Microwave-promoted N-arylation of imidazole and amino acids in the presence of Cu2O and CuO in poly(ethylene glycol)

Article abstract of DOI:10.1007/s11172-016-1442-8

Copper(I)-catalyzed N-arylation of imidazole with iodobenzene, its derivatives, and bromobenzene in poly(ethylene glycol) under microwave irradiation was studied. The influence of the following factors on the yield of arylation product was investigated: the nature of the source of copper and ligand, type of poly(ethylene glycol) (PEG) used, and substituents in iodoarene. An optimal catalytic system was selected: CuO/l-Hys/Cs₂CO₃/PEG-400, a possibility of recycling of copper-containing catalyst was demonstrated. N-Arylation of eight natural amino acids using catalysis with Cu₂O/Cs₂CO₃/PEG-400 and microwave irradiation was studied, the dependence of the reaction results on temperature, duration of the process, and the ratio of the starting reagents was found. The highest yields of the target products were reached in the case of leucine, valine, and phenylalanine.

Full text of DOI:10.1007/s11172-016-1442-8

Russian Chemical Bulletin, International Edition, Vol. 65, No. 5, pp. 1243—1248, May, 2016
1243
Microwaveꢀpromoted Nꢀarylation of imidazole and amino acids
in the presence of Cu2O and CuO in poly(ethylene glycol)*
A. A. Yakushev,a.b A. D. Averin,a,c E. Colacino,b F. Lamaty,b and I. P. Beletskayaa,c
aM. V. Lomonosov Moscow State University, Department of Chemistry,
Build. 3, 1 Leninskie Gory, 119991 Moscow, Russian Federation.
Fax: +7 (495) 939 3618. Eꢀmail: beletska@org.chem.msu.ru
bMax Mousseron Institute of Biomolecules, Montpellier University 2,
France, Montpellier**
cA. N. Frumkin Institute of Physical Chemistry and Electrochemistry, Russian Academy of Sciences,
Korp. 4, 31 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (495) 955 4666
Copper(I)ꢀcatalyzed Nꢀarylation of imidazole with iodobenzene, its derivatives, and bromoꢀ
benzene in poly(ethylene glycol) under microwave irradiation was studied. The influence of the
following factors on the yield of arylation product was investigated: the nature of the source of
copper and ligand, type of poly(ethylene glycol) (PEG) used, and substituents in iodoarene. An
optimal catalytic system was selected: CuO/LꢀHys/Cs2CO3/PEGꢀ400, a possibility of recycling
of copperꢀcontaining catalyst was demonstrated. NꢀArylation of eight natural amino acids
using catalysis with Cu2O/Cs2CO3/PEGꢀ400 and microwave irradiation was studied, the deꢀ
pendence of the reaction results on temperature, duration of the process, and the ratio of the
starting reagents was found. The highest yields of the target products were reached in the case of
leucine, valine, and phenylalanine.
Key words: catalysis, copper(I) compounds, aryl halides, imidazole, amino acids, polyꢀ
(ethylene glycol).
