Aminoarenethiolate-copper(I)-catalyzed amination of aryl bromides

Article abstract of DOI:10.1021/ol052113z

(Chemical Equation Presented) Aminoarenethiolate-copper(I) complexes are known to be efficient catalysts for carbon-carbon bond formation. Here, we show the first examples that these thiolate-copper(I) complexes are efficient for carbon-nitrogen bond formation reactions as well. N-Arylation of benzylamine and imidazole with bromobenzene was achieved either in NMP as solvent or under solvent-free conditions in the presence of 2.5 mol % of aminoarenethiolate- copper(I) complex only.

Full text of DOI:10.1021/ol052113z

ORGANIC
LETTERS
2005
Vol. 7, No. 23
5241-5244
Aminoarenethiolate−Copper(I)-Catalyzed
Amination of Aryl Bromides
Thomas Jerphagnon,† Gerard P. M. van Klink,† Johannes G. de Vries,‡ and
Gerard van Koten*,†
Debye Institute, Organic Chemistry and Catalysis, Utrecht UniVersity, Padualaan 8,
3584 CH Utrecht, The Netherlands, and DSM Research, Life Sciences, AdVanced
Synthesis and Catalysis, P.O. Box 18, 6160 MD Geleen, The Netherlands
g.Vankoten@chem.uu.nl
Received September 2, 2005
ABSTRACT
Aminoarenethiolate
that these thiolate
imidazole with bromobenzene was achieved either in NMP as solvent or under solvent-free conditions in the presence of 2.5 mol % of
aminoarenethiolate copper(I) complex only.
−copper(I) complexes are known to be efficient catalysts for carbon−carbon bond formation. Here, we show the first examples
−
copper(I) complexes are efficient for carbon nitrogen bond formation reactions as well. N-Arylation of benzylamine and
−
−
Arylamines are attractive targets in chemical synthesis
because of their wide utility and occurrence in a number of
interesting molecules. They have been found in biologically
active compounds such as pharmaceuticals and agrochemi-
cals.1
mostly by using an in situ generated catalyst from a copper
source and ligands such as amino acids,3 diamines,4 di-
imines,5 and diols.6 Although palladium-catalyzed amination
reactions are well-known,7 copper is a by far cheaper metal,
and its environmental friendly nature led us to study the
amination reaction catalyzed by aminoarenethiolate-copper-
(I) complexes.
At this moment, the most frequently used industrial
pathway for coupling reactions is still the Ullmann-type
reaction.2 Copper-catalyzed carbon-nitrogen bond formation
from aryl halides has often been studied over the past decade,
(3) (a) Ma, D.; Xia, C.; Jiang, J.; Zhang, J.; Tang, W. J. Org. Chem.
2003, 68, 442. (b) Ma, D.; Cai, Q.; Zhang, H. Org. Lett. 2003, 5, 2453. (c)
Ma, D.; Xia, C. Org. Lett. 2001, 3, 2583. (d) Clement, J.-B.; Hayes, J. F.;
Sheldrake, H. M.; Sheldrake, P. W.; Wells, A. S. Synlett 2001, 1423. (e)
Ma, D.; Zhang, Y.; Wu, S.; Tao, F. J. Am. Chem. Soc. 1998, 120, 12459.
(4) (a) Antilla, J. C.; Baskin, J. E.; Barder, T. E.; Buchwald, S. L. J.
Org. Chem. 2004, 69, 5578. (b) Wang, X.; Porco, J. A., Jr. J. Am. Chem.
Soc. 2003, 125, 6040. (c) Padwa, A.; Crawford, K. R.; Rashatasakhon, P.;
Rose, M. J. Org. Chem. 2003, 68, 2609. (d) Fredrick, M. O.; Mulder, J.
