Mild and efficient copper-catalyzed N-arylation of alkylamines and N-H heterocycles using an oxime-phosphine oxide ligand

Article abstract of DOI:10.1016/j.tet.2005.04.053

A mild and efficient copper-catalyzed system for N-arylation of alkylamines and N-H heterocycles with aryl iodides using a novel, readily prepared and highly stable oxime-functionalized phosphine oxide ligand was developed. The coupling reactions could even be performed in solvent-free conditions with moderate to good yields.

Full text of DOI:10.1016/j.tet.2005.04.053

Tetrahedron 61 (2005) 6553–6560
Mild and efficient copper-catalyzed N-arylation of alkylamines
and N–H heterocycles using an oxime-phosphine oxide ligand
*
Lei Xu, Di Zhu, Fan Wu, Rongliang Wang and Boshun Wan
Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, People’s Republic of China
Received 20 January 2005; revised 19 April 2005; accepted 25 April 2005
Available online 23 May 2005
Abstract—A mild and efficient copper-catalyzed system for N-arylation of alkylamines and N–H heterocycles with aryl iodides using a
novel, readily prepared and highly stable oxime-functionalized phosphine oxide ligand was developed. The coupling reactions could even be
performed in solvent-free conditions with moderate to good yields.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
we attempted to find a highly efficient phosphine to achieve
this coupling and have designed two oxime-functionalized
phosphines (Fig. 1, 1a and 1b).14 To our disappointment,
neither of them were satisfying. We then tried using their
oxides (2a and 2b) as ligands considering that they have
potential chelating ability to copper.15 After a series of
experiments, we found that both of 2a and 2b were effective
supporting ligands and demonstrated excellent stability.
Herein, we report a new class of oxime-phosphine oxide
ligands (2) for copper-catalyzed N-arylation of alkylamines
and N–H heterocycles under mild conditions.
Recently, copper-catalyzed Ullmann-type C(aryl)–N bond
formation under mild conditions has become a focus of
research to include a wide range of subsrates.1–3 By using
certain copper precatalysts and ligands, successful N-ary-
lation of anilines,4,5 amides,6 amino acid,7 amino alcohols,8
hydrazides,9 oxazolidinones10 and various N–H hetero-
cycles6a,11 with aryl halides as arylating reagents was
reported. However, only limited papers have contributed to
N-arylation of alkylamines (not chelating substrates) and
just several ligands were found to be effective in these
transformation.12 Therefore, to find more efficient ligands
and expand the scope of the substrates are desirable.
2. Results and discussion
In copper-mediated cross-coupling systems, the most used
ligands were those containing nitrogen and/or oxygen
bidentated with copper, while phosphines were mainly
used in palladium-mediated systems.13 Only recently,
several phosphine ligands have been reported in Cu-
catalyzed reactions of arylamines with aryl halides.5
However, no efficient phosphine ligands for copper have
been described for cross coupling of alkylamines with aryl
halides to the best of our knowledge. In our initial studies,
The synthesis of various phosphines and phosphine oxides
was depicted in Scheme 1. Ligand 1a was conveniently
synthesized from commercially available 4 in one step. 2a
was readily prepared by oxidizing 1a. Both 1a and 2a were
obtained by recrystallization rather than using complex
column chromatography. Similarly, ligand 1b was readily
prepared from 2-(dicyclohexylphosphino)benzaldehyde (5)
which was prepared according to the literature.16 Further
Figure 1.
Keywords: N-arylation; Oxime-phosphine oxide; Aryl iodides; Copper; Catalysis.
*
Corresponding author. Tel./fax: C86 411 84379260; e-mail: bswan@dicp.ac.cn
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.04.053

6554
L. Xu et al. / Tetrahedron 61 (2005) 6553–6560
Scheme 1. Synthesis of the ligands. Reaction conditions: (a) H2N–OH$HCl, NaHCO3, H2O, EtOH; (b) H2O2, CH2Cl2; (c) H2N–OCH3$HCl, NaHCO3, H2O, EtOH.
oxidizing 1b gave 2b. As a comparison, ligand 3 was also
synthesized.
wide range of solvents including CH3CN, dioxane, DMF,
toluene or even crude CH3OH; while pyridine, THF or
DMSO were less efficient. Hence, CH3CN with lower
polarity and boiling point was chosen for subsequent
experiments.
In our initial screening experiments, iodobenzene and
n-hexylamine were used as model substrates to examine
the above ligands (Table 1). Neither 1a nor 1b were efficient
when the reactions were performed at 60 8C (entries 1 and
2). To our delight, both of their oxides (2a and 2b) were
highly effective giving the coupling product in high yields
under the same conditions (entries 3 and 4). Moreover, the
use of 1a could only give a 78% conversion of the
iodobenzene and 42% yield after 24 h at an elevated
temperature of 90 8C (entry 1 in paretheses). These results
showed that the phosphine oxides were remarkablely
superior to the corresponding phosphines. Additionally,
ligand 3 was not effective at all for the reaction (entry 5).
Apparently, both the moieties of P]O and oxime were
critical. 2a was slightly better in result and more available
than 2b, so we chose for further study.
The scope of the copper-catalyzed N-arylation of different
amines was explored generally by using 5 mol% Cu2O,
20 mol% 2a and 2.1 equiv Cs2CO3 in CH3CN. The results
of aryl iodides with primary amines are detailed in Table 3.