Catalysis for the C(sp2)—N bond formation by univaꢀ
lent copper complexes is an intensively developing trend
in modern synthetic organic chemistry, which already beꢀ
came a subject of several reviews and monographs.1—3
NꢀArylation of imidazole is used as a model reaction for
testing different catalytic systems. Aryl iodides and broꢀ
mides were used to study catalytic properties of Cu2O in
the presence of various Schiff bases and oximes.4 Arylaꢀ
tion with iodoarenes can be successfully effected using CuI
and N1,N2ꢀdimethylcyclohexaneꢀ1,2ꢀdiamine.5 Amino
acids such as proline and N,Nꢀdimethylglycine6—10 are
widely used as ligands in various copperꢀcatalyzed aminaꢀ
tion reactions. In these reactions, DMSO is used as the
solvent most frequently, however, in some case this is
acetonitrile and dioxane. Nonꢀnatural amino acids such as
pipecolic and pyrrolecarboxylic11,12 can be also used. Of
natural amino acid, hystidine13 was used in a number of
experiments, with some of them being performed in
poly(ethylene glycols) (PEG) instead of DMSO. Another
work mentioned the use of mixtures of PEG—butyroꢀ
nitrile and PEG—Nꢀmethylpyrrolidone for arylation of
imidazole in the presence of Cu2O and 4,7ꢀdimethoxyꢀ
phenanthroline.14 Note that in the indicated works, the
aspect of recyclability of the catalyst due to the use of
PEG as the medium for carrying out the catalytic process
was not developed. The multiple use of the catalyst due to
the simplicity of isolation of reaction products from
poly(ethylene glycols) was considered in the literature for
the following examples: the amidation of aryl iodides
(PEGꢀ400) catalyzed by Cu2O nanoparticles,15 the reacꢀ
tion of arylboronic acids with aryl bromides and even aryl
chlorides in the system Cu/I2 (PEGꢀ400),16 the reactions
of C—Hꢀactivation of triazoles and oxadiazoles with iodoꢀ
arenes in the system Cu(nanoparticles)/PEGꢀ40017, thioꢀ
lation of aryl bromides and aryl iodides in the presence of
CuI in PEGꢀ1000 and a mixture of PEG—water.18 Microꢀ
wave irradiation in the Nꢀarylation of indole and benzꢀ
imidazole in more highꢀmolecularꢀweight PEGꢀ3400 was
also reported.19
Based on the aboveꢀmentioned facts, we attempted to
study a possibility of Nꢀarylation of imidazole in polyꢀ
(ethylene glycols) under influence of microwave irradiaꢀ
tion. Initially, we selected the optimal source of copper in
* Dedicated to Academician of the Russian Academy of Sciences
O. G. Sinyashin on the occasion of his 60th birthday.
** Institut des Biomolécules Max Mousseron (IBMM) UMR
5247, Université Montpellier 2, Montpellier, France.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 1243—1248, May, 2016.
1066ꢀ5285/16/6505ꢀ1243 © 2016 Springer Science+Business Media, Inc.

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Russ.Chem.Bull., Int.Ed., Vol. 65, No. 5, May, 2016
Yakushev et al.
PEGꢀ400, trying the following compounds: copper(I)
oxide and copper(II) oxide, copper iodide, copper acetylꢀ
acetonate, copper nanoparticles in the presence or in the
absence of hystidine; the latter was initially chosen as the
ligand, which was successfully used in poly(ethylene glyꢀ
col) (Scheme 1, Table 1). All the reactions were carried
out under standard conditions: 10 mol.% of copper,
20 mol.% of hystidine (in the case of its addition), 2 equiv.
of aryl iodide and cesium carbonate used as a base, the
the product yield. More interesting and important concluꢀ
sions were drawn from the experiments on variation of the
source of copper. It follows from the data in Table 1 that
under the indicated conditions, the conversion of imidꢀ
azole to the product was 52—83%, with the yields more
than 70% being reached in the presence of the following
catalytic systems: CuI/LꢀHys (entry 1), CuO/LꢀHys (entry
5), Cu(acac)2/LꢀHys (entry 8), and copper nanoparticles/
LꢀHis (entry 10). A special experiment (entry 6) showed
that the use of 2 equiv. of iodobenzene is an important
factor for the increase in the yield of the arylation product.
The best result was reached in the case of application of
the catalytic system Cu(acac)2/LꢀHys (83%, entry 8),
however, in further experiments we used another system,
CuO/LꢀHys (entry 5), which gave a slightly lower
yield of compound 2, but did not contain an additional
acetylacetonate ligand, which could neutralize the influꢀ
ence of the studied ligands on the efficiency of the arylꢀ
ation reaction.
concentration of imidazole in PEGꢀ400 was 0.46 mol L–1
,
the reactions were carried out for 2 h at 150 °C, the conꢀ
version of imidazole (1) into Nꢀphenylimidazole (2) was
1
determined using H NMR spectroscopy after treatment
of the reaction mixture with diethyl ether and separation
of the reaction product and unreacted imidazole from the
catalyst and the base.
