The N-chlorination of primary amines using FeCl3 and m-CPBA

Article abstract of DOI:10.1246/cl.130883

A simple and effective method for the synthesis of N,Ndichloroamines from primary amines was conducted successfully with m-CPBA as oxidant and FeCl ₃ as chlorine source at 0 °C. Moreover, N,N-dichloroamines could be converted into nitriles or N-chloroimines in good yields.

Full text of DOI:10.1246/cl.130883

CL-130883
Received: September 24, 2013 | Accepted: October 22, 2013 | Web Released: October 30, 2013
The N-Chlorination of Primary Amines Using FeCl3 and m-CPBA
Jia Liu,1,3 Junchao Xu,1,3 Jiangmeng Ren,*1,3 and Bu-Bing Zeng*1,2,3
1Shanghai Key Laboratory of New Drug Design, East China University of Science and Technology,
Shanghai 200237, P. R. China
2Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, P. R. China
3Shanghai Key Laboratory of Chemical Biology, East China University of Science and Technology,
Shanghai 200237, P. R. China
(E-mail: renjm@ecust.edu.cn, zengbb@ecust.edu.cn)
Table 1. Optimization of reaction conditionsa
A simple and effective method for the synthesis of N,N-
dichloroamines from primary amines was conducted success-
fully with m-CPBA as oxidant and FeCl3 as chlorine source at
0 °C. Moreover, N,N-dichloroamines could be converted into
nitriles or N-chloroimines in good yields.
chlorine source, m-CPBA
solvent, 0 °C
NH2
NCl2
1a
2a
Chlorine source
(equiv)
m-CPBA
(equiv)
Yield
/%
Entry
Solvent
N-Chloroamines have made many substantial advances both
in synthetic and mechanistic categories, and the chemistry of
these compounds has experienced considerable developments
since the 1960s.1 They have been employed as potentially
reactive intermediates in organic synthesis.2-7 Previously, the N-
chloroamines were formed through the treatment of amines with
positive chlorine ion which usually came from sodium hypo-
chlorite solution, tert-butyl hypochlorite or N-chlorosuccin-
imide.8-13 N,N-Dichloroamines were also useful intermediates
since they could be easily converted into corresponding nitriles,
N-chloroimines, or carbonyl compounds.14,15 It has been
reported that N,N-dichloroamines can be obtained from primary
amines with trichloroisocyanuric acid (TCCA),14 poly(N,N¤-
N,N,N¤,N¤-tetrachlorobenzene-1,3-disulfonamide (TCBDA).15
However, these N-chlorinating agents are usually used as freshly
prepared and can only be stored for a short period under
atmospheric conditions.14,15 In 2000, a method for the N-
chlorination of amides and carbamates using Oxoneμ and
sodium chloride was reported.16 Herein an alternative oxidation
protocol was developed that could efficiently transform the
primary benzylic or cyclic amines into N,N-dichloroamines with
commercially available m-chloroperbenzoic acid (m-CPBA) as
the oxidant and low-toxicity iron(III) chloride (FeCl3) as the
chlorine source.
1
2
3
4
5
6
7
8
9
10
11
12
13
FeCl3 (0.7)
FeCl3 (1.0)
FeCl3 (1.3)
FeCl3 (0.7)
FeCl2¢4H2O (1.0)
MgCl2 (1.0)
LiCl (1.0)
CuCl2 (1.0)
CuCl (1.0)
FeCl3 (1.0)
FeCl3 (1.0)
FeCl3 (1.0)
FeCl3 (1.0)
2.1
2.1
2.1
2.6
2.1
2.1
2.1
2.1
2.1
2.1
2.1
2.1
2.1
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
90
97
94
91
22
44
21
trace
trace
68
MeCN
toluene
acetone
50
70
trace
dichloro-N-ethylbenzene-1,3-disulfonamide)
(PCBS),15
or
aReaction conditions: benzylamine (1a) (5.0 mmol), solvent
(20 mL), 0 °C, 3 h. Isolated yields.
b
FeCl3 (1.0 equiv),
NCl2
m-CPBA (2.1 equiv)
MeO
CH2Cl2, 0 °C, 3h, 85%
2g
NH2
FeCl3 (1.5 equiv),
m-CPBA (3.1 equiv)
Cl
NCl2
MeO
1g
MeO
CH2Cl2, 0 °C, 48h, 65%
2g'
Figure 1. Substrates-controlled chlorination.
In order to establish suitable reaction conditions for the N-
chlorination, a model reaction of benzylamine (1a) (5 mmol)
with m-CPBA was initially performed. The highest yield could
reach 97% (Table 1, Entry 2) when FeCl3 (1.0 equiv) was used
as chlorine source in CH2Cl2 and the usage of oxidant was
limited due to the trouble-free purifications. Then, further
investigations focused on different chlorine sources and sol-
vents. Replacement of FeCl3 with FeCl2¢4H2O, MgCl2, LiCl,
CuCl2, and CuCl either led to a drop in the yield (Table 1,
Entries 5-7) or gave complex products (Table 1, Entries 8 and
9). Meanwhile, the reactions in THF, MeCN, toluene, and
acetone only provided reduced yields as the reactions gave by-
products (Table 1, Entries 10-13). Precaution must be addressed
that FeCl3 should be added into the reaction mixture before m-
CPBA.
After confirming the optimized reaction conditions, this
protocol was applied to various primary amines to study the
reaction scope and limitations (Table 2). Overall, reactions gave
excellent results in the case of substituted benzylamine
derivatives bearing either electron-withdrawing or electron-
donating groups. What is more, the position of substituent
groups had little influence on the final yields (Entries 1-14). The
surprising result may be attributed to the presence of the
electron-donating substituent (Figure 1). 4-Methoxybenzyl-
amine (1g) could give an unexpected product of 3-chloro-4-
methoxy-N,N-dichlorobenzylamine (2g¤) by increasing the
loading of FeCl3 and m-CPBA. However, these conditions were
not applicable for the chlorination of aromatic compounds
190 | Chem. Lett. 2014, 43, 190–192 | doi:10.1246/cl.130883
© 2014 The Chemical Society of Japan

