Efficient and chemoselective direct reductive amination of aromatic aldehydes catalyzed by oxo-rhenium complexes containing heterocyclic ligands

Article abstract of DOI:10.1016/j.tet.2013.08.016

This work describes the catalytic activity of 17 oxo-rhenium complexes containing heterocyclic ligands in the direct reductive amination of 4-nitrobenzaldehyde with 4-chloroaniline, using phenylsilane as reducing agent. In general, all of the catalysts tested gave excellent yields of the secondary amine, although, the best result was obtained with the catalytic system PhSiH₃/ReOBr₂(Hhmpbta)(PPh₃) (2.5 mol %). This system was also applied to the synthesis of a large variety of secondary amines in good to excellent yields and tertiary amines in moderate yields, with tolerance of different functional groups.

Full text of DOI:10.1016/j.tet.2013.08.016

Tetrahedron 69 (2013) 9145e9154
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Tetrahedron
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Efficient and chemoselective direct reductive amination of aromatic
aldehydes catalyzed by oxoerhenium complexes containing
heterocyclic ligands
Joana R. Bernardo a, Sara C.A. Sousa a, Pedro R. Florindo a, Mariusz Wolff b,
,
Barbara Machura b, Ana C. Fernandes a
*
a
ꢀ
ꢀ
Centro de Química Estrutural, Instituto Superior Tecnico, Universidade Tecnica de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal
b Department of Crystallography, Institute of Chemistry, University of Silesia, 9 Szkolna St., 40-006 Katowice, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 April 2013
Received in revised form 18 July 2013
Accepted 9 August 2013
Available online 15 August 2013
This work describes the catalytic activity of 17 oxoerhenium complexes containing heterocyclic ligands
in the direct reductive amination of 4-nitrobenzaldehyde with 4-chloroaniline, using phenylsilane as
reducing agent. In general, all of the catalysts tested gave excellent yields of the secondary amine, al-
though, the best result was obtained with the catalytic system PhSiH3/ReOBr2(Hhmpbta)(PPh3)
(2.5 mol %). This system was also applied to the synthesis of a large variety of secondary amines in good
to excellent yields and tertiary amines in moderate yields, with tolerance of different functional groups.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Amines
Reductive amination
Oxoerhenium complexes
Silanes
1. Introduction
With increasing environmental concerns and constraints,
there exists a tremendous potential for development of new re-
Reductive amination of carbonyl compounds with amines re-
mains one of the most versatile and useful synthetic route for the
preparation of amines and their derivatives, which are synthetically
useful organic intermediates in pharmaceuticals and agrochemi-
cals.1 This reaction involves the formation of an imine or iminium
as intermediate, followed by in situ reduction. The importance of
reductive amination procedures is exemplified by the enormous
number of its synthetic uses.
There are two types of reducing agents employed for direct re-
ductive amination ofaldehydes with amines. These two strategies are
mainly based on metal catalyzed hydrogenation,1 and hydride re-
ducing agents, such as NaBH4,2 NaBH3CN,3 NaBH(OAc)3,4 and pyr-
idineeBH3.5 However, in terms of functional group tolerance and side
reactions, most of these reagents may have one or more drawbacks.
For example, catalytic hydrogenation is incompatible with com-
pounds containing other reducible functional groups, such as double
and triple bonds, nitro, and cyano groups. NaBH4 sometimes requires
harsh reaction conditions, cyanoborohydride is highly toxic and
generate toxic by-products, such as HCN or NaCN, and pyridineeBH3
is unstable to heat and must be handled with extreme care.
ductive amination methodologies. Organosilanes are mild and
environmentally benign reducing agents, and in recent years, sev-
eral reagent systems containing silanes, such as Et3SiH/InCl3,6
Et3SiH/[IrCl(cod)]2,7 PhSiH3/Bu2SnCl2,8 PhSiH3/MoO2Cl2,9 poly-
10
methylhydrosiloxane (PMHS)/Ti(OiPr)4, FeCl3/PMHS11 have also
been employed in reductive amination.
Previously, our group have demonstrated that several
oxoerhenium complexes were good catalysts for the direct re-
ductive amination of aldehydes using silanes as reducing agents.12
The results obtained demonstrate that the catalytic system PhSiH3/
ReIO2(PPh3)2 (2.5 mol %) was very efficient for the synthesis of
secondary amines in high yields and good chemoselectivity, and
also for the synthesis of tertiary amines in moderate yields. Later,
Ghorai and Das13 developed an efficient method for direct re-
ductive amination of aldehydes with electron-deficient protected
amines, such as Cbze, Boce, EtOCOe, Fmoce, Bze, ArSO2e,
Ar2POe, etc., using Re2O7 as catalyst and silanes as reducing agent.
Due to the biological and chemical importance of amines, the
search for novel catalyst systems, leading to efficient and highly
chemoselective methods for their preparation, remains an impor-
tant target in organic synthesis. The rhenium complexes containing
heterocyclic moieties constantly attract the interest of chemists and
pharmacists on account of their versatile biological activity and
* Corresponding author. Tel.: þ351 218419264; fax: þ351 218464457; e-mail
address: anacristinafernandes@ist.utl.pt (A.C. Fernandes).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.08.016

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J.R. Bernardo et al. / Tetrahedron 69 (2013) 9145e9154
industrial applications. Surprisingly, catalytic studies using rhe-
nium complexes incorporating such ligands have been relatively
rare. In continuation of our work about the use of oxo-complexes as
efficient catalysis in organic chemistry,14 herein we report the
catalytic activity of 17 oxoerhenium complexes containing het-
erocyclic ligands in direct reductive amination of aldehydes.
the faster (13 min) (Table 2, entry 1) in contrast to the reduction
with PMHS that required 24 h (Table 2, entry 4). No reaction was
observed using Ph3SiH (Table 2, entry 5) or without silane (Table 2,
entry 6).