Scheme 1
Further, in the presence of the catalyst CuO/LꢀHis
(10/20 mol.%) we carried out a series of experiments to
study the influence of the reaction medium on the effiꢀ
ciency of the arylation reaction (Table 2). A high converꢀ
sion of the starting imidazole (above 70%) was observed
for PEGꢀ400 (entry 1), PEGꢀ2000 (entry 2), and PEGꢀ
3400 (entry 5), with PEGꢀ400 being found the most prefꢀ
erable. In the cases of completely or partially methylated
poly(ethylene glycols), the conversion of imidazole was
lower (entries 3 and 4). A mixture of PEGꢀ400 and PEGꢀ
3400 turned out to be noticeably less efficient (entry 7)
than PEGꢀ400 and PEGꢀ3400 separately. A twoꢀfold deꢀ
crease in the concentration of the starting compounds leads
to a considerable decrease in the yield of compound 2
(entry 6). In the solvents in which the process cannot be
carried out at a required temperature (150 °C), the conꢀ
version of imidazole was low (entries 8 and 9). Thus, the
Reagents and conditions: PhI (2 equiv.),
[Cu]/L (10/20 mol.%), PEGꢀ400,
Cs2CO3 (2 equiv.), MW, 150 °C, 2 h.
L =
The reaction time and temperature were optimized
experimentally for several versions of catalytic systems. It
was preliminarily found that an increase in temperature
above 150 °C did not improve the result, an increase in the
reaction time beyond 2 h can only insignificantly increase
Table 1. Optimization of copper source in arylation of
imidazole
Table 2. Optimization of reaction medium in arylation
of imidazole
Entry
Source of copper
Ligand
Yield of 2
(%)
Entry
Medium
Yield of 2 (%)
1
2
3
4
5
6*
7
8
9
CuI
Cu2O
Cu2O
CuO
CuO
LꢀHys
—
LꢀHys
—
LꢀHys
LꢀHys
—
LꢀHys
—
72
52
65
62
79
50
62
83
60
79
1
2
3
4
5
6*
7
8
9
PEGꢀ400
PEGꢀ2000
PEGꢀ2000(OMe)2
PEGꢀ2000(OMe)(OH)
PEGꢀ3400
PEGꢀ3400
PEGꢀ400 +PEGꢀ3400
H2O
79
70
63
54
75
45
54
34
33
CuO
Cu(acac)2
Cu(acac)2
Cunano
Cunano
MeCN
10
LꢀHys
* The reaction was carried with half as large concentraꢀ
tions of the starting compounds.
* 1 equiv. of iodobenzene was used.

Arylation of imidazole
Russ.Chem.Bull., Int.Ed., Vol. 65, No. 5, May, 2016
1245
Scheme 2
additional studies of the influence of the reaction medium
justified the choice of PEGꢀ400 for this process.
In the following step, we studied the influence of the
ligand on the yield of the arylation product. Table 3 sumꢀ
marizes the data on 10 amino acids, which were compared
with hystidine in the standard arylation reaction of imidꢀ
azole with iodobenzene (CuO/L, 0/20 mol.%).
It was found that the following catalysts provided conꢀ
version of imidazole comparable (above 70%) with that of
hystidine (entry 1): an equimolar mixture of hystidine with
glycine (entry 3), alanine hydrochloride (entry 6), or proꢀ
line in the combination with copper iodide (entry 11). The
latter catalytic system is described in details in the literaꢀ
ture, including its use in PEG.18 The other αꢀamino acids
provided slightly lower conversion of imidazole (56—67%),
whereas βꢀalanine turned out to be even less efficient
(entry 5). These experiments confirmed the right choice of
hystidine as the ligand in PEG medium.
