A mild and efficient method for copper-catalyzed Ullmann-type N-arylation of aliphatic amines and amino acids

Article abstract of DOI:10.1055/s-2007-982564

An efficient and general protocol for copper-catalyzed N-arylation of aliphatic amines and amino acids has been developed using aryl iodides under mild conditions (coupling temperature at 25-35°C). For the N-(o-nitrophenyl) amino acid derivatives, subsequent reduction of the nitro group in the presence of tin(II) chloride resulted in 3,4-dihydroquinoxalin-2(1H)-one derivatives in good yields. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-2007-982564

1836
LETTER
A Mild and Efficient Method for Copper-Catalyzed Ullmann-Type
N-Arylation of Aliphatic Amines and Amino Acids
C
opper-Catalyzed
u
U
llmann-Ty
n
pe N-Arylation of
A
J
liphatic
A
i
mines
a
a
nd Amino
n
Acids g,a Deshou Jiang,b Yuyang Jiang,*a Hua Fu,*b Yufen Zhaob
a
Key Laboratory of Chemical Biology, Guangdong Province, College of Shenzhen, Tsinghua University, Shenzhen 518057,
P. R. of China
b
Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry,
Tsinghua University, Beijing 100084, P. R. of China
Fax +86(10)62781695; E-mail: fuhua@mail.tsinghua.edu.cn
Received 10 April 2007
presence of tin(II) chloride to produce 1,2,3,4-tetrahydro-
pyrazine derivatives in good yields.
Abstract: An efficient and general protocol for copper-catalyzed
N-arylation of aliphatic amines and amino acids has been developed
using aryl iodides under mild conditions (coupling temperature at
25–35 °C). For the N-(o-nitrophenyl) amino acid derivatives,
subsequent reduction of the nitro group in the presence of tin(II)
chloride resulted in 3,4-dihydroquinoxalin-2(1H)-one derivatives in
good yields.
We initially examined various combinations of copper
catalysts, ligands, bases, and solvents to optimize the
reaction conditions for N-arylation of aliphatic amines
using 1-chloro-4-iodobenzene and benzylamine at 30 °C.
As shown in Table 1, four ligands15 were tested in DMF
using CuI (10 mol% relative to 1-chloro-4-iodobenzene)
as the catalyst and K3PO4 as the base (entries 1–4), and L1
gave the highest yield (81%, entry 1). The nature of the
base also affected the coupling efficiency: all the tested
inorganic bases were much better than triethylamine, and
K2CO3 (entry 5) and KOH (entry 6) were poor bases. Sol-
vents were also evaluated (entries 1, 8–11), and DMF and
DMSO gave almost the similar results (entries 1 and 8).
The results showed that Cu(I) salts were good catalysts,
but Cu(II) ones did not work. CuI and CuBr gave similar
coupling yields (entries 1 and 12). After the optimization
process of catalysts, ligands, and solvents, the coupling
reactions were carried out under the following standard
conditions: CuI (10 mol%) as the catalyst, L1 (20 mol%)
as the ligand relative to aryl iodides, DMF as the solvent
and K3PO4 as the base at 25–35 °C.
As shown in Table 2, the CuI–L1 catalyst system was
successfully used in the coupling of various substrates.
