Copper-catalyzed arylation of oxadiamines and polyamines

Article abstract of DOI:10.1002/ejoc.201100483

Copper-catalyzed arylation of oxadiamines and polyamines aimed at the synthesis of N,N'-diaryl derivatives using bromo- and iodoarenes was studied. Conversion of the starting compounds, selectivity of the arylation of primary amino groups in the presence of the secondary amino groups, and the yields of target products were shown to be strongly dependent on the nature of the oxadiamines and polyamines, aryl halides, and halogen atom, as well as on reaction conditions such as ligand, solvent, and base applied. Reliable catalytic systems were found for each type of starting amine and aryl halide affording the highest possible yields of the products of N,N'-diarylation (65-96 %).

Full text of DOI:10.1002/ejoc.201100483

FULL PAPER
DOI: 10.1002/ejoc.201100483
Copper-Catalyzed Arylation of Oxadiamines and Polyamines
Maxim V. Anokhin,[a] Alexei D. Averin,[a] and Irina P. Beletskaya*[a]
Keywords: Amines / Amination / Homogeneous catalysis / Copper
Copper-catalyzed arylation of oxadiamines and polyamines
aimed at the synthesis of N,NЈ-diaryl derivatives using bro-
mo- and iodoarenes was studied. Conversion of the starting
compounds, selectivity of the arylation of primary amino
groups in the presence of the secondary amino groups, and
the yields of target products were shown to be strongly de-
pendent on the nature of the oxadiamines and polyamines,
aryl halides, and halogen atom, as well as on reaction condi-
tions such as ligand, solvent, and base applied. Reliable cata-
lytic systems were found for each type of starting amine and
aryl halide affording the highest possible yields of the prod-
ucts of N,NЈ-diarylation (65–96%).
shown to be efficient in copper-catalyzed amination,[26–28]
but the use of such ligands is restricted.
Introduction
Transition-metal catalysis of carbon–element bond for-
Di- and polyamines occupy a special place among N-
mation has become a powerful tool of modern preparative nucleophiles. On one hand, these compounds are known to
organic chemistry. An important place among these reac- form stable complexes with metal cations, including copper,
tions is occupied by the catalytic amination reactions.[1] Pd- which makes them valuable species for supramolecular
catalyzed amination of aryl halides is well-studied and is chemistry. Thus, one may suppose that complexes of CuI
now applied to the synthesis of physiologically active com- formed in situ with polyamimes in the copper-catalyzed am-
pounds and agrochemicals, etc.[2] Our contribution to this ination will influence the reaction pathway. On the other
field covers the synthesis of polyazamacrocycles by the cata- hand, N-aryl-substituted polyamines are of substantial
lytic amination of dihaloarenes with linear polyamines.[3,4] interest because they have been demonstrated, for example,
In the last years, a renaissance of so-called catalytic to regulate cancer cell growth.[29–32] From this viewpoint,
Ullmann chemistry has developed, and great interest has the study of Cu-catalyzed arylation of polyamines is an im-
been paid to the copper-catalyzed amination of haloarenes. portant task. In the present research, we focused on the
Researchers from the groups of Buchwald,[5] Ma,[6] and diarylation of primary amino groups in di- and polyamines
Taillefer[7] elaborated convenient protocols for aryl halide because we considered it to be of benefit to compare Cu-
amination, and an avalanche of publications have followed and Pd-mediated aryalation of polyamines and to provide
their pioneering work. Various types of N-nucleophiles, a reliable synthetic approach to N,NЈ-bis(bromoaryl)-sub-
such as aliphatic amines, cyclic amines, aromatic amines, stituted di- and polyamines, which are valuable precursors
NH-heterocycles, and amides, can be converted into the for polyazamacrocycles incorporating arene moieties. The
corresponding N-aryl derivatives under relatively mild con- Pd-catalyzed arylation of di- and polyamines was exten-
ditions, and a number of simple and readily available com- sively studied by us previously, and excellent selectivity for
pounds have been employed in these reactions as li- primary amino group arylation in the presence of second-
gands.[8–12] These ligands can be divided into three main ary amino groups was demonstrated.[33] Pd-catalyzed di-
groups: N,N-chelating ligands such as DMEDA,[13] phenan- arylation of 1,3-diaminopropane and N-(3-aminopropyl)-
throline, and its derivatives,[14] N,O-chelating ligands such 1,3-diaminopropane was conducted using 4-bromobiphenyl
as proline, N-methylglycine,[15–17] salicylic aldehyde oxime and 1-bromonaphthalene, and the reaction produced N,NЈ-
(salox),[18] phenylhydrazone,[19] and salicylic acid N,N-di- diaryl derivatives in 75–92% yields. In contrast, copper-cat-
methylamide,[20] and O,O-chelating ligands such as tet- alyzed arylation of diamines has not yet been investigated
ramethylheptanedione,[21] ethylene glycol,[22] 2-acetylcy- in detail, and there are few reports in literature on the
clohexanone,[23] cyclic β-keto esters,[24] and BINOL.[25] In a monoarylation of linear diamines[34] or the diarylation of
number of works, certain phosphorus compounds were 1,2-diaminocyclohexane.[35] Copper-catalyzed arylation of
triamine was described in only one case by Buchwald.[22]
[a] Department of Chemistry, Lomonosov Moscow State
Results and Discussion
We began our investigation with 1,3-dibromobenzene,
which was important for elaborating a Cu-mediated ap-
University,
Leninskie Gory, Moscow, 119991, Russian Federation
Fax: +7-495-9393618
E-mail: beletska@org.chem.msu.ru
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Copper-Catalyzed Arylation of Oxadiamines and Polyamines
proach to N,NЈ-bis(3-bromophenyl) polyamines. Initially, li-
For the aryl halides, we first employed the simplest bro-
gand-free arylation of tetraamine 1a was carried out using mobenzene and iodobenzene, to compare the reactivity of
the CuI/K3PO4 catalytic system in either boiling dioxane or the halogen atoms; we also examined their closest ana-
N,N-dimethylformamide (DMF), however, the conversion logues 3-bromotoluene, 3-iodotoluene, and 3,5-dimethyl-
of starting dibromide did not exceed 20%. The conversion iodobenzene to check whether the reactions are sensitive to
was increased to 100% by replacing K3PO4 with K2CO3, small variations in the nature of the products. 1,3-Dibro-
but the reaction was not selective and the amination of sec- mobenzene and 1-bromo-3-iodobenzene were used to
ondary amino groups in tetraamine 1a was substantial, thus elaborate an alternative copper-mediated route to N,NЈ-bis-
the target N1,N4-diarylated product could not be isolated in (bromobenzyl)polyamines. N,N-Diethyl-3-iodobenzamide,
a pure state. Another problem could be the formation of 4-bromobiphenyl, 4-iodobiphenyl, and 4-acetoxy-4Ј-iodobi-
complexes of tetraamine and its N-aryl derivatives with CuI, phenyl were applied to explore the influence of electron-
which also hindered the isolation of the desired compound. withdrawing groups on the reactivity of aryl halides in the
These negative results prompted us to conduct a more de- diamination processes, and 2-bromonaphthalene was used
tailed investigation into the influence of CuI-containing to assess the possibilities of conducting the amination of
catalytic systems and the nature of aryl halides and poly- arenes with a more active bromine atom (Figure 3).
amines on the amination reactions.
A study of the literature data on the copper-catalyzed
amination of aryl halides prompted us to test six main,
well-documented ligands: N,NЈ-dimethylethylenediamine
(L1),[13] phenanthroline (L2a), and neocuproine (L2b)[14]
(N,N ligands); ethylene glycol (L3),[22] α-acetylcyclohexa-
none (L4a), and α-isobutyrylcyclohexanone (L4b)[23] (O,O
ligands); and salicylic aldehyde oxime (salox) (L5)[18] and
proline (L6) (N,O ligands)[15–17] (Figure 1).
Figure 3. Aryl halides studied in this research.
Figure 1. Ligands studied in the CuI-catalyzed arylation of poly-
amines.
According to Buchwald, who proposed the use of the
catalytic system CuI/L3(200 mol-%)/K3PO4/iPrOH for
N1,N3-diarylation of triamine,[22] we applied this catalyst in
the arylation of tetraamine 1a with 2.5 equiv. of 3-iodotol-
Our investigation employed the following polyamines:
tetraamine 1a, triamine 1b, trioxadiamine 1c, and dioxa-
diamine 1d (Figure 2); these compounds differ in the chain
length and in the number of nitrogen and oxygen atoms
and, therefore, can outline the scope and limitations of the
Cu-catalyzed N,NЈ-diarylation.
Figure 2. Polyamines studied in this research.
Scheme 1. N,NЈ-Diarylation of tetraamine 1a with 3-iodotoluene.
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uene. The reaction was allowed to proceed for 24 h at re- corresponding base and solvent. The results are presented
flux, however, we obtained the target product of N1,N4-di- in Table 1.
arylation 2 in only 13% yield (Scheme 1), although the con-
version of starting 3-iodotoluene was complete. The selec-
tivity of the arylation of primary amino groups was also
insufficient, which led us to a search for more efficient cata-
lytic systems for the copper-catalyzed arylation of poly-
amines.
Use of bromobenzene gave similar moderate yields of
N1,N4-diphenyl tetraamine 3 with 2-acetylcyclohexanone
(L4a) in DMF and acetonitrile (Table 1, entries 1 and 2),
the result with salox (L5) in toluene at the same concentra-
tion (0.5 m) was negative because the reaction proceeded
non-selectively (Table 1, entry 3) due to competitive aryl-
ation of secondary amino groups. The desired product 3
thus could not be isolated in pure state from a mixture of
tri-, di-, and monoaryl derivatives. However, use of a lower
concentration (0.25 m) substantially improved the result
(Table 1, entry 4). It was possible to use less expensive po-
tassium carbonate instead of cesium carbonate with almost
the same yield of product (Table 1, entry 5). The best result
(65% of 3) was achieved by the application of proline (L6)
in acetonitrile.
Initially it was assumed that the more active iodobenzene
would provide better results, however, in many cases, the
selectivity of arylation was lower than with bromobenzene.
Again, salox (L5) provided a moderate yield of 3 only at
0.25 m concentration (Table 1, entry 8), at higher concentra-
tion (0.5 m) the selectivity of the process was very low be-
cause arylation of the secondary amino groups occurred
(Table 1, entry 7), and at lower concentration (0.13 m)
mainly monoarylation of tetraamine 1c took place that was
also non-selective, thus preventing the isolation of individ-
ual monoaryl derivatives (Table 1, entry 9). Acetylcy-
clohexanone (L4a) afforded 43% yield of 3 (Table 1, entry
10), which is comparable to the reaction with bromoben-
zene (Table 1, entry 1), and the best result (59%) was again
achieved with proline (L6; Table 1, entry 11). Slightly lower
yield of compound 3 in the reaction with iodobenzene
might be explained by a lower selectivity of the arylation
process due to the higher reactivity of iodine compared with
bromine.
Except for this modest result, numerous other attempts
to apply ligands L1, L2a, L2b, and L3 in the arylation of
di- and polyamines were unsuccessful due either to low con-
version of starting compounds or to non-selective transfor-
mations leading to inseparable mixtures of unidentified
compounds. On the other hand, ligands L4a, L4b, L5, and
L6 were found to be applicable to the arylation of poly-
amines. Initially, we studied the reactions of the simplest
bromobenzene and iodobenzene with tetraamine 1a
(Scheme 2). The reactions were performed using 2.5 equiv.
of halobenzene and 1 equiv. of tetraamine in the presence
of 10 mol-% CuI and 20 mol-% ligand at reflux temperature
(or at 110 °C with DMF) for 24 h. The appropriate solvent
and base were generally chosen according to the literature
data in which certain ligands are often associated with a
The catalytic system CuI/L6/Cs2CO3/CH3CN was also
thought to be suitable for N,NЈ-diarylation of trioxadimaine
1c (Scheme 3). However, the results were quite different
with this compound. Proline (L6) provided insufficient con-
version of starting halobenzenes, thus N,NЈ-diphenyl deriv-
Scheme 1. N,NЈ-Diarylation of tetraamine 1a with 3-iodotoluene.
Table 1. Copper-catalyzed arylation of tetraamine 1a [CuI /L (10/
20 mol-%), 24 h].
Entry ArHal Ligand
Base
Solvent
Conc.
