D-Glucosamine as a green ligand for copper catalyzed synthesis of primary aryl amines from aryl halides and ammonia

Article abstract of DOI:10.1039/c1cc10568j

Replacing conventional reagents with environment friendly reagents is one of the primary goals of modern synthetic methodology and in this very primitive study about utilizing green, naturally available carbohydrate molecules as ligands in transition metal catalyzed reactions, we report Cu/d-glucosamine as an efficient catalyst for aniline synthesis.

Full text of DOI:10.1039/c1cc10568j

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COMMUNICATION
D-Glucosamine as a green ligand for copper catalyzed synthesis
of primary aryl amines from aryl halides and ammoniaw
Krishna Gopal Thakur, Dhandapani Ganapathy and Govindasamy Sekar*
Received 28th January 2011, Accepted 28th February 2011
DOI: 10.1039/c1cc10568j
Replacing conventional reagents with environment friendly reagents
is one of the primary goals of modern synthetic methodology and
in this very primitive study about utilizing green, naturally
available carbohydrate molecules as ligands in transition metal
catalyzed reactions, we report Cu/D-glucosamine as an efficient
catalyst for aniline synthesis.
Scheme 1 Copper catalyzed aniline synthesis.
deviation from the exact reaction condition.3a,b,d Later on,
even though additional methodologies have been reported
using palladium,3b–d di-arylation persisted as the major problem
in many cases; may be because of the hyper catalytic activity of
palladium which reduces the selectivity. The problem has been
substantially solved3c using less reactive substrates (by means
of electronic, steric or leaving group ability factors) wherein
the selectivity is more. In recent years, copper has started
enjoying much attention not only because of its very low cost
as compared to palladium but also due to its compatibility
with much cheaper, stable oxygen and nitrogen based donor
ligands as compared to unstable, high cost phosphine ligands
(Scheme 1). While starting with copper, numerous reports
came during the last decade, especially in the last two years
on amine synthesis from aryl halides using either direct4 or indirect
amine sources.5 The major problem with indirect methods is
the requirement of multistep process and thus suffers from low
atom economy. In 2001, Lang reported copper catalyzed
amination of some heterocyclic aromatic halides using ammonia
at 100 1C wherein, ethylene glycol served the purpose of
solvent as well as ligand. Later on many improvements have been
encountered in this reaction, especially during last two years.
However, only a few of these provided successful generalized
method for aniline synthesis using aqueous ammonia.4 But
these methods often suffer from the requirement of higher
temperature, environmentally hazardous aliphatic acid solvent
system and ligands. During the course of our reaction, Zhao
and Wan separately reported efficient methods for primary
aryl amine formation from aryl halides. They covered various
classes of substrates that undergo the reaction. The high
reaction temperature, usage of very high equivalence of ammonia
(40 equivalents) and synthetic ligand make the former protocol
less attractive whereas high loading of synthetic ligand and usage
of huge amounts of quaternary ammonium salt (50 mol%) make
the latter one less attractive especially for large scale reactions.
So, there is still a requirement to develop a methodology using
low catalyst loading, cheaper, environment friendly catalyst and
solvent system.
Carbohydrates are one of the most naturally abundant organic
molecules. They are available in nature mainly as disaccharides
and polysaccharides. Many natural products as well as
molecules of high biological, medicinal and material importance
are synthesized from monosaccharide precursors.1 Organic
chemistry is enriched with an enormous number of successful
utilization of carbohydrates in many technically important
fields such as asymmetric induction in a reaction using carbo-
hydrate derivatives as chiral auxiliaries.2 Many phosphorus,
nitrogen, oxygen and sulfur based ligands with carbohydrate
backbone have been successfully utilized in a variety of asymmetric
reactions.2 In spite of the high potential, the direct use of
monosaccharide molecules as ligands is highly limited. The
very cheap, especially high environmental friendly nature of
monosaccharide molecules has driven us to explore their
capabilities as ligands in transition metal catalyzed reactions.
We started our study with D-glucose as a ligand for copper-
catalyzed primary aryl amine formation reaction from aryl
halides and ammonia through coupling reaction. Since ammonia
is the most abundant amine source, it has been selected as the
nitrogen source for this reaction. In the last decade, a lot of
work has been done on primary aryl amine synthesis from
aromatic halides through coupling reaction methodologies,
mostly using palladium3 and copper4,5 as catalyzing metals.
