Ligand-free C-N bond formation in aqueous medium using a reusable Cu-Mn bimetallic catalyst

Article abstract of DOI:10.1016/j.tetlet.2013.07.095

A general ligand-free protocol has been described for the recyclable and reusable Cu-Mn catalyzed C-N bond forming cross coupling reaction of arylboronic acids with various amines to form N-arylated amine products in aqueous medium affording excellent yields under ambient conditions, in 3-4 h.

Full text of DOI:10.1016/j.tetlet.2013.07.095

Accepted Manuscript
Ligand-free C–N bond formation in aqueous medium using a reusable Cu–Mn
bimetallic catalyst
Sanghapal D. Sawant, Mahesuni Srinivas, K.A. Aravinda Kumar, G. Lakshma
Reddy, Parvinder Pal Singh, Baldev Singh, Amit Kumar Sharma, P.R. Sharma,
Ram A. Vishwakarma
PII:
S0040-4039(13)01254-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.07.095
TETL 43293
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
12 June 2013
16 July 2013
19 July 2013
Please cite this article as: Sawant, S.D., Srinivas, M., Aravinda Kumar, K.A., Lakshma Reddy, G., Singh, P.P.,
Singh, B., Sharma, A.K., Sharma, P.R., Vishwakarma, R.A., Ligand-free C–N bond formation in aqueous medium
using a reusable Cu–Mn bimetallic catalyst, Tetrahedron Letters (2013), doi: http://dx.doi.org/10.1016/j.tetlet.
2013.07.095
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Ligand-free C–N bond formation in aqueous medium using a reusable Cu–
Mn bimetallic catalyst
Sanghapal D. Sawant,a,b* Mahesuni Srinivas,a,b K. A. Aravinda Kumar,a G. Lakshma Reddy,a,b
Parvinder Pal Singh,a,b Baldev Singh,b,c Amit Kumar Sharmae P. R. Sharma,e Ram A.
Vishwakarmaa,b*
aMedicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Jammu 180 001,
India
bAcademy of Scientific and Innovative Research, CSIR-IIIM, Canal Road, Jammu-180 001, India
cNatural Product Chemistry, CSIR-Indian Institute of Integrative Medicine, Jammu 180 001,
India
dCancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu 180 001,
India
eDepartment of Chemistry, University of Jammu, Dr. B. R. Ambedkar Road, Jammu-180 006,
India
Tel.: +91-191-2569111, Fax: +91-191-2569333, IIIM-Communication No. IIIM/1499/2012
E-mail: sdsawant@iiim.ac.in

Abstract:
A general ligand-free protocol has been described for the recyclable and reusable Cu–Mn
catalyzed C–N bond forming cross coupling reaction of arylboronic acids with various amines to
form N-arylated amine products in aqueous medium affording excellent yields under ambient
conditions, in 3–4 h.
Copper promoted cross-coupling of arylboronic acids with amines or phenols is gaining
popularity because of simple protocols and mild conditions used in the preparation of aryl
ethers, aryl amines and arylated heterocycles. Chan, Evans and Lam, more than a decade ago
reported the formation of aryl C–O, C–N or C–S using arylboronic acid with a phenol or
aniline (or other N-nucleophiles) or thiophenol, respectively, which is a modified Ullmann
condensation reaction mediated by a copper species.1 A variety of NH-containing substrates,
including amines, amides, imides, ureas, carbamates and sulfonamides are reported using
stoichiometric copper-mediated protocol for C–N bond formation reactions, coupled with
various substituted boronic acid. Usually, to be successful these reactions are typically
carried out in various Cu or Pd containing organometals, mostly using phosphine ligands.2
Use of iron or iron-copper3 and nickel-based4 catalytic systems is also reported for this

