N-(1-Oxy-2-picolyl)oxalamic Acid as an Efficient Ligand for Copper-Catalyzed Amination of Aryl Iodides at Room Temperature

Article abstract of DOI:10.1002/ejoc.201500279

N-(1-Oxy-pyridin-2-ylmethyl)oxalamic acid was identified as efficient ligand for CuI-catalyzed amination of aryl halides at room temperature. In our catalytic system, N-arylation of cyclic secondary amines, primary amines, amino acids, and ammonia proceeded with moderate to excellent yields and high functional group tolerance.

Full text of DOI:10.1002/ejoc.201500279

FULL PAPER
DOI: 10.1002/ejoc.201500279
N-(1-Oxy-2-picolyl)oxalamic Acid as an Efficient Ligand for Copper-
Catalyzed Amination of Aryl Iodides at Room Temperature
Yongbin Wang,[a] Jing Ling,[a] Yu Zhang,[b] Ao Zhang,*[c] and Qizheng Yao*[a]
Keywords: Synthetic methods / Ligand design / N,O ligands / Copper / Amination
N-(1-Oxy-pyridin-2-ylmethyl)oxalamic acid was identified as
efficient ligand for CuI-catalyzed amination of aryl halides at
room temperature. In our catalytic system, N-arylation of cy-
clic secondary amines, primary amines, amino acids, and am-
monia proceeded with moderate to excellent yields and high
functional group tolerance.
efficient ligands for the Cu-catalyzed N-arylation of azoles
with aryl halides in water.[11] The applications of these li-
gands to other coupling reactions have also been explored.
We found that N-(1-oxy-2-picolyl)oxalamic acids can also
facilitate the amination of aryl halides. Herein, we describe
our recent work on a CuI/L1 system that enables the N-
arylation of aliphatic amines and ammonia to take place
smoothly at room temperature.
Introduction
Aromatic amines are important intermediates for organic
synthesis[1] and they are building blocks of natural prod-
ucts,[2] bioactive compounds,[3] pharmaceuticals,[4] poly-
mers,[5] and other functional materials.[6] The formation of
C–N bonds through cross-coupling reactions of amines and
aryl halides catalyzed by transition metals is one of the
most useful methods for the preparation of primary or N-
alkyl-substituted aromatic amines. In addition to palla-
dium-catalyzed Buchwald–Hartwig reactions,[7] convenient
copper-catalyzed cross-coupling reactions are widely used
because of their substrate generality and the low price of
copper-catalyst systems.[8]
Results and Discussion
Although several systems for room temperature Cu-cata-
lyzed amination of aryl halides have been developed, only
The efficiency, generality, and chemoselectivity of Cu- a few also efficiently promote the reactions with secondary
catalyzed reactions are generally governed by the ligands cyclic amines.[10b–10d,10f] We first chose the coupling of 4-
that coordinate to Cu and by the reaction conditions. The iodoanisole and pyrrolidine as a model reaction to screen
development of novel Cu ligands and optimization of cata- the efficiencies of L1 and its analogues L2–L6 (Figure 1).
lytic conditions are important topics of the development of As shown in Table 1, L1 promoted the highest yielding re-
Cu-catalyzed reactions.[8] To date, several efficient Cu/li- action at room temperature (entry 2), whereas only a trace
gand systems have been developed to promote the amin- of the desired product was detected without addition of li-
ation of aryl halides.[1a,9] Room temperature Cu-catalyzed gand (entry 1). Replacement of the hydrogen on the pyr-
reactions are especially attractive because the mild condi- idine ring by other groups decreased the catalytic activities
tions are favorable for functional group tolerance and of the ligands (L2–L5) (entries 3–6), especially when a
chemoselectivity.[10] However, there is still room for the de- fluoro atom was added to the 3-position of the pyridine
velopment of more efficient ligands with high substrate gen- (entry 6). Ligand L6, for which the carboxyl group was pro-
erality and excellent chemoselectivity.
tected with a tert-butyl group, was also applied to test the
In our previous work, N-(1-oxy-2-picolyl)oxalamic acid effect of the carboxyl group on the activity of the ligand.
(L1) and its analogues as novel chelators were developed as
[a] School of Pharmacy, China Pharmaceutical University,
24 Tongjia Xiang, Nanjing 210009, P. R. China
E-mail: qz_yao@163.com
http://yjsc.cpu.edu.cn/dsjj/yaoxueyuan/yaoqizheng.htm
[b] Allist Pharmaceuticals, Inc.,
1118 Halei Road, Shanghai, P. R. China
[c] Shanghai Institute of Materia Medica, Chinese Academy of
Sciences,
Shanghai 200000, P. R. China
E-mail: aozhang@simm.ac.cn
http://www.simm.ac.cn/jgsz/yjjg/yjs/ywhxyjs/zaktz/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500279.
Figure 1. Structures of the ligands.
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The results indicated that the free carboxyl is necessary and CuI and ligands were both doubled (entry 22). Therefore,
that the tert-butyl group may hinder the coordination pro- the optimal conditions for the coupling of 4-iodianisole and
cess between the ligand and CuI (entry 7).[6c]
pyrrolidine was found to be: 10 mol-% CuI, 20 mol-% L1,
2.0 equiv. K3PO4 in DMSO/H2O (10:1 v/v) at 25 °C.