As we can see, various primary amines including n-hexyl-
amine, sec-butylamine, iso-butylamine, cyclopentylamine
were coupled successfully (entries 1–5). The reaction of
iodobenzene with benzylamine resulted in an excellent yield
of 95% with 1 mol% Cu2O, the best result reported so far
(entry 6). Both electron-donating and electron-withdrawing
group, such as methoxy, cyano, nitro, trifluoromethyl were
tolerated on the aryl iodide component (entries 8–13).
Compared with the previous reported results, the couplings
of both 3-iodobenzonitrile and 1-iodo-3-nitrobenzene with
benzylamine were more effective (entries 12 and 13).12b
Table 1. Screening of the ligandsa
Table 2. Optimization studiesa
Entry
Ligand
Conversion, %b
Yield, %b
1
2
3
4
5
1a
1b
2a
2b
3
0 (78)c
0 (42)c
Entry
[Cu]
Solvent
Conversion,
b
Yield, %b
0
95
92
0
0
92
88
0
%
1
2
3
4
5
6
7
8
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
CuO
CuBr
CuI
CuCN
Cu Power
CH3CN
Dioxane
DMF
Toluene
CH3OH
Pyridine
DMSO
THF
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
95
95
93
92
96
84
77
82
20
95
95
91
76
92c
92
91
90
89
77
70
74
a Reaction conditions: 1.0 mmol PhI, 1.2 mmol n-hexylamine, 0.05 mmol
Cu2O, 0.2 mmol ligand, 2.1 mmol Cs2CO3, 0.2 mL CH3CN, 60 8C, 18 h.
b GC yield.
c 24 h, 90 8C.
9
18
10
11
12
13
83d
83d
81d
70d
Preliminary results showed that the use of Cs2CO3 was
important to the effectiveness, while K3PO4, K2CO3 or
KOH only gave poor results.17,18 Among the copper sources
investigated, air and light stable Cu2O was optimal
(Table 2). CuBr, CuI, CuCN and Cu power only provided
inferior results, while the use of CuO resulted in bad yield.
A brief survey for solvent influence showed that the model
reaction could be conducted with comparable efficiency in a
a Reaction conditions: 1.0 mmol PhI, 1.2 mmol n-hexylamine, 10 mol%
[Cu], 20 mmol% 2a, 2.1 mmol Cs2CO3, 0.2 mL solvent, 60 8C, 18 h.
b GC yield.
c Using 5 mol% [Cu], nearly identical result could be obtained.
d Using 5 mol% [Cu].

L. Xu et al. / Tetrahedron 61 (2005) 6553–6560
6555
Table 3. Coupling of aryl iodides with primary aminesa
Entry
ArI
Amine
Product
Yield, %b
1
2
88
85c
H2N-n-Hexyl
3
4
5
NH2-sec-Bu
NH2-i-Bu
65
80
88d
6
7
95e
85c
H2NBn
8
H2N-n-Hexyl
78f
90
76
9
H2NBn
10
H2N-n-Hexyl
11
H2NBn
91
12
13
14
H2NBn 1.5 equiv
H2NBn 1.5 equiv
85d,g
87d,g
91
a Reaction conditions: 1.0 mmol ArI, 1.2 mmol amine, 0.05 mmol Cu2O, 0.2 mmol 2a, 2.1 mmol Cs2CO3, 0.6 mL CH3CN, 80 8C, 18 h.
b Isolated yield.
c 60 8C.
d 90 8C.
e 1 mol% Cu2O was used.
f
PhCH3 as solvent.
g 24 h.
Moreover, aminoalcohol could also be transformed to the
desired product in high yield (entry 14). Notably, diarylation
products were minimal in all reactions.
reactions were moderately sensitive to oxygen and have to
be performed under an inert atmosphere, neither glove-box
techniques nor further purification of the commercially
available reagents were essential. On the other hand, the key
ligand 2a could be obtained readily from commercial
available materials and it was stable and not hydroscopic.
Furthermore, we found that this newly developed protocol
could also be applied to the coupling of N–H heterocycles
with aryl iodides in mild conditions (Table 5).
The optimized reaction condition was also used to examine
the couplings of cyclic secondary amines with aryl iodides
(Table 4). Morpholine was shown to be a good substrate to
give the desired product in high yield, the best result to date
(entry 1). Other cyclic secondary amines such as piperidine,
pyrrolidine, N-ethylpiperazine and ethyl 1-piperazine-
carboxylate could also be coupled successfully with aryl
iodides (entries 2–9). In general, secondary amines gave the
corresponding arylated products in slightly lower yields.
As seen in Table 5, several N-heterocycles could be
effectively transformed to the desired products. The
arylation of pyrazole was carried out smoothly using
various aryl iodides (entries 1–4). It is noteworthy that the
reaction of pyrazole with iodobenzene could even be
performed at rt (entry 2). Imidazole was transformed to
The practical benefits of these copper-catalyzed amination
methodology were briefly noted. On one hand, although the

6556
L. Xu et al. / Tetrahedron 61 (2005) 6553–6560
Table 4. Coupling of aryl iodides with cyclic secondary aminesa
Entry
1
Amine
ArI
Product
Yield, %b
85
2
3
70c
70d
4
5
6
68d
65d
72d
7
73d
8
9
72
60e
a Reaction conditions: 1.0 mmol ArI, 1.2 mmol amine, 0.05 mmol Cu2O, 0.2 mmol 2a, 2.1 mmol Cs2CO3, 0.6 mL CH3CN, 80 8C, 18 h.
b Isolated yield.
c PhCH3 as solvent.
d 90 8C, 1.5 equiv amines.
e 24 h, 90 8C.
the desired product with high yield (entry 5). The arylation
of benzimidazole and indole also proved to be successful
under the general conditions (entries 6 and 7).
