Amination of electron deficient aryl chlorides promoted by nano sized Mg(OH)2 under transition metals free condition

Article abstract of DOI:10.1016/j.cclet.2011.11.009

This paper presents the amination reactions of electron deficient aryl chlorides promoted by Mg(OH)₂ without transition metals. Only using stoichiometric amount of nano sized Mg(OH)₂, good to moderate isolated yields could be achieved in N-methylpyrrolidone (NMP) after 24 h at 150 °C.

Full text of DOI:10.1016/j.cclet.2011.11.009

Available online at www.sciencedirect.com
Chinese Chemical Letters 23 (2012) 137–140
www.elsevier.com/locate/cclet
Amination of electron deficient aryl chlorides promoted by
nano sized Mg(OH)2 under transition metals free condition
Zhi Hao Cui, Zi Hui Meng, Yan Qing Mi, Peng Wang, Qi Wang,
*
Lin Man Zhao, Ke Jian Cui, Fang Yu, Zhi Bin Xu
Department of Applied Chemistry and Pharmaceuticals, Beijing Institute of Technology, Beijing 100081, China
Received 7 July 2011
Available online 22 December 2011
Abstract
This paper presents the amination reactions of electron deficient aryl chlorides promoted by Mg(OH)2 without transition metals.
Only using stoichiometric amount of nano sized Mg(OH)2, good to moderate isolated yields could be achieved in N-methylpyr-
rolidone (NMP) after 24 h at 150 8C.
# 2011 Published by Elsevier B.V. on behalf of Chinese Chemical Society.
Keywords: Amination; Electron deficient aryl chloride; Cyclic secondary amines; Nano sized; Magnesium hydroxide
Aromatic amines are important compounds which have been widely applied in biological, pharmaceutical and
material industry [1]. Transition metal-catalyzed carbon–heteroatom bond formation is recognized widely as a
powerful method and has been extensively investigated over the past few decades [2]. Aryl halides can successfully
transform to corresponding aryl amines catalyzed by transition metals such as palladium [3], copper [4], nickel [5],
and cobalt [6] with various ligands through cross coupling reaction. But the expensive transition metals, especially
some sensitive ligands have not widely applied in industry.
On the other hand, to meet the transition metals free amination of aryl halides required by pharmaceutical industry,
both academic and industrial chemists reported their encouraged results in this attractive area [7]. However most of
these alternative procedures still applied aryl iodines (or bromides) as substrates and were carried out under abnormal
conditions such as microwave irradiation and ionic liquids. To our knowledge, a simple and convenient methodology
had been reported recently that a coupling reaction of active aryl chlorides with cyclic secondary amines catalyzed by
stoichiometric amount of LiBr gave high conversation without noble transition metals in a sealed tube at 140 8C using
N-methylpyrrolidone (NMP) as solvent [8].
Herein we report a new method for direct amination of derivatives of 4-chloroacetophenone and cyclic secondary
amines with good to moderate isolated yields under transition metals free condition (Scheme 1).
* Corresponding author.
E-mail address: zbxu@bit.edu.cn (Z.B. Xu).
1001-8417/$ – see front matter # 2011 Published by Elsevier B.V. on behalf of Chinese Chemical Society.
doi:10.1016/j.cclet.2011.11.009

138
Z.H. Cui et al. / Chinese Chemical Letters 23 (2012) 137–140
O
R
Mg(OH)
o
O
R
2
N
X
n
+
HN
X
n
Cl
150 C, 24hours
NMP
R'
R'
R=CH , C H
R'=H, Cl
3
6
5
X=CH , O
2
n=0, 1
Scheme 1. Amination of derivatives of 4-chloroacetophenone and cyclic secondary amines.
1. Results and discussion
It was found occasionally in our lab that the coupling reaction of 4-chloroacetophenone with piperidine could gave
low isolated yield (39%) using magnesium hydroxide (3.0 eq.) in NMP at 150 8C. Encouraged by this result, the
conditions were screened in order to improve the yields of this reaction (Table 1). Because the yield increased
dramatically with the increasing amount of magnesium hydroxide, improvement of the solubility of Mg(OH)2 may be
in favour of this reaction. But the addition of phase transition catalyst such as PEG-600 and n-Bu4NI did not lead to
efficient augment as expected. With high surface of areas combined with unusual reactivity, nanomaterials are playing
a significant role in chemistry. So the nano sized Mg(OH)2 was adopted and the amount was reduced to stoichiometry.
Known as a basic solvent in several coupling reactions, NMP is more suitable solvent than DMF and DMSO in this
reaction. On the other hand, reaction temperature and time were screened and the results showed that the reaction
could not take place at 120 8C or lower temperature and the yield could not increase obviously in more than 24 h. The
best result was obtained when the piperidine and nano sized Mg(OH)2 were used in 600 mol% and 100 mol%,
respectively. It was speculated that the use of 6 eq. amount of piperidine might be relevant to high reaction
temperature.
It is reported that trace copper compounds in various oxidation states can catalyze the formation of C–N bond [9],
two experiments were carried out and the results showed that the yield is only about 30% using stoichiometric CuI and
CuCl2 at the same conditions. The main reason might be that there is no ligand used in the reaction system.
Table 1
Optimization of reaction condition for the synthesis of 1-(4-(piperidine-1-yl)phenyl)ethanonea.
Mg(OH)2
O
O
HN
Cl
+
N
NMP, 24 hours
Entry
Piperidine (mmol)b
Mg(OH)2 (mmol)b
n-Bu4NI (mmol)b
PEG-600 (mmol)b
Solvent
Temperature (8C)
Yield (%)c
1
2
2
4
6
6
6
6
6
6
6
6
6
6
6
3
–
–
–
–
–
–
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
DMSO
DMF
NMP
NMP
150
150
150
150
150
150
150
150
150
150
150
120
100
39
70
72
90
91
68
75
90
3
–
3
2
–
4
3
–
5
4
–
6
1.1
1.1
1.0d
–
0.5
–
7
1
–
–
–
–
–
–
8
–
e
8
–
–
e
9
3
–
–
e
10
11
12
3
–
–
e
3
–
–
e
3
–
–
a
The reaction was carried out at 150 8C for 24 h.
The amount of the 4-chloroacetophenone is 1 mmol.
b
c
d
e
Yields of isolated product were based on 4-chloroacetophenone.
The nano sized Mg(OH)2 was used.
The product was not detected on TLC.