Reagents and conditions: CuO/LꢀHys (10/20 mol.%), PEGꢀ400,
Cs2CO3 (2 equiv.), MW, 150 °C, 2 h.
The optimized conditions were used to study the reacꢀ
tivity of different aryl iodides containing electronꢀdonatꢀ
ing and electronꢀwithdrawing substituents, including those
in orthoꢀposition, as well as bromobenzene (Scheme 2,
Table 4). The reactions with 4ꢀiodotoluene and 4ꢀiodoꢀ
anisole under the standard conditions provided very high
yields of the arylation products 3 and 5 (entries 1 and 3),
which were higher than in the model reaction with iodoꢀ
benzene (79%). At the same time, in the reactions with
2ꢀiodotoluene and 1ꢀiodoꢀ2ꢀmethoxyꢀ4ꢀnitrobenzene the
Table 3. Optimization of ligand in arylation of imidazole
Table 4. Arylation of imidazole with aryl halides
Entry
Ligand
Yield 2 (%)
Entry
Aryl halide
Product and its
yield (%)
1
2
3
4
5
6
7
8
LꢀHys
Gly
Gly + LꢀHys (1 : 1)
LꢀAla
βꢀAla
LꢀAlaNH2•HCl
79
67
72
63
50
75
64
62
66
63
80
66
56
1
2
3
4a
5b
6
7
8
9
4ꢀMeC6H4I
2ꢀMeC6H4I
4ꢀMeOC6H4I
4ꢀMeOC6H4I
4ꢀMeOC6H4I
1,4ꢀI2C6H4
3 (90)
4 (27)
5 (89)
5 (50)
5 (74)
6c (60)
7d (65)
8 (38)
2 (34)
LꢀArg
LꢀArg(NO2)
LꢀArg(NH2)
LꢀLys•HCl
LꢀPro
3ꢀBrC6H4I
2ꢀMeOꢀ4ꢀO2NC6H3I
PhBr
9
10
11*
12
13
a PEGꢀ3400 was used.
LꢀHyp
LꢀLeu
b Proline was used instead of hystidine as the ligand.
c The product was 1ꢀ(4ꢀiodophenyl)imidazole (6).
d The product was 1ꢀ(3ꢀbromophenyl)imidazole (7).
* CuI was used instead of CuO.

1246
Russ.Chem.Bull., Int.Ed., Vol. 65, No. 5, May, 2016
Yakushev et al.
arylation products 4 and 8 were obtained in low yields
(entries 2 and 8). Apart from that, the replacement of
PEGꢀ400 with PEGꢀ3400, as well as the use of proline
instead of hystidine in the reactions with pꢀiodoanisole led
to the decrease in the yields of the target product 5 (entries
4 and 5). The arylation of 1,4ꢀdiiodobenzene and 3ꢀbromoꢀ
iodobenzene gave fairly good yields of products 6 and 7
(entries 6 and 7), a slight decrease in the yields as comꢀ
pared to iodobenzene is probably due to the side reacꢀ
tions proceeding because of the presence of the second
halogen atom.
CuI/2ꢀisobutyrylcyclohexanone was also used.25 In the
present study, we for the first time investigated arylation
of eight amino acids (AA) in PEG (Scheme 3, Table 6).
Scheme 3
Preliminary study of recyclability of the catalyst was
carried out in two catalytic systems: CuO/LꢀHys/Cs2CO3/
PEGꢀ400 and CuI/LꢀPro/Cs2CO3/PEGꢀ400 (Table 5).
From the given data, it can be concluded that in the reacꢀ
tions in the presence of ligands (hystidine and proline) the
catalytic activity of copper decreases starting from the third
cycle. More detailed conclusions will be made after further
studies of these processes, however, in this study we demꢀ
onstrated a principal possibility of the catalyst recovery.
