A general and efficient copper catalyst for the amidation of aryl halides

Article abstract of DOI:10.1021/ja0260465

An experimentally simple and inexpensive catalyst system was developed for the amidation of aryl halides by using 0.2-10 mol % of Cul, 5-20 mol % of a 1,2-diamine ligand, and K₃PO₄, K₂CO₃, or Cs₂CO₃ as base. Catalyst systems based on N, N′-dimethylethylenediamine or trans-N,N′-dimethyl-1,2-cyclohexanediamine were found to be the most active even though several other 1,2-diamine ligands could be used in the easiest cases. Aryl iodides, bromides, and in some cases even aryl chlorides can be efficiently amidated. A variety of functional groups are tolerated in the reaction, including many that are not compatible with Pd-catalyzed amidation or amination methodology.

Full text of DOI:10.1021/ja0260465

Published on Web 05/25/2002
A General and Efficient Copper Catalyst for the Amidation of
Aryl Halides
Artis Klapars, Xiaohua Huang, and Stephen L. Buchwald*
Contribution from the Department of Chemistry, Massachusetts Institute of Technology,
Cambridge, Massachusetts 02139
Received February 27, 2002
Abstract: An experimentally simple and inexpensive catalyst system was developed for the amidation of
aryl halides by using 0.2-10 mol % of CuI, 5-20 mol % of a 1,2-diamine ligand, and K3PO4, K2CO3, or
Cs2CO3 as base. Catalyst systems based on N,N′-dimethylethylenediamine or trans-N,N′-dimethyl-1,2-
cyclohexanediamine were found to be the most active even though several other 1,2-diamine ligands could
be used in the easiest cases. Aryl iodides, bromides, and in some cases even aryl chlorides can be efficiently
amidated. A variety of functional groups are tolerated in the reaction, including many that are not compatible
with Pd-catalyzed amidation or amination methodology.
Introduction
Both the Ullmann reaction (copper-catalyzed N-arylation of
amines)6 and the related Goldberg reaction (copper-catalyzed
Transition metal catalyzed C-N bond-forming processes are
extensively utilized in the medicinal chemistry and process
development groups of pharmaceutical companies and in
academic laboratories. Despite significant improvements in the
palladium-catalyzed N-arylation of amines,1 some limitations
still remain. For example, aryl halides containing free N-H
groups2 as well as certain heterocyclic halides3 are difficult
amination substrates. The palladium-catalyzed arylation of
amides, another important class of nitrogen nucleophiles, is
encumbered by further limitations. Most notably, the amidation
of electron-rich or ortho-substituted electronically neutral aryl
halides is difficult.4 Moreover, the high cost of palladium invites
less expensive alternatives.5 Finally, removal of palladium
residues from polar reaction products, particularly in the late
stage of the synthesis of a pharmaceutical substance, can be
challenging.
N-arylation of amides)7 predate the palladium-catalyzed ami-
nation methodology by many decades. While applications of
the Ullmann and Goldberg reactions in academic and industrial
laboratories are well-documented,8 the methods have remained
relatively undeveloped. The necessity to use temperatures as
high as 210 °C,9 highly polar solvents, and often large amounts
of copper reagents, as well as the modest yields often realized,
have undoubtedly prevented these reactions from being em-
ployed to their full potential. An important alternative has been
reported recently where aryl boronic acids are used as arylating
agents instead of aryl halides.10 Unfortunately, the method
suffers from high cost and poor availability of functionalized
boronic acids, as well as relatively limited scope of the process.
The traditional protocols for the Goldberg amidation reaction
prescribe simple copper salts or often copper metal as the
catalyst. It is surprising that very few reports have focused on
deliberate use of ligands to facilitate the copper-catalyzed aryl
amidation reaction.11 We have previously disclosed Ullmann-
type methodology for the N-arylation of imidazoles using a 1,10-
* Corresponding author. E-mail: sbuchwal@mit.edu.
(1) Reviews: (a) Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L.
Acc. Chem. Res. 1998, 31, 805. (b) Hartwig, J. F. Angew. Chem., Int. Ed.
Engl. 1998, 37, 2046. (c) Yang, B. H.; Buchwald, S. L. J. Organomet.
Chem. 1999, 576, 125. (d) Muci, A. R.; Buchwald, S. L. Practical Palladium
Catalysts for C-N and C-O Bond Formation. In Topics in Current
Chemistry; Miyaura, N., Ed.; Springer-Verlag: Berlin, 2002; Vol. 219, p
133.
(6) N-Arylation of anilines: (a) Ullmann, F. Ber. Dtsch. Chem. Ges. 1903,
36, 2382. (b) Gauthier, S.; Fre´chet, J. M. J. Synthesis 1987, 383. (c) Paine,
A. J. J. Am. Chem. Soc. 1987, 109, 1496. (d) Gujadhur, R.; Venkataraman,
D.; Kintigh, J. T. Tetrahedron Lett. 2001, 42, 4791. N-Arylation of
alkylamines: (e) Ma, D.; Zhang, Y.; Yao, J.; Wu, S.; Tao, F. J. Am. Chem.
Soc. 1998, 120, 12459. (f) Arterburn, J. B.; Pannala, M.; Gonzalez, A. M.
Tetrahedron Lett. 2001, 42, 1475. (g) Kwong, F. Y.; Klapars, A.; Buchwald,
S. L. Org. Lett. 2002, 4, 581. Arylation of ammonia: (h) Lang, F.; Zewge,
D.; Houpis, I. N.; Volante, R. P. Tetrahedron Lett. 2001, 42, 3251.