[M]
Yield of 3
[%][a]
1
2
3
4
5
6
7
8
PhBr L4a
PhBr L4a
PhBr L5
PhBr L5
PhBr L5
PhBr L6
Cs2CO3 DMF
Cs2CO3 CH3CN
Cs2CO3 PhMe
Cs2CO3 PhMe
0.5
0.5
0.5
0.25
0.25
0.5
35
33
0[b]
43
K2CO3
PhMe
39
Cs2CO3 CH3CN
Cs2CO3 PhMe
Cs2CO3 PhMe
65
PhI
PhI
PhI
PhI
PhI
L5
L5
L5
L4a
L6
0.5
0[b]
30
0.25
0.13
0.5
9
10
11
K2CO3
PhMe
10[c]
43
Cs2CO3 DMF
Cs2CO3 CH3CN
0.5
59
[a] Yields after column chromatography. [b] 100% conversion of
halobenzenes, complex mixture of products. [c] 100% conversion
of iodobenzene, mainly non-selective monoarylation of tetraamine
1a.
Scheme 3. N,NЈ-Diarylation of trioxadiamine 1c with bromo- and
iodobenzenes.
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Copper-Catalyzed Arylation of Oxadiamines and Polyamines
ative 4 was not obtained in either case (Table 2, entries 1 series of reactions with 3-bromo- and 3-iodotoluenes, which
and 5). On the other hand, the reaction catalyzed by salox are the closest analogues of bromo- and iodobenzenes
(L5) at 0.5 m concentration was more efficient than in the (Scheme 4).
case of tetraamine 1a, providing moderate yields of 4 (Table
First we checked whether salox (L5) ligand could be em-
2, entries 2 and 6). Acetylcyclohexanone (L4a) as well as ployed for the arylation of tetraamine 1a and trioxadiamine
its more bulky analogue 2-isopropylcarboxycyclohexanone 1c. It was found that neither 3-bromotoluene nor 3-iodotol-
(L4b) were inefficient in the amination of bromobenzene uene could provide the target N1,N4-diarylated product 2
due to the absence of any diarylation process, and only using this ligand due to low selectivity of the arylation of
monoaryl derivatives of 1c were noted in the reaction mix- primary and secondary amino groups, as described above,
tures (Table 2, entries 3 and 4) together with 100% conver- although the consumption of aryl halide was complete
sion of bromobenzene. The latter result suggests that the (Table 3, entries 1 and 2). This ligand afforded the N,NЈ-
catalytic reduction of the halogen took place to a large ex- diarylation product 7 in the reaction with trioxadiamine,
tent, but the monoaryl derivative could not be isolated in a but only in low yields (Table 3, entries 8 and 11). A better
pure state possibly due to the formation of its complexes result was achieved in the amination of 3-bromotoluene
with CuI and the presence of unreacted 1c (which has a with tetraamine using acetylcyclohexanone (L4a) in toluene
very similar Rf value) in the mixture. It is to be mentioned (Table 3, entry 3). Because similar yields were obtained for
that, in all further reactions with trioxadiamine in which the diarylation of tetraamine 1a with bromobenzene using
mainly monoarylation took place, we failed to isolate pure the same ligand in acetonitrile and DMF, it can be sup-
N-aryl derivatives of this diamine using column chromatog- posed that this ligand is not too sensitive to the nature of
raphy, unlike the case with N-aryl derivatives of triamine 1b the solvent. The best yield (67%) of the product 2 in the
(see below). Fortunately, the reaction of iodobenzene was reaction with 3-iodotoluene was obtained using proline
efficiently catalyzed by L4b, giving target compound 4 (L6) in acetonitrile (Table 3, entry 5), and the arylation
in 76% yield (Table 2, entry 7). From the data obtained, using 3-bromotoluene catalyzed with the same ligand
one can conclude that polyamines and oxadi- (Table 3, entry 4) gave the product 2 in 55% yield. These
amines require different catalytic systems to provide prepar-
ative diarylation of primary amino groups, and that iodoar-
enes are preferable for the arylation of oxadiamines,
whereas bromoarenes can equally be used for the arylation
of polyamines. To support this assumption, we made a
Table 3. Cu-catalyzed amination of bromo- and iodotoluenes [CuI/
L (10/20 mol-%), Cs2CO3, 24 h, c = 0.5 m].
Entry ArHal
Amine Ligand Solvent Prod. Yield [%][a]
1
2
3
4
5
6
m-BrC6H4CH3
1a
1a
1a
1a
1a
1a
L5
L5
L4a
L6
L6
L4a
PhMe
PhMe
PhMe
CH3CN
CH3CN
DMF
2
2
2
2
2
5
0[b]
0[b]
38
55
67
54
m-IC6H4CH3
m-IC6H4CH3
m-BrC6H4CH3
m-BrC6H4CH3
3,5-dimethyl
Table 2. Copper-catalyzed arylation of trioxadiamine 1c [CuI/L
(10/20 mol-%), Cs2CO3, 24 h, c = 0.5 m].
Entry
ArHal
Ligand
Solvent
Yield of 4
[%][a]
iodobenzene
1
2
3
4
5
6
7
PhBr
PhBr
PhBr
PhBr
PhI
PhI
PhI
L6
CH3CN
PhMe
DMF
0[b]
37
7
8
9
10
11
12
13
m-IC6H4CH3
m-BrC6H4CH3
m-BrC6H4CH3
m-BrC6H4CH3
m-IC6H4CH3
m-IC6H4CH3
m-IC6H4CH3
1b
1c
1c
1c
1c
1c
1c
L6
L5
L4a
L4b
L5
L4a
L4b
CH3CN
PhMe
DMF
DMF
PhMe
DMF
8
7
7
7
7
7
7
78
7[c]
0[c]
15[c]
20[c]
63
L5
L4a
L4b
L6
L5
L4b
0[c]
0[c]
0[d]
26
DMF
CH3CN
PhMe
DMF
76
DMF
65
[a] Yields after column chromatography. [b] 5% conversion of bro-
mobenzene. [c] 100% conversion of bromobenzene. [d] 50% conver-
sion of iodobenzene.
[a] Yield after column chromatography. [b] 100% conversion of aryl
halides, complex mixture of products. [c] 100% conversion of 3-
bromotoluene.
Scheme 4. N,NЈ-Diarylation of polyamines 1a–c with bromo- and iodotoluenes.
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results are similar to those obtained with bromo- and iodo- the synthesis of diarylated linear polyamines from dibro-
toluenes (Table 1, entries 6 and 11), which demonstrates the mobenzenes and polyamines was also conducted by apply-
reliability of the present catalytic system (CuI/proline/ ing a Pd-mediated amination protocol. The main drawback
CH3CN) for the diarylation of tetraamine. Use of the more of this approach was found to be the formation of oligo-
bulky 3,5-dimethyliodobenzene also provided good yield of meric by-products due to the diamination of dibromoben-
N1,N4-diarylated product 5 (54%; Table 3, entry 6) in the zenes, which resulted in 29–64% yields of N,NЈ-bis(3-bro-
reaction mediated by a less selective CuI/L4a catalyst, prob- mophenyl)-substituted polyamines. Thus, it was interesting
ably due to greater steric hindrance of the arylation of sec- to elaborate a copper-catalyzed version of this reaction. For
ondary amino groups, which made the reaction more selec- this purpose, tetraamine 1a and trioxadiamine 1c were re-
tive towards arylation of the primary amino groups. For acted with 2.5 equiv. of 1,3-dibromo-, 1-bromo-3-iodo-, and
comparison, the same aryl halide reacted smoothly with n- 1,3-diiodobenzenes (Scheme 5).
hexylamine at room temperature with the same catalyst,[23]
The reaction between 1,3-dibromobenzene and tet-
which clearly demonstrates that diarylation of polyamines raamine 1a catalyzed by the CuI/L5 complex was successful
needs much harsher reaction conditions. Only monoaryl- to some extent only in the presence of K2CO3 as base
ation occurred in the case of triamine 1b when the CuI/ (Table 4, entry 1); with Cs2CO3, the conversion of starting
L6 system was used (Table 3, entry 7), probably due to the aryl dihalide was only partial and the arylation was totally
reduction of 3-iodotoluene; in this case the corresponding non-selective (Table 4, entry 2). A better result (26%) was
N-(m-tolyl)-substituted triamine 8 was isolated in 78% obtained with proline (L6; Table 4, entry 3), but only in the
yield.
presence of K2CO3 and at lower concentration. The main
Trioxadiamine 1c was not normally diarylated with 3- obstacle was, again, low selectivity of the process, which
bromotoluene (Table 3, entries 8–10), and the use of 3-iodo- resulted in arylation of the secondary amino groups and
toluene with CuI/L5 catalyst was also not efficient (Table 3, consequently a drastic reduction in the isolated yield of the
entry 11). In all these reactions, although the bromo- and
iodotoluenes were fully converted, the catalytic reduction
of the halogen atom was significant, which mainly led to
formation of the monoaryl derivatives. The situation
changed with the application of acetylcyclohexanone (L4a)
or its more bulky analogue L4b, which provided 63–65%
yield of N,NЈ-diarylation product 7 (Table 3, entries 12 and
13). These results are again in a good agreement with the
data described above for the arylation of trioxadiamine 1c
with halobenzenes (Table 2). We investigated the possibility
of reducing the catalyst loading to 5 mol-%, but found that
the conversion of the aryl halides decreased dramatically,
thus, in all further investigations 10 mol-% catalyst was al-
ways used.
Table 4. Copper-catalyzed arylation of tetraamine 1a and trioxadi-
amine 1c with dihalobenzenes [CuI/L (10/20 mol-%), Cs2CO3, 24 h,
c = 0.5 m, 24 h].
Entry ArHal
Amine Ligand Solvent Prod. Yield [%][a]
1[b]
2
1,3-Br2C6H4
1a
1a
1a
1a
1a
1a
1a
1a
1c
1c
1c
L5
L5
L6
L4a
L4a
L6
L6
L6
PhMe[c]
PhMe[c]
CH3CN[e]
DMF
PhMe
CH3CN
EtCN
EtCN
DMF
PhMe
DMF
9
9
9
9
9
9
9
10
11
12
12
13
0[d]
26
28
27
0[f]
27
24
85
0[g]
53
1,3-Br2C6H4
1,3-Br2C6H4
1,3-Br2C6H4
1,3-Br2C6H4
1-Br-3-IC6H4
1-Br-3-IC6H4
1-Br-3-IC6H4
1-Br-3-IC6H4
1,3-I2C6H4
3[b]
4
5
6
7
8
9
10
11
L4b
L5
L4b
1,3-I2C6H4
Synthesis of N,NЈ-bis(halophenyl)-substituted poly-
amines is of special importance because these compounds
can be further transformed into polyazamacrocycles by re-
action with a second molecule of polyamine under Pd catal-
[a] Yield after column chromatography. [b] K2CO3 was used as
base. [c] c = 0.25 m. [d] 70% conversion of 1,3-dibromobenzene,
complex mixture of products. [e] c = 0.13 m. [f] 70% conversion
of 1-bromo-3-iodobenzene, complex mixture of products. [g] 45%
ysis. This process was described by us previously,[36] where conversion of 1,3-diiodobenzene.
Scheme 5. N,NЈ-Diarylation of polyamines 1a and 1c with dihaloarenes.
