Mild copper-catalyzed N-arylation of azaheterocycles with aryl halides

Article abstract of DOI:10.1016/j.tetlet.2005.02.074

A highly efficient copper(I)-catalyzed N-arylation of azaheterocycles with various aryl halides is reported. The N-arylation reaction can be carried out using as low as 0.5 mol % of (Cu(I)OTf)₂?PhH and 1.0 mol % of 4,7-dichloro-1,10-phenanthrol

Full text of DOI:10.1016/j.tetlet.2005.02.074

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 2405–2409
Mild copper-catalyzed N-arylation of azaheterocycles
with aryl halides
a
Mark Kuil, E. Koen Bekedam, Gerben M. Visser, Adri van den Hoogenband,
b
b
c,
*
c
a
a
Jan Willem Terpstra, Paul C. J. Kamer, PietW. N. M. van Leeuwen and
a,
*
Gino P. F. van Strijdonck
a
Van ꢀt Hoff Institute for Molecular Sciences, Nieuwe Achtergracht 166, 1018 WV Amsterdam, The Netherlands
Laboratory of Organic Chemistry, Wageningen University, Dreijenplein 8, 6703 HB Wageningen, The Netherlands
b
c
Solvay Pharmaceuticals, postbus 900, 1380 DA Weesp, The Netherlands
Received 21 December 2004; revised 4 February 2005; accepted 10 February 2005
Abstract—A highly efficientcopper(I)-ca at lyzed N-arylation of azaheterocycles with various aryl halides is reported. The N-aryl-
ation reaction can be carried out using as low as 0.5 mol % of (Cu(I)OTf) ÆPhH and 1.0 mol % of 4,7-dichloro-1,10-phenanthroline
2
as the ligand. Furthermore, cheap and stable copper precursors like Cu(I)I and Cu(II)(OAc)
K CO can be used.
2 2
ÆH O and the cheap and mild base
2
3
Ó 2005 Elsevier Ltd. All rights reserved.
The synthesis of compounds bearing an arylated nitro-
gen moiety has gained widespread interest due to their
key role in, for example, medically important species
and in materials with useful interesting electronic and
mechanical properties. Although several methods for
in the literature. It was shown that simple copper salts
in protic solvents can efficiently couple aryl boronic
8
acids with imidazole. We recently reported a base-free
9
and anaerobic modification of the Collman protocol
resulting in the efficient coupling of aryl boronic acids
with imidazole and benzimidazole in the presence of
1
the amination of aryl halides exist, only a few are also
2
–5
10
applicable to the N-arylation of azaheterocycles
the scope of the reaction is still limited. Therefore re-
and
binuclear bis-l-hydroxy copper(II) complexes.
newed interest in copper-catalyzed N-arylations of aza-
3
Unfortunately, the scope of this Cu(II) catalyzed C–N
coupling reaction is rather limited. Several other studies
have focused on the use of aryl halides to arylate aza-
heterocycles. Buchwald and co-workers reported the
use of a copper(I)-catalyst for the N-arylation of azaheter-
heterocycles has grown in recent years. In addition,
Buchwald has recently reported that the palladium-
and copper-catalyzed coupling of 5-aminoindole with
1
1
6
an aryl halide provides complementary products.
Moreover, as the cost of palladium is high, copper is
more attractive for large-scale C–N coupling reactions.
1
1g
ocycles.
This methodology employs copper(I) iodide
0
and racemic trans-N,N -dimethyl-1,2-cyclohexanedi-
amine for the N-arylation of many azaheterocycles.
Cristau et al. have shown that cuprous oxide in the pres-
ence of oxime ligands couple many azoles with aryl
The classical copper-catalyzed Ullmann coupling reac-
7
tion suffers from harsh reaction conditions, low to
moderate yields, and the requirement of stoichiometric
amounts of copper. Milder methods involving various
arylating agents such as boronic acids, have appeared
1
1j,k
halides under mild conditions.