4. Experimental
4.1. Materials and methods
The use of such stable, readily available and efficient ligand
as well as mild reaction condition made this protocol
attractive. Furthermore, as seen in Table 6, different amine
could be coupled with aryl iodides successfully in the
solvent-free condition with moderate to good yields. This
enhanced the attractiveness for practical utility.12a,19
Melting points were measured on a Yazawa micro melting
point apparatus (uncorrected). 1H, 31P and 13C NMR spectra
were measured on a Bruker DRX-400 NMR spectrometer
(400 MHz) with TMS as an internal reference. CDCl3 was
used as the solvent for all NMR spectra unless otherwise
stated. High-resolution mass spectra (HRMS) were recorded
on a Mariner 5303 (Applied Biosystems, USA). All
1
products were characterized by H NMR and HRMS and
compared with the previously reported data.11,12a,b,c All
reactions were carried out under an argon atmosphere.
Column chromatography purifications were performed
using silica gel. All solvents were dried and degassed by
standard methods and all starting materials were com-
mercially available. Petroleum ether refers to the boiling
range 60–90 8C. When solvent gradient was used, the
increase of polarity was made gradually from petroleum
ether to mixtures of petroleum ether/ethyl acetate until the
isolation of the product.
3. Conclusion
In summary, we have developed a mild and efficient copper-
catalyzed system for N-arylation of alkylamines and N–H
heterocycles with aryl iodides using a novel, readily
prepared and highly stable oxime-functionalized phosphine
oxide ligand. The reaction could even be performed in
solvent-free conditions. Although this method is restricted
to the coupling of aryl iodides, the readily available ligand
with excellent stability and high efficiency makes this
protocol of potentially practical utility in many cases.
Further studies to expand the application of this method to
other catalytic reactions are currently underway.
4.2. Synthesis of ligands
4.2.1. 2-(Diphenylphosphino)-benzaldoxime (1a). An

L. Xu et al. / Tetrahedron 61 (2005) 6553–6560
Table 5. Coupling of aryl iodides with various N-heterocyclesa
6557
Entry
Amine
ArI
Product
Yield, %b
1
2
94
65c
3
4
5
95
81
92
6
7
60
64
a Reaction conditions: 1.0 mmol ArI, 1.2 mmol amine, 0.05 mmol Cu2O, 0.2 mmol 2a, 2.1 mmol Cs2CO3, 0.6 mL CH3CN, 80 8C, 18 h.
b Isolated yield.
c Performed at rt.
aqueous solution (20 mL) containing hydroxylamine hydro-
chloride (938.0 mg, 13.5 mmol) was prepared and NaHCO3
(1.51 g, 18 mmol) was added under stirring. 2-(Diphenyl-
phosphino)benzaldehyde (4) (3.34 g, 9 mmol) was dis-
solved in EtOH (50 mL) in reflux and the above aqueous
solution was added dropwise. After the reaction mixture was
refluxed continuously for 2 h, the mixture was cooled to rt
with stirring. The white solid was filtered (1.8 g) and the
filtrate was concentrated, exacted with Et2O, washed with
H2O, dried (Na2SO4). The solution was concentrated to give
the product (0.8 g). The two portions weighed 2.6 g of crude
product (95%). The crude product could be used directly in
the next step without further purifications, or can be
recrystallized from ethanol to give the product 1a as a
white solid in 83% yield. Mp 176–177 8C. 1H NMR d 8.81
(d, 1H, JZ4.4 Hz), 7.81–7.84 (m, 1H), 7.67(s, 1H), 7.23–
7.38 (m, 12H), 6.90–6.93 (m, 1H). 31P NMR d K13.4. 13
NMR d 149.3, 149.1, 136.8, 136.6, 136.2, 136.0, 135.9,
C
Table 6. Solvent-free Cu-catalyzed amination of aryl iodidesa
Entry
1
ArI
Amine
Product
Yield, %b
78
H2N-n-Hexyl
2
3
4
H2NBn
87
64c
62c
5
70
a Reaction conditions: 1.0 mmol ArI, 1.2 mmol amine, 0.05 mmol Cu2O, 0.2 mmol 2a, 2.1 mmol Cs2CO3, 80 8C, 18 h.
b Isolated yield.
c Performed 24 h at 90 8C.

6558
L. Xu et al. / Tetrahedron 61 (2005) 6553–6560
134.2, 133.9, 133.9, 130.0, 129.2, 129.1, 128.9, 128.8,
126.7. HRMS (APCI) calcd for C19H17NOP (MCHC):
306.1042, found: 306.1050.
(Na2SO4), concentrated to give the product as a white solid.
Mp 199–202 8C. 1H NMR d 9.29 (s, 1H), 7.98–8.00 (m, 1H),
7.45–7.51 (m, 3H), 1.13–2.15 (m, 22H). 31P NMR d 53.1.
13C NMR d 149.9, 131.9, 131.5, 128.8, 128.2, 36.7, 36.0,
26.5, 25.8, 25.1. HRMS (APCI) calcd for C19H29NO2 (MC
HC): 334.1930, found: 334.1918.
