Copper-catalyzed C-N coupling reactions of aryl halides with α-amino acids under focused microwave irradiation

Article abstract of DOI:10.1016/j.tetlet.2009.06.122

We have developed an efficient method for the preparation of enantiopure N-aryl-α-amino acids via copper-catalyzed N-arylation of α-amino acids and aryl halides under microwave irradiation. This protocol only needs less than 30 min to obtain the products,

Full text of DOI:10.1016/j.tetlet.2009.06.122

Tetrahedron Letters 50 (2009) 5159–5161
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Tetrahedron Letters
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Copper-catalyzed C–N coupling reactions of aryl halides with
acids under focused microwave irradiation
a-amino
*
Nasani Narendar, Sivan Velmathi
Organic and Polymer Synthesis Laboratory, Department of Chemistry, National Institute of Technology, Tiruchirapalli 620 015, India
a r t i c l e i n f o
a b s t r a c t
Article history:
We have developed an efficient method for the preparation of enantiopure N-aryl-
a-amino acids via cop-
Received 3 June 2009
Revised 26 June 2009
Accepted 29 June 2009
Available online 3 July 2009
per-catalyzed N-arylation of -amino acids and aryl halides under microwave irradiation. This protocol
a
only needs less than 30 min to obtain the products, which are far superior to those obtained under con-
ventional heating.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Copper iodide
Microwave
a-Amino acids
Aryl halides
Coupling reaction
1. Introduction
mon core structures for a number of synthetically challenging and
medicinally important agents such as protein kinase C (PKC) activa-
The formation of the carbon–nitrogen bond by the copper-cata-
lyzed coupling of aryl halides with -amino acids is one of the typical
tors, indolactam-V15,16 and its analogue benzolactam-V8;17 fibrino-
gen receptor antagonist SB 214857;18 NMDA receptor antagonist
L68956019 and tricyclic quinoxalinedions;20 ACE inhibitors;21 and
antiulcer agents.22 In the past years, these structures were synthe-
sized via several steps to get the desired enantiomerically pure form.
Themoredirectandeconomicaloption, thecouplingofan arylhalide
with an amino acid derivative was achieved only when the aromatic
ring was activated with an electron-withdrawing substituent.23 An
alternative method for N-arylation is the Cu-catalyzed reaction. This
method is attractive from an economic standpoint because Cu is
much cheaper than Pd and the removal of Pd residues from polar
reaction products is difficult.24–26 Some of the Cu-catalyzed C–N
coupling reactions have been reported with 2-dimethylaminoetha-
nol ligand,26 N,N-diethylsalicylamide,27 polymer-supported com-
pounds (PS-PEG resin),28 and Pd–Cu over TEBA.6,29,30 Without Pd
catalyst the CuI itself could catalyze the C–N coupling reaction under
the reported procedure and a good yield can be obtained. The main
drawbacks of the above reported methods among others are the
bulkiness of ligands, the difficulty to remove the polymer support
from the product, more reaction time, limited substrates and a low
yield. Therefore, a general Cu-catalyzed C–N coupling reaction of
a
Ullmann condensation reactions.1 The research on palladium- and
copper-catalyzed arylations of amines was pioneered by Buchwald
and Hartwig.2,3 Nowadays, copper-catalyzed N-aryl bond forma-
tions rank among the most powerful methods in organic synthe-
sis.4,5 These copper-catalyzed N-arylations of amino acids offer
many advantages,6–9 but the reported transformations are in most
cases both sluggish and time-consuming; normally these reactions
suffer from problems such as harsh conditions, limited generality,
and numerous synthetic steps.4,6,10,11 Several Pd-catalyzed C–N for-
mation methods have been introduced, which upon using some ste-
rically hindered phosphine ligands,11,12 carbocyclic carbene ligands8
allowed many coupling reactions of aryl halides with N-containing
compounds to proceed under relatively mild conditions and low
temperature.6 However, industrial use of these methods is ham-
pered by the higher costs of Pd catalysts and the ligands, as well as
by air and moisture sensitivity.7 Although recent advances have
made this route more attractive, a simpler, cost-effective develop-
ment and a more efficient metal catalyst which can be suitable for
the synthesis of chiral N-aryl-
Among numerous functionalized amines,
building block in organic synthesis because of its further conver-
sions.13,14 Furthermore, chiral N-aryl-
-amino acids are the com-
L
-amino acids, are highly desirable.
a-amino acid is a key
aryl halides with
value.
a-amino acids appears attractive and is of great
a
However, the C–N coupling reaction requires longer reaction
time and is performed in the presence of ligands, usually, at high
temperature.6 So, there is a need to decrease the reaction time as
well as to simplify the purification procedure. Thus, high-density
* Corresponding author. Tel.: +91 09486067404; fax: +91 431 2500133.
E-mail address: velmathis@nitt.edu (S. Velmathi).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.06.122

