Manganese-catalyzed cross-coupling reactions of aliphatic amines with aryl halides

Article abstract of DOI:10.1016/j.tetlet.2010.05.098

An efficient and convenient protocol has been developed for the N-arylation of aliphatic amines with differently substituted aryl halides using a MnCl₂·4H₂O/l-proline catalyst and NaOt-Bu as the base in DMSO.

Full text of DOI:10.1016/j.tetlet.2010.05.098

Tetrahedron Letters 51 (2010) 3910–3912
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Manganese-catalyzed cross-coupling reactions of aliphatic amines
with aryl halides
*
Fui-Fong Yong, Yong-Chua Teo
Natural Sciences and Science Education, National Institute of Education, Nanyang Technological University, 1 Nanyang Walk, Singapore 637616, Singapore
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 23 March 2010
Revised 4 May 2010
Accepted 21 May 2010
Available online 27 May 2010
An efficient and convenient protocol has been developed for the N-arylation of aliphatic amines with
differently substituted aryl halides using a MnCl2Á4H2O/
L
-proline catalyst and NaOt-Bu as the base in
DMSO.
Ó 2010 Elsevier Ltd. All rights reserved.
The aliphatic amination of aryl halides is an important and fre-
quently employed reaction for the synthesis of organic compounds
containing the N-aryl moiety, which are present in many bioactive
pharmaceuticals and conducting materials.1
the reaction. The best assisting ligand was found to be L-proline
in combination with MnCl2Á4H2O, which gave the product in a
Table 1
The most widely employed methods for such carbon–nitrogen
bond-forming processes have been realized using copper,2 palla-
dium3 and nickel4 metal salts, and high yields can be attained in
most instances. In the past decade, promising strategies involving
the use of iron salts have also emerged as alternatives to perform
transition metal-mediated C–N cross-coupling reactions. Bolm and
Correa reported a ligand-assisted direct FeCl3/DMEDA-catalytic sys-
tem for the arylation of various nitrogen nucleophiles5 and
Optimization studies on the manganese-catalyzed cross-coupling of iodobenzene and
morpholinea
[Mn] (5 mol%)
O
ligand (10 mol%)
+
PhI
O
N
base
N
H
solvent, 135 oC, 24 h
1a
sulfoximines,6 while Guo et al. described an efficient Fe2O3/
L-pro-
line-catalyzed N-arylation of various amines.7 Although significant
progress has been made on the aforementioned transformation,
there still remains a need to develop new catalytic systems that
are cheap and environmentally safe.
Me2N
NHMe
NMe2
COOH MeHN
N
H
H2N
NH2
L2 = L-Proline
L4 = TMEDA
L1 = trans-1,2-diamino
L3 = DMEDA
cyclohexane
Recently, our group developed an efficient protocol for the
cross-coupling reaction of azoles with substituted aryl iodides in
water using a combination of MnCl2Á4H2O and trans-1,2-diamino-
cyclohexane as the catalytic system.8 Encouraged by these prece-
dents and to expand our interest in manganese catalysis, we
envisaged the application of manganese salts for the N-arylation
Entry
[Mn] source
Ligand
Base
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
MnCl2Á4H2O
MnCl2Á4H2O
MnCl2Á4H2O
MnCl2Á4H2O
MnCl2Á4H2O
MnCl2Á4H2O
MnCl2Á4H2O
MnCl2Á4H2O
MnCl2Á4H2O
MnCl2Á4H2O
Mn(ClO4)ÁH2O
Mn(acac)2
MnF2
L1
L2
L3
L4
L2
L2
L2
L2
L2
L2
L2
L2
L2
L2
L2
NaOt-Bu
NaOt-Bu
NaOt-Bu
NaOt-Bu
Cs2CO3
K2CO3
KOt-Bu
K3PO4
NaOt-Bu
NaOt-Bu
NaOt-Bu
NaOt-Bu
NaOt-Bu
NaOt-Bu
NaOt-Bu
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
Toluene
DMSO
DMSO
DMSO
DMSO
DMSO
37
72
55
67
Trace
Trace
22
Trace
Trace
0
of aliphatic amines. Herein, we report MnCl2Á4H2O/
L-proline as
an inexpensive and readily available catalyst system using NaOt-
Bu as the base to prepare N-arylated aliphatic amines.
In our initial study, the reaction between iodobenzene and mor-
pholine was chosen as a model system for optimizing the reaction
conditions. The reaction carried out using a combination of
MnCl2Á4H2O, trans-1,2-diaminocyclohexane and NaOt-Bu in DMSO
gave the product in a moderate yield of 37% (Table 1, entry 1). This
prompted us to evaluate further the merits of various ligands for
60
58
67
60
Mn(OAc)2
—
50
a
The reaction was carried out with morpholine (1.47 mmol), iodobenzene
(2.94 mmol), base (2.94 mmol), [Mn] source (5 mol %), ligand (10 mol %), solvent
(0.75 mL) at 135 °C for 24 h.
* Corresponding author. Tel.: +65 6790 3846; fax: +65 6896 9414.
E-mail address: yongchua.teo@nie.edu.sg (Y.-C. Teo).
b
Isolated yield after column chromatography.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.05.098

