Copper catalyzed coupling of aryl chlorides, bromides and iodides with amines and amides

Article abstract of DOI:10.1039/b823407h

A copper(i) catalyzed procedure for carbon-nitrogen bond formation utilizing aryl halides and either amines, including amino acids and diphenylamine, or aliphatic and aromatic amides is described. The Royal Society of Chemistry.

Full text of DOI:10.1039/b823407h

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Copper catalyzed coupling of aryl chlorides, bromides and iodides
with amines and amidesw
Hanhui Xu and Christian Wolf*
Received (in College Park, MD, USA) 5th January 2009, Accepted 9th February 2009
First published as an Advance Article on the web 24th February 2009
DOI: 10.1039/b823407h
A copper(I) catalyzed procedure for carbon–nitrogen bond
formation utilizing aryl halides and either amines, including
amino acids and diphenylamine, or aliphatic and aromatic
amides is described.
Table 1 Copper(I)-catalyzed amination of aryl bromides and iodides
The transition metal catalyzed cross-coupling of aryl halides
and amines provides an invaluable entry towards the synthesis
of a wide range of compounds, including pharmaceuticals and
natural products. In particular, catalytic carbon–nitrogen
bond formation with palladium complexes has gained
increasing attention in the past decade and several procedures
that utilize aryl iodides, bromides and chlorides have been
reported.1 The copper catalyzed variant has emerged as an
important alternative that is most promising for large-scale
industrial applications due to lower catalyst cost and toxicity.2
Despite remarkable progress in this area, copper catalyzed
amination of aryl halides generally does not match the high
efficiency and broad application spectrum of palladium
catalysis. With the exception of the amination of 2-halobenzoic
acids which is promoted by the rate-accelerating effect
of the neighboring carboxylate,3 copper-catalyzed carbon–
nitrogen bond formation with aryl chlorides or poorly nucleo-
philic anilines has remained a challenge.4 Similarly, the
palladium-catalyzed amidation of aryl halides has become an
efficient and widely useful reaction that provides convenient
access to amides,5 ureas,6 oxindoles,7 oxazolidinones,8
quinolinones and naphthyridinones.9 However, relatively few
copper catalyzed amidation methods have been developed.10
We have developed a copper(I) catalyzed coupling proce-
dure that is suitable for amination of aryl iodides, bromides
and chlorides with a wide range of primary and secondary
amines. Our method utilizes inexpensive Cu2O as catalyst and
furnishes aryl amines in good to high yields even when poorly
nucleophilic diphenylamine is employed. The reaction was
found to proceed with amino acids without significant sign
of racemization. The amidation of aryl bromides and iodides
has been achieved with aliphatic and aromatic amides under
essentially the same conditions and yields up to 97% have
been obtained.
Entrya
1
Aryl halide
Amine
Product
Yieldb (%)
95
n-PrNH2
2
3
Et2NH
84c
94
n-PrNH2
4
5
6
n-PrNH2
n-PrNH2
n-PrNH2
88
93d
91
7
8
n-PrNH2
n-PrNH2
81d
76d
9
PhNH2
Ph2NH
n-PrNH2
Et2NH
PhNH2
79e
83e
92
10
11
12
We initiated our studies by screening the copper cata-
lyzed amination of bromobenzene with n-propylamine and
71c
74e
13
Department of Chemistry, Georgetown University, Washington,
DC 20057, USA. E-mail: cw27@georgetown.edu;
Fax: (+1) 202 687 6209; Tel: (+1) 202 687 3468
w Electronic supplementary information (ESI) available: General
synthetic procedures and characterization of products. See DOI:
10.1039/b823407h
a
Reaction conditions: aryl halide (2.0 mmol), Cu2O (5 mol%), amine
b
c
(4.0 mmol) in NMP, 80 1C, 24 h. Isolated yields. NaOtBu
d
e
(4.0 mmol), 100 1C. 110 1C. NaOtBu (3.0 mmol), 90 1C.