5160
N. Narendar, S. Velmathi / Tetrahedron Letters 50 (2009) 5159–5161
Table 1
microwave heating has become an effective procedure because it
allows rapid and convenient superheating to high temperatures
in combination with excellent reaction control and low energy
consumption. It has been proven recently that microwave heating
improves the preparative efficiency and reduces the reaction time
for several different types of organic transformations.31–33
Although some of the microwave-enhanced palladium and palla-
dium–copper reactions have been reported,30,34 few references
have shown the use of microwave heating with limited scope to
the C–N and C–O cross-coupling reaction. Herein, we wish to re-
port the development of a fast microwave-enhanced C–N coupling
Copper-catalyzed coupling reaction of aryl halides and
a
-amino acidsa
Time (min)
Entry
ArX
Y
Amino acid
Catalyst
Yieldb (%)
X
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Br
B
Br
Br
Br
4-I
4-I
4-Br
4-Br
4-Br
4-Br
1-Br
1-Br
1-Br
1-Br
H
H
H
H
H
L
L
L
L
-Valine
-Valine
-Proline
-Phenylalanine
Cu(OAc)2
CuI
15
15
20
20
20
18
20
20
18
22
25
20
20
15
16
78
80
75
65
0
89
83
82
80
65
64
78
80
90
89
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
Glycine
COCH3
L-Valine
L-Proline
L-Valine
L-Proline
L-Proline
L-Valine
L-Valine
L-Proline
L-Proline
L-Valine
COCH3
COCH3
COCH3
CH3
reaction for preparing chiral N-aryl-L-amino acids by copper-cata-
lyzed coupling of -amino acids with substituted aryl halides. In
L
CH3
Cu(OAc)2
CuI
comparison with the current methods of the C–N bond formation,
our approach displays specific advantages: (i) it proceeds faster
and gives moderate to good yields; (ii) it requires only the inexpen-
sive CuI; and (iii) it is applicable to a broader substrate scope (var-
ious amino acids and electron-rich and electron-deficient aryl
halides).
COCH3
COCH3
2-NO2
2-NO2
CuI
CuI
CuI
a
Reaction conditions: 10 mol % CuI, 1.5 mmol K2CO3, ArX (1 mmol), amino acid
(1 mmol), DMF (3 mL), under microwave irradiation (140 °C).
b
Isolated yield.
2. Results and discussion
These results are consistent with the literature and the micro-
wave heating gave the same results as conventional heating but
in a very short time. 4-Iodoacetophenone gave higher yield (89%)
than 4-bromoacetophenone (78%), that is, the iodobenzene reacts
more quickly than bromobenzene and chlorobenzene. The dis-
placement of halogen from the aromatic ring is in the following
order:
Initially, the coupling reaction of bromobenzene (1 mmol) with L-
valine (1 mmol) was tried by using copper acetate (10 mol %) and
K2CO3 (1 mmol) in DMF (3 mL) which gave only 45% yield of the
C–N coupled product. After that we increased the loading of K2CO3
from 1 mmol to 1.5 mmol, which yielded 78% of the product. Further
increasing to 2 mmol did not result in any improvement of yield. All
the reactions were done under conventional heating in an oil bath at
140 °C in 6 h. Here it is worth mentioning that when the same reac-
tion was done at 90 °C under conventional heating it took 48 h for
completion. To compare the efficacy of microwave irradiation with
that of conventional heating, the reaction was repeated in focused
microwave (Biotage) oven in a sealed vessel under the same condi-
tions for 15 min (140 °C) which gave almost the same yield to that
of conventional heating (see Scheme 1). This was followed by an-
other coupling reaction of bromobenzene with glycine with identi-
cal condition, but no desired product was observed. This could be
attributed to the lack of reactivity due to the zwitterionic nature of
the amino acids. Thus, the function of K2CO3 in this reaction is to en-
hance the nucleophilicity of amino acid especially, the amine group.
Good yields (60–90%) of the N-arylated amino acids were produced
under microwave irradiation at 140 °C in 10–25 min.35 The results
obtained are summarized in Table 1.
I > Br > Cl
The synthetic utility of the present reaction methodology can be
illustrated by some reaction products. For instance N-phenyl-
L-va-
line, the direct coupling product of -valine with bromobenzene, is
L
a key precursor for synthesizing antiulcer agents,22 while the origi-
nal synthesis for this compound took several steps to yield the race-
mic product. However, the optical rotation of the product revealed
that no racemizations had occurred. Optical rotation of the coupling
product was obtained on a Rudolph Autopol IV polarimeter at a
wavelength of 50 nm. Thus the present method provides a very effi-
cient protocol to synthesize compounds with therapeutic value.
3. Mechanism studies
The C–N coupling reaction was also tested for a number of
different amino acids and ortho- and para-substituted aryl halides.
The reactivity of aryl halides was greatly improved by electron-
withdrawing groups such as NO2, COCH3, either ortho or para to
the aryl halides. 1-Bromo-2-nitrobenzene gave 90% of the C–N
coupled yield where as 4-bromotoluene gave only 64% of the
C–N coupled yield. From this we found that electron-rich aryl
halides gave lower yields than electron-deficient aryl halides.
However, aryl chlorides were poor coupling reagents. Both CuI
and Cu(OAc)2 catalyzed this reaction but CuI is more efficient than
copper acetate. Both electron-deficient and electron-rich aryl
bromides and iodides underwent the coupling reactions (entry
9–14).
On thebasis of the proposed D. Ma and co-workers’ mechanismof
the Cu(I)-catalyzed coupling reaction of aryl halides with
acid,6 we present the following mechanism for the reaction. In the
first 10 min of the bromobenzene and -valine reaction we found
a-amino
L
that a blue-colored complex was formed and, further, we increased
the time to 15 min, after which the blue-colored complex disap-
peared and formed the final product. It is a well known fact that cop-
per ions can form chelates with amino acids through amino and
carboxyl groups. This blue-colored complex was Cu(I)–
late (Scheme 2). First the cuprous ion reacts with -amino acid to
form the chelate (I), which was coordinated with a suitable aryl ha-
lide to provide the -complex (II). After that, intramolecular nucleo-
L-valine che-
a
p
philic substitution occurs at the aromatic ring to give the
intermediate (III). This step might be the rate-determining step,
and the intramolecular attack lowers the activation energy. The dis-
tancebetween aminoand carboxylategroups is increased, thesize of
the ring in the transition state (III) becomes larger, therefore (III)
would be more unstable. This might be the accelerating effect in-
duced by the structure of different amino acids which decreases in
R
Y
O
H2N
R
HN
COOH
CuI / K2CO3, DMF
MW, 15-25 min,140 ºC
OH
X
Y
the following order:
Finally, HX is removed from (III) by using K2CO3 to produce another
a-amino acid > b-amino acid > c-amino acid.
Scheme 1. Copper-catalyzed C–N coupling reaction of aryl halides with
acids.
a-amino