4.2.2. 2-(Diphenylphosphinyl)-benzaldoxime (2a). Com-
pound (1a) (2.60 g, 8.5 mmol) was dissolved in CH2Cl2
(50 mL) and 30% H2O2 (4 mL) was added at rt. The mixture
was stirred for 2 h and large amount of white solid
precipitated. The solid was filtered and washed with water
then recrystallized from MeOH to give the product as a
white solid (1.7 g, 70%). Mp 203–206 8C. 1H NMR
(400 MHz, DMSO-d6) d 11.43 (s, 1H), 8.74 (s, 1H), 8.01–
8.03 (m, 1H), 7.43–7.66 (m, 12H), 7.01–7.07 (m, 1H). 31P
NMR d 30.5. 13C NMR d 146.3, 136.6, 133.0, 132.9, 132.3,
131.8, 131.5, 131.4, 131.0, 130.0, 129.0, 128.9, 128.7,
126.3, 126.2. HRMS (APCI) calcd for C19H17NO2P (MC
HPC): 322.0991, found: 322.1021.
4.3. General procedure for copper-catalyzed N-arylation
of various amines
Cu2O (7.4 mg, 0.05 mmol), ligand (0.2 mmol), Cs2CO3
(685.0 mg, 2.1 mmol) and aryl iodides (if solid, 1.0 mmol)
were weighed in air and transferred into a dried Schlenk
tube. The tube was evacuated and back filled with argon
(3 cycles). Freshly distilled CH3CN, aryl iodides (if liquid,
1.0 mmol) and amines (1.2 mmol) were injected to the tube
successively by micro-syringe at rt. The tube was sealed and
stirred in an oil bath (preheated to reaction temperature) for
the required timeperiod. The reaction mixture was cooled to
rt, ethyl acetate (3 mL), H2O (3 mL) and tetradecane
(100 mL, GC standard) were added. The organic layer was
analyzed by GC and separated. The aqueous layer was
further extracted by ethyl acetate (10 mL!4). The com-
bined organic layers were washed with brine, dried
(Na2SO4). Then the solution was concentrated to give a
residue, which was purified by column chromatograph on
silica gel. The characterization of the products is listed
following.
4.2.3. 2-(Diphenylphosphinyl)benzaldehyde O-methyl-
oxime (3). An aqueous solution (10 mL) containing
methoxylamine hydrochloride (45.0 mg, 0.54 mmol) was
prepared and NaHCO3 (53.0 mg, 0.63 mmol) was added
with stirring. Compound 6 (138.0 mg, 0.45 mmol) was
dissolved in ethanol (10 mL) and the above aqueous
solution was added dropwise. The reaction mixture was
refluxed continuously for 1 h, The reaction mixture was
concentrated, extracted with ethyl acetate, washed with
H2O, brine and dried (Na2SO4). The solution was
concentrated to give a crude product which was purified
by column chromatograph on silica gel to afford a white
4.3.1. N-Hexylaniline (Table 3, entry 1). A liquid
(155.0 mg, 88% yield). H NMR: d 7.21–7.25 (m, 2 H),
1
1
solid 0.12 g (80%). Mp 123–125 8C. H NMR (400 MHz,
DMSO-d6) d 8.83 (s, 1H), 7.99–8.01 (m, 1H), 7.48–7.68 (m,
6.73–6.77 (m, 1 H), 6.66 (d, 2 H, JZ7.6 Hz), 3.36 (s, 1H),
3.15 (t, 2H, JZ7.2 Hz), 1.63–1.70 (m, 2H), 1.33–1.49 (m,
6H), 0.97 (t, 3H, JZ6.8 Hz). HRMS (APCI) calcd for
C12H20N (MCHC): 178.1590, found: 178.1580.
12H), 7.04–7.10 (m, 1H), 3.81 (s, 3H). 31P NMR d 30.5 13
C
NMR d 147.5, 136.9, 133.6, 133.5, 133.0, 132.2, 132.1,
128.9, 128.8, 127.6, 127.5, 62.1. HRMS (APCI) calcd for
C20H19NO2 (MCHC): 336.1148, found: 336.1134.
4.3.2. N-(sec-Butyl)aniline (Table 3, entry 3). A liquid
(97.0 mg, 65% yield). 1H NMR: d 7.13–7.17 (m, 2H),
6.63–7.67 (m, 1H), 6.57 (d, 2H, JZ8 Hz), 3.36–3.43 (m,
2H), 1.55–1.63 (m, 1H), 1.43–1.50 (m, 1H), 1.14–1.17 (m,
3H), 0.93–0.97 (m, 2H). HRMS (APCI) calcd for C10H16N
(MCHC): 150.1277, found: 150.1272.
4.2.4. 2-(Dicyclohexylphosphino)-benzaldoxime (1b).