A.; Tracey, M. R.; Hsung, R. P.; Huang, J.; Kurtz, K. C. M.; Shen, L.;
Douglas, C. J. J. Am. Chem. Soc. 2003, 125, 2368. (e) Klapars, A.;
Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 14844. (f) Antilla, J. C.;
Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 11684. (g)
Klapars, A.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124,
7421. (h) Wolter, M.; Klapars, A.; Buchwald, S. L. Org. Lett. 2001, 3803.
(i) Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L. J. Am. Chem.
Soc. 2001, 123, 7727.
† Utrecht University.
‡ DSM Research.
(1) (a) Craig, P. N. In ComprehensiVe Medicinal Chemistry; Drayton,
C. J., Ed.; Pergamon Press: New York, 1991; Vol. 8. (b) Southon, I. W.;
Buckingham, J. In Dictionary of Alkaloids; Saxton, J. E., Ed.; Chapman
and Hall: London, 1989. (c) Negwer, M. In Organic-Chemical Drugs and
their Synonyms: (An International SurVey), 7th ed.; Akademie Verlag
GmbH: Berlin, 1994.
(2) (a) Ullmann, F. Ber. Dtsch. Chem. Ges. 1903, 36, 2382. For recent
reviews, see: (b) Beletskaya, I. P.; Cheprakov, A. V. Coord. Chem. ReV.
2004, 248, 2337. (c) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed.
2003, 42, 5400. (d) Kunz, K.; Scholz, U.; Ganzer, D. Synlett 2003, 2428.
(e) Lindley, J. Tetrahedron 1984, 40, 1433.
10.1021/ol052113z CCC: $30.25
© 2005 American Chemical Society
Published on Web 10/14/2005

Aminoarenethiolate-copper(I) complexes, which have
excellent solubility in common organic solvents, have been
shown to be excellent catalysts for C-C bond formation by
allylic substitution,8 cross-coupling,9 1,4-addition,10 and 1,6-
addition reactions.11 However, to date, no investigation on
the C-N bond formation has been reported with these
species. Here, we present the first examples of C-N bond
formation catalyzed by aminoarenethiolate-copper(I) com-
plexes. Trimethylsilyl-protected aminoarenethiolate ligands
were synthesized in a three-step procedure from benzylamine
derivatives. The first step involves the heteroatom-directed
ortho-lithiation of a parent arene to generate the correspond-
ing organolithium compound. In the second step, sulfur was
inserted in the carbon-lithium bond, affording the corre-
sponding lithium arenethiolate. Subsequently, quenching by
trimethylsilyl chloride gave the trimethylsilyl-protected thio-
lates. The aminoarenethiolate-copper(I) complexes were
obtained by transmetalation with copper(I) chloride (Scheme
1).12
robust to the harsh reaction conditions usually required for
the copper-catalyzed amination reaction. It has been found
that these complexes form trimeric species both in solid state
and in solution.10,13
A first set of complexes was synthesized with variation
at the amine functionality. Dimethylamino was replaced by
either a pyrrolidinyl or a piperidinyl ring. Furthermore, tert-
butyl and trimethylsilyl groups were introduced meta to the
thiocopper moiety (Figure 1).
Scheme 1. Synthesis of Aminoarenethiolate-Copper(I)
Figure 1. Aminoarenethiolate-Copper(I) Complexes.
Complexes
The presence of tert-butyl or trimethylsilyl groups on the
ligand increased the solubility of the resulting aminoare-
nethiolate-copper(I) complexes in organic solvents such as
toluene and pentane. This effect is furthermore reinforced
by changing the dimethylamino functionality by a pyrro-
lidinyl or a piperidinyl ring.
These complexes were investigated in the copper-catalyzed
amination of aryl halides. We chose the coupling reaction
of benzylamine with bromobenzene as a model reaction to
investigate suitable reaction conditions. Initial tests in DMSO
and DMF with different bases were without success. Only
reactions at 160 °C in N-methylpyrrolidinone (NMP) as
solvent using K2CO3 as base and 2.5 mol % of copper
catalyst gave good results. The copper complexes 1-6 were
subsequently tested using these reaction conditions (Scheme
2, Table 1).