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diethylamine, respectively. Most previously reported amina-
tion procedures generally rely on the use of copper catalysts
derived from CuI and diamines, diols or amino acid ligands.11
By contrast, we found that the amination of bromobenzene
occurs in the absence of a ligand when either Cu2O or CuI are
used in water or NMP (N-methylpyrrolidinone). Variation of
typical reaction parameters, including solvent, base, tempera-
ture and catalyst loading, showed that the best results are
achieved with 5 mol% of Cu2O in NMP at 80–110 1C. For
example, the copper catalyzed coupling of bromobenzene and
n-propylamine proceeds at 80 1C to give N-propylaniline in
95% yield after 24 h while the formation of N,N-diethylaniline
requires the presence of sodium tert-butoxide and slightly
higher temperature (Table 1, entries 1 and 2).
method provides good to high yields with aryl iodides and
bromides carrying a range of functional groups (entries 4–8).
As shown in Table 2, this method is also applicable to aryl
chlorides if slightly increased temperatures and sodium
tert-butoxide are used.12 Both primary and secondary amines
can be employed in this reaction and even the coupling with
amines exhibiting low nucleophilicity is possible. For example,
triphenylamine was produced in 81–83% yield from diphenyl-
amine and chloro- and bromobenzene, respectively (entry 10
in Table 1 and entry 7 in Table 2). It is noteworthy that the
Cu2O catalyzed amination of iodobenzene with chiral amino
acids or amino esters can be accomplished in the presence of a
weak base and without significant racemization (Scheme 1).
Similar yields were obtained in significantly shorter reaction
times when the coupling reaction was conducted in a micro-
wave oven (Table 2, entry 1). Superior yields can generally be
We then tested several aliphatic and aromatic amines and
we were pleased to find that our Cu2O catalyzed amination
Table 2 Copper(I)-catalyzed amination of aryl chlorides
Table 3 Copper(I)-catalyzed amidation of aryl halides
Entrya
1
Aryl halide
Amine
Product
Yieldb (%)
92, 90c
Entrya
1
Aryl halide
Amine
Product
Yieldb (%)
97
n-PrNH2
2
3
n-PrNH2
n-PrNH2
87d
69
2
3
98
92
4
5
6
C6H11NH2
BnNH2
Et2NH
69d
72d
79d
81d
4
88c
5
6
81d
81e
7
Ph2NH
a
Reaction conditions: aryl chloride (2.0 mmol), Cu2O (5 mol%), amine
b
(4.0 mmol) in NMP, NaOt-Bu (4.0 mmol), 100 1C. 24 h. Isolated
yields. Microwave irradiation, 200 W, NaOtBu (4.0 mmol), 100 1C,
8 h. NaOtBu (4.0 mmol), 110 1C.
c
d
7
84f
8
72g
a
Reaction conditions: aryl halide (2.0 mmol), Cu2O (5 mol%), amide
b
(4.0 mmol), Cs2CO3 (4.0 mmol) in NMP, 90 1C, 24 h. Yields.
c
d
Cs2CO3 (4.0 mmol), 80 1C, 18 h. NaOtBu (4.0 mmol), 100 1C, 18 h.
e
f
NaOtBu (4.0 mmol), 105 1C, 32 h. NaOtBu (4.0 mmol), 105 1C,
g
48 h. NaOtBu (4.0 mmol), 110 1C, 48 h.
Scheme 1 Copper catalyzed arylation of (S)-Ala and (S)-Leu-OMe.a
1716 | Chem. Commun., 2009, 1715–1717
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expected when two amine equivalents are employed. We found
that the reaction of chlorobenzene with one equivalent of
n-propylamine gives the desired N-propylaniline in only 86%
yield. This could not be compensated by increasing the
amount of added base but it might be still the method of
choice when precious amines are used in this reaction.
We then decided to explore if cuprous oxide can be used to
catalyze the amidation of aryl halides.13 Using essentially the
same conditions as described above, we realized that aryl
bromides and iodides react with aliphatic and aromatic amides
in high yields. Benzamide and several aryl iodides gave the
corresponding N-arylbenzamides in 92–97% yields (Table 3,
entries 1–3). Coupling of primary and secondary aliphatic
amides with iodobenzene gave N-phenylacetamide and
N-methyl-N-phenylacetamide in 81–88% yield (entries 4 and 5).