2-(Dicyclohexylphosphino)-benzaldehyde (1.0 g, 3.3 mmol)
was dissolved in deoxygenated ethanol and the solution was
transferred to a flask including 30 mL of deoxygenated
ethanol flushed by nitrogen. Hydroxylamine hydrochloride
(1.39 mg, 20 mmol) was dissolved in deoxygenated H2O
(40 mL) and NaHCO3 (2.5 g, 30 mmol) was added under
stirring. The aqueous solution was added dropwise to the
2-(dicyclohexylphosphino)-benzaldehyde solution, and the
reaction mixture was stirred for 1 h. The resulting mixture
was extracted with Et2O and dried over Na2SO4, concen-
trated, and purified by flash chromatograph on a short silica
gel column with N2 pressure (100% petroleum ether) to
give the product as a white solid (390 mg, 37%). Mp
4.3.3. N-(iso-Butyl)aniline (Table 3, entry 4). A liquid
(119.0 mg, 80% yield). H NMR: d 7.14–7.18 (m, 2H),
1
6.67–6.69 (m, 1H), 6.60 (d, 2H, JZ8 Hz), 3.74 (br, 1H),
2.92 (d, 2H, JZ6.8 Hz), 1.85–1.90 (m, 1H), 0.97 (d, 6H, JZ
6.8 Hz). HRMS (APCI) calcd for C10H16N (MCHC):
150.1277, found: 150.1285.
4.3.4. N-Cyclopentylaniline (Table 3, entry 5). A liquid
(142.0 mg, 88% yield). 1H NMR: d 7.13–7.20 (m,2H),
6.65–6.68 (m,1H), 6.58–6.60 (m, 2H), 3.74–3.80 (m, 1H),
3.61 (s, 1H), 1.98–2.02 (m, 2H), 1.67–1.73 (m, 2H), 1.59–
1.62 (m, 2H), 1.43–1.47 (m, 2H). HRMS (APCI) calcd for
C11H16N (MCHC): 162.1277, found: 162.1283.
1
116–118 8C. H NMR d 9.16–9.18 (m, 1H), 8.05 (s, 1H),
7.85–7.86 (m, 1H), 7.48–7.50 (m, 1H), 7.33–7.39 (m, 3H),
0.97–1.97 (m, 22H). 31P NMR d K15.9. 13C NMR d 150.7,
150.4, 135.1, 133.0, 128.9, 126.3, 33.4, 33.3, 30.5, 30.3,
28.9, 27.4, 27.2, 27.1, 26.4. HRMS (APCI) calcd for
C19H29NO (MCHC): 318.1981, found: 318.1988.
4.3.5. N-(Phenyl)benzylamine (Table 3, entry 6). A white
solid (174.0 mg, 95% yield). 1H NMR: d 7.34–7.38 (m, 4H),
7.25–7.29 (m, 1H), 7.16–7.19 (m, 2H), 6.72–6.74 (m, 1H),
6.64–6.70 (m, 2H), 4.33 (s, 2H), 4.25 (br, 1H). HRMS
(APCI) calcd for C13H14N (MCHC): 184.1121, found:
184.1119.
4.2.5. 2-(Dicyclohexylphosphinyl)-benzaldoxime (2b). To
a solution of 2-(dicyclohexylphosphino)-benzaldoxime
(159 mg, 0.5 mmol) in CH2Cl2 (20 mL), H2O2 (1.0 ml)
was added under rt. The mixture was stirred for 1 h. The
organic layer was separated and washed with water, dried

L. Xu et al. / Tetrahedron 61 (2005) 6553–6560
6559
4.3.6. 4-Methoxy-N-hexylaniline (Table 3, entry 8). A
liquid (162.0 mg, 78% yield). 1H NMR: d 6.77 (d, 2H, JZ
8.8 Hz), 6.57 (d, 2H, JZ8.8 Hz), 3.73 (s, 3H), 3.22 (br, 1H),
3.03–3.06 (m, 2H), 1.57–1.61 (m, 2H), 1.31–1.40 (m, 6H),
0.89 (t, 3H, JZ6.4 Hz). HRMS (APCI) calcd for C13H22NO
(MCHC): 208.1696, found: 208.1680.
1.74 (m, 2H), 1.57–1.62 (m, 1H). HRMS (APCI) calcd for
C12H15NF3 (MCHC): 230.1151, found: 230.1132.
4.3.16. N-(3-Nitrophenyl)piperidine (Table 4, entry 4). A
liquid (140.0 mg, 68% yield). H NMR: d 7.70 (s, 1H),
1
7.55–7.60 (m, 1H), 7.22–7.36 (m, 1H), 7.17–7.19 (m, 1H),
3.25–3.27 (m, 4H), 1.70–1.74 (m, 4H), 1.62–1.63 (m, 2H).
HRMS (APCI) calcd for C11H15NO2 (MCHC): 207.1128,
found: 207.1112.
4.3.7. N-(4-Methoxyphenyl)benzylamine (Table 3, entry
9). A solid (192.0 mg, 90% yield). H NMR: d 7.28–7.40
1
(m, 5H), 6.78–6.80 (m, 1H), 6.62 (d, 2H, JZ8.6 Hz), 4.29
(s, 2H), 3.75 (s, 3H). HRMS (APCI) calcd for C14H16NO
(MCHC): 214.1226, found: 214.1207.
4.3.17. N-(4-Methoxyphenyl)pyrrolidine (Table 4, entry
5). A liquid (115.0 mg, 65% yield). 1H NMR: d 6.85 (d, 2H,
JZ8.8 Hz), 6.54 (d, 2H, JZ7.6 Hz), 3.76 (s, 3H), 3.23 (s,
4H), 1.97–2.00 (m, 4H). HRMS (APCI) calcd for C11H16NO
(MCHC): 178.1226, found: 178.1216.