(7) (a) Goldberg, I. Ber. Dtsch. Chem. Ges. 1906, 39, 1691. (b) Freeman, H.
S.; Butler, J. R.; Freedman, L. D. J. Org. Chem. 1978, 43, 4975. (c)
Dharmasena, P. M.; Oliveira-Campos, A. M.-F.; Raposo, M. M. M.;
Shannon, P. V. R. J. Chem. Res. (S) 1994, 296. (d) Ito, A.; Saito, T.; Tanaka,
K.; Yamabe, T. Tetrahedron Lett. 1995, 36, 8809. (e) Sugahara, M.; Ukita,
T. Chem. Pharm. Bull. 1997, 45, 719. (f) Lange, J. H. M.; Hofmeyer, L.
J. F.; Hout, F. A. S.; Osnabrug, S. J. M.; Verveer, P. C.; Kruse, C. G.;
Feenstra, R. W. Tetrahedron Lett. 2002, 43, 1101.
(2) Examples are rare and include the following: (a) Ward, Y. D.; Farina, V.
Tetrahedron Lett. 1996, 37, 6993. (b) Willoughby, C. A.; Chapman, K. T.
Tetrahedron Lett. 1996, 37, 7181. (c) Batch, A.; Dodd, R. H. J. Org. Chem.
1998, 63, 872. (d) Prashad, M.; Hu, B.; Lu, Y.; Draper, R.; Har, D.; Repic,
O.; Blacklock, T. J. J. Org. Chem. 2000, 65, 2612. (e) Link, J. T.; Sorensen,
B.; Liu, G.; Pei, Z.; Reilly, E. B.; Leitza, S.; Okasinski, G. Bioorg. Med.
Chem. Lett. 2001, 11, 973.
(3) (a) Watanabe, M.; Yamamoto, T.; Nishiyama, M. Chem. Commun. 2000,
133. (b) Luker, T. J.; Beaton, H. G.; Whiting, M.; Mete, A.; Cheshire, D.
R. Tetrahedron Lett. 2000, 41, 7731.
(4) (a) Shakespeare, W. C. Tetrahedron Lett. 1999, 40, 2035. (b) Yin, J.;
Buchwald, S. L. Org. Lett. 2000, 2, 1101. (c) Artamkina, G. A.; Sergeev,
A. G.; Beletskaya, I. P. Tetrahedron Lett. 2001, 42, 4381. (d) Cacchi, S.;
Fabrizi, G.; Goggiamani, A.; Zappia, G. Org. Lett. 2001, 3, 2539.
(5) Ni-catalyzed amination of aryl chlorides: (a) Wolfe, J. P.; Buchwald, S.
L. J. Am. Chem. Soc. 1997, 119, 6054. (b) Brenner, E.; Schneider, R.;
Fort, Y. Tetrahedron 1999, 55, 12829. (c) Lipshutz, B. H.; Ueda, H. Angew.
Chem., Int. Ed. 2000, 39, 4492.
(8) For a review, see: Lindley, J. Tetrahedron 1984, 40, 1433.
(9) Yamamoto, T.; Kurata, Y. Can. J. Chem. 1983, 61, 86.
(10) Lam, P. Y. S.; Deudon, S.; Hauptman, E.; Clark, C. G. Tetrahedron Lett.
2001, 42, 2427 and references therein.
9
10.1021/ja0260465 CCC: $22.00 © 2002 American Chemical Society
J. AM. CHEM. SOC. 2002, 124, 7421-7428
7421

A R T I C L E S
Klapars et al.
Figure 1. Effect of various diamine ligands on the efficiency of the aryl amidation reaction. The reactions were performed with 5 mol % of CuI, 10 mol
% of ligand, 1.0 equiv of aryl bromide 15, 1.2 equiv of amide 16 or 17, and 2 equiv of K2CO3 in toluene. All experiments have been performed twice and
the resulting GC yields have been averaged. The conversion of the aryl halide was also determined by GC and in all cases was found to be 0-10% higher
than the GC yield. Reaction conditions: coupling of 15 and 16, 100 °C for 22 h; coupling of 15 and 17, 110 °C for 22 h.
phenanthroline/(CuOTf)2‚benzene catalyst system.12 This led us
to examine the efficiency of other chelating nitrogen ligands in
copper-catalyzed carbon-nitrogen bond-forming processes. We
recently demonstrated that the combination of air-stable CuI
and inexpensive 1,2-diamine ligands in the presence of K3PO4
or K2CO3 comprises an extremely efficient and general catalyst
system for the N-amidation of aryl and heteroaryl iodides and
bromides, and in some cases even unactivated aryl chlorides
(eq 1).13 Since then we have examined this process in more
pronounced effect on their ability to facilitate the copper-
catalyzed aryl amidation reactions. A set of 13 ligands was
screened for the coupling of aryl bromide 15 with two different
amides, 16 and 17. The two reactions were performed at slightly
different temperatures, 100 and 110 °C, to ensure partial
conversion of the aryl bromide and therefore better comparison
of the ligand effects. As shown in Figure 1, both of the coupling
reactions show similar trends with respect to the structure of
the diamine ligands. The degree of substitution and consequently
the steric bulk of the diamine ligands play the most important
role. The N,N′-dimethyl diamines 3 and 11 have higher activity
than the unsubstituted diamines 1, 8, 9, and 10. On the other
hand, bulky N-substituents on the ligands, e.g., the isopropyl
(13) and even ethyl groups (12), decrease the rate of aryl
amidation reaction. Further substitution at the nitrogen center
leads to a completely inactive ligand (e.g., TMEDA (7)). The
ligand 11 and the commercially available ligand 3 are recom-
mended in most cases. Ligand 11 is slightly more active than
3; the difference becomes significant in more difficult reactions
such as in the amidation of aryl chlorides (see below).
detail and have significantly extended the reaction scope using
N,N′-dimethylethylenediamine and trans-N,N′-dimethyl-1,2-
cyclohexanediamine as ligands. Herein, we report in full the
results of this investigation.