The copper(I) catalyzed reaction of aryl bromides gave slightly
lower yields. For example, arylation of benzamide with
iodobenzene and bromobenzene furnished N-phenylbenzamide
in 97 and 81% yield, respectively (entries 1 and 6). The same
trend was observed with acetamide (entries 4 and 8). Various
attempts to extend the Cu2O catalyzed amidation method
to aryl chlorides were unsuccessful. This is not surprising
as copper-catalyzed amidation of aryl chlorides generally
requires harsh reaction conditions or the use of the aryl halide
as solvent.10a,14
R. J. Twieg, Tetrahedron Lett., 2005, 46, 2997–3001; (g) H. Zhang,
Q. Cai and D. Ma, J. Org. Chem., 2005, 70, 5164–5173; (h) H. Rao,
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H. Song, G. Chen, D. Liang and Y. Wan, Synthesis, 2006,
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S. L. Buchwald, J. Org. Chem., 2007, 72, 6190–6199;
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and S. L. Buchwald, J. Org. Chem., 2008, 73, 284–286.
3 Selected examples of copper-catalyzed amination of 2-halobenzoic
acids: (a) C. Wolf and X. Mei, J. Am. Chem. Soc., 2003, 125,
10651–10658; (b) M. L. Docampo Palacios and R. F. Pellon
Comdom, Synth. Commun., 2003, 33, 1771–1775; (c) X. Mei and
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C. Wolf, J. Am. Chem. Soc., 2004, 126, 14736–14737; (e) X. Mei
and C. Wolf, Chem. Commun., 2004, 2078–2079; (f) X. Mei,
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J. Org. Chem., 2006, 71, 3270–3273; (h) S. Liu, J. P. C. Pestano and
C. Wolf, Synthesis, 2007, 3519–3527.
4 (a) X. Guo, H. Rao, H. Fu, Y. Jiang and Y. Zhao, Adv. Synth.
Catal., 2006, 348, 2197–2202; (b) R. A. Altman, K. W. Anderson
and S. L. Buchwald, J. Org. Chem., 2008, 73, 5167–5169.
5 (a) J. F. Hartwig, M. Kawatsura, S. I. Hauck, K. Shaughnessy and
L. M. Alcazar-Roman, J. Org. Chem., 1999, 64, 5575–5580;
(b) J. Yin and S. L. Buchwald, Org. Lett., 2000, 2, 1101–1104;
(c) J. Yin and S. L. Buchwald, J. Am. Chem. Soc., 2002, 124,
6043–6048; (d) X. Huang, K. W. Anderson, D. Zim, L. Jiang,
A. Klapars and S. L. Buchwald, J. Am. Chem. Soc., 2003, 125,
6653–6655; (e) F. Shi, M. R. Smith III and R. E. Maleczka Jr, Org.
Lett., 2006, 8, 1411–1414; (f) Q. Shen and J. F. Hartwig, J. Am.
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M. R. Biscoe and S. L. Buchwald, J. Am. Chem. Soc., 2007, 129,
13001–13007; (h) B. P. Fors, P. Krattiger, E. Strieter and
S. L. Buchwald, Org. Lett., 2008, 10, 3505–3508.
In summary, we have developed an efficient cuprous oxide
catalyzed procedure for the amination and amidation of
aryl halides. A wide range of primary and secondary amines
including aniline and diphenylamine were found to react with
aryl iodides, bromides and chlorides in the presence of 5 mol%
of Cu2O in NMP. The corresponding arylated amines were
obtained in up to 95% yield. The same catalyst has been
successfully employed in the amidation of aryl bromides and
iodides. The introduction of this generally useful amination
and amidation method, which utilizes inexpensive cuprous
oxide as catalyst and does not require the use of precious
ligands, is expected to be particularly useful in industrial
applications.