purpose.
Here, it is important to note about the limitation of the conventional protocol, i.e., these
reactions are environmentally unfriendly as they require stoichiometric amounts of copper or
copper salts, which produces huge amounts of waste. There are several methods for copper-
mediated Ullmann-type reactions5 or palladium-mediated Buchwald-Hartwig amination
reactions.6 This discovery was extensively exploited in the subsequent years by many
research groups, and presently there are several reports available on these methods. This can
be evidenced by the enormous popularity of C–N bond forming reactions. Moreover, the
application of these methods allows incorporating an aryl amine motif in the construction of
many natural products and potentially biologically active molecules. Aryl amines are
important compounds found in many pharmaceuticals, agrochemicals and many other
preparations.7
Even though significant progress has been made with regard to C–N bond formation, there
is an increasing demand for low-cost and environment-friendly catalysts. Our continued
interest in Cu–Mn catalyzed reactions prompted us to explore its utility in expanding the
potential of this catalyst in various applications and method development. In this direction,
we conceptualized and envisioned the scope of using this catalyst for C–N bond forming
reaction.8 Furthermore, copper-manganese spinels have attracted significant attention for
their potential applications in catalysis. Despite their low surface areas, these catalysts
displayed activity comparable to commercially available catalysts.9
The designer Cu–Mn catalyst works as spinel, where Mn stabilizes the copper and avoids
use of expensive ligands. The catalyst is heterogeneous and reusable, which provides an
advantage over the homogeneous Cu-catalyst. In the Cu–Mn bimetallic catalyst, the reaction

between CuO and Mn2O3 through electron transfer from Mn3+ to Cu2+ may result in the
formation of Mn4+ ion having a bias for d2sp3 bonds preferring the octahedral site, and a Cu+
ion by virtue of its preference to form sp3 bonds will be stabilized at the tetrahedral site thus
obviating the need for an external reagent like using ligands; moreover, in this bimetallic
composition, despite its low intrinsic catalytic activity, Mn can significantly influence the
activity and selectivity of a Cu–Mn and can play an important role.
We explored the protocol, which describes the importance of Cu–Mn catalyst for N-
arylations. Primary and secondary alkyl/aryl/heteroaryl amines were monoarylated
successfully using arylboronic acids under ligand-free conditions in the presence of K2CO3
base. This protocol offers a simple strategy as the reactions can be carried out in the open
atmosphere under ambient conditions in aqueous medium and it does not require the
stoichiometric quantity of the catalyst unlike conventional methods.
We initiated our studies by choosing phenyl boronic acid 1 and aniline 2 as a standard to
first examine the possibility of forming the diphenylamine product 3a by using Cu–Mn
catalyst. We were pleased to observe the formation of expected product in minor amount by
TLC, in this preliminary experiment, which was carried out in the organic solvent
tetrahydrofuran using pyridine. Further, we started the optimization of reaction conditions.
OH
H
B
H2N
+
N
Cu-Mn 25wt%
OH
K2CO3 (2 eq); Water
2
3a
1
Scheme 1: Cu–Mn catalyzed synthesis of diphenylamine
At very initial level of our study, all the optimization reactions were performed using
10wt% of catalyst. The conversion of the reaction was monitored using various solvents as
they played an important role. The best result was obtained in water (Table 1A),which gave

yields up to 80%. The use of various bases/base-free condition affected the results and
yields. There was no product formation observed in methanol, in this case self coupled
biphenyl was formed as major product. The reaction in dichloromethane, tetrahydrofuran,
acetonitrile or dioxane did not give the desired products in good yields but gave a mixture of
arylated amines and biphenyl along with the unreacted starting materials. This reaction was
also tried in a mixture of organic and aqueous solvents and the results are given in Table 1A.
Acetonitrile:water or tetrahydrofuran:water has given moderate yields, 55 and 58%
respectively (Table 1A; entry 1-5). The maximum yields >65%, were noted in water:dioxane
(1:1) mixture in the presence of pyridine as base, and the use of other bases like K2CO3,
Cs2CO3 and triethylamine using this solvent gave 55%, 50% and 25% yields respectively.
However, when the reaction was carried out in water using various bases viz. pyridine,
K2CO3, Cs2CO3 and triethyl amine, the maximum yields (80%) were obtained in the presence
of K2CO3 using 10 wt% catalyst and this was the highest conversion observed amongst all
the solvents. Therefore, water was selected for carrying out all further reactions. Reaction
without base did not give any product.
Table 1: Optimization of catalyst and solvent conditions