Results and Discussion
In our initial disclosure we showed that trans-1,2-cyclohex-
anediamine (8) was an excellent ligand for coupling amides with
aryl iodides. In fact, a variety of 1,2-diamine ligands are
effective. In the easiest examples even ethylenediamine can be
employed. The structure of the 1,2-diamine ligands has a
To determine if a chelating ligand is a prerequisite for the
success of our amidation protocol, we evaluated a monodentate
ligand, n-hexylamine. The coupling of aryl iodide 18 and amide
16 (eq 2) in the presence of 5 mol % of CuI in toluene at 80 °C
(11) (a) Yamamoto, T.; Ehara, Y.; Kubota, M.; Yamamoto, A. Bull. Chem. Soc.
Jpn. 1980, 53, 1299. (b) Shen, R.; Porco, J. A., Jr. Org. Lett. 2000, 2,
1333. See also: (c) Goodbrand, H. B.; Hu, N.-X. J. Org. Chem. 1999, 64,
670. (d) Fagan, P. J.; Hauptman, E.; Shapiro, R.; Casalnuovo, A. J. Am.
Chem. Soc. 2000, 122, 5043. (e) Wolter, M.; Nordmann, G.; Job, G. E.;
Buchwald, S. L. Org. Lett. 2002, 4, 973.
(12) Kiyomori, A.; Marcoux, J.-F.; Buchwald, S. L. Tetrahedron Lett. 1999,
40, 2657.
(13) (a) Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L. J. Am. Chem.
Soc. 2001, 123, 7727. See also: (b) Wolter, M.; Klapars, A.; Buchwald,
S. L. Org. Lett. 2001, 3, 3803.
was unaffected by the addition of 20 mol % of n-hexylamine
and provided 12-15% yield of the product (Table 1, entries 1
and 2). Significant rate enhancement was observed, however,
9
7422 J. AM. CHEM. SOC. VOL. 124, NO. 25, 2002

An Efficient Cu Catalyst for the Amidation of Aryl Halides
A R T I C L E S
Table 3. Base Effects on the Efficiency of the Aryl Amidation
Table 1. N-Arylation of 2-Pyrrolidinone with Amine Additivesa
Reaction
amine
additive
amount of
amine
conversion
of ArI 18, %
amount of
base, equiv
conversion
of ArI,b %
entry
solvent
yield,b %
entry
base
conditionsa
yield, %
1
2
3
4
none
none
PhMe
PhMe
none
19
17
>99
11
15
12
98c
8
1
2
3
4
KHMDS
KHMDS
NaOtBu
1.2c
90 °C, 4 h
<1
98
10
96
<1b
92e
3b
n-HexNH2
n-HexNH2
i-Pr2NH
20 mol %
7 equiv
7 equiv
1.2 (slow)d 90 °C, 4 h
1.2c
90 °C, 21 h
90 °C, 21 h
none
phosphazenef 2.0c
93e
a Performed with 5 mol % of CuI, 1.0 equiv of aryl iodide 18, 1.2 equiv
of amide 16, and 2.0 equiv of K3PO4 at 80 °C for 23 h. b Average yield
(GC) for two runs. c Isolated yield (average of 2 runs); >95% purity as
a Performed with 5 mol % of CuI, 10 mol % of ligand 11, 1.0 equiv of
aryl iodide 18, and 1.2 equiv of amide 16 in toluene. b Measured by GC
(average of two runs). c Base was added in a single portion. d A solution
of the base in toluene was added dropwise over 4 h using a syringe pump.
e Isolated yields (average of 2 runs); >95% purity as determined by GC
1
determined by GC and H NMR.
Table 2. Arylation of N-Methylformamide with Various Copper
1
and H NMR. f tert-Butyliminotris(pyrrolidino)phosphorane.
Sourcesa
conversion
of ArI, %
Scheme 1
entry
copper source
yield,b %
1
2
3
4
5
6
7
8
9
Cu powder (bronze)
CuI
CuCl
CuSCN
Cu2O
CuCl2
CuSO4‚5H2O
CuO
89
97
95
92
94
58
81
3
86
97
93
85
91
55
79
<0.5
71
Cu(OAc)2
Cu(acac)2
75
85
10
83
a Performed with 5 mol % of Cu, 10 mol % of ligand 3, 1.0 equiv of
aryl iodide 18, 1.2 equiv of N-methylformamide, and 2.0 equiv of K3PO4
in toluene at 80 °C for 7 h. b Average yield (GC) for two runs.
KHMDS, was slowly added to a reaction mixture including aryl
iodide 18 and amide 16 (eq 2; Table 3). Nearly complete
conversion of the aryl iodide and 92% yield of the N-arylated
amide was observed (entry 2). However, less than 1% conver-
sion of the aryl iodide was detected if KHMDS was added in
a single portion (entry 1). These observations suggest that the
rate of deprotonation of the amide has to match the rate of the
amidation reaction. If an excess of the deprotonated amide is
formed, it impedes the desired aryl amidation reaction presum-
ably via formation of an unreactive cuprate complex (Scheme
1). A similar suggestion has been provided by Bacon and Karim
to explain the effects of imide/copper ratio on the efficiency of
the arylation of potassium phthalimide.15
if n-hexylamine was used as the solvent (98% yield; entry 3).