In a search for a more efficientand general me ht od we
report here our recent results in the field of copper-cat-
alyzed N-arylation of azaheterocycles with aryl halides
using various substituted 1,10-phenanthroline ligands.
*
Corresponding authors. Tel.: +31 0 294 479605; fax: +31 0 294
77138 (A.H.); tel.: +31 0 20 525 6938; fax: +31 0 20 525 5604
G.P.F.S.); e-mail addresses: adri.vandenhoogenband@solvay.com;
4
(
For our initial screening studies we investigated the N-
arylation of benzimidazole with 5-bromo-m-xylene in
gino@science.uva.nl
0
040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.02.074

2
406
M. Kuil et al. / Tetrahedron Letters 46 (2005) 2405–2409
Table 2. N-Arylation of indole-derivatives
12
the presence of 5 mol % of (Cu(I)OTf) ÆPhH and
2
1
.1 equiv of Cs CO in NMP as solventat125 °C.
2
3
(Cu(I)OTf) .PhH (5 mol%)
2
R
Br +
R
ligand (10 mol%)
First, we investigated the effect of the presence of donor
ligands on the outcome of the reaction. Monodentate
Cs CO (1.1 eq)
R'
N
H
2 3
N
o
125 C, NMP
and
P(C H ) , P(OPh) , P(o-tolyl) , PPh , dppe, dppf, and
bidentate
phosphorus
ligands
(P(n-Bu)3,
(1eq)
(1.5 eq)
R'
6
11 3
3
3
3
Xantphos) afforded low to moderate yields (results not
shown). Therefore, we changed to chelating nitrogen
ligands in the copper(I)-catalyzed N-arylation of benz-
imidazole. Since Buchwald had reported the efficient
N-arylation of imidazoles using the 1,10-phenanthro-
Entry ArBr
R
Ligand % Conv. % Conv. % Conv.
(
h)
(h)
(h)
a
1
H
A
F
F
F
A
F
F
A
F
33 (17)
85 (17)
86 (17)
58 (17)
35 (17)
85 (17)
100 (17)
100 (17)
80 (3)
57 (41)
100 (89)
94 (41)
100 (89)
60 (89)
100 (89)
100 (113)
a
2
H
b
a
a
a
a
c
5
a
3
4
5
6
7
8
9
H
100 (113)
line/(Cu(I)OTf) ÆPhH system, we focused on the use
2
MeO
CN
CN
H
of similar ligands in the copper(I)-catalyzed N-arylation
of benzimidazole with 5-bromo-m-xylene. Applying a
variety of chelating 1,10-phenanthroline ligands (see
Fig. 1) revealed a large ligand effecton th e yield ( Table
d
d
H
1
). The parent1,10-phenan th roline ( A) afforded a mod-
H
100 (17)
erate yield after 44 h. Substitution on the phenanthro-
line-ring (ligands B–E) gave a slightincrease in ht e
yield. Much to our surprise, 1,10-phenanthroline carry-
ing two electron withdrawing chlorine groups (F) affor-
ded excellent conversions; this system resulted in almost
complete conversion (98%) after 44 h. The use of the
more active 5-iodo-m-xylene as an aryl halide substrate
resulted in 100% yield within 16 h. In none of the reac-
tions were homo-coupled and dehalogenated products
observed.
a
b
c
Aryl bromide is 5-bromo-m-xylene.
equiv of the azole was taken.
1
Aryl bromide is 4-bromopyridine.
Aryl bromide is 5-bromopyrimidine.
d
Next, the scope of this N-arylation reaction was ex-
tended to other azaheterocycles and aryl halides. Table
2 shows that 5-bromo-m-xylene could be coupled to a
variety of indoles using 5 mol % of (Cu(I)OTf) ÆPhH
2
and 10 mol % of 4,7-dichloro-1,10-phenanthroline. The
presence of a strong electron-donating substituent at
the 5-position of the indole showed no significant effect
on the yield (entry 4). Additionally, heteroaryl bromides
like pyridines and pyrimidines were also converted
quantitatively into C–N coupled products. In all cases,
the reaction proceeded without the formation of side
products.