Next, we intended to optimize the quantities of catalyst required for the maximum
conversion in water for the formation of 3a. When the reaction was conducted using 10wt%
catalyst as discussed above, gave 80% of product and 25 and 50 wt% catalyst gave around
95% conversion to afford 3a. Therefore, all the reactions were performed using 25 wt%
catalyst in aqueous solvent in the presence of K2CO3 (2 eq.) as a base (Table 1B: entry: 2),
and in all the cases starting materials were completely consumed within 3–4 h time period.10
Having optimized the conditions, we initiated exploration of the generality of this method
on various substrates. Arylboronic acids have given the desired product in good yields. When
the reaction on heteroarylboronic acid was tried, typically in the case of coupling of 5-

pyridylboronic acid with aniline, the expected heteroarylated amine product was not formed
at the optimized conditions. To understand the applicability and diversity with respect to
amines, we used different amines, both primary and secondary amines gave required product
in good to excellent yields and aryl, alkyl as well as heteroarylamines afforded the desired
products. Aryl amines gave excellent yields and alkyl or heteroarylamines afforded
comparatively lower yields (Table 2). In our further experiments, we were interested in
examining the selectivity of the arylation. Reaction with 4-amino phenol and phenylboronic
under the optimized conditions yielded in diarylated product exclusively and the arylation
was taken place at both the functional groups (-NH and -OH).
Table 2: Arylated amine products
R2
R= any substitution;
R1 and R2 = aryl, alkyl or heteroaryl group
N
R1
R
Yields: 70-95%)
H
H
H
N
H
N
H
H
N
H
N
N
OHC
N
H3COC
N
F
MeO
Cl
3a: 95%
3g: 95%
3b: 93%
3c: 90%
3d: 91%
3e: 90%
3f: 95%
H
N
H
N
H
N
H
H
N
H
N
Cl
F
N
MeO
F
F3CO
3m: 93%
3h: 90%
3i: 93%
3j: 94%
3k: 95%
3l: 93%
OCH3
H
N
H
H
N
H
H
H
N
N
N
N
OCH3
OMe
O
3r: 79%
3s: 76%
3p: 82%
3q: 80%
3o: 95%
3n: 90%
H
H
H
N
H
H
N
H
N
H
N
N
N
N
MeO
3x: 79%
3z: 75%
3t: 72%
3u: 72%
3v 71%
3w: 76%
3y: 78%
COOCH3
H
H
N
N
N
O
N
N
S
N
O
3ab: 70%
3ac: 73%
3ad: 75%
3aa: 72%
We prepared the catalyst as reported earlier,8,11 and in order to see the robustness of the
Cu–Mn catalyst, we conducted experiments of recycling and reusing the catalyst, and it was

found that the catalyst does not lose its original shape, it retains its morphology as shown in
the SEM images (Fig. 2 in SI). X-ray diffraction data (Fig. 1 in SI) for 8th recycle and reuse
experiment shows very minor variation in composition of catalyst. In the recycle and reuse
experiments, in subsequent cycles it was observed that the catalyst gives consistantly good
yields (around 90%) in each experiment as depicted in the graph shown below (Fig. 1).
Fig. 3: Graph with % yields in recycle-reuse experiments of Cu–Mn catalyst used up to 8th run
The SEM patterns of the catalyst (A) represents before use and (B) and (C) represents after use at
5th and 8th run (Fig. 2 in SI). After reaction and on regeneration these nano-spherical particles have
appeared almost same as fresh catalyst. It can be seen that the morphology is retained as before
and this indicates that the catalyst maintains high structural stability, during the reaction.
In conclusion, we have developed a strategy for the arylation of alkyl/aryl and
heteroarylamines using bimetallic catalyst Cu–Mn under ligand-free conditions in aqueous
media. This is an environmentally benign and safe protocol that offers several advantages
like mild reaction conditions and setup, excellent yields and less time with added benefit of
recycling and reusing the catalyst.

Acknowledgements:
MS, KA, GLR thank CSIR for the award of fellowship. The authors gratefully acknowledge the
support of Instrumentation Division of IIIM-J.
1
Supporting information: HNMR and mass for all the compounds as well as SEM images and
XRD data for catalyst is given in supporting information.

