Amination of Aromatic Halides and Exploration of the Reactivity Sequence of Aromatic Halides

Article abstract of DOI:10.1021/acs.joc.8b02588

A base-promoted amination of aromatic halides has been developed using a limited amount of dimethylformamide (DMF) or amine as an amino source. Various aryl halides, including F, Cl, Br, and I, have been successfully aminated in good to excellent yields. Although the amination of aromatic halides with amines or DMF is usually considered as an aromatic nucleophilic substitution (S_NAr) process, and the reactivity of an aromatic halide is F > Cl > Br > I, the reactivity of aromatic halides in this system was found to be I > Br a‰ F > Cl. This protocol also showed a good regioselectivity for multihalogenated aromatics. This protocol is valuable for industrial application due to the simplicity of operation, the unrestricted availability of amino sources and aromatic halides, transition metal-free conditions, no requirement for solvent, and scalability.

Full text of DOI:10.1021/acs.joc.8b02588

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Article
Amination of Aromatic Halides and Exploration
of the Reactivity Sequence of Aromatic Halides
Chu Yang, Feng Zhang, Guo-Jun Deng, and Hang Gong
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02588 • Publication Date (Web): 17 Dec 2018
Downloaded from http://pubs.acs.org on December 17, 2018
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Amination of Aromatic Halides and Exploration of the Reactivity Sequence of
Aromatic Halides
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Chu Yang,† Feng Zhang,‡ Guo-Jun Deng,† and Hang Gong*,†
9
†The Key Laboratory for Green Organic Synthesis and Application of Hunan
Province; The Key Laboratory of Environmentally Friendly Chemistry and
Application of the Ministry of Education, College of Chemistry, Xiangtan University,
Xiangtan 411105 China.
‡College of Science, Hunan Agricultural University, Changsha, 410128, (China)
*E-mail: hgong@xtu.edu.cn
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Table of Contents:
R
R
DMF(7 equiv.)
X
NMe2
Ar
Ar
KOH(2.5 equiv.)
100 oC, air
Metal-free Solvent-free Regio-selectivity Scalable
Reactivity: I>BrF>Cl) Applicable to a variety of ArX (X = F, Cl, Br, I)
ABSTRACT: A base-promoted amination of aromatic halides has been developed
using a limited amount of dimethylformamide (DMF) or amines as amino source.
Various aryl halides, including F, Cl, Br and I, have been successfully aminated in
good to excellent yields. Although the amination of aromatic halides with amines or
DMF was usually considered as an aromatic nucleophilic substitution (SNAr) process,
and the reactivity of aromatic halide is F > Cl > Br > I, the reactivity of
aromatic halides in this system was found to be I>Br≈F>Cl. This protocol also
showed a good regioselectivity for multi-halogenated aromatics. This protocol is
valuable for industrial application due to the simplicity of operation, the unrestricted
availability of amino sources and aromatic halides, transition metal-free conditions,
solvent-free and scalability.
INTRODUCTION
The amination of aromatic halides by aromatic nucleophilic substitution (SNAr) has
been widely applied in the synthesis of various valuable compounds,1 especially
bioactive molecules with medicinal activity, such as antitumor,2 anti-HIV,3
antiseptic,4 antagonist,5 hormone receptor modulator.6 And this reaction also applied
in the synthesis of natural products.7 It is generally known that the reactivity of aryl
halides in the SNAr reaction follows the order of F > Cl > Br > I, which is completely
opposite to the rule for the SN2 reactions of aliphatic halides.8 The great contrast is
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attributed to a difference in the rate-determining step. In the mechanism of the SNAr
reaction, addition and elimination processes are involved, and the addition process is
the rate-determining step (Scheme 1, A). Thus, the halogen atoms with strong
electronegativity and small steric hindrance is favorable for the addition step in the
SNAr reaction. In addition, the breaking of the C-halogen bond plays an important
role in the rate-determining step of the SN2 reaction, so that the strength of the
C-halogen bond and nucleofugality of halogen determine the reaction rate (Scheme 1,
B).
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Nu
R
R
R
Nu
X
r.d.s.
slow
-X
(A)
(B)
X
Nu
fast
Nu
Nu
X
Nu
X
+
X
SNAr
SN2
vs
Aromatic Halides
Aliphatic Halides
Reactivity:
F > Cl > Br > I
I > Br > Cl > F
Scheme 1. Comparison of the SNAr and SN2 mechanisms.
The amination of aryl halides is known as one of the most common SNAr reactions,
and the reported literature indicated that the reactivity of aromatic halides is also as
that in other SNAr reactions.9 For instance, Singaram et al. reported the tandem SNAr
amination-reduction reactions.9a When using ortho-halo-benzonitriles as substrates,
the yield of the desired product was found to be 100% (X = F), 70% (X = Cl) and
10% (X = Br), respectively (Scheme 2, A). Ulven and coworkers developed a flow
amination reaction of aryl halides at high temperature (240 ℃) and high pressure (25
bar).9b When 2-Cl or 2-Br quinoline was used as substrate, the amination product
yield was 89% (X = Cl) and 10% (X =Br), respectively (Scheme 2, B). Ibata et al.
reported the amination of aromatic halides under high pressure, and in the case of
para-halo-nitrobenzenes (halo = Cl, Br, I) as substrates, the quantitative yields were
obtained at different pressure (halo = Cl, at 6.0 kbar; halo = Br, at 8.5 kbar; halo = I,
at 12.0 kbar).9c Additionally, when the reaction was conducted with different halogens
(Cl, Br, and I) under 1 atm at 80 ℃ the product yield varied among the halogens with
92, 51 and 14% for Cl, Br and I, respectively (Scheme 2, C). Woydziak et al.
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conducted a study on hydroxide-assisted amination of aryl fluorides and chlorides and
also found that the reactivity of aryl fluorides is better than that of aryl chlorides
(Scheme 2, D).9d These research findings indicated that the reactivity of aryl halides
obeys the SNAr reaction rule. However, when we conducted the amination reaction of
aryl halides using limited amount of DMF as amine source in the presence of KOH,
an unexpected result was obtained, which suggested that the reactivity of aryl halides
follows the order I > Br ≈ F > Cl (Scheme 2, E). This is an interesting result not only
for the unusual order of reactivity of aryl halides, but also the finding of a useful
strategy for the amination of various ArX (X = I, Br, F, Cl) producing high yield
under metal-free conditions.
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The conventional methods for the synthesis of aromatic amines include the
Ullmann-type amination10 and Buchwald–Hartwig amination.11 Normally, the
Ullmann-type reaction requires a large amount of a highly polar solvent, high
temperature, and consumes a stoichiometric amount of copper salts.10 The Buchwald–
Hartwig amination requires palladium and various ligands as catalyst.11 More
recently, the amination reaction has been modified and improved by using various
metals as catalysts, including Cu,12 Pd,13 Fe,14 Ni,15 Ru,16 Co,17 and Ag.18 However,
the use of metal catalyst is undesirable for the synthesis of pharmaceuticals, as the
metal-catalyzed processes waste metal resources and increase the cost of the synthesis
process.19 Consequently, the metal-free process for the synthesis of aromatic amines
is attractive.
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(A) Singaram (Tandem SNAr amination-reduction reactions, F>Cl>Br)
NH2
CN
X = F, 100%
X = Cl, 70%
X = Br, 10%
LiH3BPyrr
X
N
7
8
(B) Ulven (Flow SNAr amination reactions, Cl>Br)
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DMF/NH3(aq.)
240 oC, 25 bar
X = Cl, 89%
X = Br, 77%
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X
NMe2
N
N
(C) Ibata (SNAr amination reactions, Cl>Br>I)
X = Cl, 92%
X = Br, 51%
X = I, 14%
pyrrolidine, THF
X
O2N
N
O2N
1 atm., 50h
(D) Woydziak (SNAr amination reactions, F>Cl)
DMF (2 mL)
X = F, 91%
X = Cl, 45%
X
Ac
NMe2
Ac
KOH (aq.)
(E) This work (Unknown mechanism, I>Br F>Cl):
X= I, 89%
X= Br, 83%
X= Cl, 71%
X= F, 81%
DMF (7 equiv)
X
NMe2
O2N
O2N
KOH (2.5 equiv)
100 oC, 24 h, air
Scheme 2. Reported reactivity of aromatic halides in amination reactions and our
experiment results.
