Copper-catalyzed aryl amination in aqueous media with 2- dimethylaminoethanol ligand

Article abstract of DOI:10.1016/j.tetlet.2005.03.027

Copper-catalyzed amination of aryl bromides and iodides under mild conditions has been developed with 2-dimethylaminoethanol as ligand and water as solvent. A variety of hydrophilic and hydrophobic aryl halide substrates have been aminated in good yield with a variety of amino acids, amino alcohols and peptides. This method has successfully N-arylated some hydrophilic amino compounds not available by other methods.

Full text of DOI:10.1016/j.tetlet.2005.03.027

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 2997–3001
Copper-catalyzed aryl amination in aqueous media with
2-dimethylaminoethanol ligandq
Zhikuan Lu and Robert J. Twieg*
Department of Chemistry, Kent State University, Kent, OH 44242-0001, USA
Received 24 February 2005; accepted 4 March 2005
Abstract—Copper-catalyzed amination of aryl bromides and iodides under mild conditions has been developed with 2-dimethyl-
aminoethanol as ligand and water as solvent. A variety of hydrophilic and hydrophobic aryl halide substrates have been aminated
in good yield with a variety of amino acids, amino alcohols and peptides. This method has successfully N-arylated some hydrophilic
amino compounds not available by other methods.
Ó 2005 Published by Elsevier Ltd.
Reactions in aqueous media are of great interest for
large-scale industrial processes due to the issues of econ-
omy and safety.1 Transition metal-catalyzed reactions in
aqueous media have been widely explored.2 Here, suffi-
cient miscibility of the catalyst in both aqueous phase
and organic phase is required.3 For example, a variety
of water-soluble triarylphosphines were designed and
applied to applications particularly for palladium cata-
lysts used in Suzuki, Heck and amination reactions.4
Water-soluble and sterically demanding alkylphosphines
have also been applied to Suzuki, Heck and Sonogashira
reactions in aqueous media.5 Attempts have been made
to increase the solubility of copper species in organic sol-
vents. Copper(II) pivalate was chosen as a catalyst for
coupling between pentavalent organobismuth reagents
and amines because of its high solubility in common
organic solvents.6 The phosphazene base P4-t-Bu has
successfully promoted CuBr-catalyzed coupling of aryl
halides with phenols probably due to the enhanced
solubility of CuBr in the presence of P4-t-Bu.7
idine with Cu2O catalyst accompanied by 22% of
hydroxypyridine byproduct.9 However, water has rarely
been used as a solvent for the recently developed copper-
catalyzed aminations under mild conditions, particu-
larly when arylhalides are starting materials.10 Amino
acids and peptides are usually arylated by aromatic
nucleophilic reaction or substitution reaction of a pro-
tected carboxylic acid and subsequent hydrolysis.11 Ma
et al. have found that amino acids are good ligands to
accelerate the Ullmann condensation with an additional
amine in DMSO as solvent.12 The same group reported
a successful copper- catalyzed amination between aryl
halides and a variety of amino acids in DME and
DMF.13 However, this method appears to be limited
to a- and b-amino acids bearing hydrophobic substitu-
ents. Amino acids other than a- and b-amino acids
failed to give any arylamine products. The b-amino
acids are less effective than a- amino acids and highly
hydrophilic amino acids such as L-glutamic acid, L-ser-
ine and glycine failed to couple at all with aryl halides
under these conditions.14 It was recognized that the
low solubility of the highly hydrophilic amino acids in
typical organic solvents could be responsible for this
failure.13 This problem was partially alleviated by solu-
bilizing the amino acids as their tetrabutylammonium
salts in the dipolar aprotic solvents N,N-dimethylacet-
amide and acetonitrile.15 Using this protocol, moderate
yields were reported for the amino acids examined but it
is interesting that in this approach water was removed
prior to the addition of copper catalyst, even though
water is expected to be a good solvent for such
substrates.
Water was chosen as a solvent for Ullmann condens-
ations to make p-phenylenediamine from halobenzenes
under traditional conditions in a bomb under high pres-
sure and temperature.8 In a recent report, water was
used as solvent to convert bromopyridine to aminopyr-
Keywords: Amination; Copper catalysis; Amino acid.
q Presented in part at the 227th ACS National Meeting, Anaheim, CA,
United States, March 28, April 1, 2004.
*
Corresponding author. Tel.: +1 330 672 2791; fax: +1 330 672
3816; e-mail: rtwieg@lci.kent.edu
0040-4039/$ - see front matter Ó 2005 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2005.03.027