These complexes are characterized by a nontransferable
sulfur-copper bond, which makes these catalysts more
(5) (a) Kuil, M.; Bekedam, E. K.; Visser, G. M.; van den Hoogenband,
A.; Terpstra, J. W.; Kamer, P. C. J.; van Leeuwen, P. W. N. M.; van
Strijdonck, G. P. F. Tetrahedron Lett. 2005, 46, 2405. (b) Antilla, J. C.;
Baskin, J. E.; Barder, T. E.; Buchwald, S. L. J. Org. Chem. 2004, 69, 5578.
(c) Kelkar, A. A.; Patil, N. M.; Chaudhari, R. V. Tetrahedron Lett. 2002,
43, 7143. (d) Kiyomori, A.; Marcoux, J.-F.; Buchwald, S. L. Tetrahedron
Lett. 1999, 40, 2657.
Scheme 2. N-Arylation of Benzylamine with Bromobenzene
(6) (a) Enguehard, C.; Allouchi, H.; Gueiffier, A.; Buchwald, S. L. J.
Org. Chem. 2003, 68, 4367. (b) Buchwald, S. L.; Klapars, A.; Antilla, J.
C.; Job, G. E.; Wolter, M.; Kwong, F. Y.; Nordmann, G. Hennessy, E. J.
Patent WO 02/085838 A1, 2002.
(7) For reviews, see: (a) Muci, A. R.; Buchwald, S. L. Top. Curr. Chem.
2002, 219, 131. (b) Yang, B. H.; Buchwald, S. L. J. Organomet. Chem.
1999, 576, 125. (c) Hartwig, J. F. Angew. Chem., Int. Ed. 1998, 37, 2046.
(d) Hartwig, J. F. Acc. Chem. Res. 1998, 31, 852. (e) Wolfe, J. P.; Wagan,
S.; Marcoux, J.-F.; Buchwald, S. L. Acc. Chem. Res. 1998, 31, 805. (f)
Hartwig, J. F. Synlett 1997, 329.
(8) (a) Meuzelaar, G. J.; Karlstrom, A. S. E.; van Klaveren, M.; Persson,
E. S. M.; del Villar, A.; van Koten, G.; Ba¨ckvall, J.-E. Tetrahedron 2000,
56, 2895. (b) van Klaveren, M.; Persson, E. S. M.; del Villar, A.; Grove,
D. M.; Ba¨ckvall, J.-E.; van Koten, G. Tetrahedron Lett. 1995, 36, 3059.
(c) van Klaveren, M.; Persson, E. S. M.; Grove, D. M.; Ba¨ckvall, J.-E.;
van Koten, G. Tetrahedron Lett. 1994, 35, 5931.
The aminoarenethiolate-copper(I) complexes show mod-
erate reactivities in NMP (5 M) as N-benzylaniline could be
(10) (a) Arink, A. M.; Braam, T. W.; Keeris, R.; Jastrzebski, J. T. B.
H.; Benhaim, C.; Rosset, S.; Alexakis, A.; van Koten, G. Org. Lett. 2004,
6, 1959. (b) Arink, A. M.; van de Coevering, R.; Wieczorek, B.; Firet, J.;
Jastrzebski, J. T. B. H.; Klein Gebbink, R. J. M.; van Koten, G. J.
Organomet. Chem. 2004, 689, 3813. (c) van Klaveren, M.; Lambert, F.;
Eijkelkamp, D. J. F. M.; Grove, D. M.; van Koten, G. Tetrahedron Lett.
1994, 35, 5931.
(11) Haubrich, A.; van Klaveren, M.; van Koten, G.; Handke, G.; Krause,
N. J. Org. Chem. 1993, 58, 5849.
(9) van Klaveren, M. Ph.D. Thesis, Utrecht University, Utrecht, 1996.
(12) Dry copper(I) chloride was freshly synthesized before use.