RESULTS AND DISCUSSION
Initially, the coupling of 4-iodonitrobenzene with DMF in the presence of a base was
selected as a model reaction to optimize the conditions (Table 1). At first, the reaction
temperature and base were optimized. The results indicated that the optimal reaction
temperature reaction temperature is 100 ℃ (entries 1-4). Additionally, it was
determined that the most suitable bases are KOH, NaOEt and NaOtBu, but after
consideration of the cost, KOH was selected as base for further optimization
experiments (entries 5-12). Subsequently, the amount of DMF and KOH was
optimized (entries 5, 3-16), and the optimization results revealed that this reaction can
be conducted well with only 5 or 7 equiv of DMF in the presence of 2.5 equiv of
KOH. The optimization experiments also showed that this reaction can be completed
within 24 h and the argon atmosphere is unnecessary.
Table 1. Optimizing experiments. a
O
Base (5 equiv)
air, T oC, 24 h
I
O2N
NMe2
+
O2N
NMe2
H
Entry
DMF
Base
T(oC)
60
80
100
120
Yield(%)
1
2
3
4
1 mL
1 mL
1 mL
1 mL
KOtBu
KOtBu
KOtBu
KOtBu
12
33
42
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13b
14b
15b
16c
17d
18e
1 mL
1 mL
1 mL
1 mL
1 mL
1 mL
1 mL
1 mL
10 equiv
7 equiv
5 equiv
7 equiv
7 equiv
7 equiv
KOH
NaOH
NaOtBu
NaOEt
K3PO4
K2CO3
KI
KOAc
KOH
KOH
100
100
100
100
100
100
100
100
100
100
100
100
100
100
89
39
90
90
31
trace
trace
trace
89
89
86
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KOH
KOH
KOH
KOH
54
78
80
a Unless otherwise noted, all reactions were conducted on a 0.2 mmol scale in a sealed
b
tube in air for 24 h; NMR yields were given using CH3NO2 as internal standard.
KOH 2.5 equiv. c KOH 2 equiv. d reaction time is 18 h. e Under atmosphere of argon.
With the optimized reaction conditions in hand [DMF 7 equiv, KOH 2.5 equiv,
100 ℃ under air atmosphere for 24 h], the amination reactions of 4-halonitrobenzenes
with DMF were then conducted (Table 2). Remarkably, the results obtained were
unexpected, as the reactivity of the aryl halides was not consistent with that of SNAr
or SN2 reaction, but instead follows the order I > Br ≈ F > Cl (entries 1-4).
Accordingly, to establish whether these results are an anomaly or a generalization, the
coupling of 4-halo-nitrobenzenes with N-monosubstituted formamide and aliphatic
amine as well as cyclic amine was conducted, and similar results were obtained
(entries 5-16). Likewise, the reaction of 2-halopyridine with DMF also produced a
similar result (entries 17-20). In addition, to exclude the interference of metal, the
reaction of 4-halo-nitrobenzenes and DMF using high purity KOH (99.999%) as
catalyst with new glass apparatus and new stir bar also was conducted, and 2a was
found as 89% (X = I), 81% (X = Br), 75% (X = Cl), 90% (X = F) [NMR yields].
These results are almost the same as the results obtained from standard reaction
conditions (entries 1-4), indicating the influence of metal impurities in this reaction
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can be ignored.
5
6
Table 2. The investigation of reactivity of aromatic halides.a
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R1
N
R2
amine source (7 equiv)
X
Ar
Ar
KOH (2.5 equiv)
100 oC, air
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1
2
Entry
1
X
I
Br
Cl
F
Amine source
Product
Yield(%)
89
O
O2N
NMe2
NHEt
2
3
4
5
6
7
8
9
10
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13
14
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20
83
71
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85
75
62
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81
73
51
77
71
65
52
73
71
H
H
NMe2
2a
I
O
O2N
Br
Cl
F
N
H
2b
I
O2N
NHnC4H9
Br
Cl
F
NH2
2c
2d
2e
I
O2N
N
Br
Cl
F
N
H
I
O
NMe2
Br
Cl
F
41(55)
(5)
40(51)
N
H
NMe2
a Unless otherwise noted, all reactions were conducted on a 0.2 mmol scale in a sealed
tube at 100 oC in air for 24 h; Isolated yields were given outside of parentheses, NMR
yields were given in parentheses using CH3NO2 as internal standard.
Afterward, the application of this approach was further extended to the amination
of aromatic halides using DMF as amine source (Table 3). Almost all the selected
electron-deficient (aza)aromatic halides could be converted to the amination product
with high yields. Moreover, when the same aromatic compound with different
halogens was used as substrate, the yield of the desired product also almost follows
the order I > Br ≈ F > Cl (2f, j, zc-zf). In particular, the aryl fluorides gave a
satisfactory yield. It was also found that when fluorine and other halogens are at the
same position, fluorine will be substituted first (2v, w). Another interesting finding is
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that the reactivity of the ortho position is higher than that of the other positions (2k-m,
q, r, t, z). Iodopentafluorobenzene could also be transferred to amination product, in
this case, the reaction occurred on the C-F bond (2zk).
9
Table 3. Substrate scope of aromatic halides.a
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O
KOH, 100 o
24 h, air
C
R
R
X
+
NMe2
Ar
Ar
NMe2
7 equiv
NMe2
H
1
2
NMe2
NMe2
NMe2
NMe2
I
NO2
NMe2
N
NO2
N
CF3
X=F 49
Ac
X=F 83
2f
2g
2h
2i
2j
2k
X=F 77
X=Cl 61
X=Br 75
X=I 83
X=F 71
X=Cl (21)
X=Br 73
X=I 82
Cl
Cl
NO2
CN
CF3 F3C
Br
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
N
N
N
N
N
N
2l
2m
2n
2o
2p
2q
X=F 57
X=F 75
X=F 71
X=F 77
F
X=F 76
H3C
X=F 47
I
CH3
NMe2
Br
N
NMe2
N
NMe2
NMe2
NMe2
N
N
N
2r
2s
2t
2u
2v
X=F 78
X=F 57
X=F 81
X=F 51
X=F 75
NMe2
NMe2
Cl
N
NMe2
NMe2 H3CO
Cl
N
N
NMe2
N
N
CH3
2w
2x
2y
2z
2za
X=F 71
X=F 73
X=F 72
X=I 85
N
X=Br 67
NMe2
NMe2
N
N
NMe2
N
NMe2
X=F 58
N
NMe2
X=Cl 65
X=Br 72
N
2zb
OCH3
X=F 83
N
2zc
2zd
2ze
2zf
X=Br 87
X=F 65
X=Cl 49
X=Br 61
X=I 69
X=Cl 81
X=Cl 74
X=Br 71
X=I 82
NMe2
N
N
Ph
Ph Me2N
NMe2
NMe2
F
F
F
F
N
N
N
N
NMe2
N
NMe2
Cl
Ph
X=Cl 31
N
I
2zg
2zh
2zi
2zj
2zk
X=F 40
X=Br 78
X=Cl 73
X=Cl 35
a Unless otherwise noted, all reactions were conducted on a 0.2 mmol scale in a sealed
o
tube at 100 C in air for 24 h; Isolated yields (%) were given outside of parentheses,
NMR yields were given in parentheses using CH3NO2 as internal standard.
Although amination of various aromatic halides were succeeded based on this
protocol, some limitations still remained (Table 4). The unsubstituted aryl halides
(entry 1) or aryl halides with electron donating group (entry 2) are not applicable to
this reaction. When the meta-nitroiodobenzene was used, the amination reaction also
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did not occurred due to the activation of nitro to metasite is weak (entry 3).
Unusually, ortho-fluoronitrobenzene is insert to this reaction (entry 4), but other
ortho-halo-nitrobenzenes can be aminated with good yields (Table 3, 2f). This
reaction is not compatible with carboxyl or carboxylate group (entries 5-7). When
cyano substituted substrates were used, the cyano group would be hydrolyzed to
amide (entries 8-9). Halogenated heteroaromatics with less reactivity also could not
be transformed to amination products (entries 10-14).
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Table 4. Limitation of aromatic halides.a
O
KOH, 100 oC
24 h, air
R
R
X
NMe2
+
I
Ar
Ar
NMe2
H
1
2
7 equiv.
I
I
I
X
I
F
CO2H
NO2
NO2
X = F,I
entry 1
CO2CH3
entry 7
OMe
entry 2
CO2H
entry 3
I
entry 4
entry 5
entry 6
I
X
Br
N
I
Br
OH
N
CN
N
N
N
I
N
N
X = F,Cl,Br
H
CN
entry 8 entry 9
entry 10
entry 11
entry 12
entry 13
entry 14
a
o
All reactions were conducted on a 0.2 mmol scale in a sealed tube at 100 C in air
for 24 h.
The amination of aryl iodides using formamide derivatives as amine source was
also studied (Table 5). This reaction proceeded well under metal-free conditions using
formamide derivatives, such as primary (2A), secondary (2b, B, C), tertiary amides
(2D) as well as cyclic tertiary amides (2E, F) as amine source. However, aromatic
amides are unfavorable to this reaction due to their low nucleophilicity (2G, H).