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Copper-Catalyzed Arylation of Oxadiamines and Polyamines
target product 9. Almost the same results were obtained tuted oxadiamines and polyamines favors the Pd chemistry
when acetylcyclohexanone (L4a) was applied either in in the case of the tetraamine derivative because the yields
DMF or toluene (Table 4, entries 4 and 5). The use of 1- of the corresponding derivatives with polyamines reached
bromo-3-iodobenzene in the reaction with tetraamine 1a 64%.[36] For N,NЈ-bis(3-bromophenyl)-substituted trioxadi-
under conditions that were optimal for iodobenzene and 3- amine, the Cu-mediated diarylation using 1-bromo-3-iodo-
iodotoluene (CuI/L6, CH3CN) led to a non-selective reac- benzene was found to be much more efficient than the Pd-
tion, and the conversion of 1-bromo-3-iodobenzene was not catalyzed process, which provided only 29% yield of the
complete (Table 4, entry 6); however, changing acetonitrile same product.
for propionitrile (with a higher boiling point) provided the
To gain information on the behavior of aryl halides with
target diarylated product in 27% yield (Table 4, entry 7). It more active halogen atoms in the N,NЈ-diarylation process,
is interesting that the arylation with 1,3-diiodobenzene un- we introduced 4-bromo- and 4-iodobiphenyl, N,N-diethyl-
der the same conditions was of the same efficiency due to 3-iodobenzamide, 4-acetoxy-4Ј-iodobiphenyl, and 2-bromo-
the low selectivity of the process, and compound 10 was naphthalene into the Cu-catalyzed reactions with di-, tri-,
isolated in 24% yield (Table 4, entry 8).
and tetraamines (Scheme 6). The reaction of 4-bromobi-
The reactions of 1,3-dibromobenzene with trioxadiamine phenyl with tetraamine 1a gave a modest result (Table 5,
1c were all inefficient, although the CuI/L5 catalytic system, entry 1), and with trioxadiamine 1c the arylation did not
which promoted the synthesis of diarylation products with occur at all (Table 5, entry 2). Better results were achieved
bromobenzene and 3-bromotolune, was tried. Even with with 4-iodobiphenyl (Table 5, entries 3 and 4), in which two
1,3-diiodobenzene, this catalyst provided only 45% conver- catalytic systems were found to be suitable for tetraamine
sion of dihaloarene (Table 4, entry 10). However, switching and trioxadiamine and both gave similar results. The intro-
to 1-bromo-3-iodobenzene afforded an excellent 85% yield duction of an electron-withdrawing acetoxy group im-
of the target diarylated compound 11 (Table 4, entry 9) in proved the results of N,NЈ-diarylation; with tetraamine 1a,
the reaction catalyzed by CuI/L4b, which was also the most the target product 15 was isolated in 68% yield (Table 5,
efficient for 3-iodotoluene amination with the same trioxa- entry 5), triamine 1b gave a moderate yield of 16 (Table 5,
diamine (Table 3, entry 13). The formation of N,NЈ-bis(3- entry 6), whereas N,NЈ-diarylation of oxadiamines 1c and
iodophenyl)-substituted trioxadiamine 12 under the same 1d resulted in good yields of corresponding products 17 and
conditions was somewhat less efficient (Table 4, entry 11), 18 (Table 5, entries 7 and 8). The reactions with another
possibly due to the higher reactivity of the C–I bond in the iodoarene containing an electron-withdrawing amide group
reduction process.
were all successful for di- and polyamines 1a–d, and the
A comparison of Pd and Cu-catalyzed amination reac- highest observed yield in this investigation was obtained
tions for the synthesis of N,NЈ-bis(3-bromophenyl)-substi- with triamine 1b (96%; Table 5, entry 10). In all cases the
Scheme 6. N,NЈ-Diarylation of polyamines 1a–d with activated haloarenes.
Eur. J. Org. Chem. 2011, 6240–6253
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6245

I. P. Beletskaya et al.
Table 5. Copper-catalyzed arylation of di- and polyamines 1a–d with activated haloarenes [CuI/L (10/20 mol-%), Cs2CO3, c = 0.5 m, 24 h].
FULL PAPER
Entry
ArHal
Amine
Ligand
Solvent
Prod.
Yield
[%][a]
1
2
3
4
5
6
7
8
4-bromobiphenyl
4-bromobiphenyl
4-iodobiphenyl
4-iodobiphenyl
4-acetoxy-4Ј-iodobiphenyl
4-acetoxy-4Ј-iodobiphenyl
4-acetoxy-4Ј-iodobiphenyl
4-acetoxy-4Ј-iodobiphenyl
N,N-diethyl-3-iodobenzamide
N,N-diethyl-3-iodobenzamide
N,N-diethyl-3-iodobenzamide
N,N-diethyl-3-iodobenzamide
2-bromonaphtalene
1a
1c
1a
1c
1a
1b
1c
1d
1a
1b
1c
1d
1a
1a
1b
1c
1d
L5
PhMe[b]
PhMe
CH3CN
DMF
EtCN
EtCN
DMF
DMF
EtCN
EtCN
DMF
DMF
CH3CN
DMF
CH3CN
DMF
DMF
13
14
13
14
15
16
17
18
19
20
21
22
23
23
24
27
0[c]
43
46
68
32
72
60
L5
L6
L4b
L6
L6
L4b
L4b
L6
9
58
96
52
10
11
12
13
14
15
16
17
L6
L4b
L4b
L6
52
0[d]
28[e]
99[f]
2-bromonaphtalene
2-bromonaphtalene
2-bromonaphtalene
2-bromonaphtalene
L4b
L6
L4b
L4b
[g]
–
[h]
–
[a] Yield after column chromatography. [b] c = 0.25 m. [c] 2% conversion of 4-bromobiphenyl. [d] 50% conversion of 2-bromonaphthalene.
[e] 40% conversion of 2-bromonaphthalene. [f] 60% conversion of 2-bromonaphthalene. [g] 20% conversion of 2-bromonaphthalene. [h]
3% conversion of 2-bromonaphthalene.
CuI/L6 catalyst was applied in propionitrile for the di-
arylation of tri- and tetraamines, and CuI/L4b catalyst in
DMF in the case of oxadiamines. Surprisingly, 2-bromo-
naphthalene, which proved to be an active substrate in Pd-
catalyzed amination according to our previous investi-
gations,[37] was more problematic in copper catalysis. The
CuI/L6 system was not efficient in the reaction with tet-
raamine 1a (Table 5, entry 13), however, although the CuI/
L4b catalyst was of similar activity, compound 23 could be
isolated in a moderate 28% yield (Table 5, entry 14). With
triamine 1b, due to only partial conversion of 2-bromo-
naphthalene, only the product of monoarylation 24 could
be obtained, but in almost quantitative yield (Table 5, entry
15). The contrasting behavior of tetraamine 1a and triamine
1b is notable: the former afforded the diarylated derivative
with a lower degree of conversion of 2-bromonaphthalene
(40%), whereas the latter gave only the product of monoar-
ylation with a higher degree of conversion (60%) of 2-bro-
monaphthalene. Attempts to introduce oxadiamines in the
reaction with 2-bromonaphthalene failed (Table 5, entries
16 and 17), also due to very low conversion of the aryl
bromide.
We then investigated the dependence of the reactivity of
substituted aryl iodides on the nature of the substituent on
the phenyl ring (electron-donating or electron-withdrawing
group), and also assessed several ortho-substituted aryl ha-
lides to delineate the influence of steric factors (Scheme 7).
Optimized catalytic systems were chosen in accordance with
Scheme 7. Copper-catalyzed arylation of polyamines 1a and 1c
with iodoarenes.
previously obtained data: CuI/L6/boiling EtCN for the
arylation of tetraamine 1a and CuI/L4b/DMF (110 °C) for
the arylation of trioxadiamine 1c.
The reactions with o-diiodobenzene and o-bromoiodo- with o-iodotoluene was somewhat more successful (Table 6,
benzene with tetraamine 1a did not proceed at all due to entry 3), however, in this case the yield of diarylated prod-
the steric hindrance in these molecules (Table 6, entries 1 uct 25 was too small, and N1-aryl-substituted compound 26
and 2), and only starting compounds were detected in the was also isolated in a moderate 27% yield due to competi-
reaction mixtures after prolonged heating. The reaction tive arylation of the dialkylamino group. Arylation of tri-
6246
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 6240–6253

Copper-Catalyzed Arylation of Oxadiamines and Polyamines
oxadiamine 1c with the same aryl iodide provided a slightly those described above. In the coupling with tetraamine 1a,
better result, giving 7% yield of the diaryl-substituted prod- the reaction produced only 12% of the desired N1,N4-diaryl
uct 27 and 39% yield of the mono-arylated compound 28 derivative 37 (Table 6, entry 9); the main products were
(Table 6, entry 4). These data show that copper-catalyzed N1,N1,N4,N4-tetraaryl-substituted tetraamine 35 and
arylation of polyamines is more sensitive to steric factors N1,N1,N4-triaryl-substituted tetraamine 36, which were iso-
than palladium-catalyzed reactions because previously we lated as a mixture in approximately 35% yield. Compound
showed that facile amination of o-dibromobenzene and 2,6- 36 was additionally obtained as an individual product in
dichlorobromobenzene occurred.[39]
33% yield. The formation of the products of N,N-di-
arylation was shown by a strong downfield shift of the pro-
tons of the CH2NAr2 group (δH = 4.0 ppm) and the benz-
ene ring (δH = 7.3 and 8.15 ppm). For comparison, the pro-
Table 6. Copper-catalyzed arylation of tetraamine 1a and trioxadi-
amine 1c with aryl iodides [CuI/L (10/20 mol-%), Cs2CO3, c =
0.5 m, 24 h].
1
tons of the CH2NHAr group have H NMR shifts at δ =
Entry ArHal
Amine Ligand Solvent Prod. Yield [%][a]
3.2 ppm, and benzene protons at δ = 6.6 and 7.9 ppm. The
formation of tetraaryl derivative 35 was also proven by the
presence of the corresponding pseudomolecular peak in the
MALDI mass-spectrum (m/z = 659 [M + H]+). Trioxadi-
amine 1c was less reactive, nevertheless, its reaction with p-
nitroiodobenzene (Table 6, entry 10) also afforded a mix-
ture of tri- and tetraaryl-substituted compounds 38 and 39
(combined yield approximately 25%), and the triarylated
derivative 39 was also isolated separately in 5% yield. Tar-
get N1,N2-diaryl compound 40 was obtained in 26% yield,
and a part of it was isolated as a mixture with N1,N1-diaryl
derivative 41 (combined yield 16%), whereas monoarylated
product 42 was obtained in 28% yield. These reactions
demonstrated for the first time the possibility of N,N-di-
arylation of primary alkylamines; such processes until now
have been well-known for only Pd-catalyzed reactions.[1] We
tried to reduce the ratio of polyaryl derivatives by using
a less active catalytic system and by lowering the reaction
temperature [CuI/L6/MeCN and CuI/L5/MeCN for the re-
actions with 1a, CuI/L4a/DMF (80 °C) with 1c], however,
this approach did not notably decrease the formation of the
_
1
2
1,2-I2C6H4
1-Br-2-I-
C6H4
1a
1a
L6
L6
EtCN
EtCN
_
3
4
2-iodotoluene
1a
1c
L6
EtCN
DMF
25
26
27
28
29
30
31
32
33
34
2
27
7
2-iodotoluene
L4b
39
52
17
51
42
28
42
35[b]
33
12
25[b]
5
5
6
4-MeOC6H4I
4-MeOC6H4I
1a
1c
L6
L4b
EtCN
DMF
7
8
1-Cl-4-IC6H4
1-Cl-4-IC6H4
1a
1c
L6
L4b
EtCN
DMF
9
4-NO2C6H4I
4-NO2C6H4I
1a
L6
EtCN 35 + 36
36
37
10
1c
L4b
DMF 38 + 39
39
40
40 + 41
42
26
16[b]
28
[a] Yield after column chromatography. [b] Yields of inseparable
mixtures.
The N1,N4-diarylation of tetraamine 1a with electron- products of N,N-diarylation but, rather, led to insufficient
rich p-methoxyiodobenzene proceeded normally, and the conversion of the starting aryl iodide (60% in the case of
target product 29 was isolated in 52% yield (Table 6, entry 1a and 40% in the case of 1c). These results suggest that
5). In this reaction other isomeric diaryl and monoaryl the reactions with aryl halides containing strong electron-
compounds were also obtained as inseparable fractions. withdrawing substituents need individually tailored cata-
The reaction with trioxadiamine 1c was not so successful, lytic systems, and changing the more reactive iodine for less
and the main product was the monarylated derivative 31, active bromine atom; these questions will be addressed in
whereas the diarylated product 30 was obtained in a small further investigations into heteroaromatic halides pos-
amount (Table 6, entry 6). Similar results were obtained sessing halogen atoms. Conditions for exhaustive N,N-di-
when the substrate contained a moderate electron-with- arylation of primary alkylamines will also be established.
drawing group, for example, p-chloroiodobenzene; in this
case, the reaction with tetraamine 1a resulted in 42% pre-
parative yield of the product of N1,N4-diarylation 32
Conclusions
(Table 6, entry 7), and the formation of N1,N2,N4-triaryl de-
rivative was notable. However, the latter compound was ob-
The experimental data obtained in this research demon-
served only as a mixture with the target product 32, and strate that primary amino groups of di- and polyamines can
1
it was identified by a characteristic signal in its H NMR be preparatively diarylated with aryl bromides and aryl io-
spectrum (triplet at δ = 3.65 ppm, which corresponds to dides under CuI catalysis. Generally, the arylation of tet-
ArNHCH2CH2CH2NArCH2 protons). The reaction of the raamine was more exhaustive than the arylation of oxa-
same iodide with trioxadiamine afforded N,NЈ-diaryl prod- diamines, possibly due to additional coordination of copper
uct 33 in 28% yield, whereas monoaryl derivative 34 was by ethylenediamine and trimethylenediamine fragments.
isolated in 42% yield (Table 6, entry 8).
