Amino acid-mediated Goldberg reactions between amides and aryl iodides

Article abstract of DOI:10.1016/j.tetlet.2004.01.119

A highly general, experimentally simple, and inexpensive catalyst system was developed for the amidation of aryl iodides by using 5mol% of CuI as catalyst, 20mol% of an amino acid as ligand, and K₃PO₄ as base.

Full text of DOI:10.1016/j.tetlet.2004.01.119

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 2311–2315
Amino acid-mediated Goldberg reactions between amides and
aryl iodides
Wei Deng, Ye-Feng Wang, Yan Zou, Lei Liu*, and Qing-Xiang Guo*
Department of Chemistry, University of Science and Technology of China, Hefei 230026, China
Received 3 December 2003; revised 18 December 2003; accepted 23 January 2004
Abstract—A highly general, experimentally simple, and inexpensive catalyst system was developed for the amidation of aryl iodides
by using 5 mol % of CuI as catalyst, 20 mol % of an amino acid as ligand, and K3PO4 as base.
Ó 2004 Elsevier Ltd. All rights reserved.
Transition metal-catalyzed amide arylation is a widely
utilized reaction in academic and industrial laboratories
and therefore, has been a focus of interest recently.1 So
far significant improvements have been achieved in Pd-
catalyzed amide arylation reactions,2 but it remains hard
to apply these reactions to large and industrial scale
syntheses due to the high cost of Pd and the difficulty in
removing Pd residues from polar reaction products.
the formation of aryl–carbon and aryl–heteroatom
bonds.
Up to now, the ligands that have been found to promote
the Cu-catalyzed aryl–heteroatom coupling reactions
include thiophene-2-carboxylate,6 diamines,7 2,2,6,6-
tetramethyl-heptane-3,5-dione,8 1,10-phenanthroline,9
o-hydroxy-biphenyl,10 and neocuproine.11 A special
group of ligands, the amino acids, were found to
accelerate the Cu-catalyzed coupling reactions between
aryl halides and themselves.12
An alternative method for amide arylation is the Cu-
catalyzed Goldberg reaction.3 This method is attractive
from an economic standpoint because Cu is much
cheaper than Pd. Despite this advantage, the Goldberg
reaction is not a popular reaction in organic chemistry
due to the necessity to use temperatures as high as
210 °C, highly polar aprotic solvents, strong bases such
as alkoxides and NaH, large amounts of the nucleophile,
and often large amounts of Cu reagents.
It was originally proposed that the Cu–amino acid
chelation effect, which may trigger an intramolecular
coupling, was the cause of the observed acceleration.13
However, it was reported very recently by Ma et al. that
amino acids can also serve as ligands for the coupling
reactions of other nucleophile instead of themselves.14
Encouraged by this report, we recently initiated a sys-
tematic study on the application of amino acids as
ligands to Cu-catalyzed cross-coupling reactions. In the
present paper, we wish to report our results concerning
the Cu-catalyzed amidation reactions.
An interesting recent finding is that the Goldberg ami-
dation reaction can be greatly facilitated by certain
organic ligands.4 Similar promotion effects have also
been reported lately for other Cu-catalyzed coupling
reactions.5 These findings have given rise to a resurgence
in interest in developing mild synthetic methods using
Cu-based catalysts as an alternative to Pd catalysts for
In the first stage of the study we focused on the coupling
between caprolactam and iodobenzene using glycine as
the ligand. We examined the effects of various copper
salts, bases, solvents, reaction temperatures, and reac-
tion times on the yields of the coupling. The detailed
results are listed in Table 1.
Keywords: Copper; Goldberg reaction; Amide; Aryl halide; Coupling.
* Corresponding authors. Tel.: +1-646-515-7344; fax: +1-212-932-
1289; e-mail addresses: leiliu@chem.columbia.edu; qxguo@ustc.
edu.cn
As shown in Table 1, we found that the yield of the CuI/
glycine-catalyzed amidation reaction is highly depen-
dent on the base. Cs2CO3 surprisingly gives the lowest
Present address: Department of Chemistry, Columbia University,
New York, NY 10027, USA.
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.01.119