When N-benzylformamide and formylhydrazine were used, moderate yield of desired
products were obtained (2I, J).
Table 5. Substrate scope of amides.a
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R1
R2
R1
R2
O
H
KOH 2.5 equiv
air, 100 oC,24 h
O2N
I
N
O2N
N
+
1
2
(0.2 mmol)
7 equiv
7
8
9
H
N
H
N
Me
H
N
Et
NH2
O2N
O2N
O2N
10
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O2N
b
b
2A
2B
2b
2F
2C
2G
74
89
85
71
77
41
Et
Et
H
N
Ph
N
O2N
O2N
N
O2N
O
O2N
N
O2N
2D
2E
83
69
O2N
H
H
Me
N
O2N
N
N
NH2
Ph
Ph
c
2H
2I
2J
56
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a Unless otherwise noted, all reactions were conducted on a 0.2 mmol scale in a sealed
o
b
tube at 100 C in air for 24 h; Isolated yields (%) were given. 20 equiv amide were
used. c NMR yield, CH3NO2 was used as internal standard.
It has been reported that amide can be decomposed under alkaline conditions.20
Thus, several amines were tried in this protocol (Table 6), and good results were
obtained except with the aromatic amine due to their low nucleophilicity (Table 6,
2G).
Table 6. The amination of aryl iodide with amines.a
R2
N
R1
R1
N
R2
KOH 2.5 equiv
air, 100 oC,24 h
O2N
O2N
I
H
+
1
2
(0.2 mmol)
7 equiv
H
N
Et
H
N
O2N
O2N
N
O2N
N
O2N
O2N
nBu
Et
Ph
b
2c
2D
2G
H
2d
71
81
91
21
N
O2N
N
O2N
N
N Ph
Ph
2K
2I
2E
81
61
53
a Unless otherwise noted, all reactions were conducted on a 0.2 mmol scale in a sealed
o
b
tube at 100 C in air for 24 h; Isolated yields (%) were given. 20 equiv amine were
used.
To confirm the feasibility of this protocol, the reaction was scaled to the gram level,
and the amination products were obtained in good yields (Scheme 3).
O
KOH (2.5 equiv)
100 oC, air, 4 days
X
NMe2
O2N
+
O2N
NMe2
7 equiv
H
X X
0.58 g, 87% ( =I) 0.97 g, 83% ( =F)
1 gram
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Scheme 3. Gram-scale reactions.
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Another possible mechanism of the amination of aryl halides, which is known as
the aryne mechanism, has also been reported.21 However, whenever para- or ortho-
substituted aryl halide and meta-fluoronitrobenzene were used as substrate, the in situ
amination product was the only product detected (Scheme 4, A; see Table 1-4). In the
case of meta-halogenated pyridine, the amination did not occur due to their low
activity (Scheme 4, B). In addition, when the capture experiments of aryne
intermediate were conducted using furan as scavenger (Scheme 4, C), no
cycloaddition products were detected and only the amination products were found.
Thus, this protocol might not proceed via the benzyne mechanism, and the reactivity
of aryl halides is not consistent with the SNAr. Then, the reaction of ArF and DMF in
polar aprotic solvent (DMSO) or non-polar solvent (toluene) were performed (Scheme
4, D). And moderate to good yield were detected whenever these reaction conducted
under argon or air. These results indicated that the polarity of solvents and atmosphere
have little influence on this reaction. However, when ArI was used as substrate, only
poor yields were achieved (Scheme 4, E). So, maybe there are different mechanism
operating for different aryl halides. Since the homolytic cleavage of the Ar-X bond
under elevated temperature maybe occurred, especially for Ar-I and Ar-Br, the radical
inhibition experiments were conducted using 1 equiv 1,1-diphenylethylene or
TEMPO as radical inhibitor (Scheme 4, F). However, the desired product 2a was
detected with good yield, indicating the reaction is not a radical procedure whenever
ArF, ArCl, ArBr or ArI were used as substrates. Accordingly, the mechanism of this
protocol with a limited amount of amino source in the presence of KOH is unclear.
Finally, the reaction rate of different Aryl halides were investigated via monitoring
the reaction of p-NO2PhX and DMF (Scheme 4, G). The results indicate that the
reaction of p-NO2PhF is the fastest one, and there is no obviously difference between
the remaining aryl halides.
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R1
N
R2
R1
R2
(A)
X
X
N
O2N
N
N
O2N
R1
R2
O
H
N
R1
R2
F
N
Standard
conditions
R1
N
R1
N
O2N
O2N
X
X
R2
R2
O2N
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N
O2N
+
N
R1
R2
(B)
(C)
O
Standard conditions
X
N
No reaction occurred
N
H
O
(7 equiv.)
O
X
N
O2N
O2N
DMF(7 equiv.)
Standard conditions
O2N
I
II
(0.2 mmol)
( ) Detected by GC-Ms
( ) N.D.
X= I, Br, Cl, F
(D)
O2N
(0.2 mmol)
KOH (2.5 equiv)
F
N
O2N
DMF
+
100 oC, 24 h, atmosphere
Solvent (0.5mL)
2a
(3 equiv)
atmosphere: air, Solvent: DMSO, NMR yield: 62%
atmosphere: air, Solvent: toluene, NMR yield: 52%
atmosphere: Ar, Solvent: DMSO, NMR yield: 71%
atmosphere: Ar, Solvent: toluene, NMR yield: 75%
(E)
O2N
(0.2 mmol)
KOH (2.5 equiv)
I
N
O2N
DMF
+
100 oC, 24 h, atmosphere
Solvent (0.5mL)
2a
(3 equiv)
atmosphere: air, Solvent: DMSO, NMR yield: 10%
atmosphere: air, Solvent: toluene, NMR yield: 10%
atmosphere: Ar, Solvent: DMSO, NMR yield: 7%
atmosphere: Ar, Solvent: toluene, NMR yield: 7%
(F)
O2N
Standard conditions
X
N
O2N
DMF
+
Radical inhibitor (1 equiv)
(7 equiv)
Radical inhibitor: 1,1-diphenylethylene,
2a
(0.2 mmol)
X
X
X
X
NMR yield: 87% ( = F), 73% ( =Cl), 80% ( = Br), 86% ( = I)
Radical inhibitor: TEMPO
X
X
X
X
NMR yield: 83% ( = F), 67% ( =Cl), 78% ( = Br), 85% ( = I)
(G)
Br
I
Cl
F
N
KOH (0.5 mmol)
DMF
+
+
+
(1.4 mmol)
100 oC, t h, air
NO2
NO2
NO2
NO2
NO2
(0.05 mmol for each)
(Detected by NMR) Residue of substrate
Total yield
27%
X
X
X
X
X
X
X
X
X
X
X
X
t = 0.5 h, 40% ( = F), 69% ( =Cl), 75% ( = Br), 71% ( = I);
t = 1.0 h, 31% ( = F), 61% ( =Cl), 65% ( = Br), 61% ( = I);
t = 2.0 h, 21% ( = F), 54% ( =Cl), 54% ( = Br), 51% ( = I);
39%
51%
Scheme 4. Control experiments.
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CONCLUSION
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In summary, a simple and practical protocol for the amination of aryl halides was
developed. Aryl halides, including ArI, ArBr, ArCl and ArF, were appropriate for this
reaction. Moreover, this protocol has several advantages such as being metal- and
solvent-free, scalability, compatibility with air, and requiring relatively mild reaction
temperature. The reactivity of aryl halides is not consistent with the SNAr reaction,
and the benzyne mechanism and radical mechanism were also excluded. The
mechanism of this protocol remains unclear.
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EXPERIMENTAL SECTION
General Remarks. Preparative thin-layer chromatography was performed for
product purification using Sorbent Silica Gel 60 F254 TLC plates and visualized with
ultraviolet light. IR spectra were recorded on a new Fourier transform infrared
1
spectroscopy. H, 13C and 19F NMR spectra were recorded on 400, 100, 377 MHz
NMR spectrometer using CDCl3 as solvent unless otherwise stated. HRMS were
made by means of ESI (AB-Q-TOF/MS5600+). Melting points were measured on
micro melting point apparatus and uncorrected. Unless otherwise noted, all reagents
were weighed and handled in air, and all reactions were carried out in a sealed tube
under an atmosphere of air. Unless otherwise noted, all reagents were purchased on
reagent company, and used without further purifications.