Interestingly, a more hindered amine, diisopropylamine, failed
to accelerate the aryl amidation reaction (entry 4). We speculate
that the equilibrium leading to the copper-amine complex is
unfavorable unless a large excess of an unhindered amine is
used. If that is indeed the case, the role of a chelating diamine
ligand could simply be to increase the stability constant of the
catalytically active copper-amine complex. Further studies are
required to ascertain this hypothesis.
A brief study of several readily available copper compounds
as alternative catalyst precursors was also carried out. As shown
in Table 2, copper metal, Cu2O, CuI, and CuCl (among others)
produced acceptable results in the arylation of N-methylforma-
mide. For more difficult substrates, the air-stable and inexpen-
sive CuI gave the best results. Consequently, CuI was chosen
as the catalyst precursor for subsequent experiments although
it is conceivable that other copper compounds could be used
with comparable or greater success for some of the reactions.
It is interesting to note that copper compounds in various
oxidation states are catalytically active and presumably are
transformed to the same active catalyst under the reaction
conditions.14
The choice of the base plays a more important role than the
nature of the copper precatalyst. Amidation of aryl iodides
proceeds best with K3PO4 as the base; the reaction is much
slower if K2CO3 is used instead. In contrast, many amidation
reactions of aryl bromides, which typically react more slowly
than aryl iodides, fail in the presence of K3PO4. In those cases,
complete conversion of the aryl bromide can nevertheless be
achieved if K3PO4 is replaced with a weaker base such as
K2CO3. Further insight into this interesting phenomenon was
provided by an experiment where a solution of a strong base,
Comparison of the pKHA values of the amide substrate and
the bases used in the arylation reaction reveals another interest-
ing relationship (Table 3). KHMDS (pKHA ) 26 in DMSO,16
entry 1) and NaOtBu (pKHA ) 32 in DMSO,17 entry 3) both
fail in the arylation of 2-pyrrolidinone (pKHA ) 24 in DMSO).17
On the other hand, a phosphazene base, tert-butyliminotris-
(pyrrolidino)phosphorane (pKBH ) 18 in DMSO),18 is a
+
proficient base and provides 93% yield of the desired N-aryl
amide (entry 4). This suggests that the pKHA of the base
employed in the arylation reaction should be below the pKHA
of the amide substrate unless the base is delivered gradually as
the reaction proceeds (entry 2). A similar rationale can be
applied to inorganic bases such as K3PO4 or K2CO3. Presumably,
these bases are thermodynamically very strong in aprotic
solvents;19 nevertheless, their extremely low solubility in
nonpolar organic solvents ensures the rates of deprotonation that
are optimal for the arylation of amides.
(15) Bacon, R. G. R.; Karim, A. J. Chem. Soc., Perkin Trans. 1 1973, 272.
(16) Grimm, D. T.; Bartmess, J. E. J. Am. Chem. Soc. 1992, 114, 1227.
(17) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456.
+
(18) Extrapolated from pKBH ) 28 (in acetonitrile) reported by: Schwesinger,
R.; Hasenfratz, C.; Schlemper, H.; Walz, L.; Peters, E.-M.; Peters, K.; von
Schnering, H. G. Angew. Chem., Int. Ed. Engl. 1993, 32, 1361.
(19) Although we are not aware of any reported pKHA values for K3PO4 or K2CO3
in non-hydrogen-bond-donor solvents, the hydroxide has pKHA ) 31 in
DMSO.17
(14) Weston, P. E.; Adkins, H. J. Am. Chem. Soc. 1928, 50, 859.
9
J. AM. CHEM. SOC. VOL. 124, NO. 25, 2002 7423

A R T I C L E S
Klapars et al.
Table 4. Coupling of Aryl Iodides with Primary Amidesa
a Performed using 10 mol % of ligand, 1.0 equiv of aryl iodide, 1.2 equiv of amide, and 2 equiv of K3PO4. b Isolated yields (average of 2 runs); >95%
1
purity as determined by GC and H NMR. c With 1 equiv of water and 1.5 equiv of Cs2CO3 as base. d Without water; using 1.5 equiv of Cs2CO3 as base;
average yield (GC) for two runs. e Racemic trans-N-(4-methylphenyl)-1,2-cyclohexanediamine; reaction was performed with 2 equiv of Cs2CO3 as base.
The scope of the copper-catalyzed aryl amidation reaction
was explored by using 0.2-10 mol % of the air-stable CuI as
the copper source, 5-20 mol % of a diamine ligand, and K3PO4,
Cs2CO3, or K2CO3 as the base. The reactions of aryl iodides
with primary amides are detailed in Table 4. The amidation of
aryl iodides can be successfully performed by using various
1,2-diamine ligands. Although the N,N′-dimethyl diamines such
as the commercially available ligand 3 generally provide higher
reaction rates, the ligand 8 has an advantage of significantly
lower price. Cs2CO3 and K3PO4 are far more efficient bases
for the amidation of aryl iodides than is K2CO3. In most cases,
K3PO4 is the recommended base20 as it is less expensive than
Cs2CO3. The amidation reactions can be carried out at 60-110
°C and with benzamide even at room temperature (entries 5
and 6). Interestingly, the arylation of benzamide is dramatically
accelerated by addition of water (1 equiv) to the reaction mixture
(entry 5). We speculate that a small amount of water increases
the rate of the arylation reaction by solubilizing the base,
Cs2CO3, and thus facilitating deprotonation of benzamide.