In Table 3 are summarized the results of the search for the ap-
propriate solvent. We found that THF was the best solvent for this
reaction at reflux temperature, affording the amine in 98% con-
version after only 13 min (Table 3, entry 1). At room temperature,
this reaction required 24 h and only moderate conversion of the
amine was obtained (Table 3, entry 2). Chloroform, toluene, and
benzene also gave good to excellent conversions of the product, but
these reductions required 24 h (Table 3, entries 3e5). Finally, the
reductions performed in acetonitrile and dichloromethane pro-
duced the amine in moderate conversions after 24 h (Table 3, en-
tries 6 and 7).
In order to study the scope and the limitations of the catalytic
system PhSiH3/ReOBr2(Hhmpbta)(PPh3) (2.5 mol %), the direct re-
ductive amination was explored with a variety of aldehydes and
aniline (Table 4). In general, all the secondary amines were ob-
tained in good to excellent yields within short reaction times, in-
cluding the amines prepared from aldehydes bearing electron-
withdrawing or electron-donating groups. This reaction showed
broad substrate scope, tolerating several functional groups, such as
eNO2, eCF3, eSO2R, eBr, eCO2R, eOCH3, eSCH3, eNCOR, and fur-
furyl ring.
Another interesting result was the chemoselective reductive
amination of cinnamaldehyde with aniline in 81% yield without
affecting the double bond (Table 4, entry 11). Heteroaromatic al-
dehyde 2-furaldehyde also reacted with aniline affording the cor-
responding secondary amine in excellent yield (Table 4, entry 2).
In this work, we have also studied the reductive amination of 4-
methoxybenzaldehyde with different anilines (Table 5). All the
reactions afforded the corresponding secondary amines in good to
excellent yields. The reactions carried out with anilines containing
electron-withdrawing groups were much faster (Table 5, entries
2. Results and discussion
Initially, we studied the catalytic activity of the 17 oxoerhenium
complexes containing the heterocyclic ligands namely 2-(20-hy-
droxy-50-methylphenyl)benzotriazole
(Hhmpbta),15
2-(2-
hydroxyphenyl)-2-benzothiazole (Hhpbt),16 2-(2-hydroxyphenyl)-
2-benzoxazole (Hhpbo),17 2-(2-hydroxyphenyl)-1H-benzimidazole
(Hhpbi)18 (Fig. 1) in the direct reductive amination of 4-
nitrobenzaldehyde with 4-chloroaniline, using PhSiH3 as reducing
agent (Table 1). In general, all the oxoerhenium complexes were
very efficient, affording high yields of the secondary amine. The
reaction catalyzed by 2.5 mol % of ReOBr2(Hhmpbta)(PPh3) at
refluxing THF gave the best result, producing the amine in 98% yield
after only 13 min (Table 1, entry 1). The results obtained also
demonstrate that in general the catalysts with Br ligands (Table 1,
entries 1, 2, 6, 7,10,11, and 14) are more reactive than the complexes
containing Cl ligands. Comparison between the oxoerhenium
complexes containing the heterocyclic ligands with the similar
complexes without the heterocyclic ligands shows that the cata-
lysts ReOBr2(L)(PPh3) (Table 1, entries 1, 7, 10, and 14) are more
efficient than ReOBr3(PPh3)2 (Table 1, entry 18), in contrast, the
reactions with the catalysts ReOCl2(L)(PPh3) (Table 1, entries 3, 9,
13, and 16) or ReOCl2(L)(AsPh3) (Table 1, entries 4, 8, 12, and 15)
required more time than the reactions with the complexes
ReOCl3(PPh3)2 or ReOCl3(AsPh3)2 (Table 1, entries 19 and 20). Fi-
nally, no reductive amination was observed with phenylsilane in
the absence of catalyst (Table 1, entry 21), demonstrating the cat-
alytic role of the oxoerhenium complex.
Fig. 1. Structure of heterocyclic ligands.
Direct reductive amination of 4-nitrobenzaldehyde with aniline
was studied using several silanes namely phenylsilane, dimethyl-
phenylsilane (DMPSH), triethylsilane, triphenylsilane, and poly-
methylhydrosiloxane (PMHS). The reductions carried out with
PhSiH3, DMPSH, Et3SiH, and PMHS produced the amine in excellent
yields (Table 2, entries 1e4), although, the reaction with PhSiH3 is
1e3) than the reactions with anilines containing electron-donating
groups (Table 5, entries 4 and 5).
The catalytic activityof the system PhSiH3/ReOBr2(Hhmpbta)(PPh3)
(2.5 mol %) was also explored for the synthesis of tertiary amines in
the reactions between N-methylaniline and several aldehydes (Table
6). These reductions were carried out with heteroaromatic aldehydes

J.R. Bernardo et al. / Tetrahedron 69 (2013) 9145e9154
9147
Table 1
Direct reductive amination of 4-nitrobenzaldehyde with 4-chloroaniline catalyzed by oxoerhenium complexesa
Entry
1
Catalyst
Ligand
Time
Yieldb (%)
[ReOBr2(L)(PPh3)]
13 min
98
2
3
4
5
[ReOBr2(L)(AsPh3)]
[ReOCl2(L)(PPh3)]
[ReOCl2(L)(AsPh3)]
[ReOBr(L)2]
22 min
30 min
60 min
6 h
99
95
92
87
6
[ReOBr2(L)(AsPh3)]
14 min
94
7
8
9
[ReOBr2(L)(PPh3)]
[ReOCl2(L)(AsPh3)]
[ReOCl2(L)(PPh3)]
20 min
1 h
1 h 30 min
94
89
86
10
[ReOBr2(L)(PPh3)]
15 min
93
11
12
13
[ReOBr2(L)(AsPh3)]
[ReOCl2(L)(AsPh3)]
[ReOCl2(L)(PPh3)]
22 min
1 h 16 min
1 h 20 min
94
90
91
14
[ReOBr2(L)(PPh3)]
23 min
99
15
16
17
[ReOCl2(L)(AsPh3)]
[ReOCl2(L)(PPh3)]
[ReOBr2(L)(AsPh3)]
2 h 40 min
3 h
6 h
98
98
96
18
19
20
21
ReOBr3(PPh3)2
ReOCl3(PPh3)2
ReOCl3(AsPh3)2
Without catalyst
d
d
d
d
25 min
20 min
40 min
24 h
92
94
91
No reaction
a
All reactions were carried out with 1.0 mmol of aldehyde, 1.0 mmol of 4-chloroaniline, and 120 mol % of PhSiH3 and 2.5 mol % of catalyst.