Table 1. L1 and its analogues as ligands for CuI-catalyzed N-aryl-
Under the optimized conditions, the scope of aryl halides
was investigated by using the CuI/L1 system; the results are
summarized in Table 2. Various functionalized aryl iodides
were subjected to this protocol at room temperature and
the reactions worked well in almost all cases. Aryl iodides,
including either electron-rich or -deficient aryl iodides, af-
forded desired N-arylpyrrolidines in excellent yields in 24 to
30 h. Notably, various functional groups, such as free aro-
matic amine, hydroxyl, and ketone, were well tolerated (en-
tries 5, 6, and 10). In the case of ethyl 4-iodobenzoate, the
desired product was isolated with excellent yield when the
solvent was changed to DMSO without addition of water
to avoid the hydrolysis of the ester (entry 11). However, aryl
iodides with an ortho-substituent did not readily participate
in the reaction. For instance, 2-iodoanisole gave 2c in only
42% isolated yield (entry 3). 2-Iodo- and 3-iodopyridine as
heteroaryl iodides were found to be highly reactive sub-
strates in this coupling process (entries 12 and 13).
ation of pyrrolidine.[a]
Entry Cu source
Ligand Solvent
Base
Yield [%][b]
1
2
3
4
5
6
7
8
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
none
L1
L2
L3
L4
L5
L6
L1
L1
L1
L1
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
NMP
CH3CN
DMF
DMSO/H2O
(5:1)
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
trace
75
49
24
50
5.0
41
19
3
9
10
11
28
80
12
13
14
15
16
17
18
19
20
21
22
CuI
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
DMSO/H2O
(10:1)
DMSO/H2O
(20:1)
DMSO/H2O
(10:1)
DMSO/H2O
(10:1)
DMSO/H2O
(10:1)
DMSO/H2O
(10:1)
DMSO/H2O
(10:1)
DMSO/H2O
(10:1)
DMSO/H2O
(10:1)
DMSO/H2O
(10:1)
DMSO/H2O
(10:1)
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
Cs2CO3
KOH
86
63
79
81
79
78
70
11
68
10
92[c]
Table 2. Couplings of pyrrolidine with aryl iodides in DMSO.[a]
CuI
CuBr
CuCl
Cu(OAc)2·H2O
CuSO4·H2O
CuI
CuI
Entry
Ar
Product
Yield [%][b]
CuI
K2CO3
TEA
1
2
3
4
5
6
7
8
4-MeOC6H4
3-MeOC6H4
2-MeOC6H4
3,5-Me2C6H4
3-NH2C6H4
3-HOC6H4
4-FC6H4
C6H5
4-CF3C6H4
4-AcC6H4
2a
2b
2c
2d
2e
2f
92
94
42
CuI
CuI
K3PO4
93
80
84[c]
88
[a] Unless otherwise noted, the reactions were carried out with 4-
iodoanisole (1.0 mmol), pyrrolidine (1.5 mmol), Cu (5 mol-%), li-
gand (10 mol-%), base (2.0 mmol) and solvent (1.0 mL) in a reac-
tion tube at room temperature under N2 atmosphere for 48 h. [b]
Isolated yield. [c] CuI (10 mol-%), ligand (20 mol-%) for 24 h.
2g
2h
2i
85
94
9
10
11
12
13
2j
98
4-EtOOCC6H4
pyridine-3-yl
pyridine-2-yl
2k
2l
95[d]
87
Ligand L1 was selected to optimize the catalytic condi-
tions including solvents, copper source, and base. The mix-
ture of dimethyl sulfoxide (DMSO) and water (10:1) as a
polar solvent system was the most favorable; this solvent
system maintained a solubility balance between the base
and the lipophilic iodobenzene (entries 8–13). Reactions
employing different copper source, including CuI and CuII
salts, were explored (entries 14–17). The efforts demon-
strated that CuI gave the highest yield, although other cop-
2m
97
[a] Unless otherwise noted, the reactions were carried out with aryl
iodides (1.0 mmol), pyrrolidine (1.5 mmol), CuI (10 mol-%), L1
(20 mol-%), K3PO4 (2.0 mmol), and DMSO/H2O (1.0 mL, 10:1 v/
v) at room temperature under N2 atmosphere for 24–30 h. [b] Iso-
lated yield. [c] K3PO4 (3.0 mmol). [d] The solvent was DMSO
(1 mL) without addition of water.
To expand the substrate scope of this methodology fur-
per salts could be utilized in this coupling (entry 12). ther, the CuI/L1 system was explored with other amines, as
Among various bases tested, K3PO4 was found to be prom- shown in Table 3. A variety of other cyclic secondary
ising for the transformation (entries 18–21). The model re- amines, such as functionalized pyrrolidine, piperidines,
action was almost complete in 24 h when the amount of piperazine, morpholine, and azetidine, were examined (en-
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Copper-Catalyzed Amination of Aryl Iodides
tries 1–6). To our delight, they were all effective nucleophilic amines were isolated when sterically less hindered primary
amines in our catalytic system and good to excellent yields amines were applied in this process (entries 11–13).
of products were isolated, even when the reaction was per-
Moreover, L1 promoted the Cu-catalyzed N-arylation of
formed with aryl iodides possessing electron-donating ammonia with 1.5 equiv aqueous ammonia smoothly at
groups. Our catalytic system showed high selectivity in the room temperature (entries 14–17). This process avoided
presence of free hydroxyl groups, which is a desirable fea- harsh conditions and the use of liquid ammonia or a large
ture for the construction of complex molecules (entries 1, excess of aqueous ammonia, which was necessary in several
5, and 6). Extension of this amination process to primary reported Cu-catalyzed amination systems.[9b,9c,9e,10g,12] Ex-
aliphatic amines furnished promising results. Various cyclo- cellent yields of anilines were isolated, and a trace amount
alkylamines coupled successfully with aryl iodides pos- of byproduct (dimer, 3,3Ј-diaminodiphenylamine) was de-
sessing electron-donating groups in good to excellent yields tected only in the case of 3n.[13] The carboxyl groups re-
(entries 7–10). Satisfactory yields of secondary aromatic mained and high yields were observed when both α- and β-
Table 3. Room temperature amination of aryl iodides.[a]
[a] Unless otherwise noted, the reactions were carried out with aryl iodides (1.0 mmol), amine (1.5 mmol), CuI (10 mol-%), L1 (20 mol-
%), K3PO4 (2.0 mmol), and DMSO/H2O (1.0 mL, 10:1 v/v) at room temperature under N2 atmosphere for 24–48 h. [b] Isolated yield. [c]
K3PO4 (3.0 mmol) was used.