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Z. Lu, R. J. Twieg / Tetrahedron Letters 46 (2005) 2997–3001
Recently, we reported that 2-dimethylaminoethanol
(deanol) is an efficient solvent for the copper-catalyzed
amination reaction. In this system the addition of water
slows down the reaction yet it has the advantage of sup-
pressing the arylether byproduct from arylation of dea-
nol.16 This earlier study prompted us to explore the
possibility of coupling hydrophilic substrates in aqueous
media. Here we demonstrate a copper-catalyzed amin-
ation of amino acids and especially those amino acids
that have failed to undergo arylation reaction by other
methods. Examples include glycine, glutamic acid,
non-a- and b-amino acids and amino alcohols and other
amines.
here in the presence of added water (entry 10). Both cup-
ric chloride and cuprous oxide are effective and cuprous
oxide has equivalent catalytic effect in regards to iso-
lated yield (entries 11 and 12). However, higher racem-
ization was observed for the reactions with cuprous
oxide catalyst than that with CuI as catalyst. Chiral
HPLC analysis of the N-phenylvaline from L-valine
indicated that it contains 1.5% of N-phenyl-D-valine
and 98.5% of N-phenyl-L-valine with CuI as catalyst.
Table 2. Copper-catalyzed coupling of non-polar a-amino acids with
bromobenzene and iodobenzene
In order to systematically evaluate the roles of catalyst
precursor, ligand and base the coupling of DL-valine
with bromobenzene was examined (Table 1). Control
experiments indicate that deanol is essential for this
reaction, in part by providing a soluble catalytic species
(entry 1). An attempt to use deanol as the only solvent
(no water, entry 3) provided only a moderate amination
yield and an incomplete conversion of bromobenzene.
We also examined ethylene glycol as a ligand instead
of deanol (entry 4), and observed significant insoluble
components in the reaction mixture. A moderate yield
of aryl amino acid and incomplete conversion of bromo-
benzene was observed. Both glycolic acid and tartaric
acid (entries 5 and 6) were proved to be copper solubiliz-
ing ligands but were ineffective in this particular reac-
tion. It seems that the solubility of copper species is
not the only criteria for this catalytic reaction, as some
chelation modes are not catalytically effective. As base,
potassium carbonate and sodium phosphate are useful
but less effective than potassium phosphate (entries 7
and 8). In contrast, potassium hydroxide (entry 9) gave
a low conversion with bromobenzene and only <5%
arylamine was isolated. The strongly basic conditions
likely impair the stability of copper complex with deanol
and degrade the catalytic effect. Copper metal is a supe-
rior catalyst precursor for the amination reaction using
deanol as solvent,16 but alone it is much less effective
CuI 10%mol
Deanol 2 - 3 eq
R
R
N
H
CO2H
Br(I)+
H2N
CO2H
K3PO4·H2O 2.0 eq.
H2O, 80-90°C
Entry ArX
1
Product
Yielda (%)
88
CH3
CO2H
Br
(DL)
N
H
2
3
(DL, D and L) 90
Br
Br
N
H
CO2H
Ph
(DL)
80
N
H
CO2H
4
5
(DL)
(DL)
85
82
I
I
N
H
CO2H
CH3
CO2H
N
H
CO2H
6
(DL)
80
I
N
H
a Isolated yield.
Table 1. Catalyst, base and ligand optimization study for the amination of bromobenzene with DL-valine in aqueous media
"Cu" 10%mol
Ligand 2 - 3 eq
base 2.0 eq., solvent
90°C, 48h, N2
CO2H
N
H
Br
10 mmol
+
DL-Valine
15 mmol
Entry
ÔCuÕ
Ligand
Base
Solvent
Yielda (%)
1
CuI
CuI
Nil
Deanol
Deanol
K3PO4
H2O
H2O
Deanol
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
<5
90
46
62
<5
<5
67
52
<5
21
73
88
2
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K2CO3
Na3PO4
KOH
3
CuI
CuI
4
Ethylene glycol
Glycolic acid
Tartaric acid
Deanol
5
CuI
CuI
6
7
CuI
CuI
8
Deanol
Deanol
9
CuI
10
11
12
Cu(0)
CuCl2
Cu2O
Deanol
Deanol
Deanol
K3PO4
K3PO4
K3PO4
a Isolated yield.