Arylation of other amides is less sensitive to water, and coupling
of the less reactive (more hindered) substrates is in fact inhibited
by water, which is expected if the rate of deprotonation of the
amide exceeds the rate of the aryl amidation reaction (see
Scheme 1).
amidation reaction.4 Notably, the amido group in lactamide
(entry 9) can be selectively arylated in the presence of the
potentially chelating hydroxy group. Although amidation of
1-nitro-2-iodobenzene proceeded in only 69% yield if ligand 8
and dioxane were used (entry 1), a much cleaner reaction took
place utilizing ligand 3 and toluene (88% yield, entry 2).
Generally, amidation of aryl iodides can be performed in a wide
spectrum of aprotic solvents encompassing toluene, dioxane,
THF, and even DMF. The arylations of highly polar amides,
acetamide and lactamide (entries 8 and 9), actually proceed
better if DMF rather than toluene is used as the solvent.
The practical benefits of the copper-diamine-catalyzed ami-
dation methodology must be briefly noted. Although the
reactions are moderately sensitive to oxygen and have to be
performed under an inert atmosphere, there is no need to use
glovebox techniques nor to purify the commercially available
reagents. Most of the reactions are extremely clean; no reduction
or homocoupling of the aryl halide, which often takes place in
the Pd-catalyzed cross-coupling reactions, is normally observed.
Another notable feature of the process is the low molecular
weight of diamine ligands, for example, only 88.15 g/mol in
the case of ligand 3. This is a definite advantage if the cost per
mole of the ligand is considered.
The reactions of aryl iodides with secondary amides (Table
5) were conducted under conditions similar to those in Table
4. Lactams (entries 1-4) and formamides (entries 8-12) are
excellent substrates. In addition, N-acetyl and N-Boc anilines
provide good yields of the arylated products despite slightly
lower reactivity (entries 5-7). In the case of N-methylforma-
mide, the reaction could be carried out with 0.2 mol % of CuI
(S/C ) 500) and proceeded in 98% yield. The commercial
mixture of the cis and trans diastereomers of 1,2-cyclohex-
anediamine21 could be used instead of the pure trans-isomer 8
A variety of functional groups are tolerated in the aryl
amidation reaction (Table 4). Of particular interest are entries
7 (free NH2 in nitrogen nucleophile) and 4 (allyl ester) in which
substrates not compatible with the Pd-catalyzed methodology
are transformed in high yield. A strongly electron-donating
substituent at the ortho position of the aryl iodide (entry 3) has
no deleterious effects in contrast to the Pd-catalyzed aryl
(20) The quality of K3PO4 is important. See the Experimental Section for more
information.
9
7424 J. AM. CHEM. SOC. VOL. 124, NO. 25, 2002

An Efficient Cu Catalyst for the Amidation of Aryl Halides
A R T I C L E S
Table 5. Coupling of Aryl Iodides with Secondary Amidesa
a Performed using 10 mol % of ligand, 1.0 equiv of aryl iodide, 1.2 equiv of amide, and 2 equiv of K3PO4. b Isolated yields (average of 2 runs); >95%
1
purity as determined by GC and H NMR. c The commercial mixture of the cis and trans diastereomers of ligand 8 was used. d With 20 mol % of ligand.
e With 5 mol % of ligand. f trans-N,N′-Diphenyl-1,2-cyclohexanediamine was also isolated in 5% yield. g With 20 mol % of ligand 3 and 3.0 equiv of amide
substrate; isolated yield (average of 2 runs). h With 10 mol % of ligand 3 and 1.2 equiv of amide substrate; GC yield (average of 2 runs).
as the ligand with comparable results (entry 5). The amidation
reaction tolerates a variety of functional groups including the
nitrile (entry 7), free NH2 (entries 1 and 6), and aliphatic OH
(entry 3). The selective amidation of an aryl iodide containing
an aliphatic amino group (entry 1) is particularly interesting
since we have recently reported a method for selective copper-
catalyzed N-arylation of aliphatic amines using copper(I) iodide
and an O-donor ligand (ethylene glycol or an ortho-substituted
phenol).6g Therefore, it is possible to reverse the selectivity of
the copper-catalyzed C-N bond-forming reactions simply by
choosing an appropriate ligand. We hypothesize that this
remarkable change in selectivity is due to differences in the
σ-donating ability of the 1,2-diamine (presumably neutral,
moderately donating) and O-donor (presumably anionic, strongly
donating) ligands; a more detailed study is in progress.
A high level of selectivity was also observed in the amidation
of an aryl iodide containing another amide group (Table 5, entry
11). Unfortunately, this result has less desirable implications
as well; namely, acyclic N-alkylamides other than N-alkylfor-
mamides are problematic arylation substrates. Even N-alkyl-
(21) The mixture of the cis and trans diastereomers of 1,2-cyclohexanediamine
is very inexpensive because it is a byproduct in the preparation of Nylon.
9
J. AM. CHEM. SOC. VOL. 124, NO. 25, 2002 7425

A R T I C L E S
Klapars et al.
Table 6. Amidation of Aryl Bromidesa
a Performed with 10 mol % of ligand, 1.0 equiv of aryl bromide, 1.2 equiv of amide, and 2 equiv of K2CO3 at 110 °C for 15-24 h. b Isolated yields
1
(average of 2 runs); >95% purity as determined by GC and H NMR. c With 2 equiv of K3PO4 as base. d With 1.2 equiv of aryl bromide and 1.0 equiv of
amide. e At 120 °C for 24 h. f With 20 mol % of ligand; isolated yield (average of 2 runs). g With 10 mol % of ligand, GC yield.
formamides react poorly if the alkyl substituent is bulky enough
(entry 13). Moreover, significant N-arylation of the diamine
ligand (g5% with respect to the aryl halide) is observed if
hindered, unreactive amide substrates are used. The resulting
N-arylated diamines are less catalytically active then the starting
diamine,22 which further aggravates the reactions involving
hindered amides. Slightly improved yields can be obtained by
using a higher concentration (20 mol %) of the diamine ligand
(entries 13 and 14). In the case of N-methyl acetamide (entry
14), the yield of the desired N-arylated amide can be further
improved by increasing the amount of the amide substrate to 3
equiv. Interestingly, the reactivity of acyclic N-alkylamides and
hindered amides is equally problematic in the Pd-catalyzed
amidation methodology.