N
N
N
N
N
N
A
D
B
E
C
F
F
F
F
F
Even though the described procedure is effective, all reac-
tions showed the existence of an induction period. Since
solubility of the catalyst seems to be the limiting factor
we tried to improve the efficiency of the new (Cu(I)OTf)2Æ
PhH/4,7-dichloro-1,10-phenanthroline system. Only
Cl
Cl
N
N
N
N
N
N
0
1
.5 mol % (Cu(I)OTf) ÆPhH and 1.0 mol % 4,7-dichloro-
,10-phenanthroline were premixed overnight at 125 °C
2
Figure 1. Substituted 1,10-phenanthroline ligands used in this study.
before the reaction was initiated by the addition
of Cs CO , the azaheterocycle and the aryl halide. Sur-
2
3
prisingly, the N-arylation of benzimidazole with 5-iodo-
m-xylene had already reached 100% conversion within
5 h (see Fig. 2). The use of 5-bromo-m-xylene under
the same reaction conditions, using 1 mol % of copper-
catalyst, afforded an 87% yield after 22 h.
12
Table 1. N-Arylation using substituted 1,10-phenanthroline ligands
(
Cu(I)OTf) .PhH (5 mol%)
2
N
ligand (20 mol%)
N
N
Br +
Cs CO (1.1 eq)
N
H
2
3
o
125 C, NMP
(
1eq)
(1.5 eq)
We screened various copper precursors in the reaction of
benzimidazole with 5-bromo-m-xylene (Table 3).
a
Entry
Ligand
% Conv. (22 h)
% Conv. (44 h)
From Table 3 we can conclude that most Cu(I) salts give
reasonable to high conversions after 22 h. Cu(I)I was al-
1
2
3
4
5
6
A
B
C
D
E
F
12
17
14
26
24
79
43
50
54
60
64
98
mostas efficientas (Cu(I)OTf) ÆPhH in this N-arylation.
2
Cu(I)I, however, is cheaper and more stable than
(Cu(I)OTf) ÆPhH. The use of Cu(II) salts resulted in
2
similar yields to those obtained with Cu(I) salts. The
cheap Cu(II)(OAc) saltafforded 98% conversion af et r
22 h. The presence of water did not influence the perfor-
a
13
E
14
Ligands
procedures.
and
F
were prepared according to literature
2

M. Kuil et al. / Tetrahedron Letters 46 (2005) 2405–2409
Table 4. N-Arylation of benzimidazole with Cu(II)(OAc)
2407
ÆH
2 2
O using a
100
15
series of bases
premixing
no premix
7
5
2
5
0
5
0
Cu(II)(OAc) .H O (5 mol%)
2
2
N
ligand F (10 mol%)
N
N
Br +
base (1.1 eq)
N
H
o
125 C, NMP
(
1eq)
(1.5 eq)
Entry
Base
Cs CO
PO
CO
% Conv. (22 h)
0
5
1
0
1
5
20
time (h)
1
2
3
4
5
6
7
2
3
98
85
94
99
5
K
K
3
4
Figure 2. Premixing of ligand F in the presence of (Cu(I)OTf)
2
ÆPhH
CO
2
3
overnight before starting the reaction by addition of Cs
2
3
,
t-BuOK
NaOAc
DABCO
benzimidazole, and 5-iodo-m-xylene. The lines through the points
are drawn for clarity.
10
0
3
Et N
Table 3. N-Arylation of benzimidazole with 5-bromo-m-xylene using
various copper precursors
15
K CO as bases at80 and 125 °C (for reaction condi-
2
3
tions see Table 3). At125 °C, the conversions were
8% and 94% (22 h) using Cs CO and K CO as bases,
Cu-precursor (10 mol%)
ligand F (10 mol%)
9
N
N
N
2
3
2
3
Br +
respectively. At 80 °C, the same reaction profile was ob-
served, although the reaction rate was somewhat lower.
