The copper-nicotinamide complex: Sustainable applications in coupling and cycloaddition reactions

Article abstract of DOI:10.1039/c4gc02047b

The crystalline copper(ii)-nicotinamide complex, synthesized via simple mixing of copper chloride and nicotinamide solution at room temperature, catalyzes the C-S, C-N bond forming and cycloaddition reactions under a variety of sustainable reaction conditions.

Full text of DOI:10.1039/c4gc02047b

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Copper-nicotinamide complex: sustainable applications in
coupling and cycloaddition reactions
R. B. Nasir Baig,a, # Buchi Reddy Vaddula,a, # Mallikarjuna N. Nadagouda,b, * and
Rajender S. Varmaa, *
Abstract:
Crystalline copper (II)-nicotinamide complex, synthesized via simple mixing of copper
chloride and nicotinamide solution at room temperature, catalyzes the C-S, C-N bond
forming and cycloaddition reactions under a variety of sustainable reaction conditions.
Carbon-hetero atom cross-coupling and cycloaddition reactions play a seminal role in organic
synthesis1-5 and they constitute a key step in accomplishing the synthesis of biologically and
industrially significant materials. These reactions have been utilized in the synthesis of
therapeutics for the treatment of inflammation, diabetes, alzheimer’s, HIV and cancer.6-12
Traditionally, C-S and C-N couplings have been achieved under harsh reaction conditions with
the use of toxic and high boiling polar solvents such as DMF, quinoline, N,N-dimethylacetamide
or HMPA in presence of a base and expensive palladium complexes. Alternatively, aryl
disulfides could be prepared from aryl sulfones or aryl sulfoxides by reducing them using air
sensitive LiAlH4 and DIBAL-H.13-14 Similarly, the Buchwald-Hartwig amination reaction using
palladium complexes has been well explored.15-16 However, these methods require highly
expensive N-heterocyclic carbenes, phosphine and any other complex organic ligand as an
additive.15 Many of these ligands are air-sensitive and require longer reaction times for
completion of the reaction. On the other hand, Co and Ni catalysis is associated with toxicity.17-22
Recently, there has been significant progress in the discovery of copper-catalyzed coupling
reaction of aryl halides with
______________________________________________________________________________
a
Sustainable Technology Division, National Risk Management Research Laboratory, U.S.
Environmental Protection Agency, 26 West Martin Luther King Drive, MS 443,Cincinnati, Ohio
45268, USA. Fax: +1 513-569-7677; Tel: +1 513-487-2701
E-mail: Varma.Rajender@epa.gov
b
WQMB, National Risk Management Research Laboratory, U.S. Environmental Protection
Agency, 26 West Martin Luther King Drive, Cincinnati, Ohio 45268, USA.
1

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*Corresponding authors; #equal contribution from both the authors
amines and thiols.15,23-29 Majority of these reactions are highly dependent on the use of organic
ligands which play an important role in accelerating copper-catalyzed coupling of aryl halides
with amines and thiols. However, none of them have displayed general reactivity for promoting
these coupling reactions. On the other hand, copper-catalyzed azide alkyne cycloaddition
requires Cu(I) or Cu(II) catalyst in the presence of suitable additives such as sodium ascorbate.
The void of expensive transition metals and ligands in modern organic synthesis has become
difficult because it allows many impossible reactions to proceed under mild reaction conditions.
Due to the environmental concerns, however, the focus has shifted to the development of
inexpensive, easily available, active, multi-tasking and benign catalysts. Engaged in the
development of sustainable methods for efficacious organic synthesis,30-34 herein, we report a
mild, versatile and biomaterial-derived, copper-nicotinamide complex, which serves as efficient
catalyst for aryl C-S, C-N coupling and cycloaddition reactions.
The copper (II)-nicotinamide complex was simply prepared by addition of copper chloride to
aqueous solution of nicotinamide. Immediately after the addition, crystals of copper (II)-
nicotinamide complex started appearing with a beautiful morphology (Figure 1). The application
of this complex were studied in some common but important organic transformations.
Figure 1. SEM image of copper (II)-nicotinamide
2

