring and reflux.
After the reaction was complete (TLC), the resulting mixture was
diluted with brine (2–3 mL) and extracted with ethyl acetate
(4 Â 7 mL). Then the organic phase was dried over anhydrous so-
dium sulfate, filtered under Celite, and the solvent was eliminated
by vacuum. The crude product was then analyzed by 1H NMR.
When necessary, the mixture was purified by column chromatog-
raphy on silica gel or by thin layer chromatography plates with UV
254 nm to afford the desired product.
N1-(4-nitrophenyl)-1,2-ethanediamine (3a):13 Reddish brown so-
lid. 1H NMR (200 MHz, CDCl3): d 8.10 (d, 2H, J = 9.15 Hz); 6.56 (d,
2H, J = 9.15 Hz); 5.10 (br s, NH); 3.33–3.20 (m, 2H); 3.08–2.98
(m, 2H); 1.53 (br s, NH2); 13C NMR (50 MHz, CDCl3): d 153.63;
137.4; 126.62; 111.35; 45.49; 40.75; IR (KBr, cmÀ1): 3360; 3297;
3226; 3173; 2953; 1602; 1293.
Acknowledgments
We are grateful to CNPq, CAPES, and FAPERJ for their financial
support.
References and notes
In addition, we carried out reactions for 48 h employing 1 mol %
microparticulate CuO, under N2 atmosphere, and the ratio of
1:2 equiv between aryl halides and diamines. For this part of the
work we chose to use the most reactive substrates essayed so
far. The results are presented in entries 13–19.
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