4.3.8. 3-Trifluoromethyl-N-hexylaniline (Table 3, entry
10). A liquid (186.0 mg, 76% yield). 1H NMR: d 7.20–7.24
(m, 1H), 6.89–6.90 (d, 1H, JZ7.6 Hz), 6.78 (s, 1Hz), 6.71
(d, 1H, JZ8.0 Hz), 3.68 (br, 1H), 3.10 (t, 2H, JZ7.2 Hz),
1.57–1.63 (m, 2H), 1.32–1.41 (m, 6H), 0.90 (t, 3H, JZ
6.4 Hz). HRMS (APCI) calcd for C8H19N3O2F3 (MCHC):
246.1424, found: 246.1441.
4.3.18. N-(3-Trifluoromethylphenyl)pyrrolidine (Table 4,
entry 6). A solid (155.0 mg, 72% yield). 1H NMR: d 7.26–7.30
(m, 1H), 6.87(d, 1H, JZ8.0 Hz), 6.73(s, 1H), 6.67(d, 1H, JZ
8.0 Hz), 3.27–3.31 (m, 4H), 2.02 (m, 4H). HRMS (APCI)
calcd for C11H13NF3 (MCHC): 216.0995, found: 216.0979.
4.3.9. N-(3-Trifluoromethylphenyl)benzylamine (Table 3,
entry 11). A liquid (228.0 mg, 91% yield). 1H NMR: d 7.18–
7.33 (m, 6Hz), 6.92 (d, 1H, JZ7.6 Hz), 6.82 (s, 1H), 6.71 (d,
1H, JZ8.0 Hz), 4.30 (s, 2H), 4.15 (br, 1H). HRMS (APCI)
calcd for C9H13N3O2F3 (MCHC): 252.0954, found:
252.0967.
4.3.19. N-(3-Nitrophenyl)pyrrolidine (Table 4, entry 7).
An orange solid (140.0 mg, 73% yield). 1H NMR: d 7.52 (d,
1H, JZ8.0 Hz), 7.40 (s, 1H), 7.31–7.35 (m, 1H), 6.91 (d,
1H, JZ8.0 Hz), 3.36–3.37 (m, 4H), 2.07–2.09 (m, 4H).
HRMS (APCI) calcd for C10H13N2O2 (MCHC): 193.0972,
found: 193.0959.
4.3.10. N-(3-Cyanophenyl)benzylamine (Table 3, entry
12). A white solid (176.0 mg, 85% yield). 1H NMR: d 7.30–
7.38 (m, 5H), 7.20–7.26 (m, 1H), 6.99 (d, 1H, JZ7.2 Hz),
6.82–6.84 (m, 2H), 4.64 (br, 1H), 4.34 (s, 2H). HRMS
(APCI) calcd for C14H13N2 (MCHC): 209.1073, found:
209.1064.
4.3.20. N-Phenyl-N-(ethyl)piperazine (Table 4, entry 8).
A solid (136.0 mg, 72% yield). H NMR: d 7.25–7.29 (m,
2H), 6.93–6.95 (m, 1H), 6.84–6.87 (m, 1H), 3.22–3.24 (m,
4H), 2.61–2.63 (m, 4H), 2.45–2.51 (m, 2H), 1.12–1.15 (m,
3H). HRMS (APCI) calcd for C12H19N2 (MCHC):
191.1543, found: 191.1534.
1
4.3.11. N-(3-Nitrophenyl)benzylamine (Table 3, entry
13). An orange solid (198.0 mg, 87% yield). H NMR: d
7.55 (d, 1H, JZ7.6 Hz), 7.46 (s, 1H), 7.26–7.38 (m, 6H),
6.90 (d, 1H, JZ7.6 Hz), 4.39 (s, 2H). HRMS (APCI) calcd
for C13H13N2 O2 (MCHC): 229.0972, found: 229.0959.
1
4.3.21. Ethyl N-(4-Methoxyphenyl)piperazinecarboxyl-
ate (Table 4, entry 9).. A solid (158.0 mg, 60% yield). H
NMR: d 6.83–6.92 (m, 4H), 4.14–4.19 (m, 2H), 3.76–3.77
(m, 3H), 3.63 (s, 4H), 3.02 (s, 4H), 1.28 (t, 3H, JZ7.2 Hz).
HRMS (APCI) calcd for C14H21N2 O3 (MCHC): 265.1547,
found: 265.1531.
1
4.3.12. 2-Phenyl-2-(phenylamino)ethanol (Table 3, entry
16). A colorless liquid (193.0 mg, 91% yield). H NMR: d
1
7.25–7.38 (m, 5H), 7.08–7.12 (m, 2H), 6.66–6.69 (m, 1H),
6.56 (d, 2H, JZ8.0 Hz), 4.49–4.52 (m, 2H), 3.92–3.95 (m,
1H), 3.73–3.77 (m, 1H), 1.77 (br, 1H). HRMS (APCI) calcd
for C14H16NO (MCHC): 214.1226, found: 214.1209.
4.3.22. N-(Phenyl)pyrozole (Table 5, entry 1). A liquid
(134.0 mg, 94% yield). 1H NMR: d 7.88 (d, 1H, JZ2.4 Hz),
7.66–7.71 (m, 3H), 7.39–7.43 (m, 2H), 7.23–7.27 (m, 1H),
6.42–6.43 (m, 1H). HRMS (APCI) calcd for C9H9N2 (MC
HC): 145.0760, found: 145.0751.