However, the main problem was a lower selectivity of the
Finally, the arylation of polyamines using more electron- arylation of primary amino groups in the presence of sec-
withdrawing p-nitroiodobenzene was investigated. The re- ondary amino groups compared to Pd-mediated amination.
sults of the reactions were found to be notably different to The general idea is that more bulky ligands should prevent
Eur. J. Org. Chem. 2011, 6240–6253
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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6247

I. P. Beletskaya et al.
FULL PAPER
lowing sequence of eluents: petroleum ether/CH2Cl2 10:1–1:1,
CH2Cl2, CH2Cl2/MeOH 500:1–3:1, CH2Cl2/MeOH/NH3(aq)
100:20:1–10:4:1. As the majority of diaryl-substituted oxadiamines
and polyamines were obtained by using several catalytic systems,
only the best methods are described below for each compound.
arylation of more sterically hindered secondary amino
groups, however, this may simultaneously hinder the N,NЈ-
diarylation process, giving rise to monoarylated derivatives.
In the present investigation, proline was found to be opti-
mal for the synthesis of N1,N4-diaryl derivatives of a model
tetraamine. Another consistent feature is that tetraamines
can be successfully diarylated not only with aryl iodides
but also with aryl bromides, at least in some cases, whereas
oxadiamines, due to their lower reactivity, can be success-
fully transformed into their N,NЈ-diaryl derivatives only
using aryl iodides. The main advantage of the copper-cata-
lyzed amination of dihalobenzenes over the palladium-me-
diated protocol is the total absence of a diamination pro-
cess, which could lead to linear oligomers. Unlike the Pd-
catalyzed arylation of polyamines, the reactions catalyzed
by CuI demanded a tailored approach to each particular
aryl halide/polyamine pair. The following catalytic systems
were found to be most suitable: CuI/L6/Cs2CO3/MeCN or
EtCN for the N,NЈ-diarylation of tetraamines, and CuI/
L4a,b/Cs2CO3/DMF for the N,NЈ-diarylation of oxadi-
amines. Thus, the best catalytic systems for the synthesis of
almost all the desired N,NЈ-diaryl-substituted polyamines
were established and the products were obtained in high
yields. Cu-catalyzed arylation of polyamines was found to
be sensitive to steric hindrance in the aryl halides, and the
application of ortho-substituted substrates retarded the pro-
cess. By investigating the reactions with an active p-nitro-
iodobenzene, we revealed an easy N,N-diarylation process
that was previously unknown for Cu-catalyzed arylation of
primary alkylamines. The study will be continued to extend
the approach to a greater variety of benzene functional de-
rivatives, condensed aromatics, and heteroaromatic com-
pounds.
N1,N1Ј-(Ethane-1,2-diyl)bis(N3-m-tolylpropane-1,3-diamine)
(2):
Synthesized from 3-iodotoluene (1.25 mmol, 273 mg), and tet-
raamine 1a (0.5 mmol, 87 mg), in the presence of CuI (9.6 mg),
ligand L6 (11.5 mg), and Cs2CO3 (408 mg), in acetonitrile (1 mL).
Eluent: CH2Cl2/MeOH/NH3(aq) 100:20:1–100:20:2; yield 118 mg
(67%); pale-yellow oil. 1H NMR (400 MHz, CDCl3): δ = 1.78
(quint., J = 6.6 Hz, 4 H), 2.26 (s, 6 H), 2.73 (t, J = 6.6 Hz, 4 H),
2.74 (s, 4 H), 3.16 (t, J = 6.6 Hz, 4 H), 6.41 (d, J = 7.6 Hz, 2 H),
6.42 (s, 2 H), 6.50 (d, J = 7.5 Hz, 2 H), 7.05 (t, J = 7.5 Hz, 2
H) ppm; NH protons were not assigned. 13C NMR (100.6 MHz,
CDCl3): δ = 21.5 (2 C), 29.4 (2 C), 42.5 (2 C), 48.0 (2 C), 49.3 (2
C), 109.7 (2 C), 113.3 (2 C), 117.9 (2 C), 128.9 (2 C), 138.7 (2 C),
148.4 (2 C) ppm. HRMS (MALDI-TOF): calcd. for [C22H34N4 +
H]+ 355.2862; found 355.2898.
N1,N1Ј-(Ethane-1,2-diyl)bis(N3-phenylpropane-1,3-diamine)
(3):
Synthesized from bromobenzene (1.25 mmol, 196 mg) and tet-
raamine 1a (0.5 mmol, 87 mg), in the presence of CuI (9.6 mg),
ligand L6 (11.5 mg), and Cs2CO3 (408 mg) in acetonitrile (1 mL).
Eluent: CH2Cl2/MeOH/NH3(aq) 100:20:1–100:20:2; yield 107 mg
(65%); pale-yellow oil. 1H NMR (400 MHz, CDCl3): δ = 1.82
(quint., J = 6.0 Hz, 4 H), 2.80 (t, J = 5.7 Hz, 4 H), 2.85 (s, 4 H),
3.16 (t, J = 5.9 Hz, 4 H), 4.16 (br. s, 2 H), 6.61 (d, J = 7.7 Hz, 4
H), 6.67 (t, J = 7.3 Hz, 2 H), 7.14 (t, J = 7.4 Hz, 4 H) ppm ; 2 NH
protons were not assigned. 13C NMR (100.6 MHz, CDCl3): δ =
29.1 (2 C), 42.4 (2 C), 47.8 (2 C), 48.8 (2 C), 112.6 (4 C), 117.0 (2
C), 129.1 (4 C), 148.4 (2 C) ppm. HRMS (MALDI-TOF): calcd.
for [C20H30N4 + H]+ 327.2549; found 327.2557.
N,NЈ-{3,3Ј-[2,2Ј-Oxybis(ethane-2,1-diyl)bis(oxy)]bis(propane-3,1-
diyl)}dianiline (4): Synthesized from iodobenzene (1.25 mmol,
255 mg) and trioxadiamine 1c (0.5 mmol, 110 mg), in the presence
of CuI (9.6 mg), ligand L4a (14 mg), and Cs2CO3 (408 mg) in DMF
(1 mL). Eluent: CH2Cl2; yield 144 mg (76%); pale-yellow oil. 1H
NMR (400 MHz, CDCl3): δ = 1.91 (quint., J = 6.2 Hz, 4 H), 3.25
(t, J = 6.5 Hz, 4 H), 3.62 (t, J = 5.9 Hz, 4 H), 3.63–3.67 (m, 4 H),
3.68–3.72 (m, 4 H), 3.98 (br. s, 2 H), 6.63 (d, J = 8.5 Hz, 4 H), 6.71
(t, J = 7.3 Hz, 2 H), 7.20 (t, J = 7.8 Hz, 4 H) ppm. 13C NMR
(100.6 MHz, CDCl3): δ = 29.8 (2 C), 41.5 (2 C), 69.5 (2 C), 70.1 (2
C), 70.4 (2 C), 112.5 (2 C), 116.7 (2 C), 129.0 (2 C), 148.4 (2
C) ppm. HRMS (MALDI-TOF): calcd. for [C22H32N2O3 + H]+
373.2491; found 373.2448.
N1,N1Ј-(Ethane-1,2-diyl)bis[N3-(3,5-dimethylphenyl)propane-1,3-
diamine] (5): Synthesized from 3,5-dimethyliodobenzene
(1.25 mmol, 290 mg) and tetraamine 1a (0.5 mmol, 87 mg), in the
presence of CuI (9.6 mg), ligand L4a (14 mg), and Cs2CO3
(408 mg) in DMF (1 mL). Eluent: CH2Cl2/MeOH/NH3(aq)
100:20:1–100:20:2; yield 103 mg (54%); pale-yellow oil. 1H NMR
(400 MHz, CDCl3): δ = 1.89 (br. s, 4 H), 2.20 (s, 12 H), 2.90 (br.
s, 4 H), 3.01 (br. s, 4 H), 3.16 (br. s, 4 H), 5.25 (br. s, 2 H), 6.26
(br. s, 4 H), 6.34 (br. s, 1 H) ppm; 2 NH protons were not assigned.
13C NMR (100.6 MHz, CDCl3): δ = 21.4 (4 C), 27.3 (2 C), 41.8 (2
C), 45.9 (2 C), 46.8 (2 C), 111.0 (4 C), 119.6 (2 C), 138.7 (4 C),
148.1 (2 C) ppm. HRMS (MALDI-TOF): calcd. for [C24H38N4 +
H]+ 383.3175; found 383.3128.
Experimental Section
General: Aryl halides, di- and polyamines 1a–d, ligands L1–L6, and
CuI were purchased from commercial suppliers and used without
further purification. Silica gel 40–60 mesh was purchased from
Fluka Chemical Co. Acetonitrile and DMF were purified by distil-
lation over CaH2, toluene was distilled from sodium, propionitrile
was used as purchased, dichloromethane and methanol were freshly
1
distilled before use. H and 13C NMR spectra were recorded with
a Bruker Avance-400 spectrometer; chemical shifts are given in ppm
and are referenced to TMS. Mass spectra were recorded with a
Bruker Ultraflex spectrometer using 1,8,9-trihydroxyanthracene as
matrix and PEGs as internal standards.
General Procedure for the Synthesis of N,NЈ-Diaryl-Substituted
Oxadiamines and Polyamines: A two-necked flask equipped with
magnetic stirrer and condenser, flushed with dry argon, was
charged with aryl halide (0.625–2.5 mmol), CuI (4.8–19.2 mg,
10 mol-%), appropriate ligand (20 mol-%), and solvent (1–2 mL).
The reaction mixture was stirred for several minutes, then amine
(0.25–1 mmol) and base (0.625–2.5 mmol) were added and the re-
action mixture was stirred for 24 h either at reflux temperature
(acetonitrile, propionitrile, toluene) or at 110 °C (DMF). Upon
completion of reaction, the reaction mixture was diluted with
CH2Cl2 (5 mL), the solution was filtered, evaporated in vacuo, and
the residue was subjected to column chromatography using the fol-
N,NЈ-{3,3Ј-[2,2Ј-Oxybis(ethane-2,1-diyl)bis(oxy)]bis(propane-3,1-
diyl)}bis(3-methylaniline) (7): Synthesized from 3-iodotoluene
(1.25 mmol, 273 mg) and trioxadiamine 1c (0.5 mmol, 110 mg), in
the presence of CuI (9.6 mg), ligand L4b (17 mg), and Cs2CO3
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Copper-Catalyzed Arylation of Oxadiamines and Polyamines
(408 mg) in DMF (1 mL). Eluent: CH2Cl2, CH2Cl2/MeOH 500:1;
70.2 (2 C), 70.5 (2 C), 70.5 (2 C), 95.3 (2 C), 111.9 (2 C), 121.0 (2
C), 125.6 (2 C), 130.5 (2 C), 149.7 (2 C) ppm. HRMS (MALDI-
TOF): calcd. for [C22H30I2N2O3 + H]+ 625.0424; found 625.0480.
1
yield 130 mg (65%); pale-yellow oil. H NMR (400 MHz, CDCl3):
δ = 1.92 (quint., J = 6.2 Hz, 4 H), 2.32 (s, 6 H), 3.25 (t, J = 6.5 Hz,
4 H), 3.63 (t, J = 5.9 Hz, 4 H), 3.64–3.68 (m, 4 H), 3.70–3.74 (m,
4 H), 3.83 (br. s, 2 H), 6.46 (d, J = 6.2 Hz, 2 H), 6.47 (s, 2 H), 6.55
(d, J = 7.3 Hz, 2 H), 7.10 (t, J = 8.1 Hz, 2 H) ppm. 13C NMR
(100.6 MHz, CDCl3): δ = 21.5 (2 C), 29.0 (2 C), 41.5 (2 C), 69.5 (2
C), 70.1 (2 C), 70.5 (2 C), 109.7 (2 C), 113.3 (2 C), 117.8 (2 C),
128.9 (2 C), 138.7 (2 C), 148.4 (2 C) ppm. HRMS (MALDI-TOF):
calcd. for [C24H36N2O3 + H]+ 401.2804; found 401.2820.