In the reactions catalyzed by univalent copper involvꢀ
ing amino acids with a primary amino group as ligands,
they themselves undergo partial arylation. This process
can be made a predominant, there are literature data deꢀ
scribing conditions for the efficient Nꢀarylation of amino
acids. Thus, aryl iodides and aryl bromides were used to
arylate amino acids in the presence of CuI in dimethoxyꢀ
ethane without addition of extra ligands.20 Additional
ligands were not used either in the amination of 4ꢀiodoꢀ,
4ꢀbromoꢀ, and 5ꢀbromoꢀNꢀtosylindoles with amino acids
in DMSO.21 The system CuI/KI was used for the arylaꢀ
tion of amino acids and their esters with bromoarenes,22
the same catalyst was applied for the arylation of amino
acids with aryl iodides and aryl bromides in DMF with
microwave assistance.23 Additional ligands are used selꢀ
dom in these processes: thus, the reactions of aryl iodides
and aryl bromides with amino acids in water in the presꢀ
ence of N,Nꢀdimethylaminoethanol were catalyzed by an
equimolar mixture of Cu : CuI,24 a more traditional system
Reagents and conditions: 5 equiv. ArX, Cu2O (10 mol.%), Cs2CO3
(3 equiv.), PEGꢀ400, MW.
Based on the preliminarily obtained data, Cu2O was
used as a source of copper, the reactions were carried
out with iodobenzene (1—5 equiv.) at a temperature of
100—150 °C and a concentration of amino acids of
0.46 mol L–1. In a number of cases, the reaction time was
varied within the range of 10—120 min. The studies reꢀ
sulted in finding the following specific features.
The reaction of a considerable excess of iodobenzene
(5 equiv.) with the parent amino acid glycine gave arylaꢀ
tion product 9 in only 10% yield (entry 1). Under the same
conditions, alanine gave 57% of compound 10 (entry 2).
When 2 equiv. of iodobenzene was used instead of 5 equiv.
(entry 3) with even longer reaction time and higher temꢀ
perature, the yield of arylation product 10 decreased
almost by a factor of 2. Valine has proved even more active
than alanine: its reaction with 2 equiv. of iodobenzene an
increase in temperature from 100 to 150 °C initially led to
a noticeable increase in the reaction rate (entries 4 and 5),
then the rate of the process decreased, and the difference
between the results of arylation after 30 min and after 2 h
became insignificant (entries 6 and 7). The good choice of
PEGꢀ400 as a reaction medium was confirmed by the
experiment in PEGꢀ3400, which showed a twoꢀfold deꢀ
crease in the yield of compound 11 (entry 8). The higher
Table 5. Study of recyclability of catalyst in arylation of
imidazole with iodobenzene (10 mol.% [Cu], 20 mol.%
ligand, MW, 150 °C, 2 h)
Entry
Catalytic system
I
N
Yield of 2 (%)
1
2
3
4
5
6
1
2
3
1
2
3
79
87
54
78
71
52
II
Note. Catalytic systems: CuO/LꢀHys/Cs2CO3/PEGꢀ400
(I) and CuI/LꢀPro/Cs2CO3/PEGꢀ400 (II); N is the numꢀ
ber of the catalytic cycles.

Arylation of imidazole
Russ.Chem.Bull., Int.Ed., Vol. 65, No. 5, May, 2016
1247
Table 6. NꢀArylation of amino acids with aryl halides
catalytic Nꢀarylation of a number of amino acids showed
that leucine, valine and phenylalanine containing more
bulky hydrophobic substituents were the most active in
the reactions catalyzed by Cu2O/Cs2CO3 in PEGꢀ400.
Entry Amino
acid
ArX
(n/equiv.)