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Table 4. Cu-catalyzed amination of aryl bromides at 20–80 °C.
[a] Unless otherwise noted, the reactions were carried out with aryl bromide (1.0 mmol), amine (1.5 mmol), CuI (10 mol-%), L1 (20 mol-
%), K3PO4 (2.0 mmol), and DMSO/H2O (1.0 mL, 10:1 v/v) at room temperature under N2 for 48 h. [b] Isolated yield. [c] K3PO4
(3.0 mmol) was used. [d] The solvent was DMSO (1 mL) without addition of water.
amino acids without any protection groups were applied in Cu-catalyzed N-arylation of azoles in water, whereas L8
the C–N coupling (entries 18–20).
was inefficient. These ligands were also applied in room
The application of aryl bromides in copper-catalyzed C– temperature Cu-catalyzed coupling of pyrrolidine and 4-
N coupling at room temperature is challenging because of iodoanisole; the results are summarized in Table 5. As bi-
their generally low activity. In our catalytic system, some dentate analogues of L1, L7 showed very poor activity,
electron-deficient aryl bromides, such as 2-bromopyridine whereas L8 could promote the coupling of pyrrolidine and
and bromobenzenes with nitro or cyano groups, coupled 4-iodoanisole to provide the desired product with slightly
smoothly with aliphatic amines, ammonia, or glycine in lower yield than L1. These results indicated that the oxam-
moderate to excellent yields at 20–25 °C for 48 h, as shown atic acid groups of the ligands play a decisive role in the
in Table 4 (entries 1–6). Amination reactions of unactivated catalytic process and that L1 may act as diverse types of
aryl bromides with aliphatic amines were conducted at ele- ligand under different conditions. Additionally, the N-oxide
vated temperature (60–80 °C) to afford satisfactory yields group may elevate the efficiency of the ligand through coor-
of the corresponding products (entries 6–10). For example, dination to Cu.[9d,14]
3-bromoanisole coupled with pyrrolidine to give 2b in 71%
yield at 80 °C (entry 10). No byproducts were detected be-
cause of the relatively anhydrous conditions when heated.
Mechanism Study
The efficiency and chemoselectivity of the Cu/ligand sys-
tem for coupling reactions are governed by several factors,
and ligands that coordinate to Cu play an important role
in this process.[8,10] In our previous work, L1 and its ana-
logues were identified as O,O-bidentate ligands and the
carboxyl group was not necessary when the N-arylation of
azoles was promoted in water.[11] This presumption was
Figure 2. Structures of L1 and its analogues.
Structural feature analysis of previously reported Cu-ox-
based on the results of several control experiments involv- alamic acid complexes reveals that the oxalamic acid group,
ing several newly designed ligands (L7–L9; Figure 2). Li- functioning as a bidentate ligand, could efficiently coordi-
gands L7 and L9 were as efficient as L1 in promoting the nate to copper in either N,O- or O,O-coordinate form, and
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Copper-Catalyzed Amination of Aryl Iodides
Table 5. Ligands for CuI-catalyzed N-arylation of pyrrolidine at lead to the formation of intermediate C easier.[16a,18] Nu-
room temperature.[a]
cleophile coordination of aliphatic amines to C and depro-
tonation of the amine produces another anionic species D.
Reductive elimination of D would deliver N-arylation prod-
uct (ArNR1R2) and regenerate the reactive species A; thus,
the coupling reaction could proceed smoothly.
Ligand
Yield [%][b]
None
trace
L1
L7
L8
L9
75
11
57
8
Conclusions
[a] Unless otherwise noted, the reactions were carried out with 4-
iodoanisole (1.0 mmol), pyrrolidine (1.5 mmol), Cu (5 mol-%), li-
gand (10 mol-%), K3PO4 (2.0 mmol), and DMSO (1.0 mL) in a
reaction tube at room temperature under N2 for 48 h. [b] Isolated
yield.
We have developed a useful catalytic CuI/L1 system for
the amination of aryl halides with aliphatic amines or am-
monia at room temperature. A number of unactivated aryl
bromides successfully coupled with aliphatic amines at ele-
vated temperature (50–80 °C). The coupling reactions with
ligand L1, which is easily prepared, proceeded with high
efficiency, generality, and excellent chemoselectivity, and the
process avoided harsh conditions and the use of expensive
bases. A catalytic mechanism was proposed based on the
results of several control experiments, which indicated that
L1 may act as diverse types of ligand under different condi-
tions. Applications of this type of ligand to other coupling
reactions are being explored in our laboratory.