N1-(3-Aminopropyl)-N3-m-tolylpropane-1,3-diamine (8): Synthe-
sized from 3-iodotoluene (1.25 mmol, 273 mg) and triamine 1b
(0.5 mmol, 65 mg), in the presence of CuI (9.6 mg), ligand L6
(11.5 mg), and Cs2CO3 (408 mg) in acetonitrile (1 mL). Eluent:
CH2Cl2/MeOH/NH3(aq) 100:20:3–100:25:5; yield 86 mg (78 %);
pale-yellow oil. 1H NMR (400 MHz, CDCl3): δ = 1.63 (quint., J =
6.8 Hz, 2 H), 1.78 (quint., J = 6.6 Hz, 2 H), 2.25 (s, 3 H), 2.66 (t,
J = 7.0 Hz, 2 H), 2.72 (t, J = 6.7 Hz, 2 H), 2.76 (t, J = 6.9 Hz, 2
H), 6.40 (d, J = 7.0 Hz, 1 H), 6.41 (s, 1 H), 6.49 (d, J = 7.5 Hz, 1
H), 7.03 (t, J = 7.4 Hz, 1 H) ppm; NH protons were not assigned.
13C NMR (100.6 MHz, CDCl3): δ = 21.6, 29.4, 33.2, 40.3, 42.7,
47.8, 48.3, 109.9, 113.4, 118.0, 129.0, 138.8, 148.5 ppm. HRMS
(MALDI-TOF): calcd. for [C13H23N3 + H]+ 222.1970; found
222.1968.
N1,N1Ј-(Ethane-1,2-diyl)bis[N3-(biphenyl-4-yl)propane-1,3-diamine]
(13): Synthesized from 4-iodobiphenyl (1.25 mmol, 351 mg) and
tetraamine 1a (0.5 mmol, 87 mg), in the presence of CuI (9.6 mg),
ligand L6 (11.5 mg), and Cs2CO3 (408 mg) in acetonitrile (1 mL).
Eluent: CH2Cl2/MeOH/NH3(aq) 100:20:2; yield 90 mg (43%); be-
1
ige crystals; m.p. 72–74 °C. H NMR (400 MHz, CDCl3): δ = 1.81
(quint., 4 H, J = 6.5 Hz), 2.75 (s, 4 H), 2.76 (t, J = 6.7 Hz, 4 H),
3.22 (t, J = 6.5 Hz, 4 H), 6.66 (d, J = 8.6 Hz, 4 H), 7.25 (t, J =
7.3 Hz, 2 H), 7.38 (t, J = 7.5 Hz, 4 H), 7.43 (d, J = 8.5 Hz, 4 H),
7.53 (d, J = 7.2 Hz, 4 H) ppm; NH protons were not assigned. 13
C
NMR (100.6 MHz, CDCl3): δ = 29.4 (2 C), 42.6 (2 C), 48.0 (2 C),
49.3 (2 C), 112.9 (4 C), 125.9 (2 C), 126.1 (4 C), 127.8 (4 C), 128.6
(4 C), 129.9 (2 C), 141.2 (2 C), 147.9 (2 C) ppm. HRMS (MALDI-
TOF): calcd. for [C32H38N4 + H]+ 479.3175; found 479.3205.
N,NЈ-{3,3Ј-[2,2Ј-Oxybis(ethane-2,1-diyl)bis(oxy)]bis(propane-3,1-
diyl)}dibiphenyl-4-amine (14): Synthesized from 4-iodobiphenyl
(1.25 mmol, 351 mg) and trioxadiamine 1c (0.5 mmol, 110 mg), in
the presence of CuI (9.6 mg), ligand L4b (17 mg), and Cs2CO3
(408 mg) in DMF (1 mL). Eluent: CH2Cl2/MeOH 500:1–100:1;
yield 121 mg (46%); pale-yellow oil. Spectral data have previously
been reported.[38]
N1,N1Ј-(Ethane-1,2-diyl)bis[N3-(3-bromophenyl)propane-1,3-di-
amine] (9): Synthesized from 1,3-dibromobenzene (1.25 mmol,
295 mg) and tetraamine 1a (0.5 mmol, 87 mg), in the presence of
CuI (9.6 mg), ligand L4a (14 mg), and Cs2CO3 (408 mg) in DMF
(1 mL). Eluent: CH2Cl2/MeOH/NH3(aq) 100:20:1–100:20:2; yield
65 mg (28%); pale-yellow oil. Spectral data have previously been
reported.[36]
1,1Ј-(4Ј,4ЈЈ-{3,3Ј-[Ethane-1,2-diylbis(azanediyl)]bis(propane-3,1-
diyl)}bis(azanediyl)bis(biphenyl-4Ј,4-diyl))diethanone (15): Synthe-
sized from 4-acetoxy-4Ј-iodobiphenyl (2.5 mmol, 808 mg) and tet-
raamine 1a (1 mmol, 174 mg), in the presence of CuI (19.2 mg),
ligand L6 (23 mg), and Cs2CO3 (816 mg) in propionitrile (2 mL).
Eluent: CH2Cl2/MeOH/NH3(aq) 100:20:3; yield 381 mg (68%); be-
ige crystals; m.p. 153–155 °C. 1H NMR (400 MHz, CDCl3): δ =
N1,N1Ј-(Ethane-1,2-diyl)bis[N3-(3-iodophenyl)propane-1,3-diamine] 1.82 (quint., J = 6.4 Hz, 4 H), 2.59 (s, 6 H), 2.76 (s, 6 H), 2.78 (t,
(10): Synthesized from 1,3-diiodobenzene (1.25 mmol, 412 mg) and
tetraamine 1a (0.5 mmol, 87 mg), in the presence of CuI (9.6 mg),
J = 6.6 Hz, 4 H), 3.24 (t, J = 6.1 Hz, 4 H), 6.65 (d, J = 8.3 Hz, 4
H), 7.46 (d, J = 8.6 Hz, 4 H), 7.59 (d, J = 8.6 Hz, 4 H), 7.95 (d, J
ligand L6 (11.5 mg), and Cs2CO3 (408 mg) in propionitrile (1 mL). = 8.3 Hz, 4 H) ppm; NH protons were not assigned. 13C NMR
Eluent: CH2Cl2/MeOH/NH3(aq) 100:20:1–100:20:2; yield 69 mg (100.6 MHz, [D6]DMSO): δ = 26.5 (2 C), 29.0 (2 C), 41.0 (2 C),
(24 %); pale-yellow oil. 1H NMR (400 MHz, CDCl3): δ = 1.79
47.1 (2 C), 49.0 (2 C), 112.2 (4 C), 124.9 (4 C), 127.6 (4 C), 128.9
(quint., J = 5.9 Hz, 4 H), 2.78 (br. s, 8 H), 3.14 (t, J = 5.9 Hz, 4 (4 C), 133.8 (2 C), 141.6 (2 C), 145.0 (2 C), 149.5 (2 C), 197.1 (2
H), 6.53 (d, J = 7.8 Hz, 2 H), 6.84 (t, J = 7.8 Hz, 2 H), 6.93 (s, 2 C) ppm. HRMS (MALDI-TOF): calcd. for [C36H42N4O2 + H]+
H), 6.97 (d, J = 7.5 Hz, 2 H) ppm; NH protons were not assigned.
13C NMR (100.6 MHz, CDCl3): δ = 28.7 (2 C), 42.4 (2 C), 47.9 (2
C), 48.6 (2 C), 95.3 (2 C), 112.1 (2 C), 121.1 (2 C), 126.0 (2 C),
130.6 (2 C), 149.7 (2 C) ppm. HRMS (MALDI-TOF): calcd. for
[C20H28I2N4 + H]+ 579.0482; found 579.0471.
563.3386; found 563.3407.
1,1Ј-{4Ј,4ЈЈ-[3,3Ј-Azanediylbis(propane-3,1-diyl)bis(azanediyl)]bis-
(biphenyl-4Ј,4-diyl)}diethanone (16): Synthesized from 4-acetoxy-4Ј-
iodobiphenyl (2.5 mmol, 808 mg) and triamine 1b (1 mmol,
131 mg), in the presence of CuI (19.2 mg), ligand L6 (23 mg), and
N,NЈ-{3,3Ј-[2,2Ј-Oxybis(ethane-2,1-diyl)bis(oxy)]bis(propane-3,1- Cs2CO3 (816 mg), in propionitrile (2 mL). Eluent: CH2Cl2/MeOH
diyl)}bis(3-bromoaniline) (11): Synthesized from 1-bromo-3-iodo-
benzene (1.25 mmol, 353 mg) and trioxadiamine 1c (0.5 mmol,
110 mg), in the presence of CuI (9.6 mg), ligand L4b (17 mg), and
Cs2CO3 (408 mg) in DMF (1 mL). Eluent: CH2Cl2, CH2Cl2/MeOH
3:1, CH2Cl2/MeOH/NH3(aq) 100:20:1; yield 167 mg (32%); beige
crystals; m.p. 190–192 °C. 1H NMR (400 MHz, [D6]DMSO): δ =
1.81 (quint., J = 7.2 Hz, 4 H), 2.55 (s, 6 H), 2.88 (t, J = 7.0 Hz, 4
H), 3.14 (br. s, 4 H), 6.05 (br. s, 2 H), 6.67 (d, J = 8.6 Hz, 4 H),
500:1; yield 226 mg (85%); pale-yellow oil. Spectral data have pre- 7.53 (d, J = 8.7 Hz, 4 H), 7.69 (d, J = 8.5 Hz, 4 H), 7.93 (d, J
viously been reported.[36]
= 8.5 Hz, 4 H) ppm; 1 NH proton was not assigned. 13C NMR
(100.6 MHz, [D6]DMSO): δ = 26.0 (2 C), 26.6 (2 C), 39.9 (2 C),
45.5 (2 C), 112.4 (4 C), 125.0 (4 C), 125.7 (2 C), 127.7 (4 C), 128.9
(4 C), 134.0 (2 C), 144.9 (2 C), 149.1 (2 C), 197.2 (2 C) ppm. HRMS
(MALDI-TOF): calcd. for [C34H37N3O2 + H]+ 520.2964; found
520.2897.