The substituted iodobenzenes containing electron-with-
drawing groups displayed higher reactivity than those
containing electron-donating groups. The primary ali-
phatic amines were somewhat better substrates than the
cyclic secondary ones, and pyrrole because of its lower
basicity showed slightly lower activity than the saturated
cyclic secondary amines.15
Key words: copper-catalyzed, aliphatic amine, amino acid, Ull-
mann reaction
There is a high demand for new methods of facilitating
aryl amination because the products are of great signifi-
cance in the pharmaceutical, agrochemical and materials
world. In the last few years, great progress in the copper-
catalyzed N-arylation of amines/amides has been made,1–12
but a simple and general procedure for the copper-cata-
lyzed coupling of aliphatic amines and amino acids with
aryl halides under mild conditions still remains elusive.2c
Since 2003, several ligands have been introduced to pro-
mote copper-catalyzed N-arylation of aliphatic amines,
most notably N,N-diethylsalicylamide,2c amino acids,3
amino alcohols,4 phosphoramidite5 and oxime-phosphine
oxide.6 Despite these progresses, these reactions still suf-
fer from the need for high reaction temperatures (60–120
°C), which may pose problems for substrates carrying
thermally sensitive molecules or in situations such as
combinatorial chemistry applications, where it is inconve-
nient to heat reactions. Very recently, Buchwald’s group13
and our group14 have successfully utilized copper(I) io-
dide–cyclic b-diketone and copper(I) bromide–rac-1,1¢-
binaphthol (BINOL), respectively, as the catalysts to
realize the N-Arylation of aliphatic amines at room tem-
perature. However, these catalytic systems were rarely
used in the N-arylation of amino acids. Herein, we report
an improved catalyst system CuI–2-hydroxybenz-
aldehyde N-phenylhydrazone to catalyze N-arylation of
aliphatic amines and amino acids under mild conditions
(coupling temperature at 25–35 °C), and the subsequent
reduction of N-(o-nitrophenyl) amino acids in the
N-Arylation of amino acids was also investigated under
our standard catalytic conditions.15 As shown in Table 3,
all the tested amino acids were N-arylated in good to
excellent yields at 25–35 °C. Interestingly, the coupling
reactions showed high selectivity. For aryl halides,
the coupling of the iodobenzenes containing Cl (entries
1–10), Br (entry 16), COOH (entry 17) and NO2 (entries
18–21) groups took place only on the C–I bond. For
amino acids and amino acid ester, the coupling reactions
exclusively occurred on the amino group, while the other
functional groups such as hydroxyl (entries 6, 12, 15 and
22), carboxyl (entries 1–21) and ester groups (entry 22)
remained intact. Furthermore, the N,N¢-diarylation
SYNLETT 2007, No. 12, pp 1836–1842
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4
.0
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Advanced online publication: 25.06.2007
DOI: 10.1055/s-2007-982564; Art ID: W07207ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Copper-Catalyzed Ullmann-Type N-Arylation of Aliphatic Amines and Amino Acids
1837
product of lysine was obtained in 56% yield using 1-chlo- chloro-4-iodobenzene produced N-monoarylation on the
ro-4-iodobenzene as the partner under our standard cata- a-amino group rather than on the imino group of indole
lytic conditions (entry 10). Reaction of tryptophan with 1- ring (entry 7).
Table 1 Copper-Catalyzed Coupling of 1-Chloro-4-iodobenzene and Benzylamine: Optimization of the Catalytic Conditionsa
cat., ligand, base
Cl
I
+
H2NH2C
Cl
NHCH2
solvent, 30 °C
OH
NHPh
NHPh
N
N
N
N
OH
OH
OH
NO2
L1
L2
L3
L4
Entry
1
Ligand
L1
Catalyst
Solvent
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
toluene
THF
Base
Yield (%)b
81
CuI
K3PO4
K3PO4
K3PO4
K3PO4
K2CO3
KOH
2
L2
CuI
74
3
L3
CuI
41
4
L4
CuI
trace
56
5
L1
CuI
6
L1
CuI
51
7
L1
CuI
Et3N
12
8
L1
CuI
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
77
9
L1
CuI
12
10
11
12
13
14
15
L1
CuI
68
L1
CuI
pyridine
DMF
DMF
DMF
DMF
trace
78
L1
CuBr
CuSO4
Cu(Ac)2
CuO
L1
0
L1
trace
trace
L1
a Reaction conditions: 1-chloro-4-iodobenzene (1.0 mmol), benzylamine (1.5 mmol), copper catalyst (0.1 mmol), ligand (0.2 mmol), base (2.0
mmol), solvent (1.5 mL).
b Isolated yields.