that deprotonation of the amide was generally required in
the former case.[6c,15] Ligand L9, for which the oxamatic
acid group can only act as O,O-ligand due to the absence
of hydrogen on the amide, did not promote the efficient N-
arylation of pyrrolidine.[15a,15c] Therefore, we presumed that
L1 may act as an O,N,O-tridentate ligand and that the reac-
tive anion A was formed by chelating CuI with L1 in the
catalytic process. In this type of reaction with acidic ligand,
the established catalytic mechanism generally involves oxi-
dative addition, nucleophilic substitution, and subsequent
reductive elimination.[1a,9d,16] In Jutand’s computational
mechanism study, the oxidative addition of aryl halides and
nucleophile coordination of amines to anionic copper com-
plexes proceed with removal of the halides.[17] Based on
these studies, we proposed a catalytic cycle as depicted in
Experimental Section
General Procedure for the Reactions in DMSO: A reaction tube
(Schlenk tube if heated) was charged with copper salt (5–10 mol-
%), ligand (10–20 mol-%), nucleophilic amine (solid, 1.5 equiv.),
aryl halide (solid, 1.0 mmol), K3PO4 (2.0 mmol), and a magnetic
stir bar, and the reaction tube was fitted with a rubber septum. The
vessel was evacuated and back filled with nitrogen, and this se-
Scheme 1. Neutral CuIII complex C is formed through oxi- quence was repeated twice. Nucleophilic amines or aqueous ammo-
nia (liquid, 1.5 equiv.), aryl halide (liquid, 1.0 mmol), and DMSO/
H2O (1 mL, 10:1 v/v) were then added successively. The reaction
tube was sealed and stirred at 25 °C for 24–48 h. The reaction mix-
ture was diluted with water (20 mL) and extracted with ethyl acet-
ate (EtOAc) (2ϫ 20 mL). The organic layer was combined, washed
with brine, dried with Na2SO4, and concentrated. The resulting
residue was purified by silica gel chromatograph using a mixture
of petroleum ether (PE) and EtOAc to give the desired product.
Representative examples are as follows.
dative addition of the aryl halide to A followed by dehalo-
genation. The electronic nature of the present ligand might
The ligands L1–L6 were synthesized according to our previous
studies.[11]
N-(4-Methoxylphenyl)pyrrolidine (2a):[7a,7b,19] White solid; m.p. 42–
1
43 °C. H NMR (300 MHz, CDCl3): δ = 6.82 (d, J = 9.0 Hz, 2 H),
6.50 (d, J = 9.0 Hz, 2 H), 3.71 (s, 3 H), 3.19 (t, J = 6.6 Hz, 4 H),
2.03–1.86 (m, 4 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 150.9,
143.1, 115.1, 112.7, 56.0, 48.3, 25.5 ppm. HRMS: m/z calcd. for
C11H16NO [M + H]+ 178.1226; found 178.1233.
N-(3-Methoxyphenyl)pyrrolidine (2b):[9d,19b,20] Colorless oil. 1H
NMR (300 MHz, CDCl3): δ = 7.12 (t, J = 8.1 Hz, 1 H), 6.29–6.14
(m, 2 H), 6.10 (s, 1 H), 3.78 (s, 3 H), 3.25 (t, J = 6.3 Hz, 4 H), 1.96
(d, J = 6.4 Hz, 4 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 160.8,
149.3, 129.9, 105.0, 100.5, 97.9, 55.1, 47.7, 25.5 ppm. MS (ESI):
m/z calcd. for C12H16NO [M + H]+ 178.1; found 178.1.
N-(2-Methoxyphenyl)pyrrolidine (2c):[1a,7a,19b] Colorless oil. 1H
NMR (300 MHz, CDCl3): δ = 6.93–6.73 (m, 4 H), 3.82 (s, 3 H),
3.27 (t, J = 6.5 Hz, 4 H), 1.99–1.84 (m, 4 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 150.5, 140.0, 121.1, 119.7, 115.5, 111.6, 55.6,
Scheme 1. The presumed catalytic mechanism of CuI/L1 in pro-
moting the amination of aryl halides.
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50.5, 24.7 ppm. MS (ESI): m/z calcd. for C12H16NO [M + H]+
178.1; found 178.1.
123.5, 117.7, 47.2, 25.4 ppm. MS (ESI): m/z calcd. for C9H13N2 [M
+ H]+ 149.1; found 149.1.
N-(Pyridine-2-yl)pyrrolidine (2m):[1a,20c,26] Colorless oil. 1H NMR
(300 MHz, CDCl3): δ = 8.15 (dd, J = 5.0, 1.1 Hz, 1 H), 7.50–7.34
(m, 1 H), 6.49 (dd, J = 6.7, 5.6 Hz, 1 H), 6.33 (d, J = 8.5 Hz, 1 H),
3.44 (t, J = 6.7 Hz, 4 H), 2.08–1.92 (m, 4 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 157.3, 148.1, 136.9, 111.0, 106.5, 46.6,
25.5 ppm. HRMS: m/z calcd. for C9H13N2 [M + H]+ 149.1073;
found 149.1072.
1
N-(3,5-Dimethylphenyl)pyrrolidine (2d):[19b] Colorless oil. H NMR
(300 MHz, CDCl3): δ = 6.32 (s, 1 H), 6.20 (s, 2 H), 3.24 (t, J =
6.5 Hz, 4 H), 2.27 (s, 3 H), 2.03–1.86 (m, 4 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 148.3, 138.8, 117.6, 109.7, 47.7, 25.6,
21.8 ppm. MS (ESI): m/z calcd. for C12H18N [M + H]+ 176.1;
found 176.1.
N-(3-Aminophenyl)pyrrolidine (2e):[21] Brown oil. 1H NMR
(300 MHz, CDCl3): δ = 7.00 (t, J = 8.0 Hz, 1 H), 6.08–5.97 (m, 2
H), 5.89 (t, J = 2.1 Hz, 1 H), 3.56 (s, 2 H), 3.23 (t, J = 6.6 Hz, 4 H),
2.03–1.87 (m, 4 H), 1.52–1.36 (m, 2 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 149.1, 147.5, 130.0, 103.3, 103.0, 98.6, 47.6, 25.5 ppm.
HRMS: m/z calcd. for C10H15N2 [M + H]+ 163.1230; found
163.1234.