4.3.13. N-(Phenyl)morpholine (Table 4, entry 1). A white
solid (138.0 mg, 85% yield). 1H NMR: d 7.25–7.30 (m, 2H),
6.87–6.94 (m, 3H), 3.87 (t, 4H, JZ4.0 Hz), 3.16 (t, 4H, JZ
4.0 Hz). HRMS (APCI) calcd for C10H14NO (MCHC):
164.1070, found: 164.1080.
4.3.23. N-(4-Methoxyphenyl)pyrozole (Table 5, entry 3).
A liquid (165.0 mg, 95% yield). 1H NMR: d 7.83 (d, 1H, JZ
4.0 Hz), 7.70 (s, 1H), 7.58–7.60 (m, 2H), 6.96–6.98 (m, 2H),
6.44 (s, 1H), 3.84 (s, 3H). HRMS (APCI) calcd for
C10H11N2 O(MCHC): 175.0866, found: 175.0856.
4.3.14. N-(4-Methoxyphenyl)morpholine (Table 4, entry
2). A liquid (135.0 mg, 70% yield). H NMR: d 6.76–6.83
(m, 4H), 3.78 (t, 4H, JZ5.2Hz), 3.69 (s, 3H), 2.97 (t, 4H,
JZ4.8Hz). HRMS (APCI) calcd for C11H16NO2 (MCHC):
194.1176, found: 194.1165.
1
4.3.24. N-(3-Trifluoromethylphenyl)pyrozole (Table 5,
entry 4). A liquid (172.0 mg, 81% yield). 1H NMR: d 7.74–
7.89 (m, 4H), 7.51–7.57 (m, 2H), 6.48–6.49 (m, 1H). HRMS
(APCI) calcd for C10H8NF3 (MCHC): 213.0634, found:
213.0610.
4.3.15. N-(3-Trifluoromethylphenyl)piperidine (Table 4,
entry 3). A liquid (160.0 mg, 70% yield). 1H NMR: d 7.29–
7.33 (m, 2H), 7.01–7.11 (m, 2H), 3.19–3.21 (m, 2H), 1.68–
4.3.25. N-(Phenyl)imidazole (Table 5, entry 5). A liquid
(132.0 mg, 92% yield). 1H NMR: d 7.86 (m, 1H), 7.46–7.50

6560
L. Xu et al. / Tetrahedron 61 (2005) 6553–6560
Y.; Yao, J.; Wu, S.; Tao, F. J. Am. Chem. Soc. 1998, 120,
12459–12467. (b) Ma, D.; Xia, C. Org. Lett. 2001, 3,
2583–2586. (c) Clement, J. B.; Hayes, J. F.; Sheldrake,
H. M.; Sheldrake, P. W.; Wells, A. S. Synlett 2001,
1423–1427.
(m, 2H), 7.35–7.39 (m, 3H), 7.28 (s, 1H), 7.21 (s, 1H).
HRMS (APCI) calcd for C9H9N2 (MCHC): 145.0760,
found:145.0773.
4.3.26. N-(Phenyl)benzimidazole (Table 5, entry 6). A
solid (125.0 mg, 64% yield). 1H NMR: d 8.07 (s, 1H), 7.87–
7.89 (m, 1H), 7.46–7.50 (m, 3H), 7.36–7.41 (m, 3H), 7.24–
7.31 (m, 2H). HRMS (APCI) calcd for C13H11N2 (MCHC):
195.0917, found: 195.0895.
8. For amino alcohols as substrates, see: Job, G. E.; Buchwald,
S. L. Org. Lett. 2002, 4, 3703–3706.
9. (a) Wolter, M.; Klapars, A.; Buchwald, S. L. Org. Lett. 2001,
3, 3803–3805. (b) Steinhuebel, D.; Palucki, M.; Askin, D.;
Dolling, U. Tetrahedron Lett. 2004, 45, 3305–3307.
10. Mallesham, B.; Rajesh, M.; Rajmohan-Reddy, P.; Srinivas, D.;
Trehan, S. Org. Lett. 2003, 5, 963–965.
4.3.27. N-(Phenyl)indole (Table 5, entry 7). A solid
(116.0 mg, 60% yield). H NMR: d 7.67–7.69 (m, 1H),
1
7.55 (d, 1H, JZ7.6 Hz), 7.44–7.47 (m, 4H), 7.28–7.33 (m,
2H), 7.14–7.22 (m, 2H), 7.67 (d, 1H, JZ3.6 Hz). HRMS
(APCI) calcd for C14H12N (MCHC): 194.0964, found:
194.0975.
11. (a) Antilla, J. C.; Klapars, A.; Buchwald, S. L. J. Am. Chem.
Soc. 2002, 124, 11684–11688. (b) Antilla, J. C.; Baskin, J. M.;
Barder, T. E.; Buchwald, S. L. J. Org. Chem. 2004, 69,
5578–5587. (c) Cristau, H. J.; Cellier, P. P.; Spindler, J. F.;
Taillefer, M. Eur. J. Org. Chem. 2004, 695–709. (d) Son, S. K.;
Park, I. K.; Park, J.; Hyeon, T. Chem. Commun. 2004,
778–779. (e) Ma, D. W.; Cai, Q. Synlett 2004, 128–130.