Aryl bromides react more slowly than aryl iodides and
typically require heating at 110 °C for 24 h (Table 6). The best
conditions for most substrates utilize 5 mol % of CuI, K2CO3
as the base, toluene as the solvent, and 10 mol % of N,N′-
dimethylated diamines 3 or 11 as the ligands. In the easiest cases,
a combination of CuI, ligand 8, K3PO4, and dioxane could be
used as well (entries 1, 7, and 12).23 The reaction is applicable
(23) In contrast to reactions with K2CO3 as the base, the coupling of aryl
bromides with unhindered amides (particularly primary amides and lactams)
utilizing K3PO4 as the base is very poor (<10% yield) if less than about
10 mol % or in some cases even 20 mol % of CuI is used. We tentatively
(22) We have found that only reactions of aryl iodides with benzamide are
significantly accelerated by N-aryl-1,2-diamines as ligands (Table 4, entry
6).
9
7426 J. AM. CHEM. SOC. VOL. 124, NO. 25, 2002

An Efficient Cu Catalyst for the Amidation of Aryl Halides
A R T I C L E S
Scheme 2. Intramolecular Aryl Amidationa
Table 7. Amidation of Aryl Chlorides
a Performed with 1.5 equiv of Cs2CO3 as base and 1 equiv of water in
THF at 25 °C for 4 h. bWith 2 equiv of K2CO3 as base in toluene at 100 °C
for 23 h.
to primary amides and unhindered secondary amides including
an R,â-unsaturated amide (entry 4), tert-butyl carbamate (entry
5), and a sensitive â-lactam (entry 6). The aryl bromide can
contain strongly electron-donating para substituents (entries 4
and 6), and moderately C-H acidic groups as well (entries 3
and 13). The bromo group in 4-bromo-1-chlorobenzene can be
selectively amidated in the presence of the chloro substituent
(entry 5). While p-bromothioanisole is an excellent substrate
(entry 14), the o-bromothioanisole reacts extremely slowly.24
This is an unexpected result since chelating aryl halides are
usually the best substrates for copper-catalyzed coupling reac-
tions.25 Significant steric hindrance in the aryl halide can be
tolerated if the amide coupling partner is not hindered. For
example, 2-bromo-1-isopropylbenzene reacted with 2-pyrroli-
dinone to give 94% yield of the product (entry 9). Unfortunately,
when slightly more hindered amide substrates are used, hin-
drance in the aryl bromide coupling partner is poorly tolerated
(entry 11). A variety of heteroaryl bromides are excellent
substrates, including 3-bromoquinoline (entry 8) and 5-bromo-
pyrimidine (entry 2), as well as both 2- and 3-bromothiophene
(entries 1, 7, and 12), the latter a substrate only moderately
amenable to Pd-catalyzed amination.
The 1,2-diamine ligands can be used to facilitate intra-
molecular amidation reactions.26 For example, five-membered-
ring formation via intramolecular amidation of an aryl bromide
in the presence of ligand 3 could be performed at room
temperature in quantitative yield (Scheme 2). In contrast, only
a trace of the desired product was observed even at 80 °C if no
ligand was added to the reaction mixture. Even an aryl chloride
provided an 88% yield of the cyclized product with ligand 3,
although heating at 100 °C for 23 h was necessary.27 These
preliminary results indicate that intramolecular amidation reac-
tions are more facile than the corresponding intermolecular
versions, which has been observed for the analogous Pd-
catalyzed amidation reactions as well.28
a Performed neat with 4 equiv of ArCl. b Isolated yields (average of 2
runs); >95% purity as determined by GC and H NMR.
1
11, and an excess (4 equiv) of the aryl chloride as the solvent
(Table 7). For aryl chlorides, ligand 11 performs much better
than related diamine 3. The reaction of p-chlorotoluene with
benzamide occurred in 93% yield after 23 h at 110 °C (entry
1). The corresponding reaction with 2-pyrrolidinone was slower;
nevertheless, it still proceeded in 95% yield at 130 °C (entry
2). Functionalized aryl chlorides provided lower yields of the
desired N-aryl amides (entries 3 and 4). Although further work
is required to improve the reaction conditions and to expand
the reaction scope, the coupling reactions reported here are
already performed at temperatures that are significantly lower
than in the very few cases of copper-catalyzed amidation of
aryl chlorides reported previously.29
Conclusion
We have developed a general, mild, and experimentally
simple method for the amidation of aryl halides, a radically
improved version of the classic Goldberg reaction. The best
results are realized by using the inexpensive and air-stable
copper(I) iodide and N,N′-dimethylated 1,2-diamine ligands 3
or 11 as the pre-catalyst. In some cases, other 1,2-diamine
ligands including ethylenediamine (1) and 1,2-cyclohexane-
diamine (10) can be utilized as a very inexpensive alternative
to ligands 3 and 11. We believe that this catalyst system provides
an excellent complement to the Pd-catalyzed methodology,
particularly if aryl halides containing strongly electron-donating
groups or free N-H groups have to be amidated. Efforts to
expand the scope of the method to other nitrogen nucleophiles
and to improve the reactivity of hindered amides in combination
with mechanistic studies are in progress in our laboratory.