N. Narendar, S. Velmathi / Tetrahedron Letters 50 (2009) 5159–5161
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O
H2N
O
O
(I)
R
Cu
Cu
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X
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4. Conclusion
In brief, we have successfully developed a general method for
the microwave-assisted N-arylation of amino acids in DMF provid-
ing moderate to high yields, high catalytic activity, and selectivity.
The catalyst system is inexpensive, safe, and encounters fewer
environmental problems. CuI is an effective catalyst for this C–N
coupling reaction. We have reported a convenient microwave-en-
hanced, high speed, short, and economic way for the synthesis of
34. Larhed, M.; Lindeberg, G.; Hallberg, A. Tetrahedron Lett. 1996, 37, 8219.
35. General procedure for reaction of amino acid and aryl halides: Typically, a mixture
of
L-valine (1 mmol), 4-iodoacetophenone (1 mmol), CuI or Cu(OAc)2
(10 mol %), K2CO3 (1.5 mmol), and DMF (3 mL) was heated for 18 min in a
10 mL vessel. The vessel was sealed with a septum and placed inside the
microwave cavity in the Biotage microwave reactor and subjected to
microwave irradiation. The temperature was fixed at 140 °C. Initial
microwave irradiation of 150 W was used, with the temperature being
ramped from room temperature to the desired temperature of 140 °C
(measured using the built-in IR temperature device). Once this was reached,
the reaction mixture was held at this temperature until a total time of 15 min
had elapsed. During this time, the power was modulated automatically to hold
the reaction mixture at 140 °C. The mixture was not stirred during the reaction.
In order to cool the reaction mixture vessel, nitrogen gas was passed to the
surroundings of the vessel in microwave cavity, and after being cooled to room
temperature the reaction mixture was diluted with 10 mL of ethyl acetate and
10 mL of water. Under cooling with ice/water, concentrated HCl was added to
adjust the pH to 2–3. Then the organic layer was separated, and the aqueous
layer was extracted with ethyl acetate (5 Â 20 mL). The combined organic
layers were washed with brine, dried over MgSO4, and concentrated to dryness
by rotovapor. The resulting residual oil was loaded on a silica gel column and
eluted with ethyl acetate/petroleum ether (5:95) to afford the desired pure
coupling product. 1H NMR spectra were recorded with TMS as an internal
N-aryl-a-amino acids, which are common core structures for a
number of biologically active compounds. Though the present pro-
tocol uses DMF as a solvent further research is under progress with
alternative reaction conditions.
Acknowledgments
We gratefully acknowledge the support and funding from Dr.
M. Chidambaram, the Director of NITT and DST (SR/FTP/CS-142-
2006). We also wish to thank Dr. S. Perumal from Madurai Kamaraj
University, for extending the microwave reactor (Biotage) facility
for carrying out these reactions.
References and notes
standard on
(acetylphenyl)-
a
L
Brucker AM-400 spectrometer. Spectral data for N-
-valine: 1H NMR (400 MHz, CDCl3) d ppm, 7.8 (m, 2H), 6.5–
1. For a review, see: Lindley, J. Tetrahedron 1984, 40, 1433.
2. Yang, B.; Buchwald, S. L. J. Organomet. Chem. 1999, 576, 125.
3. Hartwig, J. F. Angew. Chem., Int. Ed. 1998, 110, 2154.
6.6 (m, 2H), 4.0 (d, 1H), 2.5 (d, 1H), 2.1 (s, 3H), 1.05–1.1 (m, 6H).
Optical rotation [
a
]
50 = À222.00 (c 0.2, EtOH).