For palladium catalyzed reactions, in 2006, Hartwig and
co-workers for the first time reported aniline formation from
aryl halides and ammonia using ferrocene based phosphine
ligands.3a Although having high substrate scopes, these methods
often suffer from appreciable amounts of secondary and
tertiary amine formation as by-product even if there is a little
Department of Chemistry, Indian Institute of Technology Madras,
Chennai, 600 036, India. E-mail: gsekar@iitm.ac.in;
Fax: +91 44 2257 4202; Tel: +91 44 2257 4229
w Electronic supplementary information (ESI) available: Experimental
procedures and characterization data, full spectroscopic data for all
compounds, 1H NMR & 13C NMR spectra for all the compounds. See
DOI: 10.1039/c1cc10568j
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5076 Chem. Commun., 2011, 47, 5076–5078
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Fig. 2 Optimization of copper salts.
Table 1 CuI-L5 catalyzed reaction between various aryl halides and
aq. ammonia
Fig. 1 Optimization and comparison of reactivity between mono-
saccharide ligands and conventional ligands.
As part of our ongoing research towards the development of
eco-friendly organic transformations, we recently reported
aerobic oxidation methodologies for various alcohols.6 In a
parallel research, we developed various copper catalyzed
carbon–carbon and carbon–heteroatom bond forming reactions.7
In this communication, we report our initial finding about
D-glucosamine/CuI complex catalyzed aryl amine formation
using aq. NH3 as the amine source. This procedure is very
simple, economic and environmentally friendly. D-Glucosamine
is one of the most naturally abundant molecules. It is present in
the exoskeleton of several arthropods, in the cell wall and bones
of higher organisms.
Entry Aryl halide
Time (h) Product
12
Yield (%)a
80
1
2
28
96
3
4
24
21
90
85
We started our preliminary study with CuI as copper source
and D-glucose L1 (Fig. 1) as ligand in acetone/H2O (1 : 1)
mixture as solvent system for the coupling of 4-iodoanisole
and ammonia. In the very first reaction, we obtained 65%
isolated yield of the product. This encouraged us to continue
the screening using other monosaccharide molecules as ligands.
Some of the very well known conventional ligands were also
used for coupling reactions for a better comparison and under-
standing. The results have been shown in Fig. 1. We found that
D-glucosamine L5 as ligand performs the best by providing a
maximum of 90% yield for the product 4-methoxyaniline.
Upon considering reactions with carbohydrate based ligands,
many of them outperformed some well known conventional
ligands in coupling chemistry. Then the reaction was carried
out without ligand L5 using 10 mol% of CuI and the coupling
reaction provided only 9% of product 4-methoxy aniline after
24 h at 90 1C. This result clearly shows that ligand L5 is
necessary for the best performance of the coupling reaction.
Then we carried out copper salt screening for better performance
of the reaction and CuI has been found as the best copper salt
with L5 for this coupling reaction (Fig. 2).
5
6
7
24
24
30
80
90
57
8
28
28
26
98
98
80
9
10
11
12
13
24
29
28
95
85
95
We also screened several organic solvent/H2O (1 : 1) mixtures,
bases and various temperatures for this reaction.8 It has been
found that acetone/H2O performed most efficiently as solvent
system among the various solvent mixtures screened, whereas
K2CO3 is the best base among the several bases screened. All
the bases, either milder like NaOAc or stronger like NaOMe,
compared to K2CO3 provided lesser yield of the product
aniline. While checking the minimum requirement of catalyst
14
30
50
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Table 1 (continued )
very well towards the reaction. Many base sensitive carbonyl
groups were well survived within the course of reaction.
Herein, for the first time we have reported the amination of
some aryl iodides (entries 12–15, and 17) which contain ketone
group as substitution, among these, all ortho-amino ketones
(entries 14–15 and 17) have high potential to be used as
precursor for various inhibitor synthesis.9 It is very important
to mention that the water soluble ligand L5 along with copper
can be easily removed from product aniline by simple water
workup process. However, along with ligand L5, inorganic
components such as K2CO3, KI and copper are also water
soluble and making the recovery of ligand L5 in pure form
difficult.