General procedure for the synthesis of aromatic amines. A solution of
aromatic halides compound (0.2mmol), KOH (2.5 equiv) in N,N-dimethylformamide
(7 equiv) or amine (7 equiv) were stirred in a sealed tube under an atmosphere of air
at 100°C for 24 h. After being cooled to room temperature, the reaction mixture was
filtered, washed with ethyl acetate (5 mL). Afterward, the solution was added 1 mL
water and extracted with ethyl acetate (4×5 mL), the combined organic layers were
dried with over anhydrous Na2SO4. The solvent was evaporated under vacuum and
the crude product was purified by preparative thin-layer chromatography (TLC)
onsilica gel with petroleum ether and ethyl acetate to achieve the pure product.
N,N-dimethyl-4-nitroaniline (2a).12b Purified by TLC: (petroleum ether/ethyl
acetate = 5/1). Yellow solid (29 mg, 89% yield, prepared by 1-iodo-4-nitrobenzene,
Table 2, entry 1) mp: 162–163 °C. 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 9.2Hz,
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2H), 6.61 (d, J = 9.2Hz, 2H), 3.12 (s, 6H). 13C{1H} NMR (100 MHz, CDCl3) δ
154.22, 137.01, 126.13, 110.24, 40.27. IR (KBr) 3140, 3025, 2378, 1750, 1584, 1439,
1401, 1343, 1282, 1164, 930, 814, 751, 640, 477 cm-1. HRMS (ESI) m/z: [M+H]+
Calcd for C8H11N2O2, 167.0815; found 167.0824.
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N-ethyl-4-nitroaniline (2b).22 Purified by TLC: (petroleum ether/ethyl acetate =
8/1). Yellow solid (27 mg, 85% yield, prepared by 1-iodo-4-nitrobenzene, Table 2,
entry 5) mp: 94–95 °C. 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 9.2 Hz, 2H), 6.52
(d, J = 8.8 Hz, 2H), 4.45 (s, 1H), 3.28–3.25 (m, 2H), 1.31 (t, J = 7.2 Hz, 3H). 13C{1H}
NMR (100 MHz, CDCl3) δ 153.31, 137.89, 126.48, 110.92, 38.04, 14.44. IR (KBr)
3140, 2320, 1716, 1541, 1401, 1183, 1111, 1036, 736 cm-1. HRMS (ESI) m/z:
[M+H]+ Calcd for C8H11N2O2, 167.0815; found 167.0810.
N-butyl-4-nitroaniline (2c).23 Purified by TLC: (petroleum ether/ethyl acetate =
4/1). Yellow solid (31 mg, 81% yield, prepared by 1-iodo-4-nitrobenzene, Table 2,
entry 9) mp: 54–55 °C. 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 9.2 Hz, 2H), 6.51
(d, J = 9.2 Hz, 2H), 4.47 (s, 1H), 3.24–3.19 (m, 2H), 1.67–1.60 (m, 2H), 1.47–1.42 (m,
2H), 0.99–0.96 (m, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 153.42, 137.85, 126.48,
110.90, 43.14, 31.21, 20.16, 13.79. IR (KBr) 3121, 2961, 2871, 2409, 1610, 1440,
1332, 1142, 1116, 1049, 998, 814, 751, 675, 476 cm-1. HRMS (ESI) m/z: [M+H]+
Calcd for C10H15N2O2, 195.1128; found 195.1127.
1-(4-nitrophenyl)pyrrolidine (2d).24 Purified by TLC: (petroleum ether/ethyl acetate
= 5/1). Yellow solid (27 mg, 71% yield, prepared by 1-iodo-4-nitrobenzene, Table 2,
1
entry 13) mp: 165–167 °C. H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 9.2 Hz, 2H),
13
6.46 (d, J = 9.2 Hz, 2H), 3.40 (t, J = 6.4 Hz, 4H), 2.10–2.06 (m, 4H). C{1H} NMR
(100 MHz, CDCl3) δ 151.86, 136.49, 126.38, 110.43, 47.93, 25.46. IR (KBr) 3025,
1654, 1466, 1401, 1343, 1282, 1197, 1049, 930, 882, 710, 675, 474 cm-1. HRMS
(ESI) m/z: [M+H]+ Calcd for C10H13N2O2, 193.0972; found 193.0971.
N,N-dimethylpyridin-2-amine (2e).12b Purified by TLC: (petroleum ether/ethyl
acetate = 5/1). Colorless oil (17 mg, 71% yield, prepared by 2-iodopyridine, Table 2,
entry 17). 1H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 3.6 Hz, 1H), 7.47–7.43 (m, 1H),
6.55–6.50 (m, 2H), 3.09 (s, 6H). 13C{1H} NMR (100 MHz, CDCl3) δ 159.37, 147.88,
137.11, 111.43, 105.85, 38.14. IR (neat) 3662, 3140, 2350, 1666, 1401, 1314, 1148,
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824, 706, 567 cm-1; HRMS (ESI) m/z: [M+H]+ Calcd for C7H11N2, 123.0916; found
123.0914.
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N,N-dimethyl-2-nitroaniline (2f).25 Purified by TLC: (petroleum ether/ethyl acetate
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= 5/1). Yellow oil (28 mg, 83% yield, prepared by 1-iodo-2-nitrobenzene). H NMR
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(400 MHz, CDCl3) δ 7.77 (dd, J = 8.0, 1.6 Hz, 1H), 7.42–7.38 (m, 1H), 7.02 (dd, J =
8.8, 1.2 Hz, 1H), 6.85–6.80 (m, 1H), 2.90 (s, 6H). 13C{1H} NMR (100 MHz, CDCl3)
δ 146.27, 133.22, 126.75, 118.10, 117.93, 42.47. IR (KBr) 3121, 2530, 1465, 1402,
1159, 1092, 747, 608, 531, 416 cm-1. HRMS (ESI) m/z: [M-H]- Calcd for C8H9N2O2,
165.0669; found 165.0663.
N,N-dimethyl-3-nitroaniline (2g).26 Purified by TLC: (petroleum ether/ethyl acetate
= 8/1). Yellow solid (23.5 mg, 71% yield) mp: 59–60 °C. 1H NMR (400 MHz, CDCl3)
δ 7.53–7.49 (m, 2H), 7.33 (t, J = 8.0 Hz, 1H), 6.96 (dd, J = 8.4, 2.4 Hz, 1H), 3.04 (s,
6H). 13C{1H} NMR (100 MHz, CDCl3) δ 150.74, 149.29, 129.51, 117.58, 110.65,
106.11, 40.34. IR (KBr) 3140, 2350, 2123, 1530, 1401, 1314, 1230, 1187, 995, 723,
624, 531 cm-1. HRMS (ESI) m/z: [M+H]+ Calcd for C8H11N2O2, 167.0815; found
167.0811.
N,N-dimethyl-4-(trifluoromethyl)aniline (2h).12b Purified by TLC: (petroleum
ether/ethyl acetate = 8/1). Yellow solid (18.5 mg, 49% yield) mp: 68–69 °C. 1H NMR
(400 MHz, CDCl3) δ 7.46 (d, J = 8.4 Hz, 2H), 6.70 (d, J = 8.8 Hz, 2H), 3.02 (s, 6H).
13C{1H} NMR (100 MHz, CDCl3) δ 152.30, 126.33 (q, J = 3.7 Hz), 125.21 (q, J =
19
268.5 Hz), 117.51 (q, J = 32.5 Hz), 111.16, 40.14. F NMR (377 MHz, CDCl3) δ
-60.81. IR (KBr) 3138, 2350, 1658, 1530, 1401, 1112, 831, 571 cm-1. HRMS (ESI)
m/z: [M+K]+ Calcd for C9H10NF3K, 228.0396; found 228.0393.
1-(4-(dimethylamino)phenyl)ethanone (2i).12b Purified by TLC: (petroleum
1
ether/ethyl acetate = 8/1). colorless solid (27 mg, 83% yield) mp: 103–104 °C. H
NMR (400 MHz, CDCl3) δ 7.88 (d, J = 8.8 Hz, 2H), 6.65 (d, J = 8.8 Hz, 2H), 3.06 (s,
6H), 2.52 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 196.44, 153.40, 130.54, 125.36,
110.60, 40.06, 26.02. IR (KBr) 3153, 2350, 1712, 1658, 1401, 1358, 1194, 820, 642,
594 cm-1. HRMS (ESI) m/z: [M+H]+ Calcd for C10H14NO, 164.1069; found 164.1070.
N,N-dimethylpyridin-4-amine (2j).12b Purified by TLC: (petroleum ether/ethyl
acetate = 5/1). Colorless oil (20 mg, 82% yield, prepared by 4-iodopyridine). 1H NMR
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(400 MHz, CDCl3) δ 8.22 (d, J = 6.4 Hz, 2H), 6.49 (dd, J = 5.2, 1.6 Hz, 2H), 3.01 (s,
6H). 13C{1H} (100 MHz, CDCl3) δ 154.27, 149.42, 106.52, 38.99. IR (KBr) 3131,
2350, 2284, 1638, 1645, 1401, 1228, 995, 805, 650, 533 cm-1. HRMS (ESI) m/z:
[M+H]+ Calcd for C7H11N2, 123.0916; found 123.0921.