References:
1. a) Chan, D. M. T.; Monaco, K. L.; Wang, R.-P.; Winters, M. P. Tetrahedron Lett. 1998,
39, 2933; (b) Evans, D. A.; Katz, J. L;. West, T. R. Tetrahedron Lett. 1998, 39, 2937; (c)
Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Winters, M. P.; Chan, D. M. T.;
Combs, A. Tetrahedron Lett. 1998, 39, 2941.
2. a) Wolfe, J.P.; Wagaw, S.; Marcoux, J.F.; Buchwald, S.L. Acc. Chem. Res. 1998, 31, 805;
(b) Muci, A. R.; Buchwald, S. L. Topics in Curr. Chem. 2002, 219, 131; (c) Surry, D. S.;
Buchwald, S. L. Chem. Sci. 2011, 2, 27
3. a) Guo, D.; Huang, H.; Xu, J.; Jiang, H.; Liu, H. Org. Lett., 2008, 10(20), 4513; (b)
Taillefer, M.; Xia, N.; Oualli, A. Angew. Chem., Int. Ed. 2007, 46, 934; (c) Correa, A.;
Bolm, C. Angew. Chem., Int. Ed. 2007, 46, 8862; (d) Correa, A.; Elmore, S.; Bolm, C.
Chem. –Eur. J. 2008, 14, 3527.
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Klapars, A.; Buchwald, S. L. Org. Lett., 2002, 4, 581; (c) Quach, T. D.; Batey, R. A. Org.
Lett., 2003, 5, 4397; (d) Jiang, D. S.; Fu, H.; Jiang, Y. Y.; Zhao, Y. F. J. Org. Chem.,
2007, 72, 672.
6. a) Hartwig, J. F. Angew. Chem., Int. Ed., 1998, 37, 2046; (b) Buchwald, S. L.; Mauger,
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New York, 1991, Vol. 8. Bringmann, G.; Walter, R.; Weirich, R. Angew. Chem., Int. Ed.
1990, 27, 977.
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Sharma, A. K.; Sharma, P. R.; Singh, D.; Vishwakarma, R. A. J. Org. Chem., 2012, 77,
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10. General procedure for preparation of arylated amines: In a typical example,
phenylboronic acid 1 (1.22 g, 1 mmol) was charged in the flask containing K2CO3 (2 eq.)
in water as solvent (2 mL). To this was added aniline 2 (0.93 g, 1 mmol) and Cu–Mn
catalyst, and the reaction mixture was allowed to stir at room temperature. The
completion of the reaction was monitored by TLC. After completion, the base was
neutralized using 2N HCl and the catalyst was filtered off, thorough washings of water
were given, extracted with ethyl acetate, organic layer separated and dried under reduced
vacuum. The crude product obtained was purified on silica gel column chromatography
(solvents, ratio?), to obtain white crystalline product diphenylamine 3a (1.60 g) with 95%
yield. All reactions were similarly carried out.
11. Preparation of Cu–Mn Catalyst: Copper-manganese mixed oxide was prepared by co-
adding the aqueous solutions of CuCl2·2H2O and MnCl2·4H2O in a molecular weight
ratio (1:0.25) at a rate of 1 mL min−1 under vigorous mechanical stirring at room
temperature to form a uniform solution. To this, was added drop-wise ammonia solution

until pH 8.5 to 8.7 and allowed to stand overnight to form a gel, filtered and washed with
double distilled water till free from chloride ions. After keeping overnight at room
temperature the cake was allowed to dry in an air oven at 110 °C for 24 h and finally
calcined (10 °C min−1) in a muffle furnace at 425 °C for 3h.

Figures and legends
Fig. 1: Powder X-ray diffraction (XRD) of the Cu-Mn catalyst
Fig. 2: SEM images of Cu-Mn catalyst: before use (A); after use of 5th run (B) and after use of 8th run (C)

Graphical Abstract
Leave this area blank for abstract info.
Ligand free C–N bond formation in aqueous
medium using a reusable Cu–Mn bimetallic
catalyst
Sanghapal D. Sawant,* Mahesuni Srinivas, K. A. Aravinda Kumar, G. Lakshma Reddy, Parvinder Pal Singh,
Baldev Singh, Amit Kumar Sharma, P. R. Sharma, Ram A. Vishwakarma*