Cs CO (1.1 eq)
N
H
2
3
o
125 C, NMP
So, using Cs CO and K CO as bases afforded 63% and
2
(
1eq)
(1.5 eq)
2
3
3
5
7% conversion, respectively, after 54 h. Thus it is pos-
sible to conduct the N-arylation reaction at lower tem-
peratures using the cheap and mild base K CO .
Entry
Cu-precursor
% Conv.
22 h)
% Conv.
(44 h)
(
2
3
1
2
3
4
5
6
7
8
9
Cu(0) powder (<200 mesh)
Cu(I)CN
Cu(I)Cl
20
22
62
73
79
100
81
70
98
98
44
48
99
98
98
Another approach to lower the reaction temperature in-
volves using a microwave. Microwave irradiation has
become increasingly popular in recentyears to improve
the yield and to shorten reaction times in a variety of
Cu(I)Br
Cu(I)I
a
16
(Cu(I)OTf)
Cu(II)Cl
Cu(II)Br
2
ÆPhH
reactions. Since microwave heating has also been suc-
cessfully applied in several copper mediated N-arylation
2
99
1
7
2
94
reactions, we tested this methodology in the Cu(I)I/
,7-dichloro-1,10-phenanthroline catalyzed N-arylation
Cu(II)(OAc)
Cu(II)(OAc)
2
anhydrous
ÆH
100
100
4
1
0
2
2
O
of benzimidazole. The use of microwave irradiation re-
sulted not in the formation of the desired product but
in substitution of the chloro group of the ligand for a
a
5
2
mol % of (Cu(I)OTf) ÆPhH.
1
8
benzimidazole. Even in the absence of Cu(I)I, this
product was formed. We did not observe the formation
of this coupling product when conventional heating was
applied.
mance of this catalytic system. Buchwald and co-work-
ers also reported the successful use of several copper pre-
cursors in the arylation of N-methylformamide.
1
1b
From these studies we conclude that relatively cheap
and stable copper salts such as Cu(I)I and Cu(II)(OAc)2Æ
H O can be used to arylate benzimidazole with aryl
2
At present, the mechanism of Cu(I) catalyzed coupling
1
9
reactions is still under debate. For example, Buchwald
proposed a catalytic cycle that starts with coordination
of the amine, followed by oxidative addition of the aryl
halide and then reductive elimination yielding the N-aryl-
ated compound and the catalytic copper-mediated
bromides in an efficientmanner.
Since Cs CO is a rather expensive base we tested the
2
3
1
1b
activity of a series of bases to make our methodology
broadly applicable (Table 4).
species.
Deng et al. reported that the oxidative addi-
tion of the aryl halide precedes coordination of the
2
0
11k
amine.
Recently, Cristau et al.
ruled ou ht te
The organic amine bases DABCO and triethylamine
possibility of radical intermediates and proposed two
alternative oxidative addition/reductive elimination
mechanistic pathways. To the best of our knowledge,
no mechanistic studies on the copper-catalyzed N-aryla-
tion resulting in the full elucidation of the catalytic
pathway have been reported in the literature.
(
entries 6 and 7) give low yields. The stronger inorganic
bases (entries 1–4) all resulted in high conversions after
2 h. Similar results were obtained using Cu(I) iodide as
2
a copper precursor. These studies have shown that the
expensive Cs CO can be replaced by the cheaper bases
t-BuOK, K CO , and K PO .
2
3
2
3
3
4
Figure 3 shows the reaction profile of the N-arylation of
benzimidazole using the Cu(I)I/4,7-dichloro-1,10-phe-
nanthroline catalyst. It was concluded that the presence
We conducted the Cu(I)-catalyzed N-arylation of benz-
imidazole with 5-bromo-m-xylene using Cs CO and
2
3

2408
M. Kuil et al. / Tetrahedron Letters 46 (2005) 2405–2409
1
00
the ligand leads to similar reaction rates as when using
copper(I)-precursors. Preliminary mechanistic work is
discussed and more detailed studies are in progress.