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To demonstrate the efficacious use of copper (II)-nicotinamide complex in cycloaddition
reactions, a mixture of benzyl bromide, sodium azide, aliphatic alkyne and catalyst complex was
irradiated with microwaves under solvent-free conditions (Scheme 1). This protocol was studied
for an array of substrates and in all the cases (Table 1, entries 1-11), reactions proceeded
o
smoothly at 100 C to afford the desired 1,2,3-triazoles in 8-15 min. with the exception of ethyl
propionate (Table 1, entry 12), where the reaction gave a mixture of products. To counter this
problem and to minimize the formation of undesired products due to possible decomposition of
o
ethyl propionate, the reaction temperature was reduced to 60 C which led to an increase in the
reaction time to 30 min (require, Table 1, entry 12) to furnish the corresponding triazole in 82 %
yield.
Scheme 1. Copper (II)-nicotinamide catalyzed synthesis of 1,2,3-triazoles under solvent-free
conditions
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Table 1. Azide-Alkyne Cycloaddition using copper(II) nicotinamide complex
Entry
Alkyl halide
Alkyne
Times
Product
Yield
N
N
N
Br
Br
Ph
1
2
8 min
8 min
97%
98%
N
N
N
N
N
N
Ph
Ph
Ph
MeO
OHC
O2N
OMe
N
N
Br
Br
Br
3
4
5
6
8 min
10 min
8 min
8 min
97%
88%
CHO
NO2
N
N
N
Ph
N
N
N
95%
93%
N
O2N
F
Br
N
N
Ph
Ph
O2N
N
N
Br
N
7
13 min
95%
F
H2N
N
N
Br
Br
Ph
85%b
94%
N
8
9
10 min
15 min
NH2
N
N
N
Ph
N
N
N
N
Ph
Br
95%
88%
10
11
15 min
15 min
N
N
Br
Br
Ph
Ph
OH
OH
N
N
N
O
O
82% c
O
12
30 min
O
a) Reaction conditions: 1.2 mmol of alkyl halides, 1.5 mmol of NaN3, 1.0 mmol of alkyne, 10 mg (0.025
mol%) of catalyst. MW, 100 oC, Power: 100 W. b) (i)1.2 mmol of alkyl halides, 1.5 mmol of NaN3, MW,
o
o
100 C, Power: 100 W, 5 min; (ii)1.0 mmol of alkyne, 10 mg (0.025 mol %) of catalyst. MW, 100 C,
Power: 100 W, 8 min.c) Reaction was performed at 60oC
4

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The copper-nicotinamide catalyst was then employed for the expeditious C-S cross-coupling of
aryl iodides and aryl thiols under microwave (MW) irradiation conditions. The initial
experiments were optimized for the C-S coupling reactions using the reaction of iodobenzene
o
and thiophenol as a model (Scheme 2). The reactants up on MW heating at 100 C for 30
minutes in presence of copper (II)-nicotinamide catalyst (10 mg) and K2CO3 (2 equiv) afforded
the product in moderate yields. The transformation was studied in various solvents, such as
water, polyethylene glycol-400 (PEG-400), DMF, THF, toluene and bases such as K2CO3,
Cs2CO3, and KOH. The optimum yield (91%) of the corresponding thiol (Table 2, entry 1) was
o
obtained in PEG-400 using Cs2CO3 as the base at 150 C for 15 minutes under MW heating
conditions. It was observed that during the reaction process, the copper-nicotinamide catalyst
forms a homogeneous mixture with the reaction solvent. The optimized protocol was then
extended to other aryl iodides and aryl thiols (Table 2, entries 1-12).
Scheme 2. C-S cross-coupling of aryl iodides and thiophenol
In almost all the cases, reaction progressed effectively to offer the corresponding diaryl sulfides
in high yields (Table 2. Entries 1-12). The gas chromatography-mass spectrometer (GC-MS)
profiles of the crude reaction mixtures show the smooth reaction progress (Figure 2); the
presence of the slightly excess reactant, aryl iodide (1.1 eq.), over aryl thiols (1.0 eq.) was
apparent from the GC profiles (Figure 2).
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Figure 2. GC-MS profiles of some of the crude reaction mixtures.
The presence of nitro (-NO2) or chloro (-Cl) substituent on thiophenol counterpart did not affect
the reaction outcome delivering the corresponding products (Table 2, entries 11 and 12) in high
yields. Aryl iodides containing electron donating (-OMe, -Me; Table 2, entries 2, 5, 7, 9, and 10)
as well as electron withdrawing groups (-NO2, -COMe; Table 2, entries 3, 4, 6, and 8)
participated smoothly in the reactions that delivered the corresponding product in high yields.
The sterically hindered mesityl iodide also underwent cross-coupling efficiently to afford diaryl
sulfides (Table 2, entry 5) in 84% yield.
With the aforementioned encouraging results, we further explored the amination of aryl halides,
a reaction that has been explored predominantly using palladium as a catalyst. However, many of
these methods involve the use of air-sensitive and expensive organic ligands and require longer
reaction times and excess amount of bases which could complicate the reaction especially where
base sensitive substrates are employed. Interestingly, we observed a unique reactivity of copper-
nicotinamide catalyst which allows amination of aryl halides to proceed under solvent-free and
base-free conditions (Table 3).
6