T/°C
τ
Product and its
yield (%)
/min
1
2
3
4
5
6
7
8*
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
LꢀGly
LꢀAla
LꢀAla
LꢀVal
LꢀVal
LꢀVal
LꢀVal
LꢀVal
LꢀVal
LꢀVal
LꢀLeu
LꢀLeu
LꢀLeu
LꢀPhe
LꢀIle
PhI (5)
PhI (5)
PhI (2)
PhI (2)
PhI (2)
PhI (2)
PhI (2)
PhI (2)
PhI (5)
PhI (5)
PhI (1)
PhI (5)
PhI (5)
PhI (5)
PhI (5)
PhI (5)
PhI (5)
100
100
150
100
150
150
150
150
100
150
100
100
100
100
100
150
150
140
140
160
110
110
130
120
160
120
160
120
115
130
120
120
160
120
140
140
120
120
160
160
19 (10)
10 (57)
10 (30)
11 (15)
11 (43)
11 (51)
11 (57)
11 (29)
11 (70)
11 (63)
12 (41)
12 (55)
12 (88)
13 (72)
14 (59)
—
Experimental
All the experiments on Cuꢀcatalyzed arylation of imidazole
and amino acids were conducted using commercially available
reagents. The reactions were carried out in a Biotage Initiaꢀ
tor+ microwave reactor (600 W) in hermetically sealable vials
suitable for the solution volume of 2 mL. 1H NMR spectra were
recorded on a Bruker Avance 300 spectrometer (300 MHz) in
CDCl3. Chemical shifts in the 1H NMR spectra are given in the
δ scale relative to Me4Si as a reference. Dibromomethane was
used as an internal standard in calculating yields of arylation
products.
Catalytic Nꢀarylation of imidazole (general procedure). Imidꢀ
azole (0.23 mmol), aryl halide (0.46 mmol), CuO (1.8 mg,
10 mol.%), Lꢀhystidine (7.1 mg, 20 mol.%), cesium carbonate
(150 mg, 0.46 mmol), and PEGꢀ400 (0.5 mL) were placed into
a vial equipped with a magnetic stirrer. The vial was hermetically
sealed and kept in the microwave reactor at a temperature of
150 °C for 2 h. After the reaction reached completion, the mixꢀ
ture was diluted with water (1 mL), transferred into a separatoꢀ
ry funnel, and extracted with cyclohexane or diethyl ether
(3—5 times 10 mL each). The combined organic phases were
concentrated in vacuo and analyzed by 1H NMR. The spectra of
compounds 2, 3, 5, and 6 agree with those reported in the literaꢀ
ture,26 the spectra of compounds 4, 7, and 8 are identical to
those reported in the corresponding publications.27—29
LꢀLys
LꢀHys
—
LꢀLeu 4ꢀMeC6H4I 100
LꢀLeu 3ꢀBrC6H4I 100
LꢀLeu
LꢀLeu
LꢀLeu
LꢀVal
15 (41)
16 (60)
—
12 (60)
—
PhBr
PhBr
PhCl
100
150
150
1,4ꢀI2C6H4 150
17 (79)
* PEGꢀ3400 was used instead of PEGꢀ400.
Catalytic Nꢀarylation of amino acids (general procedure).
A corresponding amino acid (0.23 mmol), aryl halide
(0.46—1.15 mmol), Cu2O (3.3 mg, 10 mol.%), cesium carbonate
(225 mg, 0.69 mmol), and PEGꢀ400 (0.5 mL) were placed into
a vial equipped with a magnetic stirrer. The vial was hermeticalꢀ
ly sealed and kept in the microwave reactor at a temperature of
100—150 °C for 0.5—2 h. After the reaction reached compleꢀ
tion, the mixture was diluted with water (1 mL), treated with 1 M
hydrochloric acid to adjust pH 1, transferred into a separatory
funnel, and extracted with diethyl ether (3—5 times 10 mL each).
The combined organic phases were concentrated in vacuo and
yields of the target product 11 can be obtained using
5 equiv. of iodobenzene (entries 9 and 10). Leucine turned
to be the most active amino acid: even with 1 equiv. of
iodobenzene, the yield of compound 12 was 41% (entry 11),
while in the presence of 5 equiv. of iodobenzene the product
was obtained in 88% yield already after 30 min (entry 13).