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3-iodo-N,N-dimethylpyridin-2-amine (2k). Purified by TLC: (petroleum ether/ethyl
1
acetate = 8/1). Colorless oil (38 mg, 77% yield). H NMR (400 MHz, CDCl3) δ 8.23
(dd, J = 3.2, 1.6 Hz, 1H), 8.04 (dd, J = 8.0, 2.0 Hz, 1H), 6.61–6.57 (m, 1H), 2.94 (s,
6H), 13C{1H} NMR (100 MHz, CDCl3) δ 163.17, 149.15, 146.77, 118.32, 85.93,
42.78. IR (KBr) 3138, 2791, 1738, 1574, 1403, 1189, 1157, 1105, 998, 782, 531 cm-1.
HRMS (ESI) m/z: [M+H]+ Calcd for C7H10IN2, 248.9883; found 248.9879.
3-bromo-N,N-dimethylpyridin-2-amine (2l). Purified by TLC: (petroleum
1
ether/ethyl acetate = 8/1). Colorless oil (30 mg, 75% yield). H NMR (400 MHz,
CDCl3) δ 8.20 (dd, J = 4.8, 1.6 Hz, 1H), 7.76 (dd, J = 7.6, 1.6 Hz, 1H), 6.71 (J = 7.6,
4.8 Hz, 1H), 2.99 (s, 6H). 13C{1H} NMR (100 MHz, CDCl3) δ 160.30, 146.01, 142.39,
117.45, 111.10, 41.93. IR (KBr) 3138, 2350, 1710, 1531, 1401, 1166, 998, 651, 531
cm-1. HRMS (ESI) m/z: [M-H]- Calcd for C7H8BrN2, 198.9876; found 198.9882.
3-chloro-N,N-dimethylpyridin-2-amine (2m). Purified by TLC: (petroleum
1
ether/ethyl acetate = 8/1). Colorless oil (22 mg, 71% yield). H NMR (400 MHz,
CDCl3) δ 8.15 (dd, J = 4.8, 1.6 Hz, 1H), 7.56 (dd, J = 8.0, 1.6 Hz, 1H), 6.77 (dd, J =
7.6, 4.8 Hz, 3.00 (s, 6H). 13C{1H} NMR (100 MHz, CDCl3) δ 159.11, 145.44, 138.86,
121.19, 116.75, 41.45. IR (KBr) 3138, 2350, 1723, 1638, 1401, 1164, 998, 651, 531
cm-1. HRMS (ESI) m/z: [M+H]+ Calcd for C7H10ClN2, 157.0527; found 157.0519.
N,N-dimethyl-3-nitropyridin-2-amine (2n).9b Purified by TLC: (petroleum
1
ether/ethyl acetate = 8/1). Colorless oil (26 mg, 77% yield). H NMR (400 MHz,
CDCl3) δ 8.31 (dd, J = 4.4, 1.6 Hz, 1H), 8.12 (dd, J = 8.0, 1.6 Hz, 1H), 6.67 (dd, J =
13
8.0, 4.8 Hz, 1H), 3.06 (s, 6H). C{1H} NMR (100 MHz, CDCl3) δ 153.07, 151.48,
135.48, 131.71, 111.79, 40.21. IR (KBr) 3117, 1559, 1403, 1332, 1284, 1081, 705,
529 cm-1. HRMS (ESI) m/z: [M+H]+ Calcd for C7H10N3O2, 168.0767; found
168.0760.
2-(dimethylamino)nicotinonitrile (2o).27 Purified by TLC: (petroleum ether/ethyl
1
acetate = 8/1). Colorless oil (22 mg, 76% yield). H NMR (400 MHz, CDCl3) δ 8.29
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(dd, J = 4.4, 1.6 Hz, 1H), 7.72 (dd, J = 7.6, 1.6 Hz, 1H), 6.62 (dd, J = 7.6, 4.8 Hz, 1H),
3.29 (s, 6H). 13C{1H} NMR (100 MHz, CDCl3) δ 159.47, 151.84, 144.44, 119.23,
111.99, 91.02, 40.32. IR (KBr) 3142, 2350, 1658, 1401, 1246, 961, 762, 682, 528
cm-1. HRMS (ESI) m/z: [M+Li]+ Calcd for C8H9N3Li, 154.0951; found 154.0952.
N,N-dimethyl-3-(trifluoromethyl)pyridin-2-amine (2p). Purified by TLC:
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(petroleum ether/ethyl acetate = 8/1). Colorless oil (17.8 mg, 47% yield). H NMR
(400 MHz, CDCl3) δ 8.37–8.30 (m, 1H), 7.80 (d, J = 7.6 Hz, 2H), 6.83–6.76 (m, 1H),
3.03 (s, 6H). C{1H} NMR (100 MHz, CDCl3) δ 158.88, 150.37, 137.48 (q, J = 5.3
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Hz), 124.32 (q, J = 270.2 Hz), 122.66 (q, J = 31.7 Hz), 113.81, 41.70. 19F NMR (377
MHz, CDCl3) δ -57.90. IR (KBr) 3138, 2350, 1787, 1640, 1401, 1114, 761, 531 cm-1.
－
HRMS (ESI) m/z: [M+HCO2H-H] Calcd for C9H10F3N2O2, 235.0688; found
235.0685.
3-chloro-N,N-dimethyl-5-(trifluoromethyl)pyridin-2-amine (2q).28 Purified by TLC:
(petroleum ether/ethyl acetate = 8/1). Colorless oil (25 mg, 57% yield). 1H NMR (400
MHz, CDCl3) δ 8.33 (s, 1H), 7.70 (s, 1H), 3.13 (s, 6H). C{1H} NMR (100 MHz,
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CDCl3) δ 159.84, 142.67 (q, J = 4.3 Hz), 136.03 (q, J= 3.3 Hz), 123.58 (q, J = 269.5
19
Hz), 118.16, 117.91, 41.13. F NMR (377 MHz, CDCl3) δ -61.24. IR (KBr) 3123,
2350, 1761, 1510, 1402, 1161, 1081, 779, 532 cm-1. HRMS (ESI) m/z: [M+Na]+
Calcd for C8H8ClF3N2Na, 247.0220; found 247.0227.
4-iodo-N,N-dimethylpyridin-2-amine (2r). Purified by TLC: (petroleum ether/ethyl
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acetate = 11/1). Colorless solid (39 mg, 78% yield) mp: 58–59 °C. H NMR (400
MHz, CDCl3) δ 7.81 (d, J = 5.2 Hz, 1H), 6.88–6.86 (m, 2H), 3.05 (s, 6H). C{1H}
13
NMR (100 MHz, CDCl3) δ 159.48, 148.18, 120.27, 114.78, 106.35, 38.03. IR (KBr)
3140, 1675, 1616, 1519, 1329, 1251, 1161, 1113, 1068, 837, 703, 527 cm-1. HRMS
(ESI) m/z: [M+H]+ Calcd for C7H10IN2, 248.9883; found 248.9881.
N,N,4-trimethylpyridin-2-amine (2s).29 Purified by TLC: (petroleum ether/ethyl
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acetate = 8/1). Colorless oil (16 mg, 57% yield). H NMR (400 MHz, CDCl3) δ 8.04
(d, J = 5.2 Hz, 1H), 6.39 (d, J = 5.2 Hz, 1H), 6.33 (s, 1H), 3.07 (s, 6H), 2.26 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3) δ 159.70, 147.99, 147.46, 113.13, 106.25, 38.22,
21.45. IR (KBr) 3140, 2927, 2350, 1710, 1401, 1165, 1112, 961, 526 cm-1. HRMS
(ESI) m/z: [M+H]+ Calcd for C8H12N2, 137.1073; found 137.1072.
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4-fluoro-N,N-dimethylpyridin-2-amine (2t). Purified by TLC: (petroleum
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ether/ethyl acetate = 3/1). Colorless oil (22.6 mg, 81% yield). H NMR (400 MHz,
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CDCl3) δ 7.83 (dd, J= 6.4, 2.0 Hz, 1H), 6.39–6.37 (m, 1H), 6.00 (s, 1H), 3.01 (s, 6H).