N-(3,5-Dimethylphenyl)-2-hydroxymethylpyrrolidine (3a): Yellowish
1
oil. H NMR (300 MHz, CDCl3): δ = 6.38 (s, 1 H), 6.32 (s, 2 H),
3.86–3.76 (m, 1 H), 3.68–3.51 (m, 2 H), 3.50–3.41 (m, 1 H), 3.16–
3.04 (m, 1 H), 2.27 (s, 6 H), 2.11 (br., 1 H), 2.07–1.87 (m, 4 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 148.3, 138.9, 118.5, 110.3, 63.7,
60.1, 49.6, 28.8, 23.8, 21.8 ppm. HRMS: m/z calcd. for C13H20NO
[M + H]+ 206.1539; found 206.1543.
N-(3-Hydroxyphenyl)pyrrolidine (2f):[20b] White solid; m.p. 125–
128 °C. 1H NMR (300 MHz, CDCl3): δ = 7.07 (t, J = 8.1 Hz, 1 H),
6.22–6.09 (m, 2 H), 6.05 (t, J = 2.2 Hz, 1 H), 4.88 (br., 1 H), 3.25
(t, J = 6.6 Hz, 4 H), 2.06–1.90 (m, 4 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 156.5, 149.4, 130.1, 104.8, 102.6, 98.7, 47.7, 25.4 ppm.
HRMS: m/z calcd. for C10H14NO [M + H]+ 164.1070; found
164.1072.
N-(4-Methoxylphenyl)piperidine (3b):[10a,20c,27] Yellowish solid; m.p.
1
63–64 °C. H NMR (300 MHz, CDCl3): δ = 6.90 (d, J = 9.1 Hz, 2
H), 6.81 (d, J = 9.1 Hz, 2 H), 3.74 (s, 3 H), 3.01 (t, J = 5.3 Hz, 4 H),
1.80–1.63 (m, 4 H), 1.60–1.46 (m, 2 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 153.6, 147.0, 118.8, 114.3, 55.5, 52.3, 26.2, 24.2 ppm.
MS (ESI): m/z calcd. for C12H18NO [M + H]+ 192.1; found 192.1.
N-(3-Methoxyphenyl)morpholine (3c):[20c] Yellowish oil. 1H NMR
(300 MHz, CDCl3): δ = 7.17 (t, J = 7.9 Hz, 1 H), 6.51 (dd, J = 7.4,
1.7 Hz, 1 H), 6.47–6.38 (m, 2 H), 3.82 (t, J = 4.7 Hz, 1 H), 3.76 (s,
3 H), 3.12 (t, J = 4.9 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 160.7, 152.7, 129.9, 108.5, 104.7, 102.2, 66.9, 55.2, 49.3 ppm.
HRMS: m/z calcd. for C11H16NO2 [M + H]+ 194.1176; found
194.1173.
N-(4-Fluorophenyl)pyrrolidine (2g):[20a] Pale-brown oil. 1H NMR
(300 MHz, CDCl3): δ = 6.98–6.85 (m, 2 H), 6.49–6.39 (m, 2 H),
3.21 (t, J = 6.5 Hz, 4 H), 2.06–1.90 (m, 4 H) ppm. 13C NMR
1
(75 MHz, CDCl3): δ = 154.8 (q, JC,F = 231.5 Hz), 144.8, 115.5 (q,
2JC,F = 21.8 Hz), 112.1 (q, 3JC,F = 7.1 Hz), 48.1, 25.5 ppm. HRMS:
m/z calcd. for C10H13FN [M + H]+ 166.1027; found 166.1026.
N-Phenylpyrrolidine (2h):[19b,20a] Yellowish oil. 1H NMR (300 MHz,
CDCl3): δ = 7.21 (t, J = 8.2 Hz, 2 H), 6.64 (t, J = 7.3 Hz, 1 H),
6.55 (d, J = 8.1 Hz, 2 H), 3.26 (t, J = 6.5 Hz, 4 H), 2.04–1.87 (m,
4 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 148.0, 129.2, 115.4,
111.7, 47.6, 25.5 ppm. MS (ESI): m/z calcd. for C10H14N
[M + H]+ 148.1; found 148.1.
N-(4-Cyanophenyl)-NЈ-methylpiperazine (3d):[28] Light-brown solid;
m.p. 104–106 °C. 1H NMR (300 MHz, CDCl3): δ = 7.49 (d, J =
8.9 Hz, 2 H), 6.87 (d, J = 8.9 Hz, 2 H), 3.34 (t, J = 5.0 Hz, 4 H),
2.55 (t, J = 5.1 Hz, 4 H), 2.35 (s, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 153.3, 133.5, 120.1, 114.2, 100.1, 54.6, 47.1, 46.1 ppm.
HRMS: m/z calcd. for C12H16N3 [M + H]+ 202.1339; found
202.1346.
N-(4-Trifluoromethylphenyl)pyrrolidine (2i):[22] White solid; m.p.
1
91–93 °C. H NMR (300 MHz, CDCl3): δ = 7.42 (d, J = 8.4 Hz, 2
N-(4-Methoxylphenyl)-4-hydroxypiperidine (3e): Light-brown solid;
H), 6.52 (d, J = 8.4 Hz, 2 H), 3.47–3.15 (m, 4 H), 2.16–1.87 (m, 4
1
m.p. 73–74 °C. H NMR (300 MHz, CDCl3): δ = 6.96–6.87 (m, 2
3
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 149.7, 126.4 (q, JC,F
=
H), 6.87–6.77 (m, 2 H), 3.83–3.70 (m, 4 H), 3.44–3.32 (m, 2 H),
2.85–2.72 (m, 2 H), 2.49 (br., 1 H), 2.06–1.91 (m, 2 H), 1.79–1.61
(m, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 153.7, 145.8,
118.9, 114.4, 67.7, 55.6, 49.0, 34.4 ppm. HRMS: m/z calcd. for
C10H13N2O2 [M + H]+ 208.1332; found 2008.1336.