Table 2 Copper-Catalyzed Coupling of Aryl Iodides with Aminesa
10 mol% CuI
R1
R2
R1
R2
20 mol% L1
ArI
HN
+
ArN
K3PO4, DMF
1
2
3
Entry
1
Amine
Time (h)
3
Product
Yield (%)b
81
Cl
NHCH2
H2NH2C
3a
Cl
NHC5H11
NHC12H25
2
3
1
79
77
NH2C5H11
3b
Cl
5
NH2C12H25
3c
Synlett 2007, No. 12, 1836–1842 © Thieme Stuttgart · New York

1838
Q. Jiang et al.
LETTER
Table 2 Copper-Catalyzed Coupling of Aryl Iodides with Aminesa (continued)
10 mol% CuI
R1
R2
R1
R2
20 mol% L1
ArI
HN
+
ArN
K3PO4, DMF
1
2
3
Entry
4
Amine
Time (h)
8
Product
Yield (%)b
H
N
Cl
3d
Cl
70
64
68
67
82
H2N
N
N
5
6
7
8
8
9
HN
HN
HN
3e
Cl
3f
Cl
N
14
3
3g
NHCH2
H2NH2C
3h
3i
H
N
9
9
67
H2N
NHCH2
10
11
12
13
14
15
4
2
76
73
71
62
66
64
H2NH2C
3j
NHC5H11
NH2C5H11
3k
3l
NHC12H25
5
NH2C12H25
H
N
10
10
14
H2N
HN
3m
3n
3o
N
N
HN
a Reaction conditions: aryl iodide (1.0 mmol), amine (1.5 mmol), CuI (0.1 mmol), ligand (0.2 mmol), K3PO4 (2.0 mmol), solvent (1.5 mL) at
25–30 °C under N2.
b Isolated yield.
3,4-Dihydroquinoxalin-2(1H)-one derivatives are a class (entries 18–21) provided the corresponding N-(o-nitro-
of important bioactive compounds and their synthesis has phenyl) amino acids, and their further reduction in the
often required the expensive aryl fluorides as starting presence of tin(II) chloride produced 3,4-dihydroquinox-
materials in the previous studies.16 Herein, the coupling of alin-2(1H)-one derivatives in 75–81% yields15 as shown
the readily available o-nitroiodobenzene with amino acids in Table 4 according to the reported procedure.17
Synlett 2007, No. 12, 1836–1842 © Thieme Stuttgart · New York

LETTER
Copper-Catalyzed Ullmann-Type N-Arylation of Aliphatic Amines and Amino Acids
1839
Table 3 Copper-Catalyzed Coupling of Aryl Iodides with Amino Acidsa
10 mol% CuI
20 mol% L1
COOH
COOH
H
ArI
HN
+
Ar–N
R3
R3
K3PO4, DMF
1
4
5
Entry
1
Amine
Product
Yield (%)b
90
Me
H
Me
Cl
5a
Cl
N
H2N
H2N
H2N
H2N
COOH
COOH
CH(Me)2
COOH
H
CH(Me)2
COOH
N
2
3
4
88
87
88
5b
Cl
CH2CH(Me)2
COOH
CH2CH(Me)2
COOH
H
N
5c
Cl
CH(Me)Et
COOH
H
CH(Me)Et
COOH
N
5d
Cl
CH2Ph
H
CH2Ph
COOH
N
5
6
86
83
H2N
COOH
5e
CH2
OH
H
CH2
OH
Cl
N
H2N
H2N
COOH
COOH
5f
H
Cl
N
COOH
COOH
7
79
N
N
H
H
5g
CH2CH2SMe
COOH
CH2CH2SMe
COOH
H
Cl
N
8
9
76
68
H2N
5h
Cl
N
COOH
N
H
HOOC
5i
(CH2)3NH2
COOH
(CH2)3NH
COOH
Cl
10c
56
H
N
Cl
H2N
H2N
5j
CH(Me)2
COOH
H
N
CH(Me)2
COOH
11
12
84
77
5k
5l
CH2
OH
H
N
OH
CH2
H2N
COOH
COOH
Synlett 2007, No. 12, 1836–1842 © Thieme Stuttgart · New York