N,NЈ-{3,3Ј-[2,2Ј-Oxybis(ethane-2,1-diyl)bis(oxy)]bis(propane-3,1-
diyl)}bis(3-iodoaniline) (12): Synthesized from 1,3-diiodobenzene
(1.25 mmol, 412 mg) and trioxadiamine 1c (0.5 mmol, 110 mg), in
the presence of CuI (9.6 mg), ligand L4b (17 mg), and Cs2CO3
(408 mg) in DMF (1 mL). Eluent: CH2Cl2/MeOH 500:1–200:1;
yield 165 mg (53%); pale-yellow oil. H NMR (400 MHz, CDCl3):
δ = 1.84 (quint., J = 6.1 Hz, 4 H), 3.16 (t, J = 6.4 Hz, 4 H), 3.58
(t, J = 5.9 Hz, 4 H), 3.59–3.63 (m, 4 H), 3.65–3.69 (m, 4 H), 4.21
1
1,1Ј-(4Ј,4ЈЈ-{3,3Ј-[2,2Ј-Oxybis(ethane-2,1-diyl)bis(oxy)]bis(propane-
3,1-diyl)}bis(azanediyl)bis(biphenyl-4Ј,4-diyl))diethanone (17): Syn-
thesized from 4-acetoxy-4Ј-iodobiphenyl (2.5 mmol, 808 mg) and
(br. s, 2 H), 6.51 (dd, J = 8.2, 2.3 Hz), 6.83 (t, J = 7.9 Hz, 2 H), trioxadiamine 1c (1 mmol, 220 mg), in the presence of CuI
6.91 (t, J = 1.9 Hz, 2 H), 6.99 (dd, J = 7.7, 1.5 Hz, 2 H) ppm. 13C
NMR (100.6 MHz, CDCl3): δ = 28.7 (2 C), 41.6 (2 C), 69.7 (2 C),
(19.2 mg), ligand L4b (34 mg), and Cs2CO3 (816 mg), in DMF
(2 mL). Eluent: CH2Cl2/MeOH 100:1–50:1 Yield: 463 mg (72%);
Eur. J. Org. Chem. 2011, 6240–6253
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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6249

I. P. Beletskaya et al.
FULL PAPER
beige crystals; m.p. 123–125 °C. H NMR (400 MHz, CDCl3): δ =
1
(400 MHz, CDCl3): δ = 1.07 (br. s, 6 H), 1.20 (br. s, 6 H), 1.84
1.90 (quint., J = 6.1 Hz, 4 H), 2.58 (s, 6 H), 3.27 (t, J = 6.4 Hz, 4 (quint., J = 6.0 Hz, 4 H), 3.19 (t, J = 6.4 Hz, 4 H), 3.23 (br. s, 4
H), 3.61 (t, J = 5.8 Hz, 4 H), 3.63–3.65 (m, 4 H), 3.68–3.71 (m, 4 H), 3.49 (br. s, 4 H), 3.56 (t, J = 5.8 Hz, 4 H), 3.57–3.60 (m, 4 H),
H), 4.33 (br. s, 2 H), 6.65 (d, J = 8.6 Hz, 4 H), 7.46 (d, J = 8.6 Hz, 3.62–3.65 (m, 4 H), 6.53 (s, 2 H), 6.57 (d, J = 7.6 Hz, 2 H), 6.59
4 H), 7.59 (d, J = 8.3 Hz, 4 H), 7.94 (d, J = 8.3 Hz, 4 H) ppm. 13C
NMR (100.6 MHz, CDCl3): δ = 26.5 (2 C), 29.0 (2 C), 41.6 (2 C),
69.7 (2 C), 70.2 (2 C), 70.6 (2 C), 112.8 (4 C), 125.7 (4 C), 127.8 (2
(d, J = 7.6 Hz, 2 H), 7.11 (t, J = 7.6 Hz, 2 H) ppm; NH protons
were not assigned. 13C NMR (100.6 MHz, CDCl3): δ = 12.8 (2 C),
14.2 (2 C), 28.8 (2 C), 38.9 (2 C), 41.7 (2 C), 43.1 (2 C), 69.7 (2 C),
C), 128.0 (4 C), 128.9 (4 C), 134.5 (2 C), 145.8 (2 C), 148.8 (2 C), 70.2 (2 C), 70.5 (2 C), 110.1 (2 C), 113.4 (2 C), 114.4 (2 C), 129.0
197.6 (2 C) ppm. HRMS (MALDI-TOF): calcd. for [C38H44N2O5
(2 C), 138.1 (2 C), 148.5 (2 C), 171.8 (2 C) ppm. HRMS (MALDI-
+ H]+ 609.3328; found 609.3361.
TOF): calcd. for [C32H50N4O5 + H]+ 571.3859; found 571.3829.
1,1Ј-(4Ј,4ЈЈ-{2,2Ј-[Ethane-1,2-diylbis(oxy)]bis(ethane-2,1-diyl)}bis-
(azanediyl)bis(biphenyl-4Ј,4-diyl))diethanone (18): Synthesized from
4-acetoxy-4Ј-iodobiphenyl (2.5 mmol, 808 mg) and dioxadiamine
1d (1 mmol, 148 mg), in the presence of CuI (19.2 mg), ligand L4b
(34 mg), and Cs2CO3 (816 mg), in DMF (2 mL). Eluent: CH2Cl2/
3,3Ј-{2,2Ј-[Ethane-1,2-diylbis(oxy)]bis(ethane-2,1-diyl)}bis-
(azanediyl)bis(N,N-diethylbenzamide) (22): Synthesized from N,N-
diethyl-3-iodobenzamide (1.25 mmol, 379 mg) and dioxadiamine
1c (0.5 mmol, 74 mg), in the presence of CuI (9.6 mg), ligand L4b
(17 mg), and Cs2CO3 (408 mg), in DMF (1 mL). Eluent: CH2Cl2/
MeOH 50:1–20:1 Yield: 322 mg (60%); beige crystals; m.p. 180– MeOH 50:1–20:1; yield 130 mg (52 %); yellow oil. 1H NMR
1
182 °C. H NMR (400 MHz, CDCl3): δ = 2.60 (s, 6 H), 3.36 (t, J
= 5.2 Hz, 4 H), 3.69 (s, 4 H), 3.75 (t, J = 5.2 Hz, 4 H), 4.30 (br. s,
2 H), 6.68 (d, J = 8.6 Hz, 4 H), 7.46 (d, J = 8.6 Hz, 4 H), 7.59 (d,
J = 8.3 Hz, 4 H), 7.95 (d, J = 8.3 Hz, 4 H) ppm. 13C NMR
(100.6 MHz, [D6]DMSO): δ = 26.5 (2 C), 42.5 (2 C), 69.0 (2 C),
(400 MHz, CDCl3): δ = 1.04 (br. s, 6 H), 1.18 (br. s, 6 H), 3.23 (br.
s, 4 H), 3.25 (t, J = 5.0 Hz, 4 H), 3.47 (br. s, 4 H), 3.60 (s, 4 H),
3.65 (t, J = 5.0 Hz, 4 H), 4.22 (br. s, 2 H), 6.55 (s, 2 H), 6.57 (d, J
= 8.3 Hz, 2 H), 6.61 (d, J = 7.5 Hz, 2 H), 7.10 (t, J = 7.6 Hz, 2
H) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 12.8 (2 C), 14.1 (2
69.8 (2 C), 112.4 (4 C), 124.9 (4 C), 125.5 (2 C), 127.6 (4 C), 128.9 C), 38.9 (2 C), 43.1 (2 C), 43.2 (2 C), 69.4 (2 C), 70.1 (2 C), 110.3
(4 C), 133.9 (2 C), 144.9 (2 C), 149.2 (2 C), 197.1 (2 C) ppm. HRMS
(MALDI-TOF): calcd. for [C34H36N2O4 + H]+ 537.2753; found
537.2702.
(2 C), 113.7 (2 C), 114.9 (2 C), 129.1 (2 C), 138.1 (2 C), 148.2 (2
C), 171.6 (2 C) ppm. HRMS (MALDI-TOF): calcd. for
[C28H42N4O4 + H]+ 499.3284; found 499.3300.
3,3Ј-{3,3Ј-[Ethane-1,2-diylbis(azanediyl)]bis(propane-3,1-diyl)}bis-
(azanediyl)bis(N,N-diethylbenzamide) (19): Synthesized from N,N-
diethyl-3-iodobenzamide (1.25 mmol, 379 mg) and tetraamine 1a
(0.5 mmol, 87 mg), in the presence of CuI (9.6 mg), ligand L6
(11.5 mg), and Cs2CO3 (408 mg) in propionitrile (1 mL). Eluent:
CH2Cl2/MeOH/NH3(aq) 100:20:1–100:20:2; yield 151 mg (58%);
N1,N1Ј-(Ethane-1,2-diyl)bis[N3-(naphthalen-2-yl)propane-1,3-di-
amine] (23): Synthesized from 2-bromonaphthalene (1.25 mmol,
258 mg) and tetraamine 1a (0.5 mmol, 87 mg), in the presence of
CuI (9.6 mg), ligand L6 (11.5 mg), and Cs2CO3 (408 mg), in pro-
pionitrile (1 mL). Eluent: CH2Cl2/MeOH/NH3(aq) 100:20:1–
1
100:20:2; yield 61 mg (28%); pale-yellow oil. H NMR (400 MHz,
CDCl3): δ = 1.83 (quint., J = 6.6 Hz, 4 H), 2.75 (s, 4 H), 2.77 (t, J
1
yellow oil. H NMR (400 MHz, CDCl3): δ = 1.05 (br. s, 6 H), 1.18
(br. s, 6 H), 1.73 (quint., J = 6.5 Hz, 4 H), 2.68 (t, J = 6.4 Hz, 4 = 6.7 Hz, 4 H), 3.27 (t, J = 6.6 Hz, 4 H), 6.78 (d, J = 2.0 Hz, 2 H),
H), 2.69 (s, 4 H), 3.11 (t, J = 6.5 Hz, 4 H), 3.21 (br. s, 4 H), 3.47 6.84 (dd, J = 8.6, 2.0 Hz, 2 H), 7.18 (t, J = 7.5 Hz, 2 H), 7.35 (t,
(br. s, 4 H), 4.48 (br. s, 2 H), 6.52 (s, 2 H), 6.56 (d, J = 7.6 Hz, 4 3J = 7.5 Hz, 2 H), 7.59 (d, J = 8.8 Hz, 2 H), 7.60 (d, J = 8.1 Hz, 2
H), 7.08 (t, J = 7.6 Hz, 2 H) ppm; 2 NH protons were not assigned.
H), 7.65 (d, J = 8.1 Hz, 2 H) ppm; NH protons were not assigned.
13C NMR (100.6 MHz, CDCl3): δ = 12.8 (2 C), 14.2 (2 C), 28.8 (2
13C NMR (100.6 MHz, CDCl3): δ = 29.3 (2 C), 42.7 (2 C), 48.2 (2
C), 39.0 (2 C), 42.2 (2 C), 43.1 (2 C), 47.7 (2 C), 48.7 (2 C), 110.0 C), 49.3 (2 C), 104.0 (2 C), 118.0 (2 C), 121.7 (2 C), 125.8 (2 C),
(2 C), 113.2 (2 C), 114.2 (2 C), 129.0 (2 C), 137.9 (2 C), 148.6 (2 126.2 (2 C), 127.3 (2 C), 127.6 (2 C), 128.8 (2 C), 135.2 (2 C), 146.1
C), 171.8 (2 C) ppm. HRMS (MALDI-TOF): calcd. for
(2 C) ppm. HRMS (MALDI-TOF): calcd. for [C28H34N4 + H]+
427.2862; found 427.2810.
[C30H48N6O2 + H]+ 525.3917; found 525.3881.
3,3Ј-[3,3Ј-Azanediylbis(propane-3,1-diyl)bis(azanediyl)]bis(N,N-di-
ethylbenzamide) (20): Synthesized from N,N-diethyl-3-iodobenz-
N1-(3-Aminopropyl)-N3-(naphthalen-2-yl)propane-1,3-diamine (24):
Synthesized from 2-bromonaphthalene (1.25 mmol, 258 mg) and
amide (1.25 mmol, 379 mg) and triamine 1b (0.5 mmol, 65 mg), in triamine 1b (0.5 mmol, 65 mg), in the presence of CuI (9.6 mg),
the presence of CuI (9.6 mg), ligand L6 (11.5 mg), and Cs2CO3
(408 mg) in propionitrile (1 mL). Eluent: CH2Cl2/MeOH 3:1,
CH2Cl2/MeOH/NH3(aq) 100:20:1; yield 230 mg (96%); yellow oil.
1H NMR (400 MHz, CDCl3): δ = 1.01 (br. s, 6 H), 1.14 (br. s, 6
H), 1.69 (quint., J = 6.1 Hz, 4 H), 2.63 (br. s, 4 H), 3.05 (br. s, 4
H), 3.18 (br. s, 4 H), 3.42 (br. s, 4 H), 4.46 (br. s, 2 H), 6.47 (s, 2
H), 6.51 (d, J = 7.7 Hz, 4 H), 7.04 (t, J = 7.7 Hz, 2 H) ppm. 13C
NMR (100.6 MHz, CDCl3): δ = 12.6 (2 C), 14.0 (2 C), 28.2 (2 C),
38.9 (2 C),41.8 (2 C), 43.0 (2 C), 47.4 (2 C), 109.7 (2 C), 113.1 (2
C), 114.0 (2 C), 128.9 (2 C), 137.8 (2 C), 148.4 (2 C), 171.7 (2
C) ppm. HRMS (MALDI-TOF): calcd. for [C28H43N5O2 + H]+
482.3495; found 482.3560.
ligand L6 (11.5 mg), and Cs2CO3 (408 mg), in acetonitrile (1 mL).