1
2
3.5 Hz), 125.4 (q, JC,F = 268.4 Hz), 116.6 (q, JC,F = 34.4 Hz),
110.8, 47.5, 25.5 ppm. HRMS: m/z calcd. for C11H12F3N
[M + H]+ 216.0995; found 216.0994.
N-(4-Acetylphenyl)pyrrolidine (2j):[23] Yellowish solid; m.p. 126–
127 °C. 1H NMR (300 MHz, CDCl3): δ = 7.85 (d, J = 8.7 Hz, 2
H), 6.49 (d, J = 8.7 Hz, 2 H), 3.33 (s, 4 H), 2.49 (s, 3 H), 2.02 (s,
4 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 196.3, 150.9, 130.7,
124.8, 110.6, 47.5, 26.0, 25.4 ppm. MS (ESI): m/z calcd. for
C12H16NO [M + H]+ 190.1; found 190.1.
N-(3-Methoxyphenyl)-3-hydroxyazetidine (3f): Light-brown oil. 1H
NMR (300 MHz, CDCl3): δ = 7.11 (t, J = 8.0 Hz, 1 H), 6.32 (d, J
= 6.7 Hz, 1 H), 6.06 (d, J = 7.9 Hz, 1 H), 5.98 (s, 1 H), 4.63 (t, J
= 4.7 Hz, 1 H), 4.07 (t, J = 7.3 Hz, 2 H), 3.76 (s, 3 H), 3.58 (dd, J
= 7.7, 4.6 Hz, 2 H), 3.13 (br., 1 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 160.5, 152.9, 129.9, 105.0, 103.3, 98.2, 62.6, 61.8,
55.2 ppm. HRMS: m/z calcd. for C10H14NO2 [M + H]+ 180.1019;
found 180.1021.
Ethyl 4-(Pyrrolidin-1-yl)benzoate (2k):[24] Orange solid; m.p. 103–
105 °C. 1H NMR (300 MHz, CDCl3): δ = 7.90 (d, J = 8.8 Hz, 2
H), 6.48 (d, J = 8.8 Hz, 2 H), 4.31 (q, J = 7.1 Hz, 2 H), 3.31 (t, J
= 6.5 Hz, 4 H), 2.00 (t, J = 6.5 Hz, 4 H), 1.36 (d, J = 7.1 Hz, 3
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 167.2, 150.7, 131.3,
116.6, 110.6, 60.0, 7.5, 25.5, 14.5 ppm. HRMS: m/z calcd. for
C13H18NO2 [M + H]+ 220.1332; found 220.1332.
1
N-Cyclopropyl-3,5-dimethylaniline (3g):[29] Yellowish oil. H NMR
(300 MHz, CDCl3): δ = 6.39 (s, 3 H), 3.95 (br., 1 H), 2.40–2.29 (m,
1 H), 2.26 (s, 6 H), 0.76–0.60 (m, 2 H), 0.53–0.37 (m, 2 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 149.0, 138.9, 119.9, 111.3, 25.4,
21.7, 7.6 ppm. MS (ESI): m/z calcd. for C11H16N [M + H]+ 162.1;
found 162.1.
N-(Pyridine-3-yl)pyrrolidine (2l):[25] Yellowish solid; m.p. 28–30 °C.
1H NMR (300 MHz, CDCl3): δ = 7.97 (d, J = 2.3 Hz, 1 H), 7.91
(d, J = 4.2 Hz, 1 H), 7.09 (dd, J = 8.3, 4.6 Hz, 1 H), 6.79 (d, J = 2,6-Dimethyl-N-cyclobutylaniline (3h): Colorless oil. 1H NMR
6.8 Hz, 1 H), 3.28 (t, J = 6.2 Hz, 4 H), 2.01 (t, J = 6.3 Hz, 4 (300 MHz, CDCl3): δ = 6.34 (s, 1 H), 6.17 (s, 2 H), 3.97–3.81 (m,
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 143.7, 136.8, 134.3,
1 H), 3.64 (br., 1 H), 2.47–2.30 (m, 2 H), 2.21 (s, 6 H), 1.87–1.65
4158
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© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 4153–4161

Copper-Catalyzed Amination of Aryl Iodides
(m, 4 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 147.4, 138.9, N-(3,5-Dimethylphenyl)- -proline (3r): Yellow oil. 1H NMR
L
119.5, 111.1, 49.1, 31.5, 21.7, 15.4 ppm. HRMS: m/z calcd. for
(300 MHz, CDCl3): δ = 10.82 (br., 1 H), 6.42 (s, 1 H), 6.22 (s, 2
H), 4.19 (t, J = 8.2, 2.7 Hz, 1 H), 4.19 (dd, J = 8.2, 2.7 Hz, 1 H),
3.62–3.51 (m, 1 H), 3.36–3.21 (m, 1 H), 2.26 (s, 6 H), 2.23–1.92 (m,
4 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 148.3, 138.9, 118.5,
110.3, 63.7, 60.1, 49.6, 28.8, 23.8, 21.8 ppm. HRMS: m/z calcd. for
C13H16NO2 [M – H]– 218.1187; found 218.1204.
C12H18N [M + H]+ 176.1434; found 176.1445.
N-Cyclopentyl-3-methoxyaniline (3i):[30] Yellowish oil. 1H NMR
(300 MHz, CDCl3): δ = 7.05 (t, J = 8.0 Hz, 1 H), 6.29–6.17 (m, 2
H), 6.15 (t, J = 2.0 Hz, 1 H), 3.86–3.54 (m, 5 H), 2.08–1.91 (m, 2
H), 1.78–1.52 (m, 4 H), 1.52–1.36 (m, 2 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 160.8, 149.5, 129.9, 106.4, 101.9, 99.1, 55.1,
N-Phenyl-L
-alanine (3s):[34] White solid; m.p. 155–156 °C. 1H NMR
54.7, 33.6, 24.1 ppm. HRMS: m/z calcd. for C12H18NO [M + H]+ (300 MHz, [D6]DMSO): δ = 13.50–9.20 (br., 1 H), 7.06 (t, J =
192.1383; found 192.1388.