Cl
Cl
Cl
Cl
Table 2. Oxidative conversion of amines to N,N-dichloro-
NH2
NH2
NCl2
NCl2
aminesa
13
14
95
87
FeCl3, m-CPBA
RNCl2
RNH2
1m
1n
2m
2n
CH2Cl2, 0 °C
2
1
Cl
Cl
Entry
1
Substrate
Product
Yield/%b
NCl2
NCl2
NH2
97
2a
1a
1b
NH2
NH2
NCl2
NCl2
15
87
NH2
Cl
Cl
2
3
4
82
90
96
F
Cl
Br
F
1o
1p
2o
2p
2b
2c
2d
NH2
NH2
NCl2
NCl2
16
17
trace
0
NC
NC
Cl
1c
NH2
NCl2
N
N
Br
1q
2q
1d
NCl2
NH2
NH2
NCl2
NCl2
18
19
75
86
5
6
99
98
1r
2r
NCl2
1e
2e
NH2
NH2
1f
2f
1s
2s
NCl2
NH2
NH2
NCl2
7
8
9
85
80
94
MeO
F
MeO
F
20
21
91
97
1g
2g
NH2
NCl2
NCl2
1t
2t
NCl2
NH2
5
5
1h
1i
2h
1u
2u
F
F
F
F
aReaction conditions: amines
(10.5 mmol), FeCl3 (5 mmol), 0 °C, 3 h. Isolated yields.
1
(5 mmol), m-CPBA
NH2
b
2i
F
F
bearing methoxy groups such as 1,4-dimethoxybenzene and
anisaldehyde, etc. The reaction with α-methylated benzylamine
could also produce the desired product N,N-dichlorobenzyl-
amine (Entry 15). Another exception was found that only a little
desired product of N,N-dichloroamine was formed when 4-
cyanobenzylamine (1p) was used as substrate (Entry 16). And,
the heterocyclic compound 2-picolylamine (1q) remained intact
under these conditions (Entry 17). But, it was interesting that the
cyclic primary amines and alkylamine could also be converted
into the corresponding N,N-dichloroamines in good yields
(Entries 18-21).
NH2
NH2
NCl2
NCl2
10
11
12
89
85
81
F
F
F
F
1j
2j
F
F
1k
2k
F
F
It has been reported that N,N-dichloroamines could undergo
elimination to give the corresponding nitriles or N-chloroimines
in the presence of Et3N.9-11 Therefore, some N,N-dichloro-
amines were selected to treat with Et3N in CH2Cl2. The results
NH2
NCl2
F
F
1l
2l
Chem. Lett. 2014, 43, 190–192 | doi:10.1246/cl.130883
© 2014 The Chemical Society of Japan | 191

Table 3. Reaction of N,N-dichloramines with Et3N
tion on the one-pot procedure leading to benzonitrile (3a) from
benzylamine (1a) was also conducted. Unfortunately, introduc-
ing Et3N directly into the reactions under the optimized
conditions provided a mixture of benzonitrile (3a) and benzal-
dehyde, while there was no significant improvement in CH2Cl2
or DMF. Furthermore, changing the reaction temperature from
0 °C to ambient temperature or 0 to ¹20 °C still afforded similar
results. Therefore, the approach to nitriles from benzylamines
using the tandem method is still under investigation.
In conclusion, a N-Cl functionalization protocol for the
preparation of valuable N,N-dichloroamines under mild reaction
conditions was reported. It involved the use of m-CPBA as
oxidant and FeCl3 as chlorine source, which allowed the rapid
access to N,N-dichloroamines from primary amines in good
yields. N,N-Dichloroamines could be further transferred into
nitriles or N-chloroimines under Et3N conditions.17
R'
R'
Et3N
CN
NCl2
NCl
or
R
R
R
CH2Cl2
2
3
4
Entry
Substrate
Product
Yield/%c
CN
NCl2
1
94
92
2a
2d
2e
3a
CN
NCl2
2
Br
Br
3d
3e
CN
NCl2
We are grateful for financial support from The Fundamental
Research Funds for the Central Universities (No. WY1113007).
3
4
93
91
References and Notes
CN
NCl2
1
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3f
F
F
F
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CN
CN
4
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NCl2
5
79
89
81
2i
3i
3n
4n
Cl
Cl
NCl2
NCl2
6
7
6
2n
2n
Cl
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NCl
7b
8
9
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NCl
NCl2
8b
91
Cl
Cl
4o
2o
aReaction conditions: N,N-dichloroamines 2 (100 mg), Et3N
(1.5 mL), CH2Cl2 (1.5 mL), r.t. bReaction conditions: N,N-
dichloroamines 2 (200 mg), Et3N (0.25 mL, 2.0 equiv), CH2Cl2
c
(3 mL), 0 °C. Isolated yields.
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summarized in Table 3 show that nitriles (Entries 1-6) or N-
chloroimines (Entry 7) were obtained in relation to the amount
of Et3N and the reaction temperature. The reaction with α-
methylated N,N-dichloroamine could only afford the corre-
sponding N-chloroimine (Table 3, Entry 8). Further investiga-
192 | Chem. Lett. 2014, 43, 190–192 | doi:10.1246/cl.130883
© 2014 The Chemical Society of Japan