Z. Lu, R. J. Twieg / Tetrahedron Letters 46 (2005) 2997–3001
2999
But with Cu2O as catalyst, 18.4% N-phenyl-D-valine was
observed. The issue of racemization remains to be sys-
tematically examined.
tartaric acid and glycolic acid that are not good ligands
for this copper-catalyzed reaction.
Aspartic acid coupled with iodobenzene efficiently, but
when the reaction mixture was acidified during workup,
CO2 was evolved and only N-phenylalanine was
isolated. An attempt to couple iminodiacetic acid with
iodobenzene failed (entry 7).
Bromobenzene and iodobenzene are both very reactive
with a-amino acids bearing a hydrophobic substituent.
Valine afforded the best yield of N-arylamino acid prod-
uct and other amino acids with hydrophobic substitu-
ents also gave good yields (Table 2).
For the first time, to our knowledge, peptides were aryl-
ated by a transition metal-catalyzed aryl amination reac-
tion. Glycylglycine and glycyl-L-leucine reacted at the
primary amine site with iodobenzene and we obtained
40% and 46% yield of the respective arylation products
(entries 8 and 9).
Encouraged by the successful N-arylation of a-amino
acids bearing hydrophobic substitutents, we subse-
quently explored the N-arylation reactions of the amino
acids that failed to undergo arylation reaction with the
currently available transition metal-catalyzed amination
reactions.13 These are the still more hydrophilic a-amino
acids such as glutamic acid, glycine and serine and ami-
no acids other than a- and b-amino acids. The results
obtained using the deanol–water system are shown in
Table 3. We first examined the reaction of glycine, the
simplest amino acid, with iodo- and bromobenzene. Iodo-
benzene is more reactive than bromobenzene and sub-
strates other than a-amino acids hardly react with aryl
bromides. Therefore, we only examined iodobenzenes
for the couplings with these other amines. The more
water-soluble 3-iodobenzoic acid is more reactive (entry
3) and coupling of b-alanine with iodobenzene also
afforded a good yield (entry 4). Glutamic acid and serine
(entries 5 and 6) are less reactive as the reactions took
longer time and the yields dropped to around 30–50%.
This is probably related to the coordination of these
amino acids to create copper species quite similar to
We have also extended this reaction to amino acids
other than a- or b-amino acids and other amines includ-
ing amino alcohols and diamines (Table 4). In contrast
to the methods employing DME or DMF as solvent,13
this reaction in aqueous media provides efficient N-aryl-
ation for these amines. Reactions between a variety of
iodobenzene and amino acids with different alkyl chains
are all successful. The more hydrophilic 2-, 3- or 4-iodo-
benzoic acids afforded better yields and higher reaction
rates (entries 3–5) than iodobenzene. Electron rich 3-
and 4-iodoanisole reacted well with 6-aminocaproic acid
but a lower yield was observed and longer reaction time
was required (entries 6 and 7).
It should be emphasized that an amino acid is not a
requirement for this reaction in water as we also have
Table 3. Copper-catalyzed amination of ArX with hydrophilic amino acids in water solution (same reaction conditions as in Table 2)
Entry
1
RNH2
Productb
Yielda (%)
HO2CCH2NH2
87
HO2CH2CHN
2
3
HO2CCH2NH2
HO2CCH2NH2
62
90
HO2CH2CHN
CO2H
HO2CH2CHN
H
HO
NH2
HO
N
4
5
73
32
O
HO2C
O
HO2C
H
NH2
N
CO2H
CO2H
H
N
NH2
HO
HO
6
49
CO2H
CO2H
HO2C
HO2C
HO2C
HO2C
7
8
0
NH
N
O
O
H
N
NH2
40
HO2C
N
H
HO2C
N
H
CO2H
CO2H
NHCOCH2NH2
9
46
NHCOCH2NH
a Isolated yield.
b All ArX are iodobenzene except entry 2 is bromobenzene and entry 3 is 3-iodobenzoic acid.