Isolated yields.
b
Table 2
Direct reductive amination of 4-nitrobenzaldehyde with aniline using different silanesa
Entry
Silane
Silane (mol %)
Time
Conversionb (%)
1
2
3
4
5
6
PhSiH3
DMPSH
Et3SiH
PMHS
Ph3SiH
120
250
300
200
250
d
13 min
30 min
1 h 30 min
24 h
24 h
24 h
98
97
97
96
No reaction
No reaction
Without silane
a
All reactions were carried out with 1.0 mmol of aldehyde, 1.0 mmol of aniline, and 2.5 mol % of ReOBr2(Hhmpbta)(PPh3).
Conversion was determined by 1H NMR.
b

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J.R. Bernardo et al. / Tetrahedron 69 (2013) 9145e9154
Table 3
Direct reductive amination of 4-nitrobenzaldehyde with aniline in different solventsa
Entry
Solvent
Temp
Time
Conversionb (%)
1
2
3
4
5
6
7
THF
THF
Reflux
rt
13 min
24 h
24 h
24 h
24 h
24 h
24 h
98
64
98
87
85
75
69
CHCl3
Toluene
Benzene
CH3CN
CH2Cl2
Reflux
Reflux
Reflux
Reflux
Reflux
a
All reactions were carried out with 1.0 mmol of aldehyde, 1.0 mmol of aniline, 120 mol % of PhSiH3, and 2.5 mol % of ReOBr2(Hhmpbta)(PPh3).
Conversion was determined by 1H NMR.
b
Table 4
a
Direct reductive amination of aldehydes with the catalytic system PhSiH3/ReOBr2(Hhmpbta)PPh3
Entry
Aldehyde
Product
Time
Yieldb (%)
1
13 min
98
2
3
30 min
96
94
15 min
4
22 min
90
5
10 min
87

J.R. Bernardo et al. / Tetrahedron 69 (2013) 9145e9154
9149
Table 4 (continued )
Entry
Aldehyde
Product
Time
Yieldb (%)
6
10 min
85
7
10 min
85
8
7 min
82
9
5 min
80
10
15 min
76
11
1 h
81
12
23 min
71
a
All reactions were carried out with 1.0 mmol of aldehyde, 1.0 mmol of aniline, 120 mol % of PhSiH3, and 2.5 mol % of ReOBr2(Hhmpbta)(PPh3).
Isolated yield.
b

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J.R. Bernardo et al. / Tetrahedron 69 (2013) 9145e9154
Table 5
Direct reductive amination of 4-methoxybenzaldehyde with different anilines using the catalytic system PhSiH3/ReOBr2(Hhmpbta)(PPh3)a
Entry
Aniline
Product
Time
Yieldb (%)
1
5 min
93
2
3
4
10 min
94
95
77
45 min
1 h 30 min
5
4 h 30 min
72
a
All reactions were carried out with 1.0 mmol of aldehyde, 1.0 mmol of aniline, 120 mol % of PhSiH3, and 2.5 mol % of ReOBr2(Hhmpbta)(PPh3).
Isolated yield.
b
and different aromatic aldehydes bearing electron-withdrawing or
3. Conclusions
electron-donating groups, affording the corresponding tertiary amines
in moderate yields.
In conclusion, we have studied the catalytic activity of 17
oxoerhenium complexes containing the heterocyclic ligands
Hhmpbta, Hhpbt, Hhpbo, and Hhpbi as catalysts in the direct re-
ductive amination of 4-nitrobenzaldehyde with 4-chloroaniline,
using phenylsilane as reducing agent. All the catalysts tested show
good to excellent catalytic activities. The best results was obtained
with the catalytic system PhSiH3/ReOBr2(Hhmpbta)(PPh3)
(2.5 mol %), which proved to be also very efficient for the synthesis
of several secondary amines in excellent yields and for the
We propose a mechanism for the direct reductive amination of
aldehydes with the catalytic system PhSiH3/ReOBr2(Hhmpbta)(PPh3)
that should start by the formation of the imine, and coordination of
this molecule to the catalyst by substitution of the phosphine,
affording the complex ReOBr2(Hhmpbta)(imine). In the second step,
a hydride species is formed as result of the addition of the SieH bond
of the silane to the oxoerhenium bond. Then, the hydrosilylation of
the imine occurs, followed by hydrolysis to the corresponding amine.

J.R. Bernardo et al. / Tetrahedron 69 (2013) 9145e9154
Direct reductive amination of aldehydes with N-methylaniline using the catalytic system PhSiH3/ReOBr2(Hhmpbta)(PPh3)a
9151
Table 6
Entry
Aldehyde
Product
Time
Yieldb (%)
1
15 min
68
66
61
2
15 min
3
15 min
4
20 min
62
5
30 min
57
6
7
1 h 30 min
69
2 h
65
(continued on next page)

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J.R. Bernardo et al. / Tetrahedron 69 (2013) 9145e9154
Table 6 (continued )
Entry
Aldehyde
Product
Time
Yieldb (%)
8
3 h 30 min
66
a
All reactions were carried out with 1.0 mmol of aldehyde, 1.0 mmol of N-methylaniline, 120 mol % of PhSiH3, and 2.5 mol % of ReOBr2(Hhmpbta)(PPh3).
Isolated yield.
b
preparation of tertiary amines in moderate yields. This method is
(s, 2H), 4.29 (br s,1H); 13C NMR (100 MHz, CDCl3)
d 147.6, 147.4, 147.3,
also highly chemoselective, tolerating a large range of functional
groups, such as eNO2, eCF3, eSO2R, eCO2R, eF, eCl, eBr, eOH,
eOCH3, eSCH3, eNCOR, double bond and furfuryl ring.
