CuBr/rac-BINOL-catalyzed N-arylations of aliphatic amines at room temperature

Article abstract of DOI:10.1021/jo062060e

We have developed an efficient and readily available catalyst system CuBr/racemic BINOL ( 1,1′-binaphthyl-2,2′-diol) that catalyzes N-arylation of aliphatic amines at room temperature, and this inexpensive catalyst system is of high selectivity and tolerance toward various functional groups in the substrates.

Full text of DOI:10.1021/jo062060e

TABLE 1. Copper-Catalyzed C-N Bond Formation of
1-Chloro-4-iodobenzene and Pentylamine: Optimization of the
Catalytic Conditionsa
CuBr/rac-BINOL-Catalyzed N-Arylations of
Aliphatic Amines at Room Temperature
Deshou Jiang,† Hua Fu,*,† Yuyang Jiang,†,‡ and Yufen Zhao†
Key Laboratory of Bioorganic Phosphorus Chemistry and
Chemical Biology, Ministry of Education, Department of
Chemistry, Tsinghua UniVersity, Beijing 100084, P. R. China,
and Key Laboratory of Chemical Biology, Guangdong ProVince,
Graduate School of Shenzhen, Tsinghua UniVersity,
Shenzhen 518057, P. R. China
fuhua@mail.tsinghua.edu.cn
entry
catalystb
ligand
base
solvent
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
1,4-dioxane
toluene
DMF
DMF
DMF
DMF
DMF
yield (%)c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
CuI (5%)
CuI (5%)
CuI (5%)
CuI (5%)
CuI (5%)
CuI (5%)
CuSO4 (5%)
CuBr (5%)
CuCl (5%)
CuBr (5%)
CuBr (5%)
CuBr (5%)
CuBr (5%)
CuBr (5%)
CuBr (10%)
CuBr (20%)
CuBr (10%)
CuBr (20%)
A
B
C
D
E
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K2CO3
Cs2CO3
K3PO4
K3PO4
Cs2CO3
Cs2CO3
65
21
42
45
0
ReceiVed October 5, 2006
F
47
0
A
A
A
A
A
A
A
A
A
A
A
A
67
60
65
56
12
56
77
78
85
82
91
We have developed an efficient and readily available catalyst
system CuBr/racemic BINOL (1,1′-binaphthyl-2,2′-diol) that
catalyzes N-arylation of aliphatic amines at room tempera-
ture, and this inexpensive catalyst system is of high selectiv-
ity and tolerance toward various functional groups in the
substrates.
DMF
a Reaction conditions: 1-chloro-4-iodobenzene (1.0 mmol) and penty-
lamine (1.5 mmol), ligand (0.2 mmol), base (2 mmol), solvent (1 mL) at
room temperature (∼25 °C) under N2. b Amount of catalyst relative to
1-chloro-4-iodobenzene. c Isolated yield.
notably N,N-diethylsalicylamide,4 amino acids,5 amino alcohols,6
phosphoramidite,7 and oxime-phosphine oxide.8 Wan and co-
workers very recently reported their research using copper
powder/rac-BINOL or (copper+CuI)/rac-BINOL as the catalyst
system; unfortunately, the N-arylations were performed at 90-
125 °C.9 To the best of our knowledge, N-arylations at room
temperature still remain limited. Very recently, Buchwald and
co-workers have developed highly selective room temperature
copper-catalyzed C-N coupling reactions using CuI/cyclic
â-diketone as the catalyst system and Cs2CO3 as the base.10 It
is highly desirable to develop more convenient and efficient
methods for N-arylation at room temperature which are of high
tolerance toward functional groups in substrates during the
coupling reactions. In this paper, we report an inexpensive and
readily available catalyst system using CuBr as the copper
Although copper-catalyzed Ullmann reactions were developed
more than one hundred years,1 their applications are limited
because of the harsh reaction conditions such as high temper-
atures, the usual requirement of stoichiometric amounts of
copper reagents, long reaction times, and low yields.2 In the
past few years, the copper-catalyzed Ullmann reactions have
shown a renaissance because of the correct choice of copper
sources, bases, ligands, and other additives,3 and it is popular
to develop highly efficient supporting ligands for copper-
catalyzed arylations. Great progress in copper-catalyzed N-
arylation of amines/amides has been made,3 but a simple and
general procedure for the copper-catalyzed coupling of aliphatic
amines with aryl halides under mild conditions has remained
elusive.4 Since 2003, several ligands have been introduced to
promote copper-catalyzed N-arylation of aliphatic amines, most
(5) (a) Ma, D.; Cai, Q.; Zhang, H. Org. Lett. 2003, 5, 2453. (b) Cai, Q.;
Zhu, W.; Zhang, H.; Zhang, Y.; Ma, D. Synthesis 2005, 496. (c) Zhang,
H.; Cai, Q.; Ma, D. J. Org. Chem. 2005, 70, 5164.
(6) (a) Lu, Z.; Twieg, R. J.; Huang, S. D. Tetrahedron Lett. 2003, 44,
6289. (b) Lu, Z.; Twieg, R. J. Tetrahedron 2005, 61, 903.
(7) Zhang, Z.; Mao, J.; Zhu, D.; Wu, F.; Chen, H.; Wan, B. Tetrahedron
2006, 62, 4435.
(8) Xu, L.; Zhu, D.; Wu, F.; Wang, R.; Wan, B. Tetrahedron 2005, 61,
6553.
(9) Zhu, D.; Wang, R.; Mao, J.; Xu, L.; Wu, F.; Wan, B. J. Mol. Catal.
A: Chem. 2006, 256, 256.
* To whom correspondence should be addressed. Fax: 86-10-62781695.
† Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology.
‡ Key Laboratory of Chemical Biology.
(1) (a) Ullmann, F. Ber. Dtsch. Chem. Ges. 1903, 36, 2389. (b) Ullmann,
F. Ber. Dtsch. Chem. Ges. 1904, 37, 853.
(2) For a review, see: Lindley, J. Tetrahedron 1984, 40, 1433.
(3) For recent reviews, see: (a) Ley, S. V.; Thomas, A. W. Angew.
Chem., Int. Ed. 2003, 42, 5400. (b) Kunz, K.; Scholz, U.; Ganzer, D. Synlett
2003, 2428. (c) Beletskaya, I. P.; Cheprakov, A. V. Coord. Chem. Rev.
2004, 248, 2337. (d) Corbet, J.-P.; Mignani, G. Chem. ReV. 2006, 106,
2651.
(4) Kwong, F. Y.; Buchwald, S. L. Org. Lett. 2003, 5, 793.
(10) Shafir, A.; Buchwald, S. L. J. Am. Chem. Soc. 2006, 128, 8742.
10.1021/jo062060e CCC: $37.00 © 2007 American Chemical Society
Published on Web 12/07/2006
672
J. Org. Chem. 2007, 72, 672-674