Phenylalanine and isoleucine showed slightly lower activꢀ
ity (entries 14 and 15). Lysine and hystidine were absoꢀ
lutely inert (entries 16 and 17), the latter result is a good
confirmation of a rightful choice of this amino acid as
a ligand in the Nꢀarylation reactions of imidazole. 4ꢀIodoꢀ
toluene (entry 18) and 3ꢀbromoiodobenzene (entry 19)
were also coupled with leucine. For arylation with bromoꢀ
benzene, the reaction temperature was a decisive factor: at
100 °C the process did not take place (entry 20), while at
150 °C the arylation was successful and gave compound 12
in 60% yield (entry 21). Chlorobenzene did not give the
product (entry 22). Another amino acid, valine, was coupled
with 1,4ꢀdiiodobenzene giving the product 17 (entry 23)
in the yield considerably higher than the yield of similar
compound 11 obtained from iodobenzene (entry 10).
In conclusion, the studies on catalytic Nꢀarylation of
imidazole showed that the optimal catalytic system in
PEGꢀ400 is CuO/LꢀHys/Cs2CO3 when using 2 equiv. of
aryl iodide and 2 equiv. of a base. The highest product
yields reached 90% when aryl iodide contains electronꢀ
donating substituents in paraꢀposition. The studies of the
1
analyzed by H NMR. The spectra of compounds 9—14 correꢀ
sponded to those reported in the literature.25
(S)ꢀ4ꢀMethylꢀ2ꢀ(pꢀtolylamino)pentanoic acid (15). 1H NMR
(CD3OD), δ: 0.94 (d, 3 H, CH3, 3J = 6.6 Hz); 0.98 (d, 3 H, CH3,
3J = 6.6 Hz); 1.67 (t, 2 H, CH2, 3J = 7.0 Hz); 1.78—1.92 (d, 1 H,
3
CH); 2.20 (s, 3 H, CH3); 3.97 (t, 1 H, CH, J = 7.1 Hz); 6.64
(d, 2 H, HPh(2), 3J = 7.6 Hz); 6.97 (d, 2 H, HPh(3), 3J = 7.6 Hz);
the protons of the NH and COOH groups were not detected.
(S)ꢀ2ꢀ(3ꢀBromophenylamino)ꢀ4ꢀmethylpentanoic acid (16).
3
1H NMR (CDCl3), δ: 0.92 (d, 3 H, CH3, J = 6.6 Hz); 0.96
3
3
(d, 3 H, CH3, J = 6.6 Hz); 1.65 (t, 2 H, CH2, J = 7.0 Hz);
1.72—1.87 (d, 1 H, CH); 2.20 (s, 3 H, CH3); 3.97 (t, 1 H, CH,
3J = 7.1 Hz); 6.53 (d, 1 H, HPh(6), 3J = 7.1 Hz); 6.75 (br.s, 1 H,
HPh(2)); 6.82 (d, 1 H, HPh(4), 3J = 7.6 Hz); 6.99 (t, 1 H, HPh(5),
3J = 7.9 Hz); the protons of the NH and COOH groups were not
detected.
(S)ꢀ2ꢀ(4ꢀIodophenylamino)ꢀ3ꢀmethylbutanoic acid (17).
1H NMR (CDCl3), δ: 1.02 (d, 3 H, CH3, 3J = 6.8 Hz); 1.03 (d, 3 H,
CH3, 3J = 6.9 Hz); 2.04—2.25 (d, 1 H, CH); 3.83 (d, 1 H, CH,

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Yakushev et al.
3J = 5.5 Hz); 6.42 (d, 2 H, HPh(2), 3J = 8.4 Hz); 6.70 (br.s, 1 H,
COOH); 7.43 (d, 2 H, HPh(3), J = 8.4 Hz), the proton of the
14. R. A. Altman, E. D. Koval, S. L. Buchwald, J. Org. Chem.,
2007, 72, 6190.
3
NH group was not detected.
15. S. Jammi, S. Krishnamoorthy, P. Saha, D. S. Kundu,
S. Sakhtivel, M. A. Ali, R. Paul, T. Punniyamurthy, Synlett,
2009, 3323.