129.5,127.8,124.0,118.3,113.0, 47.7. IR (neat, cmꢀ1): 3419, 3052, 2849,
1602, 1517, 1345, 1267, 1109, 752, 693; Anal. Calcd (%) for C13H12N2O2:
C, 68.41; H, 5.30; N, 12.27. Found: C, 68.29; H, 5.17; N, 12.01.
In comparison to other procedures reported in the literature,
this method is more chemoselective than some hydrogenation
systems in the reductive amination of substrates containing double
bonds, nitro, and halo groups. Furthermore, this methodology has
other advantages including high isolated yields, low catalyst load-
ing (2.5 mol %), fast reactions, simple experimental operation,
stability of the catalysts toward air and moisture, allowing the re-
action to be carried out under air atmosphere. We believe that this
new procedure can be an attractive and useful alternative to the
methods described in the literature and can also bring great ben-
efits to both academia and industry for the production of fine
chemicals, such as bioactive and pharmaceutical compounds.
The results obtained confirm the use of oxoerhenium com-
plexes as effective catalysts for CeN bond formation. Further ap-
plications of the catalytic system silane/oxoerhenium complexes to
other organic reductions and CeX bond forming reactions are now
in progress in our group.
4.2.2. N-((Furan-2-yl)methyl)benzenamine (2).20 Yellow oil; 1H NMR
(300 MHz, CDCl3)
d
7.25 (s, 1H), 7.13 (t, 2H, J¼8.3, 7.5 Hz), 6.67 (t, 1H,
J¼7.6, 7.6 Hz), 6.54 (d, 2H, J¼8.3 Hz), 6.20 (t,1H, J¼3.3,1.9 Hz), 6.11 (d,
1H, J¼3.1 Hz), 4.14 (s, 2H), 3.87 (br s, 1H). 13C NMR (100 MHz, CDCl3)
d
153.0, 147.8, 141.9, 129.3, 118.0, 113.2, 110.5, 107.0, 41.4. IR (neat,
cmꢀ1): 3419, 3052, 3026, 2921, 2853, 1602, 1505, 1453, 1325, 1267,
1252, 1180, 1028, 990, 869, 750, 732, 693; Anal. Calcd (%) for
C11H11NO: C, 76.28; H, 6.40; N, 8.09. Found: C, 75.99; H, 6.27; N, 7.88.
4.2.3. N-Benzylbenzenamine (3).21 Colorless oil. 1H NMR (400 MHz,
CDCl3)
d
7.42e7.29 (m, 5H), 7.21 (t, 2H, J¼8.0 Hz), 6.76 (t, 1H,
J¼7.2 Hz), 6.67 (d, 2H, J¼8.0 Hz), 4.36 (s, 2H), 4.05 (br s, 1H); 13C
NMR (100 MHz, CDCl3) d 148.3,139.5,129.4,128.7, 127.6, 127.3, 117.7,
113.0, 48.4. IR (neat, cmꢀ1): 3418, 3051, 3022, 2925, 1603, 1513,
1329, 1181, 984, 737, 689; Anal. Calcd (%) for C13H13N: C, 85.21; H,
7.15; N, 7.64. Found: C, 85.04; H, 6.99; N, 7.48.
4. Experimental section
4.1. General information
4.2.4. N-(4-(Trifluoromethyl)benzyl)benzenamine (4).12 Yellow oil;
1H NMR (400 MHz, CDCl3)
d
7.45 (d, 2H, J¼8.4 Hz), 7.33 (d, 2H,
J¼8.4 Hz), 7.05 (t, 2H, J¼7.6, 7.2 Hz), 6.61 (t, 1H, J¼7.2 Hz), 6.47 (d,
2H, J¼7.6 Hz), 4.24 (s, 2H), 3.82 (br s, 1H); 13C NMR (100 MHz,
All the reactions were carried out in air atmosphere and without
any dry solvent. Aldehydes and anilines were obtained from com-
mercial suppliers and were used without further purification. The
catalysts were prepared according to the literature procedures.15e18
Flash chromatography was performed on MN Kieselgel 60M
230e400 mesh. 1H NMR and 13C NMR spectra were measured on
a Bruker Avance II 400 MHz and 300 MHz spectrometers. Chemical
shifts are reported in parts per million (ppm) downfield from an
internal standard.
CDCl3) d 147.8, 143.9, 129.4, 127.5, 125.7, 125.6, 122.5, 118.0, 113.0,
47.8; IR (neat, cmꢀ1): 3398, 1604, 1506, 1325, 1164, 1120, 1066, 751,
692; Anal. Calcd for C14H12F3N: C, 66.93; H, 4.81; N, 5.57. Found: C,
66.76; H, 4.61; N, 5.34.
4.2.5. Methyl 4-((phenylamino)methyl)benzoate (5).12 Colorless oil;
1H NMR (400 MHz, CDCl3)
d
8.01 (d, 2H, J¼8.4 Hz), 7.44 (d, 2H,
J¼8.4 Hz), 7.17 (t, 2H, J¼7.2, 8.0 Hz), 6.73 (t, 1H, J¼7.2, 7.2 Hz), 6.61
(d, 2H, J¼8.0 Hz), 4.41 (s, 2H), 4.13 (br s, 1H), 3.91 (s, 3H); 13C NMR
(100 MHz, CDCl3) d 166.9,147.8,145.1,129.9,129.2,128.9,127.1,117.7,
4.2. General procedure for direct reductive amination of al-
dehydes with the system PhSiH3/ReOBr2(Hhmpbta)(PPh3)
112.8, 52.0, 47.8; IR (neat, cmꢀ1): 3414, 1720, 1602, 1508, 1278, 1112,
751; Anal. Calcd for C15H15NO2: C, 74.67; H, 6.27; N, 5.81. Found: C,
74.50; H, 6.31; N, 5.71.