TABLE 2. Copper-Catalyzed Cross-Coupling of Aryl Iodides with Aminesa
a Reaction conditions: aryl iodide (1.0 mmol), amine (1.5 mmol), ligand (0.2 mmol), K3PO4 (2 mmol), solvent (1 mL) at room temperature (∼25 °C)
under N2. Amount of catalyst relative to aryl iodide. b Isolated yield. c At 40 °C. d At 50 °C.
catalyst, racemic BINOL (1,1′-binaphthyl-2,2′-diol) as the
ligand, and K3PO4 as the base to construct C(aryl)-N bonds
from aryl iodides at room temperature.
DMSO provided almost the same yields, but the others were
bad solvents. Bases also influenced the progress of the reaction,
and Cs2CO3 gave the highest yield (77% entry 14) with 5 mol
% CuBr (relative to 1-chloro-4-iodobenzene) as the catalyst.
The yield of the target product was gradually improved with
an increase in the amount of CuBr from 5 to 20 mol % (entries
8 and 14-16). K3PO4 gave a slightly lower yield than Cs2CO3;
however, it is cheaper and of practical application in N-arylation.
The corresponding yield greatly decreased when the reaction
was exposed to air, and the presence of a trace amount of water
in the reaction system did not affect the reactivity of the
substrates, which showed that it was not necessary to perform
the N-arylation in dry solvent. After the optimization process
of solvents, ligands, and catalysts, the following coupling
reactions were carried out under our standard conditions: 20
mol % CuBr as the catalyst, 20 mol % racemic BINOL as the
ligand relative to aryl iodides, DMF as the solvent, and K3PO4
as the base at room temperature.
We first chose 1-chloro-4-iodobenzene and pentylamine as
the model substrates to optimize the catalytic conditions,
including optimization of the copper catalysts, ligands, bases,
and solvents in N-arylation at room temperature as shown in
Table 1. Several ligands including racemic BINOL, 2,2′-
biphenol, catechol, ethylene glycol, salicylic acid, and 9,10-
phenanthrenequinone were tested in DMF with 5 mol % CuI
(relative to 1-chloro-4-iodobenzene) as the catalyst and K3PO4
as the base (entries 1-6), and BINOL gave the highest yield
(65%, entry 1). Although catechol and 9,10-phenanthrene-
quinone also displayed certain activity, their efficiency was poor.
In addition, no product was observed in the absence of ligand
under similar reaction conditions. Other copper salts, CuSO4,
CuBr, and CuCl (entries 7-9), were tested in N-arylation, using
DMF as the solvent and BINOL as the ligand, and the results
showed that CuBr was the best catalyst. We also studied the
effect of solvents (compare entries 8 and 10-12): DMF and
The scope of the copper-catalyzed N-arylation was explored
under our standard conditions. As shown in Table 2, the
J. Org. Chem, Vol. 72, No. 2, 2007 673