We have also begun studies on intermolecular amidation of
aryl chlorides using 5 mol % of CuI, 11 mol % of the ligand
attribute this peculiar result to formation of an unreactive cuprate complex
(Scheme 1) in the presence of an excessively strong base, K3PO4. If this is
indeed the case, increasing the amount of CuI in the reaction mixture
compensates for the amount of copper removed from the catalytic cycle
into the unreactive cuprate complex, and thus keeps the catalytic cycle
operating.
Experimental Section
General Comments. All yields refer to isolated yields (average of
two runs) of compounds estimated to be >95% pure as determined by
1H NMR and GC. The procedures described in this section are
representative, and thus the yields for the individual reactions may differ
slightly from the average yields reported in Tables 4-7. Compounds
(24) Only about 10% GC yield and 28% conversion of aryl bromide was obtained
in the arylation of N-methylformamide. 2-Pyrrolidinone provided about 40%
GC yield of the N-arylated product and 66% conversion of 2-bromothio-
anisole.
(25) (a) Kalinin, A. V.; Bower, J. F.; Riebel, P.; Snieckus, V. J. Org. Chem.
1999, 64, 2986. (b) Zhang, S.; Zhang, D.; Liebeskind, L. S. J. Org. Chem.
1997, 62, 2312.
(26) Kametani, T.; Ohsawa, T.; Ihara, M. J. Chem. Soc., Perkin Trans. 1 1981,
290.
(27) After the completion of this work, a mild procedure for intramolecular
amidation of aryl bromides and aryl iodides utilizing CuI (2 equiv except
for one case with 10 mol %) and cesium acetate (5 equiv) in DMSO was
reported: Yamada, K.; Kubo, T.; Tokuyama, H.; Fukuyama, T. Synlett
2002, 231.
(28) (a) Wolfe, J. P.; Rennels, R. A.; Buchwald, S. L. Tetrahedron 1996, 52,
7525. (b) He, F.; Foxman, B. M.; Snider, B. B. J. Am. Chem. Soc. 1998,
120, 6417. (c) Brown, J. A. Tetrahedron Lett. 2000, 41, 1623. For
intramolecular C-O bond formation, see: (d) Kuwabe, S.; Torraca, K. E.;
Buchwald, S. L. J. Am. Chem. Soc. 2001, 123, 12202.
(29) (a) Renger, B. Synthesis 1985, 856. (b) Greiner, A. Synthesis 1989, 312.
9
J. AM. CHEM. SOC. VOL. 124, NO. 25, 2002 7427

A R T I C L E S
Klapars et al.
1
described in the literature were characterized by comparing their H
and 13C NMR spectra to the previously reported data. All new
compounds were further characterized by elemental analysis.
The quality of the inorganic bases, particularly K3PO4, is quite
important. The best results were obtained with K3PO4 available from
Fluka (catalog number 04347, Riedel-de Hae¨n product; free-flowing,
fine granules of uniform size). We also tried several reactions with the
K3PO4 purchased from Alfa Aesar (particles of variable size ranging
from fine powder to large chunks) and obtained comparable results in
all cases except for entry 8 in Table 5 where use of the Alfa Aesar
product failed. The particle size of K3PO4 is very important; most
reactions worked best if the granular product available from the
commercial sources was used directly. Some reactions (particularly,
the arylation of 2-pyrrolidinone) were in fact inhibited if K3PO4 was
ground with a mortar and pestle. We found only one reaction (Table
5, entry 7) that worked slightly better if finely ground K3PO4 was used.
We believe that these observations are best explained by variable kinetic
basicity of different K3PO4 samples, which should be heavily influenced
by the particle size of this heterogeneous base. K2CO3 (powder, -325
mesh) was purchased from Aldrich. Although K3PO4 and K2CO3 were
weighed out in the air, care was taken to minimize exposure to air due
to the hygroscopicity of these bases, particularly during very humid
periods of the year.
Representative Procedures: N-(2-Methylphenyl)acetamide (Table
4, entry 8). A Schlenk tube was charged with CuI (9.6 mg, 0.050 mmol,
5.0 mol %), acetamide (90 mg, 1.5 mmol), and K3PO4 (430 mg, 2.03
mmol), evacuated, and backfilled with argon. N,N′-Dimethylethylene-
diamine (11 µL, 0.10 mmol, 10 mol %), 2-iodotoluene (128 µL, 1.01
mmol), and dimethylformamide (1.0 mL) were added under argon. The
Schlenk tube was sealed with a Teflon valve and the reaction mixture
was stirred at 80 °C for 23 h. The resulting pale brown suspension
was allowed to reach room temperature and filtered through a 0.5 × 1
cm pad of silica gel eluting with 10 mL of ethyl acetate. The filtrate
was concentrated and the residue was purified by flash chromatography
on silica gel (2 × 15 cm; hexanes-ethyl acetate 1:4; 15 mL fractions).
Fractions 8-16 provided 143 mg (95% yield) of the known30 product
as pale yellow fine needles.