7
5
2
5
0
5
0
Acknowledgements
premix F
premix F + Cu(I)I
no premix
We would like to thank Dr. M. Tromp from the Univer-
sity of Utrecht and J. A. J. den Hartog from Solvay
Pharmaceuticals for stimulating discussions. Solvay
Pharmaceuticals is kindly acknowledged for financial
support.
0
1
0
20
30
time (h)
Figure 3. Premixing of ligand F in the presence and in the absence of
Cu(I)I overnight before starting the reaction by addition of benzimid-
azole and 5-bromo-m-xylene. The lines through the points are drawn
for clarity.
References and notes
1
. For reviews see: (a) Hartwig, J. F. Synlett 1997, 329; (b)
Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L.
Acc. Chem. Res. 1998, 31, 805; (c) Hartwig, J. F. Acc.
Chem. Res. 1998, 31, 852; (d) Hartwig, J. F. Angew.
Chem., Int. Ed. 1998, 37, 2046; (e) Yang, B. H.; Buchwald,
S. L. J. Organomet. Chem. 1999, 576, 125; (f) Muci, A. R.;
Buchwald, S. L. Top. Curr. Chem. 2002, 219, 131.
100
7
5
0
5
5
2
premix F
premix F + Cu(II)(OAc)2H2O
no premix
2
3
. (a) Mann, G.; Hartwig, J. F.; Driver, M. S.; Fern a´ ndez-
Rivas, C. J. Am. Chem. Soc. 1998, 120, 827; (b) Hartwig, J.
F.; Kawatsura, M.; Hauck, S. I.; Shaughnessy, K. H.;
Alcazar-Roman, L. M. J. Org. Chem. 1999, 64, 5575; (c)
Old, D. W.; Harris, M. C.; Buchwald, S. L. Org Lett.
0
0
1
0
20
30
time (h)
2
000, 2, 1403.
. (a) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed.
003, 42, 5400; (b) Kunz, K.; Scholz, U.; Ganzer, D.
Figure 4. Premixing of ligand F in the presence and in the absence of
Cu(II)(OAc) ÆH O overnight before starting the reaction by addition
of benzimidazole and 5-bromo-m-xylene. The lines through the points
2
2
2
Synlett 2003, 2428.
. Arterburn, J. B.; Pannala, M.; Gonzalez, A. M. Tetra-
hedron Lett. 2001, 42, 1475.
. (a) Kiyomori, A.; Marcoux, J.-F.; Buchwald, S. L.
Tetrahedron Lett. 1999, 40, 2657; (b) Lam, P. Y. S.;
Vincent, G.; Clark, C. G.; Deudon, S.; Jadhav, K. J.
Tetrahedron Lett. 2001, 42, 3415; (c) Collman, J. P.;
Zhong, M.; Zhang, C.; Costanzo, S. J. Org. Chem. 2001,
4
5
are drawn for clarity.
of Cu(I)I during premixing did notaffect ht e speed of
the subsequent reaction. Premixing ligand F was suffi-
cient to increase the reaction rate. In contrast, the pres-
ence of Cu(II)(OAc) ÆH O during premixing did affect
the reaction profile (Fig. 4). If Cu(II)(OAc) ÆH O was
present during premixing, the reaction rate increased.
This may be an indication that the Cu(II) species was
which is supposed to be the cat-
Furthermore, the reaction must be
performed under an inert atmosphere, since reaction
under air did not result in product formation. Further
studies are required for complete elucidation of the
mechanism.
2
2
6
6, 7892.
2
2
6
. Huang, X.; Anderson, K. W.; Zim, D.; Jiang, L.; Klapars,
A.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 6653.
. (a) Ullmann, F. Ber. Dtsch. Chem. Ges. 1903, 36, 2382;
For reviews, see: (b) Bacon, R. G. R.; Hill, H. A. O. J.