6 M. McLaughlin, M. Palucki and I. W. Davies, Org. Lett., 2006, 8,
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7 R. R. Poondra and N. J. Turner, Org. Lett., 2005, 7, 863–866.
8 A. Ghosh, J. E. Sieser, M. Riou, W. Cai and L. Rivera-Ruiz, Org.
Lett., 2003, 5, 2207–2210.
9 P. J. Manley and M. T. Bilodeau, Org. Lett., 2004, 6, 2433–2435.
10 (a) A. Klapars, X. Huang and S. L. Buchwald, J. Am. Chem. Soc.,
2002, 124, 7421–7428; (b) L. Jiang, G. E. Job, A. Klapars and
S. L. Buchwald, Org. Lett., 2003, 5, 3667–3669;
(c) R. Hosseinzadeh, M. Tajbaksh, M. Mohadjerani and
H. Mehdinejad, Synlett, 2004, 1517–1520; (d) W. Deng,
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and S. L. Buchwald, J. Am. Chem. Soc., 2004, 126, 3529–3533;
(f) E. R. Strieter, D. G. Blackmond and S. L. Buchwald, J. Am.
Chem. Soc., 2005, 127, 4120–4121; (g) K. Moriwaki, K. Satoh,
M. Takada, Y. Ishino and T. Ohno, Tetrahedron Lett., 2005, 46,
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and N. R. Reddy, Synthesis, 2006, 839–842; L. D. S. Yadav,
B. S. Yadav and V. K. Rai, Synthesis, 2006, 1868–1872.
11 For copper catalyzed amination methods that do not rely on the use
of additional ligands, see: (a) K. Okano, H. Tokuyama and
T. Fukuyama, Org. Lett., 2003, 5, 4987–4990; (b) S. U. Son,
I. K. Park, J. Park and T. Hyeon, Chem. Commun., 2004, 778–779;
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T. Fukuyama, Tetrahedron, 2008, 64, 11230–11236.
12 Chlorobenzene and n-propylamine did not react in the absence of
catalytic amounts of Cu2O. Starting materials were recovered
almost quantitatively using the conditions given in Table 1 but
no cuprous oxide. For metal-free amination of aryl halides via the
benzyne mechanism in the presence of a strong base in refluxing
DMSO, see: L. Shi, M. Wang, C.-A. Fan, F.-M. Zhang and
Y.-Q. Tu, Org. Lett., 2003, 5, 3515–3517.
Funding from NIH (RO1 AI060792) is gratefully acknowledged.
Notes and references
1 Selected examples: (a) J. F. Hartwig, M. Kawatsura, S. I. Hauck,
K. H. Shaughnessy and L. M. Alcazar-Roman, J. Org. Chem., 1999,
64, 5575–5580; (b) J. P. Wolfe, H. Tomori, J. P. Sadighi, J. Yin and
S. L. Buchwald, J. Org. Chem., 2000, 65, 1158–1174; (c) Q. Shen,
S. Shecar, J. P. Stambuli and J. F. Hartwig, Angew. Chem., Int. Ed.,
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Chem., 2006, 71, 6522–6529; (f) A. A. Trabanco, J. A. Vega and
M. A. Fernandez, J. Org. Chem., 2007, 72, 8146–8148;
(g) B. P. Fors, P. Krattiger, E. Strieter and S. L. Buchwald, Org.
Lett., 2008, 10, 3505–3508; (h) Q. Shen and J. F. Hartwig, Org. Lett.,
2008, 10, 4109–4112; (i) D. S. Surry and S. L. Buchwald, Angew.
Chem., Int. Ed., 2008, 47, 6338–6361; (j) Q. Shen, T. Ogata and
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Soc., 1998, 120, 12459–12467; (b) F. Y. Kwong, A. Klapars and
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13 Buchwald previously reported that Cu2O catalyzes the amidation of
3,5-dimethylphenyl iodide with N-methylformamide: see ref. 10a.
14 H. Renger, Synthesis, 1985, 856–860.
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Chem. Commun., 2009, 1715–1717 | 1717