To a mixture of aldehyde (1.0 mmol), aniline (1.0 mmol), and
ReOBr2(Hhmpbta)(PPh3) (2.5 mol %) in THF (3 mL) at reflux tem-
perature was added PhSiH3 (120 mol %). The reaction mixture was
stirred under air atmosphere (the reaction times are indicated in
Tables 4e6) and the progress of the reaction was monitored by TLC.
Upon completion, the reaction mixture was evaporated and puri-
fied by silica gel column chromatography with the appropriate
mixture of n-hexane and ethyl acetate to afford the amines.
4.2.6. N-(4-(Methylsulfonyl)benzyl)benzenamine (6).12 White solid;
mp 116e117 ꢁC; 1H NMR (400 MHz, CDCl3)
d
7.81 (d, 2H, J¼8.0 Hz),
7.48 (d, 2H, J¼8.0 Hz), 7.09 (t, 2H, J¼7.6, 8.0 Hz), 6.66 (t, 1H,
J¼7.6 Hz), 6.50 (d, 2H, J¼8.0 Hz) 4.37 (s, 2H), 4.20 (br s, 1H); 2.96 (s,
3H); 13C NMR (100 MHz, CDCl3)
d 147.5, 146.5, 139.3, 129.4, 128.0,
127.8, 118.2, 113.0, 47.7, 44.6; IR (KBr, cmꢀ1): 3414, 1604, 1508, 1298,
1148, 747, 690; Anal. Calcd for C14H15NO2S: C, 64.34; H, 5.79; N,
5.36; S, 12.27. Found: C, 64.09; H, 5.51; N, 4.98; S, 11.97.
4.2.1. N-(4-Nitrobenzyl)benzenamine (1).19 Orange oil; 1H NMR
(400 MHz, CDCl3)
(t, 2H, J¼8.0, 7.6 Hz), 6.78 (t,1H, J¼7.6 Hz), 6.61 (d, 2H, J¼8.0 Hz), 4.51
d
8.21 (d, 2H, J¼8.4 Hz), 7.56 (d, 2H, J¼8.4 Hz), 7.21
4.2.7. N-(4-Bromobenzyl)benzenamine (7).12 Orange oil; 1H NMR
(400 MHz, CDCl3)
d
7.42 (d, 2H, J¼8.4 Hz), 7.20 (d, 2H, J¼8.4 Hz), 7.14

J.R. Bernardo et al. / Tetrahedron 69 (2013) 9145e9154
9153
(t, 2H, J¼8.4, 7.2 Hz), 6.70 (t, 1H, J¼7.2 Hz), 6.57 (d, 2H, J¼8.4 Hz),
114.0, 55.3, 47.9. IR (KBr, cmꢀ1): 3409, 1596, 1497, 1246, 1174, 1029,
815; Anal. Calcd (%) for C14H14ClNO: C, 67.88; H, 5.70; N, 5.65.
Found: C, 68.72; H, 5.41; N, 5.53.
4.24 (s, 2H), 3.94 (br s,1H); 13C NMR (100 MHz, CDCl3)
d 147.9,138.6,
131.8, 129.4, 129.1, 121.0, 117.9, 113.0, 47.7; IR (neat, cmꢀ1): 3419,
1603, 1506, 1486, 1324, 1070, 1011, 751, 692; Anal. Calcd for
C
13H12BrN: C, 59.56; H, 4.61; N, 5.34. Found: C, 59.39; H, 4.48; N,
4.2.15. 4-Fluoro-N-(4-methoxybenzyl)benzenamine (15).12 White
5.19.
solid; mp 70e71 ꢁC; 1H NMR (400 MHz, CDCl3)
d
7.19 (d, 2H,
J¼8.4 Hz), 6.81e6.77 (m, 4H), 6.49e6.45 (m, 2H), 4.12 (s, 2H), 3.78
(br s, 1H), 3.71 (s, 3H); 13C NMR (100 MHz, CDCl3)
159.0, 157.1,
4.2.8. N-(4-Methoxybenzyl)benzenamine (8).12 Yellow oil; 1H NMR
d
(400 MHz, CDCl3)
(d, 2H, J¼8.4 Hz), 6.63 (t, 1H, J¼7.6 Hz), 6.55 (d, 2H, J¼7.6 Hz), 4.47
(s, 1H), 4.16 (s, 2H), 3.71 (s, 3H); 13C NMR (100 MHz, CDCl3)
159.0,
148.3, 131.5, 129.4, 128.9, 117.6, 114.1, 113.0, 55.4, 47.9. IR (neat,
cmꢀ1): 3419, 3003, 2932, 2837, 1934, 1604, 1508, 1303, 1248, 1173,
1033, 815, 753, 694; Anal. Calcd (%) for C14H15NO: C, 78.84; H, 7.09;
N, 6.57. Found: C, 78.59; H, 6.88; N, 6.33.
d
7.20 (d, 2H, J¼8.4 Hz), 7.09 (t, 2H, J¼7.6 Hz), 6.79
154.8, 144.7, 144.7, 131.3, 128.9, 115.9, 115.6, 114.2, 113.8, 113.7, 55.4,
48.5; IR (KBr, cmꢀ1): 3402, 1610, 1508, 1245, 1204, 1174, 1029, 820,
741; Anal. Calcd for C14H14FNO: C, 72.71; H, 6.10; N, 6.06. Found: C,
72.44; H, 6.15; N, 5.89.