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W. Deng et al. / Tetrahedron Letters 45 (2004) 2311–2315
Table 1. Yields of the coupling reaction between caprolactam and iodobenzene under different conditions
O
N
O
I
NH
Conditions
+
Entry
Cu saltb
Base
Glycine
NaH
Ligandc
Solvent
Temp (°C)
Time (h)
Yield (%)a
1CuI
2
CaO
CuI
CuI
Dioxane00
1
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
DMF
24
58
Glycine
Glycine
Glycine
Glycine
Glycine
Glycine
Glycine
Glycine
Glycine
Glycine
100
100
100
100
100
120
70
24
24
24
24
12
24
24
24
24
24
24
24
24
24
24
24
85
13
41
97
70
98
76
79
8
3
Cs2CO3
K2CO3
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
4
CuI
CuI
5
6
CuI
CuI
7
8
CuI
THF
9
Cu2O
CuCl2
CuSO4
CuI
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
100
100
100
100
100
100
100
100
100
10
11
12
13
14
15
16
17
70
95
90
81
98
79
95
Ethylenediamine
Glycol
2,20-Bipyridine
N-Methyl glycine
CuI
CuI
CuI
CuI
N,N-Dimethyl glycine
Glycine hexyl ester
CuI
a Isolated yield.
b 5 mol %.
c 20 mol %.
yield (13%) while CaO and K2CO3 also give low yields.
NaH gives a fairly good yield (85%) and K3PO4 gives
the best yield (97%).
because it is highly soluble in water. (3) Amino acid
waste is relatively environmentally benign. (4) There are
a large number of different amino acids. Most of them
are chiral and we may use them as ligands in the syn-
thesis of atropisomeric amides.
Dioxane is a good solvent for the amidation reaction.
Use of DMF as solvent also gives a high yield (98%), but
the high boiling point of DMF is disadvantageous. Use
of THF as solvent, however, gives a relatively low yield
(76%).
Using the reaction procedure for glycine, we also
examined other amino acids as ligands for the amidation
reaction (see Table 2). It is found that in addition to
glycine, one can also use cystine, cysteine, lysine, argi-
nine, a-alanine, and b-alanine. They all give quite simi-
lar yields regardless of the properties of the side chains.
It is worthy mentioning that in all the amino acid-
In addition to CuI, we also used Cu2O, CuCl2, and
CuSO4 as the catalyst. However, the yields with the
latter three copper catalysts are much lower than the
yield with CuI. Therefore, we conclude that the air
stable and inexpensive CuI is the most desirable catalyst.
Table 2. Yields of the CuI-catalyzed coupling reactions between
iodobenzene and caprolactam or acetanilide with various amino acids
as ligands (base ¼ K3PO4, solvent ¼ dioxane, temperature ¼ 100 °C,
reaction time ¼ 24 h)
Compared to glycine ligand, use of ethylenediamine as
ligand also gives a good yield of 95%, which is in
agreement with BuchwaldÕs studies.4j Use of glycol or
2,20-bipyridine as ligand gives a relatively low yield.
Interestingly, it is found that N-methyl glycine and
glycine hexyl ester can also mediate the amidation
reaction very well (yield ¼ 98% and 95%). Nevertheless,
N,N-dimethyl glycine is much less effective (yield ¼ 79%)
possibly due to the steric problems.
Entry
Amide
Amino acid
Yield (%)a
1Caprolactam
2
Glycine
97
Cystine
Lysine
Caprolactam
92
99
98
97
97
99
84
88
84
87
89
86
87
3
Caprolactam
Caprolactam
Caprolactam
Caprolactam
Caprolactam
Acetanilide
Acetanilide
Acetanilide
Acetanilide
Acetanilide
Acetanilide
Acetanilide
4
a-Alanine
Arginine
Cysteine
b-Alanine
Glycine
5
6
On the basis of the above results, we conclude that CuI
(5 mol %)/glycine (20 mol %)/K3PO4/dioxane is a very
good catalyst system for the amidation reactions.14
Although the yield of this newly developed reaction is
similar to that reported before with other type of ligands
(e.g., diamines),4 the amino acid-mediated coupling
reaction is of interest because of the following reasons.
(1) The amino acid is cheap and safe to user. (2) The
amino acid ligand is easy to remove after the reaction
7
8
9
Cystine
Lysine
10
11
12
13
14
a-Alanine
Arginine
Cysteine
b-Alanine
a Isolated yield.