J ) 5.8 Hz, 1H), 2.60 (t, J ) 8.0 Hz, 2H), 2.16 (m, 2H). 13C NMR
(100 MHz, CDCl3): δ 174.4, 141.8, 139.3, 128.9, 123.0, 119.0, 118.5,
64.9, 48.9, 32.7, 17.9. IR (neat, cm-1): 3331, 1663. Anal. Calcd for
C11H13NO2: C, 69.09; H, 6.85. Found: C, 69.05; H, 6.81.
trans-N-(4-Dimethylaminophenyl)-3-phenylpropenamide (Table
6, entry 4). A Schlenk tube was charged with CuI (9.6 mg, 0.050 mmol,
5.0 mol %), 4-(dimethylamino)-1-bromobenzene (201 mg, 1.00 mmol),
trans-cinnamamide (178 mg, 1.21 mmol), and K2CO3 (280 mg, 2.03
mmol), briefly evacuated, and backfilled with argon. Racemic trans-
N,N′-dimethyl-1,2-cyclohexanediamine31 (16 µL, 0.10 mmol, 10 mol
%) and toluene (1.0 mL) were added under argon. The Schlenk tube
was sealed with a Teflon valve and the reaction mixture was stirred at
110 °C for 23 h. The resulting bright yellow suspension was allowed
to reach room temperature and then filtered through a 0.5 × 1 cm pad
of silica gel eluting with 1:1 ethyl acetate-dichloromethane (10 mL).
The filtrate was concentrated and the residue was dissolved in 10 mL
of dichloromethane and purified by flash chromatography on silica gel
(2 × 20 cm, ethyl acetate-dichloromethane 1:4, 15 mL fractions).
Fractions 10-20 provided 261 mg (98% yield) of the desired product
as a bright yellow solid. Mp 171-173 °C. 1H NMR (400 MHz,
CDCl3): δ 7.75-7.65 (m, 2H), 7.53-7.43 (m, 4H), 7.36-7.28 (m,
3H), 6.72-6.66 (m, 2H), 6.58 (d, J ) 15.5 Hz, 1H), 2.90 (br s, 6H).
13C NMR (100 MHz, CDCl3): δ 163.8, 147.9, 141.3, 134.8, 129.6,
128.7, 127.8, 121.7, 121.3, 113.0, 40.8. The 13C NMR spectrum contains
two overlapping signals. IR (neat, cm-1): 3236, 1652. Anal. Calcd for
C17H18N2O: C, 76.66; H, 6.81. Found: C, 76.68; H, 6.82.
N-(4-Methylphenyl)-2-pyrrolidinone (Table 7, entry 2). A Schlenk
tube was charged with CuI (20 mg, 0.11 mmol, 5.1 mol %) and K2CO3
(600 mg, 4.34 mmol), evacuated, and backfilled with argon. Racemic
trans-N,N′-dimethyl-1,2-cyclohexanediamine (35 µL, 0.22 mmol, 11
mol %), 2-pyrrolidinone (155 µL, 2.04 mmol), and 4-chlorotoluene
(1.0 mL, 8.4 mmol) were added under argon. The Schlenk tube was
sealed with a Teflon valve and the reaction mixture was stirred at 130
°C for 23 h. The resulting dark brown suspension was cooled to room
temperature and filtered through a 0.5 × 1 cm pad of silica gel eluting
with 10 mL of ethyl acetate. The filtrate was concentrated and the
residue was purified by flash chromatography on silica gel (2 × 20
cm; hexanes-ethyl acetate 1:4; 15 mL fractions). Fractions 7-15
provided 336 mg (94% yield) of the known32 product as white crystals.
N-(3-Hydroxymethylphenyl)-2-pyrrolidinone (Table 5, entry 3).
A Schlenk tube was charged with CuI (9.6 mg, 0.050 mmol, 5.0 mol
%) and K3PO4 (430 mg, 2.03 mmol), evacuated, and backfilled with
argon. N,N′-Dimethylethylenediamine (11 µL, 0.10 mmol, 10 mol %),
3-iodobenzyl alcohol (128 µL, 1.01 mmol), 2-pyrrolidinone (94 µL,
1.24 mmol), and toluene (1.0 mL) were added under argon. The Schlenk
tube was sealed with a Teflon valve and the reaction mixture was stirred
at 80 °C for 3 h. The resulting white suspension was allowed to reach
room temperature and filtered through a 0.5 × 1 cm pad of silica gel
eluting with 10 mL of ether-methanol (5:1). The filtrate was
concentrated and the residue was purified by flash chromatography on
silica gel (2 × 20 cm; dichloromethane-methanol 25:1; 15 mL
fractions). Fractions 14-19 provided 180 mg (93% yield) of the product
Acknowledgment. We thank the National Institutes of Health
(GM 45906) for support of this work. We are grateful to Pfizer,
Merck, and Bristol-Myers Squibb for additional funds. We thank
Drs. Jean-Franc¸ois Marcoux and Jingjun Yin for important
contributions to the initial phases of this work.
Supporting Information Available: Experimental procedures
and characterization data for all unknown compounds (PDF).
This material is available free of charge via the Internet at
http://pubs.acs.org.
1
as a white solid. Mp 120-121 °C. H NMR (400 MHz, CDCl3): δ
JA0260465
7.59 (m, 1H), 7.55-7.50 (m, 1H), 7.35 (t, J ) 7.8 Hz, 1H), 7.17-7.12
(m, 1H), 4.68 (d, J ) 5.8 Hz, 2H), 3.86 (t, J ) 7.0 Hz, 2H), 2.65 (t,
(31) Prepared according to: Betschart, C.; Schmidt, B.; Seebach, D. HelV. Chim.
Acta 1988, 71, 1999.
(32) Billing, D. G.; Boeyens, J. C. A.; Denner, L.; Du Plooy, K. E.; Long, G.
C.; Michael, J. P. Acta Crystallogr. (B) 1991, B47, 284.
(30) Hibbert, F.; Mills, J. F.; Nyburg, S. C.; Parkins, A. W. J. Chem. Soc., Perkin
Trans. 2 1998, 629.
9
7428 J. AM. CHEM. SOC. VOL. 124, NO. 25, 2002