13C{1H} NMR (100 MHz, CDCl3) δ 165.73 (d, J = 229.4 Hz), 158.29 (d, J = 11.7 Hz),
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147.02 (d, J = 19.0 Hz), 105.15 (d, J = 2.5 Hz), 89.68 (d, J = 42.8 Hz), 39.41. F
NMR (377 MHz, CDCl3) δ -70.44. IR (KBr) 3116, 2933, 2827, 2590, 1613, 1402,
1239, 1157, 1066, 889, 814, 689, 527 cm-1. HRMS (ESI) m/z: [M+K]+ Calcd for
C7H9FN2K, 179.0381; found 179.0390.
N,N,5-trimethylpyridin-2-amine (2u).30 Purified by TLC: (petroleum ether/ethyl
acetate = 5/1). Colorless oil (13.8 mg, 51% yield). 1H NMR (400 MHz, CDCl3) δ 7.99
(s, 1H), 7.29–7.27 (m, 1H), 6.46 (d, J= 8.8 Hz, 1H), 3.04 (s, 6H), 2.18 (s, 3H). 13C{1H}
NMR (100 MHz, CDCl3) δ 157.97, 147.50, 138.16, 120.14, 105.67, 38.36, 17.26. IR
(KBr) 3155, 2350, 1610, 1399, 1220, 1019, 807, 701, 529 cm-1. HRMS (ESI) m/z:
[M+H]+ Calcd for C8H13N2, 137.1073; found 137.1072.
6-bromo-N,N-dimethylpyridin-2-amine (2v).31 Purified by TLC: (petroleum
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ether/ethyl acetate = 10/1). Colorless solid (30 mg, 75% yield) mp: 55–57 °C. H
NMR (400 MHz, CDCl3) δ 7.26–7.22 (m, 1H), 6.66 (d, J = 7.6 Hz, 1H), 6.37 (d, J =
8.4 Hz, 1H), 3.06 (s, 6H). 13C{1H} NMR (100 MHz, CDCl3) δ 159.24, 140.18, 139.10,
114.23, 103.84, 37.94. IR (KBr) 3134, 2350, 1656, 1593, 1519, 1401, 1221, 1195,
1142, 937, 859, 766, 632 cm-1. HRMS (ESI) m/z: [M+Na]+ Calcd for C7H9BrN2Na,
222.9841; found 222.9850.
6-chloro-N,N-dimethylpyridin-2-amine (2w).32 Purified by TLC: (petroleum
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ether/ethyl acetate = 15/1). Colorless oil (22 mg, 71% yield). H NMR (400 MHz,
CDCl3) δ 7.35 (dd, J = 8.4, 7.6 Hz, 1H), 6.51 (d, J = 7.6 Hz, 1H), 6.35 (d, J = 8.4 Hz,
1H), 3.07 (s, 6H). 13C{1H} NMR (100 MHz, CDCl3) δ 159.18, 149.37, 139.31, 110.34,
103.56, 37.98. IR (KBr) 3140, 2935, 1593, 1548, 1403, 1189, 1133, 980, 769, 609,
535 cm-1. HRMS (ESI) m/z: [M+K]+ Calcd for C7H9ClN2K, 195.0085; found
195.0078.
6-methoxy-N,N-dimethylpyridin-2-amine (2x).33 Purified by TLC: (petroleum
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ether/ethyl acetate = 15/1). Colorless oil (22 mg, 73% yield). H NMR (400 MHz,
CDCl3) δ 7.37 (dd, J = 8.0, 8.0 Hz, 1H), 6.03 (d, J = 8.0 Hz, 1H), 5.99 (d, J = 8.0 Hz,
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1H), 3.88 (s, 3H), 3.05 (s, 6H). C{1H} NMR (100 MHz, CDCl3) δ 163.09, 158.45,
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139.81, 97.04, 95.76, 52.90, 37.88. IR (KBr) 3122, 1599, 1463, 1403, 1269, 1180,
997, 671, 529 cm-1. HRMS (ESI) m/z: [M+H]+ Calcd for C8H13N2O, 153.1022; found
153.1016.
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N,N,2-trimethylpyridin-4-amine (2y).34 Purified by TLC: (petroleum ether/ethyl
acetate = 1/1). Colorless oil (19.5 mg, 72% yield). 1H NMR (400 MHz, CDCl3) δ 8.13
(d, J = 6.0 Hz, 1H), 6.36–6.34 (m, 2H), 2.99 (s, 6H), 2.45 (s, 3H). 13C{1H} NMR (100
MHz, CDCl3) δ 158.06, 154.88, 148.96, 105.60, 104.26, 39.12, 24.65. IR (KBr) 3140,
1608, 1683, 1399, 1224, 1166, 1121, 1072, 805, 615, 531 cm-1. HRMS (ESI) m/z:
[M+H]+ Calcd for C8H13N2, 137.1073; found 137.1066.
5-chloro-N,N-dimethylpyridin-2-amine (2z).35 Purified by TLC: (petroleum
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ether/ethyl acetate = 10/1). Colorless oil (25.5 mg, 85% yield). H NMR (400 MHz,
CDCl3) δ 8.08 (d, J = 2.4 Hz, 1H), 7.37 (dd, J = 8.8, 2.4 Hz, 1H), 6.45–6.42 (m, 1H),
3.06 (s, 6H). 13C{1H} NMR (100 MHz, CDCl3) δ 157.66, 146.08, 136.77, 118.52,
106.49, 38.25. IR (KBr) 3140, 2350, 1595, 1552, 1436, 1395, 1310, 1213, 959, 805,
616, 527 cm-1. HRMS (ESI) m/z: [M+H]+ Calcd for C7H10ClN2, 157.0527; found
157.0522.
N,N-dimethylisoquinolin-3-amine (2za).36 Purified by TLC: (petroleum ether/ethyl
acetate = 10/1). Green oil (23 mg, 67% yield). 1H NMR (400 MHz, CDCl3) δ 8.91 (s,
1H), 7.74 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.54 (t, J = 7.6 Hz, 1H), 7.18
13
(t, J = 7.6 Hz, 1H), 6.61 (s, 1H), 3.17 (s, 6H). C{1H} NMR (100 MHz, CDCl3) δ
156.66, 151.03, 138.95, 130.12, 127.67, 124.91, 122.22, 96.77, 38.64. IR (KBr)
3179, 2859, 2361, 1713, 1584, 1454, 1402, 1318, 1282, 1197, 1049, 930, 814, 675,
505 cm-1. HRMS (ESI) m/z: [M+H]+ Calcd for C11H13N2, 173.1073; found 173.1070.
2-methoxy-N,N-dimethylpyridin-4-amine (2zb).37 Purified by TLC: (petroleum
1
ether/ethyl acetate = 1/1). Colorless oil (25 mg, 83% yield). H NMR (400 MHz,
CDCl3) δ 7.85 (d, J = 6.0 Hz, 1H), 6.24 (dd, J = 6.0, 1.2 Hz, 1H), 5.87 (d, J = 1.2 Hz,
13
1H), 3.90 (s, 3H), 2.96 (s, 6H). C{1H} NMR (100 MHz, CDCl3) δ 165.63, 156.90,
146.62, 102.68, 90.65, 53.18, 39.27. IR (KBr) 3131, 2946, 1615, 1515, 1455, 1407,
1261, 1157, 1051, 931, 792, 624, 537 cm-1. HRMS (ESI) m/z: [M+H]+ Calcd for
C8H13N2O, 153.1022; found 153.1022.
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N,N-dimethylquinolin-4-amine (2zc).38 Purified by TLC: (petroleum ether/ethyl
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acetate = 1/1). Colorless oil (28 mg, 81% yield, prepared by 4-chloroquinoline). H
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NMR (400 MHz, CDCl3) δ 8.66 (d, J = 5.2 Hz, 1H), 8.05 (t, J= 9.2 Hz, 2H), 7.64 (t, J
= 7.2 Hz, 1H), 7.64 (t, J = 7.2 Hz, 1H), 6.76 (d, J = 5.2 Hz, 1H), 3.03 (s, 6H). 13C{1H}
NMR (100 MHz, CDCl3) δ 157.59, 150.47, 149.67, 129.79, 128.87, 124.62, 124.49,
122.99, 107.29, 43.90. IR (KBr) 3136, 2795, 2273, 1574, 1401, 1135, 1049, 931, 831,
729, 534 cm-1. HRMS (ESI) m/z: [M+Cl]- Calcd for C11H12ClN2, 207.0683; found
207.0677.
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N,N-dimethylpyrazin-2-amine (2zd).36 Purified by TLC: (petroleum ether/ethyl
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acetate = 1/1). Colorless oil (20 mg, 82% yield, prepared by 2-iodopyrazine). H
NMR (400 MHz, CDCl3) δ 8.05–8.03 (m, 2H), 7.79 (d, J = 2.4 Hz, 1H), 3.13 (s, 6H).