Chem. Soc. 1964, 1097; (c) Fanta, P. E. Synthesis 1974, 9;
(d) Sainsbury, M. Tetrahedron 1980, 36, 3327; (e) Lindley,
J. Tetrahedron 1984, 40, 1433, and references cited therein.
. Lan, J.-B.; Chen, L.; Yu, X.-Q.; You, J.-S.; Xie, R.-G.
Chem. Commun. 2004, 188.
. (a) Collman, J. P.; Zhong, M.; Zhang, C.; Costanzo, S. J.
Org. Chem. 2001, 66, 7892; (b) Collman, J. P.; Zhong, M.;
Zeng, L.; Costanzo, S. J. Org. Chem. 2001, 66, 1528; (c)
Collman, J. P.; Zhong, M. Org. Lett. 2000, 2, 1233.
0. van Berkel, S. S.; van den Hoogenband, A.; Terpstra, J.
W.; Tromp, M.; van Leeuwen, P. W. N. M.; van
Strijdonck, G. P. F. Tetrahedron Lett. 2004, 45, 7659.
11. Some examples: (a) Gujadhur, R. K.; Bates, C. G.;
Venkataraman, D. Org. Lett 2001, 3, 4315; (b) Klapars,
A.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2002,
7
2
1
firstreduced to Cu(I),
2,23
2
alytic species.
8
9
In summary, we have developed a highly efficientcop-
per-catalyzed C–N coupling reaction of azaheterocycles
with aryl halides using the chelating nitrogen ligand
1
4
,7-dichloro-1,10-phenanthroline. The 4,7-dichloro-1,10-
phenanthroline ligand gave superior conversions com-
pared to the parent 1,10-phenanthroline. Aryl iodides,
aryl bromides, and heteroaryl bromides can be coupled
with a variety of azoles using this procedure. We have
shown that the cheap and stable copper precursors
Cu(I)I and Cu(II)(OAc) ÆH O can be used in this reac-
1
24, 7421; (c) Kwong, F. Y.; Klapars, A.; Buchwald, S. L.
Org. Lett. 2002, 4, 581; (d) Job, G. E.; Buchwald, S. L.
Org. Lett. 2002, 4, 3703; (e) Kwong, F. Y.; Buchwald, S.
L. Org. Lett. 2003, 5, 793; (f) Klapars, A.; Antilla, J. C.;
Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123,
7727; (g) Antilla, J. C.; Klapars, A.; Buchwald, S. L. J.
Am. Chem. Soc. 2002, 124, 11684; (h) Buchwald, S. L.;
Klapars, A.; Antilla, J. C.; Job, G. E.; Wolter, M.; Kwong,
2
2
tion. Furthermore, the cheap and mild base K CO
2
3
could be efficiently used. Predissolving the 4,7-di-
chloro-1,10-phenanthroline ligand increases initial reac-
tion rates dramatically. When copper(II)-precursors are
used, premixing the copper(II)-precursor together with

M. Kuil et al. / Tetrahedron Letters 46 (2005) 2405–2409
2409
F. Y.; Nordmann, G.; Hennessy, E. J. WO Patent 02/
85838, 2002; (i) Klapars, A.; Parris, S.; Anderson, K. W.;
1.00 mmol) and dihexyl ether as an internal standard
(118 lL, 0.502 mmol), were added to the reaction mixture,
after which stirring was continued under nitrogen at
125 °C. The conversion was verified by taking samples
0
Buchwald, S. L. J. Am. Chem. Soc. 2004, 126, 3529; (j)
Cristau, H.-J.; Cellier, P. P.; Spindler, J.-F.; Taillefer, M.
Eur. J. Org. 2004, 695; (k) Cristau, H.-J.; Cellier, P. P.;
Spindler, J.-F.; Taillefer, M. Chem. Eur. J. 2004, 10, 5607.
2. Typical procedure for the N-arylation: A Schlenk vessel
(0.05 mL) from the reaction mixture. CH
saturated solution of NH Cl were added to the sample.