5242
Org. Lett., Vol. 7, No. 23, 2005

Scheme 3. N-Arylation of Imidazole with Bromobenzene
Table 1. Screening of Aminoarenethiolate-Copper(I)
Complexes for N-Arylation of Benzylamine with
Bromobenzenea
entry
catalyst
solvent
yieldb (%)
1
2
3
4
5
6
7
8
9
1
1
2
2
3
3
4
4
5
5
6
6
NMP
-
NMP
-
NMP
-
NMP
-
NMP
-
NMP
-
32
64
40
70
69
91
31
68
imidazole with bromobenzene under the same reaction
conditions (Scheme 3 and Table 2).
Table 2. Screening of Aminoarenethiolate-Copper(I)
Complexes for N-Arylation of Imidazole with Bromobenzenea
72
94 (91)c
56
entry
catalyst
condition
yieldb (%)
10
11
12
1
2
3
4
5
6
7
8
9
1
1
2
2
3
3
4
4
5
5
6
6
NMP
-
NMP
-
NMP
-
NMP
-
NMP
-
NMP
-
82
68
84
100 (98)c
68
a Reaction conditions: benzylamine (6.5 mmol), bromobenzene (5 mmol),
K2CO3 (5.5 mmol), [Cu] (2.5 mol %), NMP (1 mL), 160 °C, 16 h, under
N2. b Determined by GC using dihexyl ether as internal standard. c Isolated
yield.
77
62
73
56
79
57
86
67
obtained in yields up to 72% (entry 9, Table 1). A major
breakthrough, however, was achieved when this reaction was
performed under solvent-free conditions.14 Neat reaction
conditions allowed us to almost double the yield up to 94%
compared to the reactions using NMP as solvent for the
synthesis of N-benzylaniline (entry 10, Table 1).
10
11
12
a Reaction conditions: imidazole (6.5 mmol), bromobenzene (5 mmol),
K2CO3 (5.5 mmol), [Cu] (2.5 mol %), NMP (1 mL), 160 °C, 16 h, under
N2. b Determined by GC using dihexyl ether as internal standard. c Isolated
yield.
Trimethylsilyl-substituted aminoarenethiolate-copper(I)
catalysts 2 and 3 show good reactivities as yields up to 91%
were obtained. The position of the trimethylsilyl moiety on
the aryl ring of the aminoarenethiolate ligand apparently
plays an important role. With complex 2 using either NMP
or neat conditions 40 and 70% yields (entries 3 and 4, Table
1) were obtained, respectively, while using 3 yields were
raised to 69 and 91% (entries 5 and 6, Table 1), respectively.
Copper complexes 4-6, which each possess a 5-tert-butyl
group, gave better conversions with yields up to 94% (for
5, entry 10, Table 1). Catalyst 4 possessing the dimethyl-
amino moiety allowed us to obtain N-phenylbenzylamine in
68% yield. However, changing the dimethylamino group for
a piperidinyl (6) or pyrrolidinyl (5) functionality yielded,
under solvent-free conditions, N-benzylaniline in 84 and 94%
yield, respectively (entries 12 and 10, Table 1). A possible
explanation for these improved yields could be the increased
solubility of the tert-butyl- or trimethylsilyl-substituted
copper complexes.
The outcome of this reaction is opposite to the results
observed with the primary amine benzylamine. Now, best
reactivities were obtained using NMP (5 M) as solvent
instead of the solvent-free conditions. As different substrates
can exhibit different reactivities, the use of solvent improves
the yield for the imidazole coupling. The nonfunctionalized
aminoarenethiolate-copper(I) complex 1 showed a good
reactivity with 82% yield of N-phenylimidazole (entry 1,
Table 2). The trimethylsilyl-substituted complexes showed
even better efficiencies. A total conversion to the desired
product was obtained with the 3-trimethylsilyl-substituted
complex 2, whereas its 5-trimethylsilyl-substituted analogue
3 afforded the product in only 77% yield. Apparently, the
buttressing effect exerted by the 3-trimethylsilyl substituent
on the conformation of the coordinating nitrogen atom of
the CH2N ligand plays a role during the carbon-nitrogen
bond-forming step. Also, the nature of the amino functional-
ity plays a role as 73% yield was obtained with the
dimethylamino-substituted copper complex 4 (entry 7, Table
2), whereas with the cyclic amines the yields improved to
79% (pyrrolydinyl 5) and 86% yield (piperidinyl 6) (entries
9 and 11, Table 2).