7.8 Hz, 2 H), 6.64–6.46 (m, 3 H), 3.92 (q, J = 6.9 Hz, 1 H), 1.36
(d, J = 7.0 Hz, 1 H) ppm. 13C NMR (75 MHz, [D6]DMSO): δ =
176.4, 148.3, 129.3, 116.6, 112.8, 51.4, 18.6 ppm. MS (ESI): m/z
calcd. for C9H11NO2 [M + H]+ 166.1; found 166.1.
N-Cyclohexyl-3-methoxyaniline (3j):[30,31] Colorless oil. 1H NMR
(300 MHz, CDCl3): δ = 7.04 (t, J = 8.1 Hz, 1 H), 6.27–6.15 (m, 2
H), 6.13 (t, J = 2.2 Hz, 1 H), 3.73 (s, 3 H), 3.52 (br., 1 H), 3.27–
3.13 (m, 1 H), 2.11–1.96 (m, 2 H), 1.81–1.68 (m, 2 H), 1.68–1.56
N-(3,5-Dimethylphenyl)-3-aminopropanoic Acid (3t): Light-brown
(m, 1 H), 1.44–1.01 (m, 5 H) ppm. 13C NMR (75 MHz, CDCl3): δ solid; m.p. 71–73 °C. H NMR (300 MHz, CDCl3): δ = 8.50 (br.,
1
= 160.9, 148.8, 130.0, 106.4, 101.8, 99.1, 55.1, 51.7, 33.5, 26.0,
25.1 ppm. MS (ESI): m/z calcd. for C13H20NO [M + H]+ 206.2;
found 206.1.
2 H), 6.49 (s, 1 H), 6.40 (s, 2 H), 3.37 (br., 2 H), 2.60 (t, J = 5.5 Hz,
2 H), 2.22 (s, 6 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 177.6,
145.5, 139.2, 122.3, 113.2, 41.5, 33.6, 21.5 ppm. HRMS: m/z calcd.
for C11H16NO2 [M + H]+ 194.1176; found 194.1186.
N-Methoxyethyl-3-methoxyaniline (3k): Yellowish oil. 1H NMR
(300 MHz, CDCl3): δ = 7.06 (t, J = 8.1 Hz, 1 H), 6.25 (t, J =
8.5 Hz, 2 H), 6.17 (s, 1 H), 4.06 (br., 1 H), 3.74 (s, 3 H), 3.56 (t, J
= 5.1 Hz, 2 H), 3.36 (s, 3 H), 3.24 (t, J = 5.2 Hz, 2 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 160.8, 149.7, 130.0, 106.2, 102.7, 99.0,
71.0, 58.7, 55.1, 43.4 ppm. HRMS: m/z calcd. for C10H16NO2 [M
+ H]+ 182.1176; found 182.1178.
N-(4-Nitrophenyl)pyrrolidine (4a):[9d,10d,19b,35] Yellow solid; m.p.
1
163–164 °C. H NMR (300 MHz, CDCl3): δ = 8.09 (d, J = 9.3 Hz,
2 H), 6.45 (d, J = 9.3 Hz, 2 H), 3.39 (t, J = 6.6 Hz, 4 H), 2.21–1.97
(m, 4 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 151.8, 136.4,
126.3, 110.4, 47.9, 25.4 ppm. HRMS: m/z calcd. for C10H13N2O2
[M + H]+ 193.0972; found 193.0971.
3-Methoxy-N-isobutylaniline (3l): Colorless oil. 1H NMR N-(2-Nitrophenyl)pyrrolidine (4b):[35] Yellow oil. 1H NMR
(300 MHz, CDCl3): δ = 7.06 (t, J = 8.1 Hz, 1 H), 6.29–6.17 (m, 2
H), 6.14 (t, J = 2.1 Hz, 1 H), 3.75 (s, 3 H), 3. 90–3.60 (br., 1 H),
(300 MHz, CDCl3): δ = 6.72 (dd, J = 8.2, 1.5 Hz,1 H), 7.41–7.29
(m, 1 H), 6.89 (d, J = 8.3 Hz, 4 H), 6.69 (t, J = 8.0 Hz, 1 H), 3.19
2.89 (d, J = 6.7 Hz, 2 H), 1.94–1.78 (m, 1 H), 0.96 (d, J = 6.7 Hz, (t, J = 6.5 Hz, 4 H), 2.04–1.89 (m, 4 H) ppm. 13C NMR (75 MHz,
6 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 160.9, 150.0, 130.0,
CDCl3): δ = 142.7, 137.0, 133.0, 126.7, 115.7, 115.4, 50.4, 25.7 ppm.
105.9, 102.0, 98.6, 55.1, 51.8, 28.0, 20.5 ppm. HRMS: m/z calcd. MS (ESI): m/z calcd. for C10H13N2O2 [M + H]+ 193.1; found 193.1.
for C11H18NO [M + H]+ 180.1383; found 180.1389.