d
4.2.16. 4-Methoxy-N-(4-methoxybenzyl)benzenamine (16).8a White
crystalline solid. Mp 91e93 ꢁC. 1H NMR (400 MHz, CDCl3)
d 7.25 (d,
2H, J¼8.8 Hz), 6.84 (d, 2H, J¼8.8 Hz), 6.74 (d, 2H, J¼8.8 Hz), 6.57 (d,
4.2.9. N-((4-Methylthio)benzyl)benzenamine (9).12 Yellow oil; 1H
2H, J¼8.8 Hz), 4.58 (s, 1H), 4.17 (s, 2H), 3.76 (s, 3H), 3.70 (s, 3H); 13
C
NMR (400 MHz, CDCl3)
d
7.38 (d, 2H, J¼8.4 Hz), 7.32 (d, 2H,
NMR (100 MHz, CDCl3) d 158.9, 152.3, 142.6, 131.8, 128.9, 115.0,
J¼8.4 Hz), 7.26 (t, 2H, J¼7.6 Hz), 6.81 (t, 1H, J¼7.6 Hz), 6.71 (d, 2H,
114.2, 114.1, 55.9, 55.4, 48.8; IR (KBr, cmꢀ1): 3373, 2925, 1611, 1513,
1248, 1032, 821; Anal. Calcd (%) for C15H17NO2: C, 74.05; H, 7.04; N,
5.76. Found: C, 73.89; H, 6.90; N, 5.67.
J¼7.6 Hz), 4.38 (s, 2H), 4.09 (br s, 1H), 2.56 (s, 3H); 13C NMR
(100 MHz, CDCl3) d 148.2,137.3,136.5,129.4,128.1,127.1,117.8,113.0,
48.0, 16.1; IR (neat, cmꢀ1): 3350, 2963, 1602, 1505, 1261, 1099, 1015,
806, 750, 694; Anal. Calcd for C14H15NS: C, 73.32; H, 6.59; N, 6.11; S,
13.98. Found: C, 73.03; H, 6.32; N, 5.87; S, 13.59.
4.2.17. 2-((4-Methoxybenzyl)amino)phenol (17).12 Brown solid; mp
117e119 ꢁC; 1H NMR (400 MHz, CDCl3)
d
7.30 (d, 2H, J¼8.4 Hz),
6.89e6.82 (m, 3H), 6.74e6.63 (m, 3H), 4.81 (br s, 1H), 4.27 (s, 2H),
4.19 (br s,1H), 3.81 (s, 3H); 13C NMR (100 MHz, CDCl3)
159.0,143.7,
4.2.10. N-(4-((Phenylamino)methyl)phenyl)acetamide (10).12 Yellow
d
solid; mp 126e128 ꢁC; 1H NMR (400 MHz, CDCl3)
d
7.39 (d, 2H,
137.1, 131.6, 129.0, 121.8, 117.9, 114.4, 114.1, 112.7, 55.4, 48.2; IR (KBr,
cmꢀ1): 3396, 3335, 1610, 1512, 1248, 1174, 1111, 1029, 824, 748. Anal.
Calcd for C14H15NO2: C, 73.34; H, 6.59; N, 6.11. Found: C, 73.02; H,
6.28; N, 6.07.
J¼8.4 Hz), 7.24 (d, 2H, J¼8.4 Hz), 7.09 (t, 2H, J¼7.6 Hz), 6.64 (t, 1H,
J¼7.6 Hz), 6.55 (d, 2H, J¼7.6 Hz), 4.21 (s, 2H), 3.94 (br s, 1H), 2.09 (s,
3H); 13C NMR (100 MHz, CDCl3)
d 168.4, 148.2, 137.0, 135.6, 129.4,
128.2,120.3,117.7,113.0, 48.0, 24.7; IR (KBr, cmꢀ1): 3427, 3301,1663,
1603, 1512, 1316, 746; Anal. Calcd for C15H16N2O: C, 74.97; H, 6.71;
N, 11.66. Found: C, 74.67; H, 6.62; N, 11.34.
4.2.18. N-Methyl-N-(4-(trifluoromethyl)benzyl)benzenamine
(18).12 Orange oil. 1H NMR (400 MHz, CDCl3)
d 7.57 (d, 2H,
J¼10.8 Hz), 7.35 (d, 2H, J¼10.8 Hz), 7.22 (d, 2H, J¼9.6 Hz), 6.74 (t, 3H,
4.2.11. N-(Cinnamyl)benzenamine (11).19 Yellow oil; 1H NMR
J¼9.6 Hz), 4.58 (s, 2H), 3.04 (s, 3H); 13C NMR (100 MHz, CDCl3)
(400 MHz, CDCl3)
d
7.42 (d, 2H, J¼7.2 Hz), 7.36 (t, 2H, J¼8.0, 7.2 Hz),
d 149.6, 143.5, 129.4, 127.1, 127.0, 125.7, 125.6, 117.2, 112.6, 56.6, 38.8;
7.30e7.23 (m, 3H), 6.79 (t, 1H, J¼7.6, 7.2 Hz), 6.73e6.65 (m, 3H),
IR (neat, cmꢀ1): 1600, 1507, 1326, 1163, 1122, 1066, 1017, 935, 822,
750, 692; Anal. Calcd for C15H14F3N: C, 67.91; H, 5.32; N, 5.28.
Found: C, 67.56; H, 5.39; N, 4.98.
6.41e6.34 (m, 1H), 3.98 (dd, 2H, J¼1.2, 5.6 Hz), 3.88 (br s, 1H); 13C
NMR (100 MHz, CDCl3) d 148.1, 136.9, 131.6, 129.4, 128.7, 127.6, 127.1,
126.4, 117.7, 113.1, 46.3. IR (neat, cmꢀ1): IR (neat, cmꢀ1): 3415, 3052,
3023, 2918, 2834, 1601, 1504, 1317, 966, 747, 691; Anal. Calcd (%) for
4.2.19. N-Methyl-N-(4-(methylthio)benzyl)benzenamine
C
14H13N: C, 86.12; H, 6.71; N, 7.17. Found: C, 86.01; H, 6.52; N, 6.98.