13C{1H} NMR (100 MHz, CDCl3) δ 154.97, 141.72, 131.48, 130.03, 37.62. IR (KBr)
3140, 2283, 1578, 1528, 1403, 1207, 1299, 1142, 1060, 1034, 997, 956, 752, 636, 535
cm-1. HRMS (ESI) m/z: [M+H]+ Calcd for C6H10N3, 124.0869; found 124.0874.
N,N-dimethylpyrimidin-2-amine (2ze).29 Purified by TLC: (petroleum ether/ethyl
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acetate = 8/1). Colorless oil (17 mg, 69% yield, prepared by 2-iodopyrimidine). H
NMR (400 MHz, CDCl3) δ 8.31 (d, J = 4.8 Hz, 2H), 6.45 (t, J = 4.8 Hz, 1H), 3.19 (s,
6H). 13C{1H} NMR (100 MHz, CDCl3) δ 162.21, 157.58, 108.87, 37.09. IR (KBr)
3140, 2927, 2350, 1709, 1690, 1401, 1112, 803, 792, 531 cm-1; HRMS (ESI) m/z:
[M+H]+ Calcd for C6H10N3, 124.0869; found 124.0871.
N,N-dimethylisoquinolin-1-amine (2zf).29 Purified by TLC: (petroleum ether/ethyl
acetate = 10/1). Colorless oil (25 mg, 72% yield, prepared by 1-bromoisoquinoline).
1H NMR (400 MHz, CDCl3) δ 8.13–8.10 (m, 2H), 7.71 (d, J = 8.0 Hz, 1H), 7.58 (t, J
= 7.2 Hz, 1H), 7.48 (t, J= 7.6 Hz, 1H), 7.16 (d, J = 4.0 Hz, 1H), 3.10 (s, 6H). 13C{1H}
NMR (100 MHz, CDCl3) δ 161.97, 140.45, 138.31, 129.49, 126.97, 126.18, 125.57,
121.31, 114.71, 43.11. IR (KBr) 3138, 2797, 2350, 1619, 1586, 1556, 1392, 1140,
1060, 941, 810, 751, 614, 596, 527 cm-1. HRMS (ESI) m/z: [M+H]+ Calcd for
C11H13N2, 173.1073; found 173.1074.
N,N-dimethylquinolin-2-amine (2zg).9b Purified by TLC: (petroleum ether/ethyl
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acetate = 8/1). Colorless oil (27 mg, 78% yield). H NMR (400 MHz, CDCl3) δ 7.83
(d, J = 9.2 Hz, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.58–7.50 (m, 2H), 7.17 (t, J = 7.6 Hz,
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1H), 6.86 (d, J = 9.2 Hz, 1H), 3.21 (s, 6H). 13C{1H} NMR (100 MHz, CDCl3) δ
157.68, 148.16, 137.21, 129.47, 127.31, 126.30, 122.44, 121.65, 109.12, 38.09. IR
(KBr) 3121, 2929, 2286, 1619, 1558, 1515, 1177, 1159, 1019, 982, 864, 810, 779,
706, 527 cm-1. HRMS (ESI) m/z: [M+H]+ Calcd for C11H13N2, 173.1073; found
173.1071.
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7-chloro-N,N-dimethylquinolin-4-amine (2zh). Purified by TLC: (petroleum
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ether/ethyl acetate = 8/1). Colorless oil (30 mg, 73% yield). H NMR (400 MHz,
CDCl3) δ 8.64 (d, J = 5.2 Hz, 1H), 8.01–7.97 (m, 2H), 7.39 (d, J = 9.2 Hz, 1H), 6.74
(d, J = 5.2 Hz, 1H), 3.03 (s, 6H). 13C{1H} NMR (100 MHz, CDCl3) δ 157.55, 151.49,
150.36, 134.65, 128.66, 126.02, 125.33, 121.32, 107.37, 43.86. IR (KBr) 3138, 2797,
2275, 1574, 1440, 1328, 1295, 1136, 1097, 1043, 939, 821, 781, 631, 505 cm-1.
HRMS (ESI) m/z: [M+H]+ Calcd for C11H12ClN2, 207.0683; found 207.0677.
N,N-dimethyl-4,6-diphenyl-1,3,5-triazin-2-amine (2zi).39 Purified by TLC:
(petroleum ether/ethyl acetate = 8/1). White solid (19 mg, 35% yield) mp: 163–
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164 °C. H NMR (400 MHz, CDCl3) δ 8.60 (dd, J = 7.6, 1.2 Hz, 4H), 7.54–7.48 (m,
6H), 3.37 (s, 6H). 13C{1H} NMR (100 MHz, CDCl3) δ 170.68, 165.71, 137.19, 131.62,
128.60, 128.30, 36.34. IR (KBr) 3140, 2350, 1513, 1466, 1399, 1161, 1028, 844, 789,
706, 576 cm-1. HRMS (ESI) m/z: [M+H]+ Calcd for C17H17N4, 277.1447; found
277.1442.
N2,N2,N4,N4-tetramethyl-6-phenyl-1,3,5-triazine-2,4-diamine (2zj).40 Purified by
TLC: (petroleum ether/ethyl acetate = 8/1). White solid (15 mg, 31% yield) mp: 93–
95 °C. 1H NMR (400 MHz, CD3OD) δ 8.14–8.12 (m, 2H), 7.67–7.63 (m, 3H), 3.39 (s,
13
12H). C{1H} NMR (100 MHz, CD3OD) δ 133.37, 130.64, 128.66, 128.59, 128.10,
127.71. IR (KBr) 3055, 2923, 2864, 1589, 1545, 1384, 1207, 962, 779, 699 cm-1.
HRMS (ESI) m/z: [M+K]+ Calcd for C13H17N5K, 282.1115; found 282.1118.
2,3,5,6-tetrafluoro-4-iodo-N,N-dimethylaniline (2zk).41 Purified by TLC:
1
(petroleum ether/ethyl acetate = 8/1). Yellow oil (25 mg, 40% yield). H NMR (400
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MHz, CDCl3) δ 2.97 (s, 6H). C{1H} NMR (100 MHz, CDCl3) δ 147.55 (dddd, J =
4.0, 7.1, 11.6, 241 Hz), 141.63 (dddd, J = 4.1, 5.5, 10.6, 246.5 Hz), 131.97 (t, J = 10.8
Hz), 60.58 (t, J = 28.0 Hz), 43.12 (t, J = 4.2 Hz). 19F NMR (377 MHz, CDCl3) δ
-123.08 (d, J = 15.1 Hz, 2F), -148.91 (d, J = 15.1 Hz, 2F). IR (KBr) 3140, 2284, 1820,
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1660, 1403, 1108, 788, 521 cm-1. HRMS (ESI) m/z: [M+H]+ Calcd for C8H7F4IN,
319.9554; found 319.9552.
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4-nitroaniline (2A).42 Purified by TLC: (petroleum ether/ethyl acetate = 1/1).
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Yellow solid (20 mg, 74% yield) mp: 146–147 °C. H NMR (400 MHz, CDCl3) δ
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8.07 (d, J = 8.8 Hz, 2H), 6.63 (d, J = 9.2 Hz, 2H), 4.41 (br, s, 2H). C{1H} NMR
(100 MHz, CDCl3) δ 152.51, 139.15, 126.37, 113.39. IR (KBr) 3140, 2288, 1694,
1401, 1308, 1105, 982, 884, 810, 779, 709, 567 cm-1. HRMS (ESI) m/z: [M+H]+
Calcd for C6H7N2O2, 139.0502; found 139.0506.
N-methyl-4-nitroaniline (2B).12b Purified by TLC: (petroleum ether/ethyl acetate =
3/1). Yellow solid (27 mg, 89% yield) mp: 148–149 °C. 1H NMR (400 MHz, CDCl3)
δ 8.10 (d, J = 9.2 Hz, 2H), 6.53 (d, J = 9.2 Hz, 2H), 4.66 (br, s, 1H), 2.95 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3) δ 154.12, 138.24, 126.41, 110.72, 30.17. IR (KBr)
3129, 2942, 1602, 1455, 1401, 1034, 1107, 1062, 982, 833, 779, 706, 579 cm-1.
HRMS (ESI) m/z: [M+Li]+ Calcd for C7H8N2LiO2, 159.0740; found 159.0747.