16. J. Mao, J. Guo, F. Fang, S.ꢀJ. Li, Tetrahedron, 2008,
64, 3905.
This work was financially supported by the Russian
Science Foundation (Project No. 14ꢀ23ꢀ00186).
17. R. Tadikonda, M. Nakka, S. Rayavarappu, S. P. K. Kalidinꢀ
di, S. Vidavalur, Tetrahedron Lett., 2015, 56, 690.
18. J. She, Z. Jiang, Y. G. Wang, Tetrahedron Lett., 2009, 50, 593.
19. E. Colacino, L. Villebrun, J. Martinez, F. Lamaty, Tetraꢀ
hedron, 2010, 66, 3730.
20. D. Ma, C. Xia, Org. Lett., 2001, 3, 2583.
21. M. Kurokawa, W. Nakanishi, T. Ishikawa, Heterocycles,
2007, 71, 847.
References
1. K. H. Shaughnessy, E. Ciganek, R. B. DeVasher, Copperꢀ
Catalyzed Amination of Aryl and Alkenyl Electrophiles,
in Organic Reactions, John Wiley & Sons, 2004.
2. K. Okano, H. Tokuyama, T. Fukuyama, Chem. Commun.,
2014, 50, 13650.
3. G. Ewano, N. Blanchard, Copperꢀmediated crossꢀcoupling
reactions, John Wiley & Sons, 2014.
22. S. Roettger, P. J. R. Sjoeberg, M. Larhed, J. Comb. Chem.,
2007, 9, 204.
4. H.ꢀJ. Cristau, P. P. Cellier, J.ꢀF. Spindler, M. Taillefer,
Chem. Eur. J., 2004, 10, 5607.
5. D. Ma, Q. Cai, H. Zhang, Org. Lett., 2003, 5, 2453.
6. H. Zhang, Q. Cai, D. Ma, J. Org. Chem., 2005, 70, 5164.
7. D. Ma, Q. Cai, Synlett, 2004, 128.
23. N. Narendar, S. Velmathi, Tetrahderon Lett., 2009, 50, 5159.
24. Z. Lu, R. J. Twieg, Tetrahedron Lett., 2005, 46, 2997.
25. K. K. Sharma, S. Sharma, A. Kudwal, R. Jain, Org. Biomol.
Chem., 2015, 13, 4637.
26. M. Yang, F. Liu, J. Org. Chem., 2007, 72, 8969.
27. H.ꢀX. Li, W. Zhao, H.ꢀY. Li, Zh.ꢀL. Xu, W.ꢀX. Wang, J.ꢀP.
Lang, Chem. Commun., 2013, 49, 4259.
8. C.ꢀT. Yang, Y. Fu, Y.ꢀB. Huang, J. Li, Q.ꢀX. Guo, L. Liu,
Angew. Chem., Int. Ed., 2009, 48, 7398.
9. J. Kim, S. Chang, Chem. Commun., 2008, 3052.
10. L. Jiang, X. Lu, H. Zhang, Y. Jiang, D. Ma, J. Org. Chem.,
2009, 74, 4542.
28. M. G. Boswell, F. G. Yeung, C. Wolf, Synlett, 2012, 1240.
29. C. Liu, T. G. M. Dhar, H. H. Gu, E. J. Iwanowicz, K. Lefꢀ
theris, W. J. Pitts, US Pat. 6399773, 2002.
11. X. Guo, H. Rao, H. Fu, Y. Jiang, Y. Zhao, Adv. Synth. Catal.,
2006, 348, 2197.
12. R. A. Altman, K. W. Anderson, S. L. Buchwald, J. Org.
Chem., 2008, 73, 5167.
13. B. Sreedhar, K. B. S. Kumar, P. Srinavas, V. Balasubrahꢀ
manyan, G. T. Venkanna, J. Mol. Cat. A: Chemical, 2007,
265, 183.
Received November 16, 2015;
in revised form February 2, 2016