12. For alkylamine as substrates, see: (a) Kwong, F. Y.; Buchwald,
S. L. Org. Lett. 2003, 5, 793–796. (b) Kwong, F. Y.; Klapars,
A.; Buchwald, S. L. Org. Lett. 2002, 4, 581–584. (c) Ma, D.;
Cai, Q.; Zhang, H. Org. Lett. 2003, 5, 2453–2455. (d) Lu, Z.;
Twieg, R. J.; Huang, S. D. Tetrahedron Lett. 2003, 44,
6289–6292. (e) Okano, K.; Tokuyama, H.; Fukuyama, T. Org.
Lett. 2003, 5, 4987–4990. (f) Yamada, K.; Kubo, T.;
Tokuyama, H.; Fukuyama, T. Synlett 2002, 231–234. (g)
Enguehard, C.; Allouchi, H.; Gueiffier, A.; Buchwald, S. L.
J. Org. Chem. 2003, 68, 4367–4370.
4.3.28. N-Cyclopentyl-4-methoxyaniline (Table 6, entry
3). A liquid (122.0 mg, 64% yield). H NMR: d 6.75–6.78
1
(m, 2H), 6.56–6.58 (m, 2H), 3.69–3.73 (m, 3H), 3.38 (s,
1H). HRMS (APCI) calcd for C12H18NO (MCHC):
192.1383, found: 194.1364.
Acknowledgements
Financial support from the National Basic Research
Program of China (2003CB114402) is gratefully
acknowledged.
13. For reviews, see: (a) Muci, A. R.; Buchwald, S. L. Top. Curr.
Chem. 2002, 219, 131–209. (b) Hartwig, J. F. In Modern
amination methods; Ricci, A., Ed.; Wiley-VCH: Weinheim,
Germany, 2000. (c) Yang, B. H.; Buchwald, S. L.
J. Organomet. Chem. 1999, 576, 125–146. (d) Wolfe, J. P.;
Wagaw, S.; Marcoux, J. F.; Buchwald, S. L. Acc. Chem. Res.
1998, 31, 805–808. (e) Hartwig, J. F. Angew. Chem., Int. Ed.
1998, 37, 2046–2047.
References and notes
1. Negwer, M. Organic-chemical Drugs and their Synonyms: (an
international survey), 7th ed.; Akademie: Berlin, 1994.
2. Ullmann, F. Ber. Dtsch. Chem. Ges. 1903, 40, 2382–2384.
3. For reviews see: (a) Lindley, J. Tetrahedron 1984, 40,
1433–1456. (b) Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz,
E.; Lemaire, M. Chem. Rev. 2002, 102, 1359–1470. (c) Ley,
S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42,
5400–5449.
14. For a recent article regarding oxime ligand, see: Cristau, H. J.;
Cellier, P. P.; Spindler, J. F.; Taillefer, M. Chem. Eur. J. 2004,
35, 5607–5622.
15. (a) Pilloni, G.; Corain, B.; Degano, M.; Longato, B.; Zanotti,
G. J. Chem. Soc., Dalton Trans. 1993, 1777. (b) Boezio, A. A.;
ˆ ´
Pytkowicz, J.; Cotet, A.; Charette, A. B. J. Am. Chem. Soc.
4. (a) Kelar, A. A.; Patil, N. M.; Chaudhari, R. V. Tetrahedron
Lett. 2002, 43, 7143–7146. (b) Goodbrand, H. B.; Hu, N. X.
J. Org. Chem. 1999, 64, 670–674.
ˆ ´
2003, 125, 14260–14261. (c) Cotet, A.; Boezio, A. A.;
Charette, A. B. Angew. Chem., Int. Ed. 1998, 43, 6525–6528.
16. Schenkel, L. B.; Ellman, J. A. Org. Lett. 2003, 5, 545–548.
17. GC yields of the desired products for the screening reactions
using other base: K3O4 (90 8C, 62%), K2CO3 (55%), KOH
(13%), KOAc (16%), CsOAc (45%), Et3N (4%). Cesium salts
were generally more soluble in organic solvents than their
potassium counterparts,18 which might partially explain the
superiority of Cs2CO3 than others.
5. For phosphines as ligands, see: (a) Gujadhur, R.; Venkataraman,
D.; Kintigh, J. T. Tetrahedron Lett. 2001, 42, 4791–4793. (b)
Gujadhur, R. K.; Bates, C. G.; Venkataraman, D. Org. Lett. 2001,
3, 4315–4317. (c) Haider, J.; Kunz, K.; Scholz, U. Adv. Synth.
Catal. 2004, 346, 717–722. (d) Gajare, A. S.; Toyota, K.;
Yoshifuji, M.; Ozawa, F. Chem. Commun. 2004, 1994–1995.
6. (a) Klapars, A.; Antilla, J. C.; Buchwald, S. L. J. Am. Chem.
Soc. 2001, 123, 7727–7729. (b) Klapars, A.; Buchwald, S. L.
J. Am. Chem. Soc. 2002, 124, 7421–7428. (c) Deng, W.; Wang,
Y.; Zou, Y.; Liu, L.; Guo, Q. Tetrahedron Lett. 2002, 44,
2311–2315. (d) Kang, S. K.; Kim, D. H.; Park, J. N. Synlett
2002, 427–230.
18. (a) Zaugg, H. E. J. Org. Chem. 1976, 41, 3419–3421. (b) Lee,
J. C.; Yuk, J. Y.; Cho, S. H. Synth. Commun. 1995, 25,
1367–1370.
19. Anastas, P. T.; Kirchhoff, M. M. Acc. Chem. Res. 2002, 35,
686–694.
7. For a- and b-amino acid as substrates, see: (a) Ma, D.; Zhang,