F.-F. Yong, Y.-C. Teo / Tetrahedron Letters 51 (2010) 3910–3912
3911
a
Table 2
The reaction was carried out with morpholine (1.47 mmol), aryl halide
N-Arylation of morpholine with various aryl halides catalyzed by MnCl2Á4H2O/
(2.94 mmol), NaOt-Bu (2.94 mmol), MnCl2Á4H2O (5 mol %),
L-proline (10 mol %),
L-prolinea
DMSO (0.75 mL) at 135 °C for 24 h.
b
Isolated yield after column chromatography.
Not isolated.
MnCl2·4H2O (5 mol%)
c
L
-proline (10 mol%)
O
O
N
Ar
+
ArX
NaOt-Bu (2.0 equiv)
DMSO, 135 oC, 24 h
N
H
good yield of 72% in DMSO (Table 1, entry 2). Next, we screened
various bases and preliminary results showed that NaOt-Bu was
the base of choice for this coupling reaction. Coupling reactions
using Cs2CO3, K2CO3, KOt-Bu and K3PO4 were shown to be less,
or not effective (Table 1, entries 5–8). Next, we probed the solvent
effect and found that DMSO was the only solvent that proved to be
effective for this coupling. Reactions in DMF and toluene gave only
traces, or none of the product, respectively (Table 1, entries 9 and
10). Finally, we evaluated the efficiency of a series of manganese
salts for the arylation reaction. The products were obtained in
moderate to good yields ranging from 58% to 67% when Mn(acac)2,
Mn(ClO4)ÁH2O, MnF2 and Mn(OAc)2 were used as the metal catalyst
(Table 1, entries 11–14). Thus, the optimum conditions for the
N-arylation of morpholine involved a combination of MnCl2Á4H2O9
Entry ArX
Product
Yieldb (%)
72
1
2
I
O
O
O
N
N
N
1a
MeO
OMe
1b (m) 16
I
Cl
Cl
3
4
Tracec
I
I
1c (m)
1d (p)
Me
Me
O
O
N
N
(5 mol %), L-proline (L2, 10 mol %) and NaOt-Bu (2 equiv), in DMSO
60
at 135 °C for 24 h. Control experiments performed without the Mn
source gave the product in moderate yield only (Table 1, entry 15).
Having determined the optimized conditions for the manga-
nese-catalyzed arylation, a study was initiated to explore the gen-
erality of the reaction of a variety of substituted aryl halides with
morpholine (Table 2). In general, ortho-substituted aryl halides
gave poor yields regardless of the electronic nature of the substitu-
ent (Table 2, entries 2 and 3) while moderate to good yields were
obtained for sterically unhindered aryl halides (Table 2, entries
4–10). It is noteworthy that aryl bromides were shown to be reac-
tive and gave good yields under these catalytic conditions (Table 2,
entries 11–13).
Me
m:p = 1.5:1
Cl
Cl
5
6
1e (m) 43
O
O
N
I
CF3
CF3
1f (m)
45
70
I
I
N
1b (m)
1g (p)
OMe
OMe
O
O
N
N
7
8
9
Interestingly, cine substitution effects could be observed in the
products shown in Table 2. The ortho-substituted aryl halides affor-
OMe
m:p = 1:1
F
1h (m)
1i (p)
Table 3
I
I
F
N-Arylation of amines with iodobenzene catalyzed by MnCl2Á4H2O/L-prolinea
O
O
N
N
Entry
1
Amine
Product
Yield (%)b
56
73
F
NH2
2a
2b
2c
2d
50
m:p 1:1
N
H
1e (m)
1j (p)
Cl
Cl
O
NH2
O
O
N
2
3
4
45
40
49
O
N
H
N
Cl
m:p = 1:2
NH2
N
H
O
O
N
CF3
10
11
I
CF3
1k (p)
43
70
H
N
NH2
Br
N
1a
OMe
OMe
1b (m)
1g (p)
NH2
NH
O
O
N
Br
Br
5
6
7
2e
2f
50
80
22
12
13
75
60
N
OMe
NH
N
m:p = 1:1
1b (m)
1g (p)
NH2
OMe
OMe
2g
N
H
O
O
N
N
OMe
a
The reaction was carried out with amine (1.47 mmol), iodobenzene
(2.94 mmol), NaOt-Bu (2.94 mmol), MnCl2Á4H2O (5 mol %),
L-proline (10 mol %),
m:p = 1:1
DMSO (0.75 mL) at 135 °C for 24 h.
b
Isolated yield after column chromatography.