After separation of the water layer, the organic layer was
filtered through a plug of MgSO . The conversion and the
2 2
Cl and a
4
1
under nitrogen was loaded with (Cu(I)OTf)
25.3 mg, 5 mol %), the appropriate 1,10-phenanthroline
ligand (10 or 20 mol %), Cs CO (360 mg, 1.10 mmol), the
2
ÆPhH
4
(
selectivity of the reaction were determined by GC and GC/
MS analysis.
2
3
appropriate aryl halide (1.00 mmol), the appropriate
azaheterocycles (1.51 mmol), and dihexyl ether as an
internal standard (118 lL, 0.502 mmol) in 0.67 mL of
dry NMP. The reaction mixture was stirred under nitrogen
at125 °C. The conversion was verified by taking samples
16. For some reviews see: (a) Perreux, L.; Loupy, A. Tetra-
hedron 2003, 57, 9199; (b) Lidstr o¨ m, P.; Tierney, J.;
Wathey, B.; Westman, J. Tetrahedron 2003, 57, 9225.
17. (a) He, H.; Wu, Y.-J. Tetrahedron Lett. 2003, 44, 3445; (b)
Perreux, L.; Loupy, A. Tetrahedron 2001, 57, 9199; (c)
Combs, A. P.; Saubern, S.; Rafalski, M.; Lam, P. Y. S.
Tetrahedron Lett. 1999, 40, 1623; (d) Lange, J. H. M.;
Hofmeyer, L. J. F.; Hout, F. A. S.; Osnabrug, S. J. M.;
Verveer, P. C.; Kruse, C. G.; Feenstra, R. Tetrahedron
Lett. 2002, 43, 1101; (e) He, H.; Wu, Y.-J. Tetrahedron
Lett. 2003, 44, 3385.
from the reaction mixture. CH
solution of NH Cl were added to the sample. After
separation of the water layer, the organic layer was filtered
through a plug of MgSO . The conversion and the
2 2
Cl and a saturated
4
4
selectivity of the reaction were determined by GC and
GC/MS analysis.
1
1
3. Meurs, J. H. H.; Eilenberg, W. Tetrahedron 1991, 47, 705.
4. (a) Price, C. C.; Roberts, R. M. J. Am. Chem. Soc. 1946,
18. Schmittel, M.; Ammon, H. Eur. J. Org. Chem. 1998,
785.
6
Soc. 1946, 68, 1320.
8, 1204; (b) Snyder, H. R.; Freier, H. E. J. Am. Chem.
19. (a) Cohen, T.; Cristeau, I. J. Am. Chem. Soc. 1976, 98,
748; (b) Savarin, C.; Srogl, J.; Liebeskind, L. S. Org. Lett.
2002, 4, 4309.
20. Deng, W.; Wang, Y.-F.; Zou, Y.; Liu, L.; Guo, Q.-X.
Tetrahedron Lett. 2004, 45, 2311.
21. Cristau, H.-J.; Desmurs, J.-R. In Ind. Chem. Libr.;
Desmurs, J.-R., Gerard, B., Goldstein, M. J., Eds.;
Elsevier: Amsterdam, 1995; Vol. 7, p 240.
22. Weingarten, H. J. Org. Chem. 1964, 29, 3624.
23. Paine, A. J. J. Am. Chem. Soc. 1987, 109, 1496.
1
5. Typical procedure for premixing several reagents over-
nightat125 °C before starting the N-arylation: A Schlenk
vessel under nitrogen was loaded with the appropriate
copper-precursor (10 mol %) and 4,7-dichloro-1,10-phe-
nanthroline (24.9 mg, 10 mol %) in 0.67 mL of dry NMP.
The reaction mixture was stirred under nitrogen overnight
at125 °C. The appropriate base (1.10 mmol), benzimid-
azole (178 mg, 1.51 mmol), 5-bromo-m-xylene (136 lL,