under nitrogen atmosphere. The flask was sealed and the mixture
was allowed to stir under 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 ethyl
acetate, the solution was filtered, and the inorganic salts were
removed. The solvent of the filtrate was removed with the aid of
a rotary evaporator, and the residue was purified by column
chromatography on silica gel, using petroleum ether/ethyl acetate
(60:1 to 4:1) as eluent to provide the desired product.
coupling reactions were performed well for all the substrates
examined, and the desired arylamines were obtained in moderate
to good yields. The substituted iodobenzenes containing an
electron-withdrawing group showed higher reactivity than those
containing an electron-donating group. Although the aryl iodides
containing an electron-donating group gave slightly lower
reaction yields, they could provide high reactivity when the
temperature was raised from 25 to 40 °C (see entries 1 and
15). The primary aliphatic amines are slightly better substrates
than the cyclic secondary ones, and pyrrole because of its lower
basicity showed lower yields than other saturated cyclic
secondary amines. Amino acids and amino acid ester showed
lower reaction activity relative to the other primary aliphatic
amines, and they also displayed high reactivity when temperature
was raised from 25 to 40 °C (entries 23-25). Interestingly,
N-arylation showed high selectivity to a number of reactive
functional groups in the presence of our catalyst system. For
aryl halides, the coupling of the iodobenzenes containing -Br
and -Cl substituents only took place on the C-I bond. We
also attempted differently substituted amines, for example,
amino alcohol, amino acids and amino acid ester (see entries
22-25), whose coupling reactions exclusively occurred on the
amino group, and the other functional groups such as hydroxyl,
carboxyl, and ester group remained, which is favorable for
construction of the complex molecules. Reaction of tryptophan
with iodobenzene produced N-monoarylation on the R-amino
group rather than on the imino group of the indole ring (see
entry 25) at 40 °C. A very electron-rich substrate 4-iodoanisole
was also tested by using pentylamine as the partner at room
temperature, and only a trace amount of product was observed.
However, the N-arylation provided a 55% yield product when
temperature was raised to 50 °C.
5-(4-Chlorophenylamino)pentan-1-ol (3v). Yellow oil, yield
1
71%. H NMR (CDCl3, 300 MHz) δ 7.07-7.12 (m, 2H), 6.47-
6.53 (m, 2H), 3.62 (t, J ) 6.18 Hz, 2H), 3.06 (t, J ) 6.87 Hz, 2H),
2.74 (s, br, 1H), 1.54-1.61 (m, 4H), 1.41-1.49 (m, 2H). 13C NMR
(CDCl3, 75 MHz) δ 146.8, 129.0, 121.6, 113.7, 62.5, 43.9, 32.3,
29.0, 23.2. HR-EI-MS [M + H]+ m/z calcd for C11H17ClNO
214.0999, found 214.1003.
General Procedure B: Coupling of Aryl Iodides with Amino
Acids. The procedure is similar to general procedure A, except
3.0 mmol of K3PO4 was used as the base, and the reaction
temperature was maintained at 40 °C for 10 h. After the coupling
the solution was cooled to 25 °C, and water (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 additional 10% NaOH (3
× 3 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 to provide the target product.
N-Phenyl-L-tryptophan (3y). Eluent: ethyl acetate/methanol
1
(10:1). Yellow oil, yield 81%. H NMR (DMSO-d6, 300 MHz) δ
7.52 (d, 2H, J ) 7.81 Hz), 7.31 (d, 1H, J ) 7.82 Hz), 7.16 (s, 1H),
6.92-7.05 (m, 4H), 6.48-6.55 (m, 3H), 4.11 (t, J ) 6.87 Hz, 1H),
3.51 (s br, 2H), 3.04-3.23 (m, 2H). 13C NMR (DMSO-d6, 75 MHz)
δ 175.6, 148.2, 136.5, 129.4, 127.7, 124.2, 121.5, 118.9, 118.7,
116.9, 112.9, 111.9, 110.5, 57.4, 28.5. HR-EI-MS [M + H]+ m/z
calcd for C17H17N2O2 281.1290, found 281.1300.
In conclusion, we have developed an efficient and readily
available catalyst system CuBr/rac-BINOL that could catalyze
N-arylation of aliphatic amines at room temperature, and the
inexpensive catalyst system is of high selectivity and tolerance
toward various functional groups in the substrates, so it can
widely be used in the synthesis of the compounds containing
the C-N bond.
Acknowledgment. This work was supported by the Excel-
lent Dissertation Foundation of the Chinese Ministry of Educa-
tion (No. 200222), Program for New Century Excellent Talents
in University (NCET) in China, the Excellent Young Teacher
Program of MOE, P. R. China, the National Natural Science
Foundation of China (Grant Nos. 20472042 and 20672065), and
the Key Subject Foundation from Beijing Department of
Education (XK100030514).
Experimental Section
General Procedure A: Room Temperature Coupling of Aryl
Iodides with Amines. A flask was charged with CuBr (28 mg, 0.2
mmol), 1,1′-binaphthyl-2.2′-diol (57 mg, 0.2 mmol), K3PO4 (424
mg, 2 mmol), and any remaining solids (amine and/or aryl halide).
The flask was evacuated and backfilled with nitrogen (this procedure
was repeated three times). Aryl halide (1 mmol, if liquid), amine
(1.5 mmol, if liquid), and DMF (1 mL) were added to the flask
Supporting Information Available: Synthetic procedures,
characterization data, and 1H, 13C NMR spectra of these synthesized
compounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO062060E
674 J. Org. Chem., Vol. 72, No. 2, 2007