W. Deng et al. / Tetrahedron Letters 45 (2004) 2311–2315
2313
Table 3. Yields of the CuI-catalyzed coupling reactions between iodo-
benzene and various amides (base ¼ K3PO4, solvent ¼ dioxane, tem-
perature ¼ 100 °C, reaction time ¼ 24 h)
Table 4. Yields of the CuI-catalyzed coupling reactions between vari-
ous aryl halides and amides (ligand ¼ glycine, base ¼ K3PO4, sol-
vent ¼ dioxane, temperature ¼ 100 °C, reaction time ¼ 24 h)
Entry Amide
Yield (%)a
-Arginine b-Alanine
Entry
Aryl halide
Amide
Yield (%)a
O
Glycine
97
L
Cl
O
NH
1
26
NH
1
97
98
O
O
Br
O
NH
NH
2
3
62
98
2
3
4
95
99
95
NH2
O
Polymers
84
Polymers
89
Polymers
87
NH2
I
CH CO
3
O
O
O
N
H
4
5
CH CO
3
I
I
98
95
NH
5
6
74
75
76
79
78
66
O
N
H
CH CO
3
NH2
NO2
O
O
N
H
6
7
CH CO
3
I
84
92
N
H
O
O
7
8
97
99
55
97
55
NH2
NH
O
I
CH
3
O
O
NH
53
98
8
9
CH
CH
O
O
I
I
95
90
3
O
NH
O
O
9
97
83
98
83
3
NH2
NH
O
O
S
10
NH2 80
NH2
10
11
12
13
14
CH
CH
O
O
I
I
71
88
98
95
86
O
3
O
H
N
O
O
11
12
9181 98
N
H
3
N
H
O
NO2
64b
63
68
HO
N
H
NH2
a Isolated yield.
I
b N-Arylation versus O-arylation ¼ 15:1 (GC–MS).
NO2
O
NH
mediated amidation reactions the coupling between
iodobenzene and the thiol or amino groups on the
amino acid moiety is negligible as tested by GC/MS.
I
NO2
O
O
N
H
I
Using glycine, -arginine, and b-alanine as ligands, we
L
examined the coupling reactions between iodobenzene
and various primary and secondary amides (see Table
3). It is found that all the alkyl and aryl amides give high
to excellent yields except for one substrate, acrylamide.
It appears that in this particular case the amino group of
amino acid does a 1,4-addition to acrylamide resulting
in the anionic polymerization.
15
16
I
I
91
93
Br
Br
NH2
O
NH
(continued on next page)

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W. Deng et al. / Tetrahedron Letters 45 (2004) 2311–2315
Table 4 (continued)
O
Base
Yield (%)a
R2
+
I-
Entry
Aryl halide
Amide
R1
N
H
R3
O
O
R3
O
17
I
80
92
Br
H2N
(III)Cu
Ar
O
N
N
H
R1
R2
H2N
(III)Cu
Ar
O
I
O
I
CH
18
3
O
NH2
R3
O
O
O
O
I
I
CH
CH
19
20
95
82
R2
3
Ar-I
H2N
(I)Cu
R1
N
NH
Ar
O
3
Scheme 1.
N
H
a Isolated yield.
In summary, amino acids have been found to be excel-
lent ligands for Cu-catalyzed amidation reactions. The
catalyst system is general, inexpensive, safe, and envi-
ronmentally benign. Efforts to expand the utility of the
method to other types of Cu-catalyzed reactions in
combination with mechanistic studies are in progress in
our group.
Interestingly, an imide (entry 8) can also participate in
the coupling reaction, although the yield is relatively low
(yield ꢀ 55%). On the other hand, sulfonamide (entry
10) works fairly well in the amino acid-mediated cou-
pling reaction (yield ꢀ 83%). Hydrazide (entry 11) gives
a very good yield in the coupling (yield ¼ 98% with b-
alanine) and the coupling occurs nearly completely at
the amide nitrogen as demonstrated by NMR. More-
over, in the coupling of N-(2-hydroxy-ethyl)-acetamide,
the N-arylation versus O-arylation ratio is 15:1 as
revealed by GC/MS.
Acknowledgements
We thank MOST, CAS, and NSFC for the financial
support.
References and notes
Finally, using glycine as ligand we examined the cou-
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(see Table 4). It is found that chlorobenzene gives a very
low yield of 26% in the coupling. Bromobenzene gives a
modest yield of 62%, which is still much lower than the
yield seen with iodobenzene (97%).
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at either ortho, meta, or para positions can be tolerated
in the amino acid-mediated amidation reaction. In
particular, electron-rich aryl iodide (e.g., entries 7–11)
works fairly well in the coupling. An aryl iodide with
ortho substituent (entries 12–14) is also not a problem
with the CuI/glycine catalyst. Compared to these Cu-
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substituted aryl halides is often difficult with the Pd
catalyst.1;2
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mechanism in which a four-coordinated Cu(III) inter-
mediate is involved (see Scheme 1).15 According to the
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is either to promote the oxidative addition of ArI to the
Cu(I) species or to stabilize the Cu(III) intermediate.
The mechanism also explains why it is not the amino
group of amino acid ligand but the amide nitrogen that
participates in the coupling, because in the Cu(III)
complex amide nitrogen is anionic (and therefore, more
reactive) whereas the NH2 group of the amino acid
ligand is neutral.
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amidation reactions are as follows: An over-dried three-
neck flask was charged with CuI (47.6 mg 0.25 mmol
5.0 mol %) amide (6.0 mmol) glycine (75.1mg 1.0 mmol
20 mol %), and K3PO4 (2.65 g 12.5 mmol). The flask was
filled with nitrogen and aryl iodide (5.0 mmol) was added
then. Dioxane (10.0 mL) was added under nitrogen. The
reaction mixture was refluxed for 24 h at 100 °C. The
resulting suspension was cooled to room temperature and
filtered through a pad of silica gel with the help of 100 mL of
ethyl acetate. The filtrate was concentrated and the residue
was purified by chromatography to afford the pure product.
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