(19).12 Orange oil. 1H NMR (400 MHz, CDCl3)
d
7.23e7.13 (m, 6H),
6.75e6.68 (m, 3H), 4.47 (s, 2H), 2.98 (s, 3H), 2.45 (s, 3H); 13C NMR
4.2.12. N-((Ferrocenyl)methyl)benzenamine (12).12 Red solid; mp
(100 MHz, CDCl3)
d 149.8, 136.8, 136.2, 129.3, 127.5, 127.2, 116.7,
79e80 ꢁC; 1H NMR (400 MHz, CDCl3)
d
7.22 (t, 2H, J¼7.6 Hz), 6.74 (t,
112.5, 56.3, 38.6, 16.2; IR (neat, cmꢀ1): 1599, 1507, 1372, 1213, 1116,
800, 749, 692; Anal. Calcd for C15H17NS: C, 74.03; H, 7.04; N, 5.76; S,
13.18. Found: C, 73.70; H, 6.77; N, 5.62; S, 12.81.
1H, J¼7.6 Hz), 6.68 (d, 2H, J¼7.6 Hz), 4.26 (s, 2H), 4.20 (s, 5H), 4.16
(br s, 2H), 4.10 (br s, 1H), 3.97 (s, 2H); 13C NMR (100 MHz, CDCl3)
d
148.4,129.4,117.7,113.0, 86.6, 68.6, 68.2, 68.0, 43.5; IR (KBr, cmꢀ1):
3401, 2923, 2853, 1605, 1505, 1105, 808, 748, 693, 486; Anal. Calcd
for C17H17FeN: C, 70.12; H, 5.88; N, 4.81. Found: C, 69.87; H, 5.61; N,
4.63.
4.2.20. 2-Methoxy-4-((methyl(phenyl)amino)methyl)phenol
(20).12 Orange oil; 1H NMR (400 MHz, CDCl3)
d
7.26 (t, 2H, J¼8.0,
8.4 Hz), 6.89 (d, 1H, J¼8.4 Hz), 6.82e6.74 (m, 5H), 5.56 (br s, 1H),
4.47 (s, 2H), 3.85 (s, 3H), 3.00 (s, 3H); 13C NMR (100 MHz, CDCl3)
4.2.13. 4-Bromo-N-(4-methoxybenzyl)benzenamine (13).12 White
d 150.2, 146.8, 144.6, 131.0, 129.3, 119.8, 116.9, 114.4, 112.8, 109.4,
solid; mp 62e64 ꢁC; 1H NMR (400 MHz, CDCl3)
d
7.22 (t, 4H,
56.8, 56.0, 38.4; IR (neat, cmꢀ1): 3507, 1599, 1506, 1373, 1270, 1120,
1034, 750, 693; Anal. Calcd for C15H17NO2: C, 74.05; H, 7.04; N, 5.76.
Found: C, 73.82; H, 6.78; N, 5.41.
J¼8.8 Hz), 6.85 (d, 2H, J¼8.8 Hz), 6.46 (d, 2H, J¼8.8 Hz), 4.18 (s, 2H),
3.95 (br s,1H), 3.77 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 159.0,147.2,
132.0, 130.9, 128.8, 114.5, 114.2, 109.1, 55.4, 47.8; IR (KBr, cmꢀ1):
3402, 1591, 1514, 1494, 1255, 1244, 1031, 814; Anal. Calcd for
4.2.21. N-Benzyl-N-methylbenzenamine (21).12 Colorless oil; 1H NMR
C
4.47.
14H14BrNO: C, 57.55; H, 4.83; N, 4.79. Found: C, 57.31; H, 4.52; N,
(400 MHz, CDCl3) d 7.28e7.16 (m, 7H), 6.72e6.66 (m, 3H), 4.47 (s,
2H), 2.95 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 149.8, 139.1, 129.3,
128.6, 126.9, 126.8, 116.6, 112.4, 56.7, 38.5; IR (neat, cmꢀ1): 1599,
1506,1452,1355,1214,1118, 749, 729, 692; Anal. Calcd for C14H15N: C,
85.24; H, 7.66; N, 7.10. Found: C, 84.98; H, 7.38; N, 6.88.
4.2.14. 4-Chloro-N-(4-methoxybenzyl)benzenamine (14).2d White
solid, mp 78e81 ꢁC. 1H NMR (400 MHz, CDCl3)
d 7.27 (d, 2H,
J¼8.8 Hz), 7.12 (d, 2H, J¼8.8 Hz), 6.89 (d, 2H, J¼8.4 Hz), 6.54 (d, 2H,
J¼8.4 Hz), 4.22 (s, 2H), 3.98 (br s, 1H), 3.81 (s, 3H); 13C NMR
4.2.22. N-(4-Bromobenzyl)-N-methylbenzenamine (22).12 Colorless
(100 MHz, CDCl3)
d
159.0, 146.8, 131.0, 129.1, 128.8, 122.0, 114.1,
oil; 1H NMR (400 MHz, CDCl3)
d
7.40 (d, 2H, J¼8.4 Hz), 7.19 (t, 2H,

9154
J.R. Bernardo et al. / Tetrahedron 69 (2013) 9145e9154
J¼8.0 Hz), 7.08 (d, 2H, J¼8.4 Hz), 6.72e6.69 (m, 3H), 4.44 (s, 2H),
BD/63471/2009), J.R.B. (SFRH/BD/90659/2012), and P.R.F. thank FCT
for grants. M.W. (DEC-2011/03/N/ST5/04522) thanks the Polish
National Science Centre for grant. Authors thank the project PEst-
OE/QUI/UI0100/2013 and the Portuguese NMR Network (IST-UTL
Center) for providing access to the NMR facilities.
2.97 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 149.6, 138.2, 131.8, 129.4,
128.6, 120.7, 117.0, 112.6, 56.4, 38.7; IR (neat, cmꢀ1): 1599, 1507, 748,
692; Anal. Calcd for C14H14BrN: C, 60.89; H, 5.11; N, 5.07. Found: C,
60.54; H, 4.89; N, 4.77.
4.2.23. N-((Furan-2-yl)methyl)-N-methylbenzenamine (23). Yellow
References and notes
oil. 1H NMR (400 MHz, CDCl3)
d
7.26 (s, 1H), 7.16 (t, J¼7.5, 7.8 Hz,
1. (a) Xing, L.; Chen, C.; Zhu, R.; Zhang, B.; Wang, X.; Hu, Y. Tetrahedron 2008, 64,
11783e11788; (b) Imao, D.; Fujihara, S.; Yamamoto, T.; Ohta, T.; Ito, Y. Tetrahe-
dron 2005, 61, 6988e6992.