1840
Q. Jiang et al.
LETTER
Table 3 Copper-Catalyzed Coupling of Aryl Iodides with Amino Acidsa (continued)
10 mol% CuI
20 mol% L1
COOH
COOH
H
ArI
HN
+
Ar–N
R3
R3
K3PO4, DMF
1
4
5
Entry
13
Amine
Product
Yield (%)b
CH(Me)2
CH(Me)2
COOH
Bu
H
N
86
80
H2N
H2N
COOH
Bu
5m
5n
H
N
14
15
COOH
COOH
CH2
OH
H
N
OH
CH2
78
58
68
H2N
H2N
COOH
COOH
5o
Br
CH(Me)2
COOH
CH(Me)2
COOH
H
16
17
N
5p
HOOC
CH(Me)2
COOH
CH(Me)2
COOH
H
H2N
N
5q
NO2
Bu
Bu
H
18
73
H2N
H2N
H2N
H2N
N
COOH
COOH
5r
NO2
CH(Me)2
COOH
CH(Me)2
COOH
H
19
20
70
68
N
5s
5t
NO2
Me
Me
H
N
COOH
COOH
NO2
CH2CH2SMe
COOH
CH2CH2SMe
COOH
H
21
68
71
N
5u
CH2
H
OH
CH2
22d
OH
Cl
N
H2N
COOMe
COOMe
5v
a Reaction conditions: aryl iodide (1.0 mmol), amine (1.5 mmol), CuI (0.1 mmol), ligand (0.2 mmol), K3PO4 (3.0 mmol), solvent (1.5 mL) at
30–35 °C under N2.
b Isolated yield.
c Reaction conditions: aryl iodide (3.0 mmol), amine (1.0 mmol), ligand (0.2 mmol).
d K3PO4 (2.0 mmol) was used.
Synlett 2007, No. 12, 1836–1842 © Thieme Stuttgart · New York

LETTER
Copper-Catalyzed Ullmann-Type N-Arylation of Aliphatic Amines and Amino Acids
1841
Table 4 Preparation of 3,4-Dihydroquinoxalin-2(1H)-one Derivatives via the Reduction N-(o-nitrophenyl) Amino Acids in the Presence of
Tin(II) Chloridea
NO2
H
N
O
R
SnCl2, MeOH
reflux, 9 h
COOH
N
H
N
H
R
5
6
Entry
1
5
Product
Yield (%)b
78
NO2
H
N
O
Bu
H
N
N
H
Bu
COOH
5r
5s
5t
6a
6b
6c
6d
H
N
NO2
O
CH(Me)2
COOH
H
2
3
4
81
80
75
N
N
H
CH(Me)2
H
N
NO2
O
Me
H
N
N
H
Me
COOH
H
N
NO2
O
CH2CH2SMe
COOH
H
N
N
H
CH2CH2SMe
5u
a Reaction conditions: 5 (1 mmol), SnCl2 (8 mmol), MeOH (15 mL).
b Isolated yield.
(3) (a) Ma, D.; Zhang, Y.; Yao, J.; Wu, S.; Tao, F. J. Am. Chem.
Soc. 1998, 120, 12459. (b) Ma, D.; Cai, Q.; Zhang, H. Org.
Lett. 2003, 5, 2453. (c) Zhang, H.; Cai, Q.; Ma, D. J. Org.
Chem. 2005, 70, 5164.
(4) (a) Lu, Z.; Twieg, R. J.; Huang, S. D. Tetrahedron Lett.
2003, 44, 6289. (b) Lu, Z.; Twieg, R. J. Tetrahedron 2005,
61, 903.
(5) Zhang, Z.; Mao, J.; Zhu, D.; Wu, F.; Chen, H.; Wan, B.
Tetrahedron 2006, 62, 4435.
(6) Xu, L.; Zhu, D.; Wu, F.; Wang, R.; Wan, B. Tetrahedron
2005, 61, 6553.
In summary, an efficient protocol for copper-catalyzed N-
arylation of aliphatic amines and amino acids under mild
conditions has been developed using readily available
copper(I) iodide–2-hydroxybenzaldehyde N-phenyl-
hydrazone as the catalyst, and the highly selective cou-
pling reactions of the various substituted iodobenzenes
with amino acids provides opportunity for construction of
the complex molecules.