Next, we tested this reaction using other phenyl halides.
However, only starting material was observed when using
either chloro- or fluorobenzene instead of bromobenzene.
With iodobenzene, a low conversion and the presence of only
small amounts of N,N-diphenylbenzylamine were detected.
Encouraged by the results with bromobenzene, we also
investigated the N-arylation of a heterocyclic amine, i.e.,
Using the optimum reaction conditions found for the
N-arylation of imidazole with bromobenzene (entry 3, Table
2), the double amination of 1,3-dibromobenzene with imi-
dazole was achieved (Scheme 4).
With the trimethylsilyl-substituted aminoarenethiolate-
copper(I) complex 2 as catalyst, 1,3-diimidazolebenzene was
(13) (a) Knotter, D. M.; van Koten, G.; van Maanen, H. L.; Grove, D.
M.; Spek, A. L. Angew. Chem., Int. Ed. Engl. 1989, 28, 341. (b) Knotter,
D. M.; Grove, D. M.; Smeets, W. J. J.; Spek, A. L.; van Koten, G. J. Am.
Chem. Soc. 1992, 114, 3400.
(14) Artamkina, G. A.; Ermolina, M. V.; Beletskaya, I. P. MendeleeV
Commun. 2003, 158.
Org. Lett., Vol. 7, No. 23, 2005
5243

Scheme 4. N-Arylation of Imidazole with 1,3-Dibromobenzene
Scheme 5. Possible Single-Electron-Transfer Pathway
obtained in quantitative yield; no trace of the monoamination
product was detected.
In conclusion, the thermally very stable aminoarene-
thiolate-copper(I) complexes have shown to be efficient in
the copper-catalyzed N-arylation of benzylamine (solvent-
free conditions) and imidazole (in NMP) with bromobenzene
at 160 °C with only 2.5 mol % of catalysts. Using this
catalytic system, the C-N coupling products, N-benzylaniline
(94%) and N-phenylimidazole (quantitative), were obtained
selectively in high yields. Moreover, we showed that the
reaction conditions (solvent free or using NMP) play a major
role to arrive at high yields for different amines.
Interestingly, the aminoarenethiolate-copper(I) (CuSR)
compounds 1-6 are the first thiolate copper complexes used
for C-X coupling catalysis. As a possible mechanistic
pathway, a single electron transfer (SET) from the electron-
rich CuSR to the aryl halide is proposed (see Scheme 5).15
Further investigations concern the study of the aggregation
behavior of CuSR (e.g., pure 1 is a trimeric (CuSR)3
aggregate in solution),13 their redox behavior (dimethylamino
vs pyrrolidinyl vs piperidinyl), catalyst-substrate interaction
(primary amines (sp3N) vs heterocyclic amines (sp2N)), and
the nature of the solvent (solvent-free conditions vs NMP).
Currently, we are further investigating the scope and
mechanistic aspects of this copper-catalyzed arylic amination.
In addition, further work is in progress on recycling of the
aminoarenethiolate-copper(I) catalysts.10b
Acknowledgment. We thank DSM, the Ministry of
Economic Affairs, NWO/CW, NRSC-C, and Chemspeed
Technologies for the financial support given to the
CW/CombiChem program.
Supporting Information Available: Experimental pro-
cedures and characterization for all new compounds synthe-
sized. This material is available free of charge via the Internet
at http://pubs.acs.org.
(15) Jerphagnon, T.; van Klink, G. P. M.; van Koten, G. Manuscript in
preparation.
OL052113Z
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