N-cyclohexyl-4-nitroaniline (2C).24 Purified by TLC: (petroleum ether/ethyl acetate
= 8/1). Yellow solid (34 mg, 77% yield) mp: 103–104 °C. 1H NMR (400 MHz, CDCl3)
δ 8.07 (d, J = 9.2 Hz, 2H), 6.49 (d, J = 9.2 Hz, 2H), 4.43 (br, s, 1H), 3.40–3.33 (m,
1H), 2.07–2.04 (m, 2H), 1.82–1.80 (m, 2H), 1.79–1.77 (m, 1H), 1.43–1.33 (m, 2H),
1.29–1.21 (m, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 152.46, 137.48, 126.59,
111.15, 51.55, 32.95, 25.58, 24.76. IR (KBr) 3140, 2937, 1600, 1531, 1504, 1401,
1302, 1112, 833, 754, 531 cm-1. HRMS (ESI) m/z: [M+H]+ Calcd for C12H17N2O2,
221.1284; found 221.1280.
N,N-diethyl-4-nitroaniline (2D).43 Purified by TLC: (petroleum ether/ethyl acetate
= 8/1). Yellow solid (32 mg, 83% yield) mp: 73–74 °C. 1H NMR (400 MHz, CDCl3)
δ 8.09 (d, J = 9.6 Hz, 2H), 6.57 (d, J = 9.2 Hz, 2H), 3.45 (q, J = 6.8 Hz, 4H), 1.23 (t, J
= 6.8 Hz, 6H). C{1H} NMR (100 MHz, CDCl3) δ 152.27, 136.16, 126.51, 109.83,
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44.98, 12.40. IR (KBr) 3121, 2929, 2286, 1619, 1558, 1515, 1177, 1159, 1019, 982,
864, 810, 779, 706, 527 cm-1. HRMS (ESI) m/z: [M+H]+ Calcd for C10H15N2O2,
195.1128; found 195.1126.
1-(4-nitrophenyl)piperidine (2E).24 Purified by TLC: (petroleum ether/ethyl acetate
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= 10/1). Yellow solid (28 mg, 69% yield) mp: 101–103 °C. H NMR (400 MHz,
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CDCl3) δ 8.10 (d, J = 9.6 Hz, 2H), 6.79 (d, J = 9.6 Hz, 2H), 3.44 (br, 4H), 1.69 (br,
6H). 13C{1H} NMR (100 MHz, CDCl3) δ 154.91, 137.46, 126.15, 112.32, 48.39,
25.29, 24.25. IR (KBr) 3131, 1597, 1507, 1457, 1401, 1319, 1110, 1021, 918, 779,
503 cm-1. HRMS (ESI) m/z: [M+H]+ Calcd for C11H15N2O2, 207.1128; found
207.1123.
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4-(4-nitrophenyl)morpholine (2F).44 Purified by TLC: (petroleum ether/ethyl
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acetate = 8/1). Yellow solid (29.5 mg, 71% yield) mp: 147–149 °C. H NMR (400
MHz, CDCl3) δ 8.15 (d, J = 9.2 Hz, 2H), 6.84 (d, J = 9.6 Hz, 2H), 3.87 (t, J = 4.8 Hz,
13
4H), 3.38 (t, J = 4.8 Hz, 4H). C{1H} NMR (100 MHz, CDCl3) δ 155.01, 139.07,
125.89, 112.67, 66.38, 47.17. IR (KBr) 3138, 1604, 1490, 1401, 1334, 1248, 1120,
928, 825, 706, 535 cm-1. HRMS (ESI) m/z: [M+HCO2H-H]+ Calcd for C11H13N2O5,
253.0819; found 253.0808.
4-nitro-N-phenylaniline (2G).45 Purified by TLC: (petroleum ether/ethyl acetate =
5/1). Yellow solid (17.5 mg, 41% yield) mp: 131–133 °C. 1H NMR (400 MHz, CDCl3)
δ 8.11 (d, J = 8.8 Hz, 2H), 7.39 (dd, J = 8.4, 7.6 Hz, 2H), 7.22–7.16 (m, 3H), 6.94 (d,
J = 9.2 Hz, 2H), 6.41 (br, s, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ 150.39, 139.54,
129.76, 126.32, 124.65, 121.93, 113.69. IR (neat) 3140, 1633, 1525, 1191, 1112, 1019,
982, 879, 779, 525 cm-1. HRMS (ESI) m/z: [M+H]+ Calcd for C12H11N2O2, 215.0815;
found 215.0814.
N-benzyl-4-nitroaniline (2I).24 Purified by TLC: (petroleum ether/ethyl acetate =
5/1). Yellow solid (24 mg, 53% yield) mp: 146–147 °C. 1H NMR (400 MHz, CDCl3)
δ 8.08 (d, J = 9.2 Hz, 2H), 7.40–7.32 (m, 5H), 6.57 (d, J = 9.2 Hz, 2H), 4.88 (br, s,
13
1H), 4.43 (d, J = 4.8 Hz, 2H). C{1H} NMR (100 MHz, CDCl3) δ 153.05, 138.38,
137.37, 128.99, 127.90, 127.38, 126.43, 111.36, 47.68. IR (KBr) 3143, 2931, 2253,
1535, 1325, 1257, 1019, 926, 899, 810, 789, 525 cm-1. HRMS (ESI) m/z: [M+H]+
Calcd for C13H13N2O2, 229.0971; found 229.0970.
(4-nitrophenyl)hydrazine (2J).46 Purified by TLC: (petroleum ether/ethyl acetate =
1/1). Yellow solid (17 mg, 56% yield) mp: 157–158 °C. 1H NMR (400 MHz, CDCl3)
δ 7.41 (d, J = 8.8 Hz, 2H), 6.47 (d, J = 8.8 Hz, 2H), 2.60 (br, 3H). 13C{1H} NMR (100
MHz, CDCl3) δ 146.01, 137.94, 117.34, 79.46. IR (KBr) 3121, 2929, 2286, 1619,
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1515, 1177, 1159, 1019, 982, 864, 810, 779, 706, 527 cm-1. HRMS (ESI) m/z:
[M+H]+ Calcd for C6H7N2O2, 139.0502; found 139.0506.
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1-(4-nitrophenyl)piperidine (2K). Purified by TLC: (petroleum ether/ethyl acetate =
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1
10/1). Yellow solid (34.5 mg, 61% yield) mp: 174–176 °C. H NMR (400 MHz,
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CDCl3) δ 8.16 (d, J = 9.2 Hz, 2H), 7.31–7.29 (m, 2H), 6.98–6.87 (m, 5H), 3.60 (t, J =
13
5.2 Hz, 4H), 3.36 (t, J = 5.2 Hz, 4H). C{1H} NMR (100 MHz, CDCl3) δ 153.04,
138.18, 128.86, 128.72, 126.89, 126.46, 111.17, 44.36, 35.11. IR (KBr) 3141, 1578,
1509, 1478, 1401, 1319, 1119, 1026, 918, 725, 542 cm-1. HRMS (ESI) m/z: [M+H]+
Calcd for C16H18N3O2, 284.1393; found 284.1405.
Gram-scale synthesis of N,N-dimethyl-4-nitroaniline (2a).
Procedure (1): 1-iodo-4-nitrobenzene (1 g, 4 mmol), KOH (0.56 g, 10 mmol) in
DMF (2.2 mL, 28 mmol) were stirred in a sealed tube under an atmosphere of air at
100 °C for 4 days. After being cooled to room temperature, the reaction mixture were
filtered, washed with ethyl acetate. Afterward, the solution was evaporated under
vacuum. The residue was purified by silica gel column chromatography with
petroleum ether and ethyl acetate to achieve the pure product
N,N-dimethyl-4-nitroaniline in a yield of 87% (0.58 g).
Procedure (2): 1-fluoro-4-nitrobenzene (1 g, 7.1 mmol), KOH (0.99 g, 17.75 mmol)
in DMF (3.9 mL, 49.7 mmol) were stirred in a sealed tube under an atmosphere of air
at 100 °C for 4 days. After being cooled to room temperature, the reaction mixture
were filtered, washed with ethyl acetate. Afterward, the solution was evaporated
under vacuum. The residue was purified by silica gel column chromatography with
petroleum ether and ethyl acetate to achieve the pure product
N,N-dimethyl-4-nitroanilinein a yield of 83% (0.97 g).
ASSOCIATED CONTENT
Supporting Information The Supporting Information is available free of
1
charge on the ACS Publications website at DOI: xxxxxxxx. Copies of H, and
13C NMR spectra for all reaction products.
AUTHOR INFORMATION
Corresponding Author
*E-mail: hgong@xtu.edu.cn
Notes
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The authors declare no competing financial interest.
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ACKNOWLEDGEMENTS
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We are grateful to the National Natural Science Foundation of Hunan Province
(No. 2018JJ2389), National Natural Science Foundation of China (No.
21402168), the Project of Innovation Team of the Ministry of Education
(IRT_17R90), Hunan 2011 Collaborative Innovation Center of Chemical
Engineering & Technology with Environmental Benignity and Effective
Resource Utilization, and “1515” academic leader team program of Hunan
Agricultural University for their support of our research.
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