Acknowledgment
(7) (a) Gujadhur, R. K.; Bates, C. G.; Venkataraman, D. Org.
Lett. 2001, 3, 4315. (b) van Allen, D.; Venkataraman, D.
J. Org. Chem. 2003, 68, 4590.
(8) (a) Cristau, H.-J.; Cellier, P. P.; Spindler, J.-F.; Taillefer, M.
Eur. J. Org. Chem. 2004, 695. (b) Cristau, H.-J.; Cellier, P.
P.; Spindler, J.-F.; Taillefer, M. Chem. Eur. J. 2004, 10,
5607.
(9) Zhang, S.; Zhang, D.; Liebeskind, L. S. J. Org. Chem. 1997,
62, 2312.
(10) Kelkar, A. A.; Patil, N. M.; Chaudhari, R. V. Tetrahedron
Lett. 2002, 43, 7143.
This work was supported by the National Natural Science Founda-
tion of China (Grant No. 20472043, 20472042 and 20672065).
Financial supports from the Programs for New Century Excellent
Talents in University (NCET) and Changjiang Scholars and Innova-
tive Research Team in University (PCSIRT) (No. IRT0404) in
China, the Excellent Young Teacher Program of MOE, P.R.C., and
the Key Subject Foundation from Beijing Department of Education
(XK100030514) are gratefully acknowledged.
(11) Gajare, A. S.; Toyota, K.; Yoshifuji, M.; Yoshifuji, F. Chem.
Commun. 2004, 1994.
References and Notes
(12) (a) Rao, H.; Fu, H.; Jiang, Y.; Zhao, Y. J. Org. Chem. 2005,
70, 8107. (b) Rao, H.; Jin, Y.; Fu, H.; Jiang, Y.; Zhao, Y.
Chem. Eur. J. 2006, 12, 3636. (c) Guo, X.; Rao, H.; Fu, H.;
Jiang, Y.; Zhao, Y. Adv. Synth. Catal. 2006, 348, 2197.
(13) Shafir, A.; Buchwald, S. L. J. Am. Chem. Soc. 2006, 128,
8742.
(1) Ley, S. V.; Thomas, A. W. Angew. Chem. Int. Ed. 2003, 42,
5400.
(2) (a) Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L. J.
Am. Chem. Soc. 2001, 123, 7727. (b) Antilla, J. C.; Klapars,
A.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 11684.
(c) Kwong, F. Y.; Buchwald, S. L. Org. Lett. 2003, 5, 793.
Synlett 2007, No. 12, 1836–1842 © Thieme Stuttgart · New York

1842
Q. Jiang et al.
LETTER
(14) Jiang, D.; Fu, H.; Jiang, Y.; Zhao, Y. J. Org. Chem. 2007, 72,
672.
2-(4-Chlorophenylamino)-4-methylpentanoic Acid (5c):
yield: 87%; yellow solid; mp 132–135 °C. 1H NMR (300
MHz, DMSO-d6): d = 7.07–7.10 (d, J = 8.94 Hz, 2 H), 6.56–
6.59 (d, J = 8.94 Hz, 2 H), 3.80–3.8.3 (t, J = 5.82 Hz, 1 H),
3.82 (br s, 1 H), 1.76–1.80 (m, 1 H), 1.56–1.63 (m, 2 H),
0.92–0.95 (d, J = 6.50 Hz, 3 H), 0.86–0.89 (d, J = 6.54 Hz, 3
H). 13C NMR (75 MHz, DMSO-d6): d = 176.0, 149.5, 129.1,
120.0, 114.2, 54.7, 41.4, 24.9, 23.3, 22.2. HRMS (EI): m/z
[M + H]+ calcd for C12H17ClNO2: 242.0948; found:
242.0953.