N-(4-Nitrophenyl)piperidine (4c):[7a,35,36] Yellow solid; m.p. 98–
N-Benzyl-3-methoxyaniline (3m):[10e] Yellowish oil. 1H NMR
100 °C. 1H NMR (300 MHz, CDCl3): δ = 8.08 (d, J = 9.4 Hz, 2
(300 MHz, CDCl3): δ = 7.41–7.21 (m, 5 H), 7.07 (t, J = 8.1 Hz, 1 H), 6.78 (d, J = 9.5 Hz, 2 H), 3.44 (s, 4 H), 1.68 (s, 4 H) ppm. 13C
H), 6.33–6.22 (m, 2 H), 6.19 (t, J = 2.2 Hz, 1 H), 4.30 (s, 2 H), 4.08
(br., 1 H), 3.74 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
160.8, 149.5, 139.3, 130.0, 128.7, 127.6, 127.3, 106.0, 102.7, 98.9,
55.1, 48.3 ppm. HRMS: m/z calcd. for C14H16NO [M + H]+
214.1226; found 214.1232.
NMR (75 MHz, CDCl3): δ = 154.9, 137.3, 126.2, 112.3, 48.4, 25.3,
24.2 ppm. MS (ESI): m/z calcd. for C11H15N2O2 [M + H]+ 207.1;
found 207.1.
1
4-Cyanoaniline (4d):[9e,10g,12] White solid; m.p. 80–82 °C. H NMR
(300 MHz, CDCl3): δ = 7.39 (d, J = 8.6 Hz, 2 H), 6.65 (d, J =
8.6 Hz, 2 H), 4.30 (br., 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ
= 150.7, 133.8, 120.4, 114.4, 99.7 ppm. MS (ESI): m/z calcd. for
1
1,3-Diaminobenzene (3n):[32] Brown solid; m.p. 59–61 °C. H NMR
(300 MHz, CDCl3): δ = 6.93 (t, J = 7.9 Hz, 1 H), 6.10 (dd, J = 7.9,
2.1 Hz, 2 H), 5.99 (t, J = 2.0 Hz, 1 H), 3.53 (s, 4 H) ppm. 13C NMR C7H7N [M + H]+ 119.1; found 119.1.
(75 MHz, CDCl3): δ = 147.6, 130.2, 106.0, 102.0 ppm. MS (ESI):
N-(4-Cyanophenyl)glycine (4e):[37] White solid; m.p. 226–228 °C. 1H
NMR (300 MHz, [D6]DMSO): δ = 12.8 (br., 1 H), 7.47 (d, J =
m/z calcd. for C6H9N2 [M + H]+ 109.1; found 109.1.
3-Methoxyaniline (3o):[9b,9c,9e,10g] Yellow oil. 1H NMR (300 MHz, 8.3 Hz, 2 H), 6.93 (s, 1 H), 6.66 (d, J = 8.3 Hz, 2 H), 3.91 (d, J =
CDCl3): δ = 7.04 (t, J = 8.0 Hz, 1 H), 6.40–6.23 (m, 2 H), 6.21 (s,
1 H), 3.73 (s, 3 H), 3.65 (br., 2 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 160.7, 147.9, 130.2, 108.0, 103.9, 101.1, 55.1 ppm.
HRMS: m/z calcd. for C7H10NO [M + H]+ 124.0757; found
124.0757.
5.0 Hz, 2 H) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 172.3,
152.3, 133.7, 121.0, 112.6, 96.8, 44.3 ppm. HRMS: m/z calcd. for
C9H7N2O2 [M – H]– 175.0513; found 175.0499.
N-Cyclohexyl-4-acetylaniline (4f):[31] White solid; m.p. 114–116 °C.
1H NMR (300 MHz, CDCl3): δ = 7.80 (d, J = 8.8 Hz, 2 H), 6.53
3,5-Dimethylaniline(3p):[9b,10g] Yellowish oil. 1H NMR (300 MHz, (d, J = 8.8 Hz, 2 H), 4.37 (br., 1 H), 3.50–3.20 (m, 1 H), 2.48 (s, 3
CDCl3): δ = 6.40 (s, 1 H), 6.30 (s, 2 H), 3.53 (br., 2 H), 2.23 (s, 6 H), 2.04 (d, J = 9.9 Hz, 2 H), 1.77 (dt, J = 13.1, 3.7 Hz, 2 H), 1.66
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 146.4, 139.0, 120.5,
113.2, 21.4 ppm. HRMS: m/z calcd. for C8H12N [M + H]+
122.0964; found 122.0966.
(dt, J = 12.5, 4.0 Hz, 1 H), 1.49–1.29 (m, 2 H), 1.29–1.06 (m, 3
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 196.3, 151.4, 130.9,
125.9, 111.5, 51.2, 33.0, 26.0, 25.7, 24.9 ppm. MS (ESI): m/z calcd.
for C14H20NO [M + H]+ 218.2; found 218.2.
4-Acetylaniline (3q):[33] Yellow solid; m.p. 98–100 °C. 1H NMR
(300 MHz, CDCl3): δ = 7.79 (d, J = 8.6 Hz, 2 H), 6.63 (d, J =
8.6 Hz, 2 H), 4.36 (br., 2 H), 2.49 (s, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 196.8, 151.6, 130.8, 127.4, 113.7, 26.1 ppm. MS (ESI):
m/z calcd. for C8H8NO [M – H]– 134.1; found 134.0.
N-(4-Cyanophenyl)piperidine (4g):[36] Yellowish solid; m.p. 52–
53 °C. 1H NMR (300 MHz, CDCl3): δ = 7.44 (d, J = 8.7 Hz, 2 H),
6.82 (d, J = 8.7 Hz, 2 H), 3.32 (s, 4 H), 1.64 (s, 6 H), 1.60–1.46 (m,
2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 153.5, 133.4, 120.5,
Eur. J. Org. Chem. 2015, 4153–4161
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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4159

Y. Wang, J. Ling, Y. Zhang, A. Zhang, Q. Yao
FULL PAPER
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C12H15N2 [M + H]+ 187.1; found 187.1.
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Received: February 27, 2015
Published Online: May 27, 2015
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