Entry
Aryl halide
Time (h) Product
Yield (%)a
15
30
50
16
17
26
30
68
70
In conclusion, we have developed an efficient and environ-
mentally friendly catalytic system which can convert various
aryl halides to corresponding primary aryl amines in the
presence of aqueous ammonia. The solvent acetone/H2O
mixture is also green in nature. The catalyst is the cheapest
among the various reports available in literature and contains
naturally available chiral ligand. This can open a new scope
for enantioselective synthesis of various important optically
active amines as well as kinetic resolution of various optically
active aryl halides in one of the most economic ways.
We thank DST (Project No.: SR/S1/OC-06/2008), and
CSIR (01(2378)/10/EMR-II), New Delhi for the financial
support. K.G.T. and D.G. thank CSIR for fellowship. We
thank IIT-Madras for research facilities.
18
30
24
62
83
19
20
28
30
78
60
21
a
Isolated yield. Reaction was performed in 0.5 mmol scale of aryl
halide.
loading for the best performance of the reaction, it has been
found that 10 mol% of CuI/L5 is the optimal catalyst require-
ment. On either decreasing or increasing the catalyst loading,
the yield of the product got affected. Surprisingly, when the
catalyst loading is as high as 20 mol%, the product yield was
drastically reduced to 49%. When the reaction was performed
at 60 1C and 80 1C, the reaction was found to be inefficient. At
60 1C, even after 48 h the product yield was only 41% whereas
at 80 1C 62% of product amine was formed. While trying the
reaction using only water as solvent, only 9% product was
obtained. However, aniline formation was increased to 20%
when 0.5 equivalent of nÀBu4NBr bromide was used as phase
transfer catalyst. The further optimization of the reaction in
water medium using phase transfer catalyst has not been
carried out because acetone is more compatible with environ-
ment than ammonium salts. Moreover use of a huge amount
of additives is not encouraged especially for bulk scale
synthesis.
Notes and references
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C. Claver, Chem. Rev., 2004, 104, 3189; (d) M. Dieguez, C. Claver
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Eur. J. Org. Chem., 2010, 6149.
After optimizing all parameters such as ligand, Cu-salt,
solvent, base, catalyst loading and reaction temperature, we
initiated our investigation into the scope of the D-glucosamine
L5-CuI catalyzed amination of several aryl halides and the
results are summarized in Table 1. Various aryl iodides and
aryl bromides provided good to excellent yield of the products.
Activated aryl iodides (entries 2, 9, 10, 12 and 13), as well as
deactivated aryl iodides (entries 3, 5, 6 and 16) with electron-
donating groups provided good to excellent yields of the
products. Activated aryl bromides (entries 1, 8, 18–19) and
deactivated aryl bromides both (entries 4,7 and 20) provided
high yields of the corresponding primary amines. Both
the iodo and bromo substrates with sterically bulky ortho
substitution (entries 5, 14, 15, 17, 19 and 20) also performed
5 (a) X. Gao, H. Fu, R. Qiao, Y. Jiang and Y. Zhao, J. Org. Chem.,
2008, 73, 6864; (b) C.-T. Yang, Y. Fu, Y.-B. Huang, J. Yi,
Q.-X. Guo and L. Liu, Angew. Chem., Int. Ed., 2009, 48, 7398.
6 (a) P. Muthupandi, S. K. Alamsetti and G. Sekar, Chem. Commun.,
2009, 3288; (b) S. K. Alamsetti and G. Sekar, Chem. Commun.,
2010, 7235.
7 (a) A. B. Naidu, E. A. Jaseer and G. Sekar, J. Org. Chem., 2009, 74,
3675; (b) R. K. Rao, A. B. Naidu and G. Sekar, Org. Lett., 2009, 11,
1923.
8 The results are summarized in Table 1 of SIw.
9 (a) A. El-Wareth, A. O. Sarthan, Z. A. Hozien and H. A. H.
El-Sherief, Bioorg. Med. Chem., 2001, 9, 2993; (b) J. A. Duplantier,
J. Med. Chem., 2009, 52, 3576.
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5078 Chem. Commun., 2011, 47, 5076–5078
This journal is The Royal Society of Chemistry 2011