(15) Synthesis of Ligands
Ligands L1–L4 were prepared according to the reported
procedures.18,19
General Procedure A: Coupling of Aryl Iodides with
Amines:
A flask was charged with CuI (19 mg, 0.1 mmol), ligand (0.2
mmol), K3PO4 (424 mg, 2 mmol), and any remaining solid
(amine and/or aryl halide). The flask was evacuated and
backfilled with nitrogen. Aryl iodide (1 mmol, if liquid) and
amine (1.5 mmol, if liquid), and DMF (1.0–1.5 mL) were
added to the flask under a nitrogen atmosphere. The mixture
was allowed to stir under the nitrogen atmosphere at the
shown temperature for the indicated period of time (see
Table 2). After completion of the reaction, the mixture was
diluted with EtOAc, the solution was filtered, and the
inorganic salts were removed. The solvent in the filtrate was
removed with the aid of a rotary evaporator, and the residue
was purified by column chromatography on silica gel using
PE–EtOAc (30:1 → 20:1) as eluent to provide the desired
product (3).
N-Benzyl-4-methylbenzenamine (3j): yield: 76%; yellow
oil. 1H NMR (300 MHz, CDCl3): d = 7.26–7.33 (m, 5 H),
6.95–6.98 (d, J = 7.89 Hz, 2 H), 6.52–6.55 (d, J = 7.89 Hz, 2
H), 4.28 (s, 2 H), 2.22 (s, 3 H). 13C NMR (75 MHz, CDCl3):
d = 146.1, 139.8, 129.9, 129.5, 128.7, 127.6, 127.3, 126.9,
113.1, 48.8, 20.6. HRMS (EI): m/z [M+] calcd for C14H15N:
197.1204; found: 197.1213.
General Procedure C: Preparation of 3,4-
Dihydroquinoxalin-2 (1H)-one Derivatives:
Tin(II) chloride (0.99 g) was added to N-(o-nitrophenyl)
amino acid 5 (0.5 mmol) in MeOH (10 mL), and the mixture
was refluxed for 9 h. The solution was cooled to r.t., and the
solvent was removed under reduced pressure. The residue
was dissolved in EtOAc (40 mL) and distilled H2O (30 mL),
and then the solution was adjusted to pH 10–11 with 1 N
NaOH. The organic phase was separated, and the aqueous
phase was extracted with EtOAc (40 mL). The combined
organic phase was dried over MgSO4. After removal of the
solvent, the residue was purified by column chromatography
on silica gel using Et2O–EtOAc–MeOH (40:8:2) as eluent to
provide the target product (6).
3-Benzyl-3,4-dihydroquinoxalin-2 (1H)-one (6a): yield:
78%; yellow oil. 1H NMR (300 MHz, DMSO-d6): d = 10.24
(s, 1 H), 7.19–7.26 (m, 5 H), 6.70–6.75 (m, 3 H), 6.57–6.59
(t, J = 8.58 Hz, 1 H), 5.82 (s, 1 H), 3.99–4.04 (m, 1 H), 2.87–
2.93 (m, 2 H). 13C NMR (75 MHz, DMSO-d6): d = 167.4,
138.0, 134.1, 130.2, 128.6, 126.7, 126.2, 123.3, 118.1,
115.1, 114.2, 57.4, 38.1. HRMS (EI): m/z [M + H]+ calcd for
C15H15N2O: 239.1184; found: 239.1193.
General Procedure B: Coupling of Aryl Iodides with
Amino Acids:
The procedure is similar to the general procedure A. K3PO4
(3.0 mmol) was used as the base. After completion of the
reaction (about 12 h), H2O (5 mL) and Et2O (5 mL) were
added to the solution. The resulting solution was partitioned
into two phases, the aqueous phase was separated, and the
organic fraction was extracted with 5% NaOH (3 × 10 mL).
The combined aqueous phase was neutralized to pH 4 with
20% HCl, and extracted with Et2O (3 × 20 mL). The
resulting organic fraction was dried over MgSO4. After
removal of the solvent, the residue was purified by column
chromatography on silica gel using PE–EtOAc–MeOH
(30:10:3) as eluent to provide the target product (5).
(16) (a) Chicharro, R.; de Castro, S.; Reino, J. L.; Aran, V. J. Eur.
J. Org. Chem. 2003, 2314. (b) Acharya, A. N.; Ostresh, J.
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