3912
F.-F. Yong, Y.-C. Teo / Tetrahedron Letters 51 (2010) 3910–3912
ded only meta-amination products due to steric reasons, while the
para-substituted aryl halides gave a mixture of meta- and para-
amination products perhaps via a benzyne intermediate. However,
in the case of meta-substituted aryl halides, the observed cine sub-
stitution effects were less pronounced (Table 2, entries 5 and 6).
This effect was also described in the report by Guo et al.7
Finally, the scope of the manganese-catalyzed cross-coupling
reaction was investigated with respect to iodobenzene. As revealed
by the data in Table 3, several amine substrates were arylated
under these manganese catalytic conditions.
Both linear and branched alkyl primary amines afforded the
expected products in moderate yields ranging from 45% to 50%
(Table 3, entries 1–4). The arylation of a representative cyclic pri-
mary amine, cyclohexylamine, gave the arylated product in 50%
yield (Table 3, entry 5) while pyrrolidine gave an excellent 80%
yield of product (Table 3, entry 6). Although satisfactory results
were obtained in the case of primary amines, a poor coupling yield
was obtained with benzylamine (Table 3, entry 7).
Supplementary data
Supplementary data (experimental procedures and compound
characterization data) associated with this article can be found,
in the online version, at doi:10.1016/j.tetlet.2010.05.098.
References and notes
1. For general reviews, see: (a) Buchwald, S. L.; Jiang, L. In Metal-Catalyzed Cross-
Coupling Reactions; Meijere, D., Diederich, A., Eds.; Wiley-VCH: Weinheim, 2004;
Vol. 2, p 699; (b) Beletskaya, I. P.; Cheprakov, A. V. Coord. Chem. Rev. 2004, 248,
2337; (c) Beccalli, E. M.; Broggini, G.; Martinelli, M.; Sottocornola, S. Chem. Rev.
2007, 107, 5318; (d) Corbert, J. P.; Mignani, G. Chem. Rev. 2006, 106, 2651; (e)
Hartwig, J. F. Nature 2009, 455, 314.
2. For representative papers on copper-mediated Ullmann aliphatic aminations,
see: (a) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400; (b) Lu, Z.;
Twieg, R. J.; Huang, S. Tetrahedron Lett. 2003, 44, 6289; (c) Ma, D.; Cai, Q.; Zhang,
H. Org. Lett. 2003, 5, 2453; (d) Okano, K.; Tokuyama, H.; Fukuyama, T. Org. Lett.
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(f) Rout, L.; Jammi, S.; Punniyamurthy, T. Org. Lett. 2007, 9, 3397; (g) Chen, S.;
Huang, H.; Liu, X.; Shen, J.; Jiang, H.; Liu, H. J. Comb. Chem. 2008, 10, 358.
3. For representative papers on palladium-mediated C–N bond formation, see: (a)
Hartwig, J. F. Angew. Chem., Int. Ed. 1998, 37, 2046; (b) Barluenga, J.; Aznar, F.;
Valdes, C. Angew. Chem., Int. Ed. 2004, 43, 343; (c) Wagaw, S.; Buchwald, S. L. J.
Org. Chem. 1996, 61, 7240; (d) Buchwald, S. L.; Mauger, C.; Mignani, G.; Scholz, U.
Adv. Synth. Catal. 2006, 348, 23; (e) Anderson, K. W.; Tundel, R. E.; Ikawa, T.;
Altman, R. A.; Buchwald, S. L. Angew. Chem., Int. Ed. 2006, 45, 6523.
4. For representative papers on nickel-mediated C–N bond formation, see: (a)
Manolikakes, G.; Gavryushin, A.; Knochel, P. J. Org. Chem. 2008, 73, 1429; (b)
Gao, C.-Y.; Yang, L.-M. J. Org. Chem. 2008, 73, 1624.
In summary, a convenient and promising route to N-arylated
aliphatic amines using a ligand-assisted manganese catalytic sys-
tem has been developed. The use of a low cost and readily available
Mn salt, the ligand L-proline, and the practical nature of the proto-
col render this transformation an attractive coupling strategy. Fur-
ther investigation to broaden Mn catalysis as a sustainable method
for other cross-coupling reactions is ongoing.
5. Correa, A.; Bolm, C. Angew. Chem., Int. Ed. 2007, 46, 8862.
6. Correa, A.; Bolm, C. Adv. Synth. Catal. 2008, 350, 391.
7. Guo, D.; He, H.; Xu, J.; Jiang, H.; Liu, H. Org. Lett. 2008, 10, 4513.
8. Teo, Y.-C.; Yong, F.-F.; Poh, C.-Y.; Yan, Y.-K.; Chua, G.-L. Chem. Commun. 2009, 6258.
9. The reaction was carried out with high purity MnCl2Á4H2O (99.99% Sigma) under
the optimized reaction conditions to afford the product in a good yield of 68%.
This excluded the participation of Cu and other metal contaminants that might
be present in the Mn salt.
Acknowledgement
We thank the National Institute of Education and Nanyang
Technological University for their generous support.