Z.H. Cui et al. / Chinese Chemical Letters 23 (2012) 137–140
139
Table 2
Amination of derivatives of 4-chloroacetophenone and amines.
Entry
1
Substituted of acetophenone
Amines
Yield (%)
90
Entry
5
Substituted of acetophenone
Amines
Yield (%)
84
O
O
HN
HN
Cl
Cl
2
3
4
75
54
21
6
7
8
69
74
22
O
O
HN
HN
HN
HN
Cl
Cl
O
O
O
O
HN
HN
O
Cl
Cl
Cl
O
Cl
O
Cl
Cl
Derivatives of 4-chloroacetophenone (1 mmol), amines (6.0 mmol), nano sized Mg(OH)2 (1.0 mmol), NMP (2.0 mL). The reaction was carried out
in Schlenk flask with N2 balloon at 150 8C for 24 h.
All yield listed refer to pure isolated products based on 4-chloroacetophenone.
All products were characterized by 1H NMR in CDCl3 and MS (ESI).
To extend the reaction scope, the derivatives of 4-chloroacetophenone and different amines were carried out in this
condition [10]. All products were isolated and purified by silica-gel column and the results were summarized in Table
2. For electron deficient aryl chlorides, such as 4-chloroacetophenone and (4-chlorophenyl)(phenyl)-methanone, the
amination reactions with piperidine, pyrrolidine and morpholine gave moderate to good yields (54À90%). But di-n-
butylamine and cyclohexylamine could not give the corresponding products. It might be correlation with the steric
hinder of acyclic or primary amines. It should also be noted that 5-chloro-1-indanone had no reaction under the same
conditions because of the electron donating effect of methylene.
In conclusion, a transition metal free method for direct amination of derivatives of 4-chloroacetophenone and cyclic
secondary amines has been developed which involves the application of stoichiometric amount of nano sized
Mg(OH)2. Although further work is required to improve the reaction conditions and to expand the reaction scope, the
coupling reaction reported here is already first attempt applying magnesium compounds in the reaction of C–N bond
formation.
References
[1] M. Kosugi, M. Kameyama, T. Migita, Chem. Lett. (1983) 927.
[2] A. Ricci, Modern Amination Methods, Wiley-VCH, Weinheim, 2000.
[3] C. Torborg, M. Beller, Adv. Synth. Catal. 351 (2009) 3027.
[4] (a) X. Zhu, Y. Ma, L. Su, et al. Synthesis (2006) 3955;
(b) B.D. Lange, M.H. Lambers-Verstappen, L. Schmieder-van de Vondovoroort, et al. Synlett (2006) 3105;
(c) R.A. Altman, E.D. Koval, S.L. Buchwald, J. Org. Chem. 72 (2007) 6190;
(d) L. Rout, S. Jammi, T. Punniyamurthy, Org. Lett. 9 (2007) 3397.
[5] (a) R. Omar-Amrani, A. Thomas, E. Brenner, et al. Org. Lett. 5 (2003) 2311;
(b) S. Tasler, B.H. Lipshutz, J. Org. Chem. 68 (2003) 1190.
[6] G. Cahiez, A. Moyeux, Chem. Rev. 110 (2010) 1435.
[7] (a) S. Narayan, T. Seelhammer, R.E. Gawley, Tetrahedron. Lett. 45 (2004) 757;
¨
(b) L. Djakovitch, K. Kohler, J. Am. Soc. Chem. 123 (2001) 5990;
(c) S.N. Gavade, R.S. Balaskar, M.S. Mane, et al. Chin. Chem. Lett. 22 (2011) 292.
¨
[8] W. Kleist, S.S. Prockl, M. Drees, et al. J. Mol. Catal. A: Chem. 303 (2009) 15.

140
Z.H. Cui et al. / Chinese Chemical Letters 23 (2012) 137–140
[9] A. Klapars, X. Huang, S.L. Buchwald, J. Am. Chem. Soc. 124 (2002) 7421.
[10] General procedure: The preparation of 1-(4-(piperidin-1-yl)phenyl)ethanone is representative for all synthesis. 4-Chloroacetophenone
(1.0 mmol), piperidine (6.0 mmol) and nano sized Mg(OH)2 (1.0 mmol) were mixed in NMP (2.0 mL). The reaction was carried out in
Schlenk flask equipped with N2 balloon at 150 8C for 24 h. The mixture was poured into water and extracted with CH2Cl2. The organic layer
was dried over anhydrous MgSO4. The product was purified by silica-gel column and gave orange crystals 0.18 g (yield 90%) [mp 83–85 8C
(lit. Ref. [11]: mp 86–87 8C)]. 1H NMR (500 MHz, CDCl3): d 1.69 (m, 6H, CH2), 2.54 (s, 3H, CH3), 3.38 (m, 4H, CH2), 6.87 (m, 2H, Ar–H),
7.88 (m, 2H, Ar–H). MS-ESI: (m/z) 204 (M+H), 226 (M+Na).
[11] X. Shu, X. Xia, Y. Yang, et al. J. Org. Chem. 74 (2009) 7464.