Eluent: CH2Cl2/MeOH/NH3(aq) 100:20:3–100:25:5; yield 120 mg
(99 %); pale-yellow oil. 1H NMR (400 MHz, CDCl3): δ = 1.65
(quint., J = 6.7 Hz, 2 H), 1.86 (quint., J = 6.4 Hz, 2 H), 2.69 (t, J
= 6.9 Hz, 2 H), 2.78 (t, J = 6.4 Hz, 4 H), 6.77 (s, 2 H), 3.28 (t, J =
6.5 Hz, 2 H), 6.86 (d, J = 8.7 Hz, 2 H), 7.16 (t, J = 7.3 Hz, 2 H),
7.33 (t, J = 7.4 Hz, 2 H), 7.59 (d, J = 8.5 Hz, 4 H), 7.64 (d, J
= 8.1 Hz, 2 H) ppm; NH protons were not assigned. 13C NMR
(100.6 MHz, CDCl3): δ = 29.0, 33.1, 40.5, 42.9, 47.9, 48.4, 104.0,
118.1, 121.7, 125.8, 126.2, 127.3, 127.6, 128.8, 135.3, 146.2 ppm.
HRMS (MALDI-TOF): calcd. for [C16H23N3 + H]+ 258.1970;
found 258.1988.
3,3Ј-{3,3Ј-[2,2Ј-Oxybis(ethane-2,1-diyl)bis(oxy)]bis(propane-3,1-
diyl)}bis(azanediyl)bis(N,N-diethylbenzamide) (21): Synthesized
from N,N-diethyl-3-iodobenzamide (1.25 mmol, 379 mg) and tri-
oxadiamine 1c (0.5 mmol, 110 mg), in the presence of CuI (9.6 mg),
ligand L4b (17 mg), and Cs2CO3 (408 mg) in DMF (1 mL). Eluent:
CH2Cl2/MeOH 50:1; yield 148 mg (52 %); yellow oil. 1H NMR
N1,N1Ј-(Ethane-1,2-diyl)bis(N3-o-tolylpropane-1,3-diamine) (25):
Synthesized from 2-iodotoluene (1.25 mmol, 273 mg) and tet-
raamine 1a (0.5 mmol, 87 mg), in the presence of CuI (9.6 mg),
ligand L6 (11.5 mg), and Cs2CO3 (408 mg) in propionitrile (1 mL).
Eluent: CH2Cl2/MeOH/NH3(aq) 100:20:2; yield 4 mg (2%); pale-
yellow oil. 1H NMR (400 MHz, CDCl3): δ = 1.83 (quint., J =
6250
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 6240–6253

Copper-Catalyzed Arylation of Oxadiamines and Polyamines
6.4 Hz, 4 H), 2.12 (s, 6 H), 2.75 (s, 4 H), 2.77 (t, J = 6.4 Hz, 4 H),
N,NЈ-{3,3Ј-[2,2Ј-Oxybis(ethane-2,1-diyl)bis(oxy)]bis(propane-3,1-
3.21 (t, J = 6.6 Hz, 4 H), 6.58 (d, J = 8.0 Hz, 2 H), 6.62 (t, J = diyl)}bis(4-methoxyaniline) (30): Synthesized from 4-iodoanisole
7.1 Hz, 2 H), 7.03 (d, J = 7.1 Hz, 2 H), 7.10 (t, J = 7.6 Hz, 2
H) ppm; NH protons were not assigned. 13C NMR (100.6 MHz,
CDCl3): δ = 17.6 (2 C), 29.3 (2 C), 42.9 (2 C), 48.4 (2 C), 49.4 (2
(1.25 mmol, 293 mg) and trioxadiamine 1c (0.5 mmol, 110 mg), in
the presence of CuI (9.6 mg), ligand L4b (17 mg), and Cs2CO3
(408 mg) in DMF (1 mL). Eluent: CH2Cl2/MeOH 100:1; yield
C), 109.4 (2 C), 116.6 (2 C), 121.9 (2 C), 127.1 (2 C), 130.0 (2 C), 36 mg (17%); pale-yellow oil. 1H NMR (400 MHz, CDCl3): δ =
146.5 (2 C) ppm. HRMS (MALDI-TOF): calcd. for [C22H34N4 +
1.86 (quint., J = 6.0 Hz, 4 H), 3.16 (t, J = 6.0 Hz, 4 H), 3.55–3.61
(m, 8 H), 3.63–3.67 (m, 4 H), 3.72 (s, 6 H), 6.56 (d, J = 8.6 Hz, 4
H), 6.76 (d, J = 8.6 Hz, 4 H) ppm; NH protons were not assigned.
13C NMR (100.6 MHz, CDCl3): δ = 29.2 (2 C), 42.6 (2 C), 55.7 (2
C), 69.8 (2 C), 70.2 (2 C), 70.6 (2 C), 114.0 (4 C), 114.8 (4 C),
142.8 (2 C), 151.8 (2 C) ppm. HRMS (MALDI-TOF): calcd. for
[C24H36N2O5 + H]+ 433.2702; found 433.2712.
H]+ 355.2862; found 355.2810.
N1-[2-(3-Aminopropylamino)ethyl]-N3-o-tolylpropane-1,3-diamine
(26): Obtained as the second product in the synthesis of compound
25. Eluent: CH2Cl2/MeOH/NH3(aq) 10:4:1; yield 36 mg (27 %);
pale-yellow oil. 1H NMR (400 MHz, CDCl3): δ = 1.60 (quint., J =
6.9 Hz, 2 H), 1.83 (quint., J = 6.4 Hz, 2 H), 2.10 (s, 3 H), 2.64 (t,
J = 6.9 Hz, 2 H), 2.71 (s, 4 H), 2.73 (t, J = 7.1 Hz, 2 H), 2.75 (t, J
= 6.4 Hz, 2 H), 3.20 (t, J = 6.3 Hz, 2 H), 6.57 (d, J = 8.1 Hz, 1 H),
6.61 (t, J = 7.6 Hz, 1 H), 7.01 (d, J = 6.8 Hz, 1 H), 7.09 (t, J
= 7.1 Hz, 1 H) ppm; NH protons were not assigned. 13C NMR
(100.6 MHz, CDCl3): δ = 17.5, 29.3, 33.4, 40.3, 42.8, 47.7, 48.4,
49.3, 49.4, 109.4, 116.5, 121.8, 127.0, 129.9, 146.5 ppm. HRMS
(MALDI-TOF): calcd. for [C15H28N4 + H]+ 265.2392; found
265.2336.
N-(3-{2-[2-(3-Aminopropoxy)ethoxy]ethoxy}propyl)-4-methoxy-
aniline (31): Obtained as the second product in the synthesis of
compound 30. Eluent: CH2Cl2/MeOH 3:1, CH2Cl2/MeOH/
NH3(aq) 100:20:2; yield 83 mg (51 %); yellow oil. 1H NMR
(400 MHz, CDCl3): δ = 1.69 (quint., J = 6.4 Hz, 2 H), 1.85 (quint.,
J = 6.2 Hz, 2 H), 2.76 (br. s, 2 H), 3.15 (t, J = 6.5 Hz, 2 H), 3.52
(t, J = 6.2 Hz, 2 H), 3.53–3.63 (m, 10 vH), 3.71 (s, 3 H), 6.53–6.57
(m, 2 H), 6.72–6.76 (m, 2 H) ppm; NH protons were not assigned.
13C NMR (100.6 MHz, CDCl3): δ = 29.2, 33.0, 39.5, 42.6, 55.8,
69.4, 69.7, 70.1, 70.2, 70.5 (2 C), 114.0 (2 C), 114.8 (2 C), 142.8,
N,NЈ-{3,3Ј-[2,2Ј-Oxybis(ethane-2,1-diyl)bis(oxy)]bis(propane-3,1-
diyl)}bis(2-methylaniline) (27): Synthesized from 2-iodotoluene
(1.25 mmol, 273 mg) and trioxadiamine 1c (0.5 mmol, 110 mg), in
the presence of CuI (9.6 mg), ligand L4b (17 mg), and Cs2CO3
(408 mg) in DMF (1 mL). Eluent: CH2Cl2/MeOH 100:1–50:1; yield
14 mg (7%); yellow oil. 1H NMR (400 MHz, CDCl3): δ = 1.94
(quint., J = 6.1 Hz, 4 H), 2.12 (s, 4 H), 3.26 (t, J = 6.4 Hz, 4 H),
3.59–3.67 (m, 12 H), 3.93 (br. s, 2 H), 6.59 (d, J = 8.2 Hz, 2 H),
6.63 (t, J = 7.3 Hz, 2 H), 7.03 (d, J = 7.1 Hz, 2 H), 7.11 (t, J =
7.6 Hz, 2 H) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 17.5 (2 C),
29.2 (2 C), 42.0 (2 C), 70.2 (2 C), 70.4 (2 C), 70.6 (2 C), 109.4 (2
C), 116.5 (2 C), 121.8 (2 C), 127.0 (2 C), 129.9 (2 C), 146.5 (2
C) ppm. HRMS (MALDI-TOF): calcd. for [C24H36N2O3 + H]+
401.2804; found 401.2790.
151.8 ppm. HRMS (MALDI-TOF): calcd. for [C17H30N2O4
+
H]+ 327.2284; found 327.2236.
N1,N1Ј-(Ethane-1,2-diyl)bis[N3-(4-chlorophenyl)propane-1,3-di-
amine] (32): Synthesized from 1-chloro-4-iodobenzene (1.25 mmol,
298 mg) and tetraamine 1a (0.5 mmol, 87 mg), in the presence of
CuI (9.6 mg), ligand L6 (11.5 mg), and Cs2CO3 (408 mg) in propio-
nitrile (1 mL). Eluent: CH2Cl2/MeOH/NH3(aq) 100:20:2; yield
83 mg (42%); pale-yellow oil. 1H NMR (400 MHz, CDCl3): δ =
1.74 (quint., J = 6.6 Hz, 4 H), 2.70 (s, 4 H), 2.71 (t, J = 6.6 Hz, 4
H), 3.11 (t, J = 6.6 Hz, 4 H), 6.48 (d, J = 8.8 Hz, 4 H), 7.07 (d, J
= 8.8 Hz, 4 H) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 29.2 (2
C), 42.7 (2 C), 48.0 (2 C), 49.3 (2 C), 113.6 (4 C), 121.3 (2 C),
128.8 (4 C), 147.0 (2 C) ppm. HRMS (MALDI-TOF): calcd. for
[C20H28Cl2N4 + H]+ 395.1769; found 395.1810.
N-(3-{2-[2-(3-Aminopropoxy)ethoxy]ethoxy}propyl)-2-methyl-
aniline (28): Obtained as the second product in the synthesis of
compound 27. Eluent: CH2Cl2/MeOH/NH3(aq) 100:20:1–100:20:2;
N,NЈ-{3,3Ј-[2,2Ј-Oxybis(ethane-2,1-diyl)bis(oxy)]bis(propane-3,1-
diyl)}bis(4-chloroaniline) (33): Synthesized from 1-chloro-4-iodo-
benzene (1.25 mmol, 293 mg) and trioxadiamine 1c (0.5 mmol,
110 mg), in the presence of CuI (9.6 mg), ligand L4b (17 mg), and
Cs2CO3 (408 mg) in DMF (1 mL). Eluent: CH2Cl2/MeOH 500:1–
100:1; yield 62 mg (28 %); pale-yellow oil. 1H NMR (400 MHz,
CDCl3): δ = 1.85 (quint., J = 6.1 Hz, 4 H), 3.18 (t, J = 6.4 Hz, 4
H), 3.58 (t, J = 5.9 Hz, 4 H), 3.59–3.61 (m, 4 H), 3.64–3.67 (m, 4
H), 4.12 (br. s, 2 H), 6.47–6.51 (m, 4 H), 7.06–7.10 (m, 4 H) ppm.
13C NMR (100.6 MHz, CDCl3): δ = 28.9 (2 C), 42.0 (2 C), 69.7 (2
C), 70.2 (2 C), 70.6 (2 C), 113.7 (4 C), 121.4 (2 C), 128.9 (4 C),
1 4 7 . 1 ( 2 C ) p p m . H R M S ( M A L D I - T O F ) : c a l c d . fo r
[C22H30Cl2N2O3 + H]+ 441.1712; found 441.1642.