2. (a) Kumar, N. U.; Reddy, B. S.; Reddy, V. P.; Bandichhor, R. Tetrahedron Lett. 2012,
53, 4354e4356; (b) Lokhande, R.; Sonawane, J.; Roy, A.; Ravishankar, L. Green
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Tetrahedron Lett. 2008, 49, 6682e6684; (d) Reddy, P. S.; Kanjilal, S.; Sunitha, S.;
Prasad, R. B. N. Tetrahedron Lett. 2007, 48, 8807e8810; (e) Heydari, A.; Khaksar,
S.; Akbari, J.; Esfandyari, M.; Pourayoubi, M.; Tajbakhsh, M. Tetrahedron Lett.
2007, 48, 1135e1138.
2H), 6.75 (d, 2H, J¼8.3 Hz), 6.67 (t, 1H, J¼7.3, J¼7.2 Hz), 6.21 (br s,
1H), 6.05 (d, 1H, J¼1.7 Hz), 4.37 (s, 2H), 2.90 (s, 3H). 13C NMR
(100 MHz, CDCl3)
d 152.9, 149.9, 142.3, 129.6, 117.6, 113.6, 110.7,
107.7, 50.3, 38.8. IR (neat, cmꢀ1): 2926, 1600, 1506, 1367, 1346, 1195,
1147, 1013, 994, 930, 748, 691, 599. Anal. Calcd for C12H13NO: C,
76.98; H, 7.00; N, 7.48. Found: C, 76.73; H, 6.79; N, 7.33.
4.2.24. N-(4-Methoxybenzyl)-N-methylbenzenamine (24).6a Light
3. Lane, C. F. Synthesis 1975, 135e146.
yellow oil; 1H NMR (400 MHz, CDCl3)
d
7.21e7.17 (m, 2H), 7.12 (d,
2H, J¼8.8 Hz), 6.82 (d, 2H, J¼8.8 Hz), 6.74e6.66 (m, 3H), 4.43 (s, 2H),
3.75 (s, 3H), 2.95 (s, 3H); 13C NMR (100 MHz, CDCl3)
158.7, 149.9,
4. (a) Gutierrez, C. D.; Bavetsias, V.; McDonald, E. Tetrahedron Lett. 2005, 46,
3595e3597; (b) Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C. A.;
Shah, R. D. J. Org. Chem. 1996, 61, 3849e3862.
5. Bomann, M. D.; Guch, I. C.; DiMare, M. J. Org. Chem. 1995, 60, 5995e5996.
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(b) Lee, O.-Y.; Law, K.-L.; Yang, D. Org. Lett. 2009, 11, 3302e3305.
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8. (a) Apodaca, R.; Ziao, W. Org. Lett. 2001, 3, 1745e1748; (b) Kangasmetsa, J. J.;
Johnson, T. Org. Lett. 2005, 7, 5653e5655.
d
131.0, 129.3, 128.1, 116.6, 114.1, 112.6, 56.2, 55.4, 38.4; IR (neat,
cmꢀ1): 3419, 2932, 2834, 1600, 1510, 1246, 1035, 748, 692; Anal.
Calcd (%) for C15H17NO: C, 79.26; H, 7.54; N, 6.16. Found: C, 79.08; H,
7.42; N, 6.07.
9. Smith, C. A.; Cross, L. E.; Hughes, K.; Davis, R. E.; Judd, D. B.; Merritt, A. T.
Tetrahedron Lett. 2009, 50, 4906e4911.
10. Chandrasekhar, S.; Reddy, C. R.; Ahmed, M. Synlett 2000, 1655e1657.
11. Enthaler, S. ChemCatChem 2010, 2, 1411e1415.
4.2.25. N-Methyl-N-(pyridin-2-ylmethyl)benzenamine (25). Orange
oil; 1H NMR (300 MHz, CDCl3)
d
8.61 (d, 1H, J¼4.7 Hz), m (1H,
7.64e7.59), 7.28e7.16 (m, 4H), 6.76e6.73 (m, 3H), 4.68 (s, 2H), 3.14
12. Sousa, S. C. A.; Fernandes, A. C. Adv. Synth. Catal. 2010, 352, 2218e2226.
13. Das, B. G.; Ghorai, P. Chem. Commun. 2012, 8276e8278.
14. (a) Sousa, S. C. A.; Cabrita, I.; Fernandes, A. C. Chem. Soc. Rev. 2012, 41,
5641e5653; (b) De Noronha, R. G.; Fernandes, A. C. Curr. Org. Chem. 2012, 16,
33e64.
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18. Machura, B.; Wolff, M.; Kusz, J.; Kruszynski, R. Polyhedron 2009, 28, 2949e2964.
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3363e3366.
(m, 3H); 13C NMR (75 MHz, CDCl3)
d 159.7, 149.8, 149.6, 137.2, 129.6,
122.3,121.1,117.0,112.6, 59.1, 39.4; IR (neat, cmꢀ1): 2924,1604,1587,
1569, 1508, 1470, 1436, 1345, 1241, 1191, 765, 757, 695; Anal. Calcd
(%) for C13H14N2: C, 78.75; H, 7.12; N, 14.13. Found: C, 78.51; H, 6.98;
N, 13.99.
Acknowledgements
20. Zhang, M.; Yang, H.; Zhang, Y.; Zhu, C.; Li, W.; Cheng, Y.; Hu, H. Chem. Commun.
2011, 6605e6607.
21. Lai, R.-Y.; Lee, C.-I.; Liu, S.-T. Tetrahedron 2008, 64, 1213e1217.
This research was supported by FCT through projects PTDC/QUI-
QUI/110080/2009 and PTDC/QUI-QUI/110532/2009. S.C.A.S. (SFRH/