3000
Z. Lu, R. J. Twieg / Tetrahedron Letters 46 (2005) 2997–3001
Table 4. Coupling of iodobenzenes with non-a- and b-amino acids and other amines in aqueous media
CuI 10%mol
Deanol 1.5 - 2 eq
R
R
I
NR1R2
+
HNR1R2
12-15 mmol
K3PO4·H2O 2.0 eq.
H2O, 80 °C, 24-48h
10 mmol
Entry
1
Amine
Productb
Yielda (%)
76
NH(CH2)5CO2H
NH(CH2)10CO2H
H2N
CO2H
2
3
H2N(CH2)10CO2H
87
92
HO2C
H2N
CO2H
CO2H
CO2H
CO2H
CO2H
NH(CH2)5CO2H
CO2H
NH(CH2)5CO2H
4
H2N
H2N
H2N
H2N
H2N
90
88
46
73
84
90
92
31
77
81
61
5
HO2C
NH(CH2)5CO2H
6
H3CO
H3CO
NH(CH2)5CO2H
NH(CH2)5CO2H
7
HO2C
8
N
H
OH
H2N
OH
9
N
H
H2N
HN
OH
N
H
OH
OH
10
11
12
13
OH
CH3
OHH OHOH
CH3
N OHH OHOH
CH2OH
CH2OH
OH
H OHH H
H OHH
O
H
O
H2N
H2N
OH
N
H
OH
N
H
OH
H
H
N
14
N
N
H
H2N
a Isolated yield.
b All ArX are iodobenzene except entries 3 and 8 are 3-iodobenzoicacid; entry 4, is 2-iodobenzoic acid, entry 5 is 4-benzoic acid, entry 6 is
4-iodoanisole and entry 7 is 3-iodoanisole.
extended this method to other hydrophilic amines
including amino alcohols and diamines. 3-Iodobenzoic
acid coupled with the simple n-butylamine in high yield
(entry 8). Job and Buchwald have observed the acceler-
ation effect of the 2-hydroxy functionality to the copper-
catalyzed arylation of amino alcohols in a study of

Z. Lu, R. J. Twieg / Tetrahedron Letters 46 (2005) 2997–3001
3001
arylation of b-amino alcohols in DMSO/H2O (2:1) sol-
References and notes
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xyl group are quite reactive in aqueous solution.
Multiple hydroxyl groups in amino alcohols can expe-
dite the reaction (entry 10). Even secondary amines with
multiple hydroxyl functionality coupled to iodobenzene
in moderate yield (entry 11). The scope of this reaction is
not limited to amines with 2-hydroxy groups. We have
found that this method could be extended to non-b-
amino alcohols and diamines such as 5-hydroxylpentyl-
amine and 2-(2-aminoethoxy)-ethanol which have been
coupled with iodobenzene under the same conditions
(entries 12 and 13). In a molecule containing both pri-
mary and secondary amine the primary amine reacts
preferentially (entry 14).
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lides under mild conditions in water has been developed
with 2-dimethylaminoethanol as ligand. Cu2O, CuCl2
and Cu(OAc)2 are effective catalysts but CuI afforded
the best results. K3PO4 works best as base while other
bases such as K2CO3 and Na3PO4 are also effective.
Amino acids including a- and b-amino acids with or
especially without hydrophobic substituents non-a-
and b-amino acids, amino alcohols, peptides and other
amines have been aminated. Both aryl iodides and bro-
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Supplementary data
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Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2005.03.027. Supplementary material is available
for general synthetic methodology, spectroscopic prop-
erties and for chiral HPLC analysis of D-, L- and DL-
N-phenylvaline obtained from the coupling reactions.
17. Job, G. E.; Buchwald, S. L. Org. Lett. 2002, 4, 3703–3706.