1
yield 61 mg (39%); pale-yellow oil. H NMR (400 MHz, CDCl3):
δ = 1.70 (quint., J = 6.4 Hz, 2 H), 1.92 (quint., J = 6.0 Hz, 2 H),
2.10 (s, 3 H), 2.77 (t, J = 6.4 Hz, 2 H), 3.24 (t, J = 6.3 Hz, 2 H),
3.51 (t, J = 6.2 Hz, 2 H), 3.52–3.65 (m, 10 H), 6.57 (d, J = 8.0 Hz,
1 H), 6.60 (t, J = 7.5 Hz, 1 H), 7.01 (d, J = 7.0 Hz, 1 H), 7.08 (t,
J = 7.6 Hz, 1 H) ppm; NH protons were not assigned. 13C NMR
(100.6 MHz, CDCl3): δ = 17.4, 29.1, 32.6, 39.4, 41.9, 69.4, 70.0,
70.1, 70.3, 70.5 (2 C), 109.3, 116.5, 121.8, 126.9, 129.9, 146.4 ppm.
HRMS (MALDI-TOF): calcd. for [C17H30N2O3 + H]+ 311.2335;
found 311.2286.
N1,N1Ј-(Ethane-1,2-diyl)bis[N3-(4-methoxyphenyl)propane-1,3-di-
amine] (29): Synthesized from 4-iodoanisole (1.25 mmol, 293 mg)
and tetraamine 1a (0.5 mmol, 87 mg), in the presence of CuI
(9.6 mg), ligand L6 (11.5 mg), and Cs2CO3 (408 mg) in propioni-
trile (1 mL). Eluent: CH2Cl2/MeOH/NH3(aq) 100:20:2; yield
N-(3-{2-[2-(3-Aminopropoxy)ethoxy]ethoxy}propyl)-4-chloroaniline
(34): Obtained as the second product in the synthesis of compound
1
33. Eluent: CH2Cl2/MeOH 5:1; yield 69 mg (42%); yellow oil. H
NMR (400 MHz, CDCl3): δ = 1.89 (quint., J = 6.1 Hz, 4 H), 3.11
(t, J = 5.9 Hz, 2 H), 3.12 (t, J = 6.4 Hz, 2 H), 3.55–3.65 (m, 12 H),
6.60 (d, J = 8.7 Hz, 2 H), 7.03 (d, J = 8.7 Hz, 2 H) ppm; NH
protons were not assigned. 13C NMR (100.6 MHz, CDCl3): δ =
25.7, 28.6, 40.1, 41.5, 69.4 (2 C), 69.5, 69.7, 70.0, 70.1, 114.2 (2 C),
121.6, 128.7 (2 C), 146.9 ppm. HRMS (MALDI-TOF): calcd. for
[C16H28ClN2O3 + H]+ 331.1788; found 331.1748.
1
101 mg (52%); beige crystals; m.p. 85–88 °C. H NMR (400 MHz,
CDCl3): δ = 1.74 (quint., J = 6.6 Hz, 4 H), 2.68–2.72 (m, 8 H),
3.09 (t, J = 6.4 Hz, 4 H), 3.70 (s, 6 H), 6.54 (d, J = 8.7 Hz, 4 H),
6.74 (d, J = 8.7 Hz, 4 H) ppm; NH protons were not assigned. 13C
NMR (100.6 MHz, CDCl3): δ = 29.3 (2 C), 43.3 (2 C), 47.8 (2 C),
48.9 (2 C), 55.6 (2 C), 113.9 (4 C), 114.7 (4 C), 142.6 (2 C), 151.8
(2 C) ppm. HRMS (MALDI-TOF): calcd. for [C22H34N4O2 + H]+ N1,N1Ј-(Ethane-1,2-diyl)bis[N3-(4-nitrophenyl)propane-1,3-di-
387.2760; found 387.2760.
amine] (37): Synthesized from 4-nitroiodobenzene (1.25 mmol,
Eur. J. Org. Chem. 2011, 6240–6253
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6251

I. P. Beletskaya et al.
FULL PAPER
311 mg) and tetraamine 1a (0.5 mmol, 87 mg), in the presence of
CuI (9.6 mg), ligand L6 (11.5 mg), and Cs2CO3 (408 mg) in propio-
nitrile (1 mL). Eluent: CH2Cl2/MeOH/NH3(aq) 100:20:2; yield
24 mg (12%); dark-yellow oil. 1H NMR (400 MHz, [D6]DMSO): δ
= 1.63 (quint., 4 H, J = 6.4 Hz), 2.54 (br. s, 8 H), 3.11 (q, J =
5.2 Hz, 4 H), 6.55 (d, J = 8.9 Hz, 4 H), 7.32 (br. s, 2 H), 7.89 (d, J
= 8.9 Hz, 4 H) ppm; 2 NH protons were not assigned. 13C NMR
(100.6 MHz, [D6]DMSO): δ = 28.4 (2 C), 40.5 (2 C), 46.6 (2 C),
48.5 (2 C), 110.7 (4 C), 126.2 (4 C), 135.4 (2 C), 154.6 (2 C) ppm.
HRMS (MALDI-TOF): calcd. for [C20H28N6O4 + H]+ 417.2250;
found 417.2311.
N1,N1-Bis(4-nitrophenyl)-N3-{2-[3-(4-nitrophenylamino)propyl-
amino]ethyl}propane-1,3-diamine (36): Obtained as the second
product in the synthesis of compound 37. Eluent: CH2Cl2/MeOH
3:1; yield 75 mg (33%); dark-yellow oil. 1H NMR (400 MHz, [D6]-
DMSO): δ = 1.79 (br. s, 4 H), 2.68 (br. s, 2 H), 2.77 (br. s, 2 H),
2.80 (br. s, 4 H), 3.20 (br. s, 2 H), 4.00 (br. s, 2 H), 6.62 (d, J =
8.6 Hz, 2 H), 7.31 (d, J = 8.5 Hz, 4 H), 7.93 (d, J = 8.6 Hz, 2 H),
8.14 (d, J = 8.5 Hz, 4 H) ppm; NH protons were not assigned. 13C
NMR (100.6 MHz, [D6]DMSO): δ = 26.1, 26.6, 45.4, 45.6, 45.9,
46.3, 49.9, 110.9 (2 C), 121.1 (4 C), 125.7 (4 C), 126.3 (2 C), 135.8
(1 C), 141.5 (2 C), 151.6 (2 C), 154.6 (1 C) ppm; one carbon atom
of polyamine chain was not assigned. HRMS (MALDI-TOF):
calcd. for [C26H31N7O6 + H]+ 538.2414; found 538.2497.
product in the synthesis of compound 40. Eluent: CH2Cl2/MeOH
500:1, isolated in a mixture with compound 39. Yield of the mix-
ture 64 mg (ca 25%); dark-yellow oil. 1H NMR (400 MHz, CDCl3):
δ = 1.92 (quint., J = 5.8 Hz, 4 H), 3.50 (t, J = 5.8 Hz, 4 H), 3.58–
3.72 (m, 8 H), 4.03 (t, J = 7.1 Hz, 4 H), 7.18 (d, J = 9.0 Hz, 8
H), 8.12 (d, J = 9.0 Hz, 8 H) ppm. MS (MALDI-TOF): calcd. for
[C34H36N6O10 – O + H]+ 689.26; found 689.38.
N-(3-{2-[2-(3-Aminopropoxy)ethoxy]ethoxy}propyl)-4-nitro-N-(4-
nitrophenyl)aniline (41): Obtained as the fourth product in the syn-
thesis of compound 40. Eluent: CH2Cl2/MeOH 50:1, isolated in a
mixture with compound 40. Yield of the mixture 37 mg (16%);
1
dark-yellow oil. H NMR (400 MHz, CDCl3): δ = 1.86–1.94 (m, 4
H), 3.29 (t, J = 5.3 Hz, 2 H), 3.46 (t, J = 5.4 Hz, 2 H), 3.58–3.68
(m, 10 H), 4.02 (t, J = 6.1 Hz, 2 H), 7.17 (d, J = 9.1 Hz, 4 H), 8.14
(d, J = 9.1 Hz, 4 H) ppm; NH protons were not assigned. 13C
NMR (100.6 MHz, CDCl3): δ = 27.4, 28.4, 41.5, 49.3, 69.6, 70.1,
70.2, 70.3, 70.4, 72.4, 120.6 (4 C), 126.4 (4 C), 142.1 (2 C), 151.7
(2 C) ppm. HRMS (MALDI-TOF): calcd. for [C22H30N4O7 + H]+
463.2193; found 463.2178.
N-(3-{2-[2-(3-Aminopropoxy)ethoxy]ethoxy}propyl)-4-nitroaniline
(42): Obtained as the fifth product in the synthesis of compound
40. Eluent: CH2Cl2/MeOH 20:1; yield 48 mg (28%); dark-yellow
1
oil. H NMR (400 MHz, CDCl3): δ = 1.73 (quint., J = 5.5 Hz, 2
H), 1.86 (quint., J = 5.4 Hz, 2 H), 3.27 (br. s, 2 H), 3.35 (q, J =
5.4 Hz, 2 H), 3.51–3.62 (m, 12 H), 5.61 (br. s, 1 H), 6.48 (d, J =
8.3 Hz, 2 H), 7.97 (d, J = 8.3 Hz, 2 H) ppm; 2 NH protons were
not assigned. 13C NMR (100.6 MHz, CDCl3): δ = 28.4 (2 C), 36.6,
41.2, 69.3, 69.6, 69.9, 70.0, 70.2, 70.3, 110.7 (2 C), 126.3 (2 C),
137.0, 153.8 ppm. HRMS (MALDI-TOF): calcd. for [C16H27N3O5
+ H]+ 342.2029; found 342.2004.
N1,N1Ј-(Ethane-1,2-diyl)bis[N3,N3-bis(4-nitrophenyl)propane-1,3-
diamine] (35): Obtained as the third product in the synthesis of
compound 37. Eluent: CH2Cl2/MeOH 10:1, isolated in a mixture
with compound 36. Yield of the mixture 77 mg (ca 35%); dark-
1
yellow oil. H NMR (400 MHz, [D6]DMSO): δ = 1.77 (br. s, 4 H),
2.63 (s, 4 H), 2.65 (br. s, 4 H), 3.98 (br. s, 4 H), 7.29 (d, J = 8.3 Hz,
8 H), 8.13 (d, J = 8.3 Hz, 8 H) ppm; NH protons were not assigned.
13C NMR (100.6 MHz, [D6]DMSO): δ = 26.5 (2 C), 45.7 (2 C),
49.7 (2 C), 49.9 (2 C), 121.0 (8 C), 125.6 (8 C), 141.5 (4 C), 151.6
(4 C) ppm. MS (MALDI-TOF): calcd. for [C32H34N8O8 + H]+
659.26; found 659.38.
Acknowledgments
This research was financially supported by the Russian Academy
of Sciences program (“Elaboration of the methods for the synthesis
of chemical compounds and construction of new materials”,
RFBR grant number 09-03-00735).
N,NЈ-{3,3Ј-[2,2Ј-Oxybis(ethane-2,1-diyl)bis(oxy)]bis(propane-3,1-
diyl)}bis(4-nitroaniline) (40): Synthesized from 4-nitroiodobenzene
(1.25 mmol, 311 mg) and trioxadiamine 1c (0.5 mmol, 110 mg), in
the presence of CuI (9.6 mg), ligand L4b (17 mg), and Cs2CO3
(408 mg) in DMF (1 mL). Eluent: CH2Cl2/MeOH 100:1; yield
61 mg (26%); dark-yellow oil. 1H NMR (400 MHz, CDCl3): δ =
1.86 (quint., J = 5.9 Hz, 4 H), 3.27 (q, J = 5.9 Hz, 4 H), 3.55–3.60
(m, 8 H), 3.63–3.67 (m, 4 H), 5.45 (br. s, 2 H), 6.46 (d, J = 9.2 Hz,
4 H), 7.97 (d, J = 9.2 Hz, 4 H) ppm. 13C NMR (100.6 MHz,
CDCl3): δ = 28.3 (2 C), 41.5 (2 C), 69.5 (2 C), 70.0 (2 C), 70.3 (2
C), 110.7 (4 C), 126.2 (4 C), 137.1 (2 C), 153.7 (2 C) ppm. HRMS
(MALDI-TOF): calcd. for [C22H30N4O7 + H]+ 463.2193; found
463.2179.
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Received: April 5, 2011
Published Online: September 7, 2011
Eur. J. Org. Chem. 2011, 6240–6253
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6253