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Table 2 Synthesized diaryl sulfides from aryl iodides and thiophenols
Product
S
Entry
1
Aryl iodide
Thiophenol
SH
Yield (%)
95%
I
I
S
S
2
3
H3CO
SH
SH
92%
88%
H3CO
I
O2N
NO2
S
S
Cl
SH
SH
O2N
I
90%
84%
4
5
O2N
Cl
I
O
S
6
7
SH
SH
SH
I
88%
86%
85%
O
S
S
Cl
Cl
H3CO
O
I
I
Cl
O
OCH3
Cl
8
9
S
SH
H3C
H3C
I
90%
H3C
H3C
S
S
S
I
Cl
O2N
Cl
SH
SH
SH
95%
91%
89%
10
Cl
I
I
11
12
NO2
Cl
a) Reaction conditions: 1.0 mmol of aryl iodide, 1.2 mmol thiophenol, 10 mg (0.025 mol %) of copper-nicotinamide
catalyst, Cs2CO3 (1.0 mmol), PEG-400 (2 mL), MWI, 150 oC, 15 min.
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Table 3. Copper (II)-nicotinamide catalyzed amination of aryl halides a
Entry
Aryl halides
Amines
Time
Yield
Prodcut
Br
N
1
60 min
97%
NH
O2N
O2N
O2N
Br
Br
N
2
3
60 min
60 min
99%
99%
NH
O2N
O2N
H
N
NH2
O2N
a) Reaction conditions: 1 mmol aryl halides, 1.2 mmol amines, 10 mg (0.025 mol %) copper (II)-nicotinamide
catalyst, Neat, MWI, 100 W, 100 oC, 60 min
Conclusion
In conclusion, a simple and morphologically appealing copper-nicotinamide complex has been
employed in the synthesis of aryl coupling and cycloaddition reactions. The attractive features of
this approach include the use of benign solvent or solventless conditions, MW-accelerated
transformations, simple, and high yielding sustainable protocols thus demonstrating the
versatility of the catalyst for a variety of reactions.
Experimental section
Synthesis of Copper (II)-nicotinamide complex.
Copper chloride (0.1N) and nicotinamide (0.1N) solutions were mixed in a 2:5 ratio. The crystals
of Copper(II)-nicotinamide complex, Cu(nicotinamide)2Cl2 start growing immediately after
o
mixing. The supernatant liquid was filtered off and dried under vacuum at 40 C and
characterized using CHN (C, 36.32%; H, 3.54%; and N, 14.13%) and TGA (ESI, Fig S1)
analysis and stored at ambient conditions.
Synthesis of diaryl sulfides
8

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Aryl iodide (1.0 mmol), thiophenol (1.2 mmol), Cs2CO3 (1.0 mmol), 10 mg (0.025 mol %) of
Copper (II)-nicotinamide complex and PEG-400 (2 mL) were added to a crimp-sealed thick-
walled glass tube. The reaction tube was placed inside the cavity of a CEM Discover focused
microwave synthesis system equipped with a pressure sensor and a magnetic stirrer. The reaction
o
conditions were set at 150 C, 100 Watts for 15 min. After completion of the reaction, the
products were extracted using ethyl acetate, washed with water and dried over sodium sulfate
followed by concentration under vacuum and purification using column chromatography.
Synthesis of 1,2,3-triazoles
1.2 mmol of alkyl halide, 1.5 mmol of NaN3, 1.0 mmol of alkyne, and 10 mg (0.025 mol %) of
catalyst were placed in a crimp-sealed thick-walled glass tube. The reaction tube was placed
inside the cavity of a CEM Discover focused microwave synthesis system equipped with a
o
pressure sensor and a magnetic stirrer. The reaction temperature was set at 100 C (temperature
monitored by a built-in infrared sensor), a power level of 100 W, and pressure 10–60 psi for a
duration of 8-30 min (Table 1). After completion of the reaction, the crude product was extracted
with ethyl acetate followed by recrystallization or purification by column chromatography.
Amination of 4-bromonitrobenzene
4-Bromonitrobenzene (1.0 mmol), aliphatic amine (1.2 mmol), and 10 mg (0.025 mol %) of
copper(II)-nicotinamide complex were placed in a crimp-sealed thick-walled glass tube. The
reaction tube was placed inside the cavity of a CEM Discover focused microwave synthesis
o
system equipped with a pressure sensor and a magnetic stirrer, operated at 100 C (temperature
monitored by a built-in infrared sensor) and a power level of 100 W for 60 min. After completion
of the reaction, the products were extracted using ethyl acetate, dried over sodium sulfate,
concentrated under reduced pressure and purified by column chromatography.
Acknowledgements
R. B. Nasir Baig and B. R. Vaddula were supported in part by an appointment to the Research
Participation Program for the U.S. Environmental Protection Agency, Office of Research and
Development, administered by the Oak Ridge Institute for Science and Education through an
interagency agreement between the U.S. Department of Energy and the EPA.
Disclaimer
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The U.S. Environmental Protection Agency, through its Office of Research and Development,
funded and managed, or partially funded and collaborated in, the research described herein. It
has been subjected to the Agency’s administrative review and has been approved for external
publication. Any opinions expressed in this paper are those of the author(s) and do not
necessarily reflect the views of the Agency, therefore, no official endorsement should be
inferred. Any mention of trade names or commercial products does not constitute endorsement or
recommendation for use.
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Graphical Abstract
Copper-nicotinamide complex: sustainable applications in coupling and
cycloaddition reactions
R. B. Nasir Baig, Buchi Reddy Vaddula, Mallikarjuna N. Nadagouda, and Rajender S. Varma*
Copper (II)-nicotinamide complex catalyzes the C-S, C-N bond forming and cycloaddition
reactions under a variety of sustainable reaction conditions.