A manganese/copper bimetallic catalyst for C-N coupling reactions under mild conditions in water

Article abstract of DOI:10.1016/j.tetlet.2011.10.128

An efficient and convenient bimetallic MnF₂/CuI catalyst in combination with trans-1,2-diaminocyclohexane has been developed for the cross-coupling of nitrogen heterocycles with aryl halides in water at moderate temperature. A variety of nitrogen nucleophiles including pyrazole, 7-azaindole, indazole, indole, pyrrole and imidazole afforded the corresponding products in moderate to good yields (up to 94%) under the described arylation conditions.

Full text of DOI:10.1016/j.tetlet.2011.10.128

Tetrahedron Letters 52 (2011) 7171–7174
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A manganese/copper bimetallic catalyst for C–N coupling reactions under
mild conditions in water
⇑
Yong-Chua Teo , Fui-Fong Yong, Gina Shiyun Lim
Natural Sciences and Science Education, National Institute of Education, Nanyang Technological University, 1 Nanyang Walk, Singapore 637616, Singapore
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient and convenient bimetallic MnF2/CuI catalyst in combination with trans-1,2-diaminocyclo-
hexane has been developed for the cross-coupling of nitrogen heterocycles with aryl halides in water
at moderate temperature. A variety of nitrogen nucleophiles including pyrazole, 7-azaindole, indazole,
indole, pyrrole and imidazole afforded the corresponding products in moderate to good yields (up to
94%) under the described arylation conditions.
Received 2 September 2011
Revised 10 October 2011
Accepted 21 October 2011
Available online 28 October 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Manganese
Copper
Bimetallic
Coupling
N-arylation
The transition metal catalyzed formation of carbon–carbon and
carbon-heteroatom bonds has emerged as a versatile and powerful
tool in chemical synthesis.1 In particular, the N-arylation of nitro-
gen nucleophiles with aryl halides has acquired importance due
to the versatility of the products, which are prevalent in com-
pounds of biological, pharmaceutical and materials interest.2
Among the various strategies developed to date, copper-catalyzed
Ullmann condensations have proven to be a convenient method for
the assembly of N-arylated compounds.3 The synthetic scope of
this reaction, however, is greatly limited by its harsh conditions
such as elevated temperature (>140 °C), long reaction time, and
stoichiometric amounts of copper reagents.4 In the past decade,
improvements on the Ullmann-type C–N cross-coupling have been
mostly concerned with the development of catalytic systems that
utilized new mono- or bidentate chelators to increase the reaction
rates and lower substantially the reaction temperatures.5–10 In
spite of the significant progress made in the aforementioned trans-
formation, most of these methodologies remain restricted to a cer-
tain degree due to the unavailability, air or moisture sensitivity and
high expense resulting from the preparation of the ligands.
as the ligand12 while Liu demonstrated a Fe2O3/Cu(acac)2 system
for the arylations of aliphatic/aryl amines under microwave irradi-
ation in DMSO/water.13 The use of an iron co-catalyst and high
temperature or microwave technology was critical for the success
of these protocols.
Recently, the development of new strategies for cross-coupling
reactions in water has stimulated interest among the synthetic
community since they avoid environmental issues arising from
the use of organic solvents.14 However, these methods often entail
the additional challenges of water tolerance for the catalyst/ligand
system15 and mostly require high reaction temperatures. There-
fore, the exploration of a cross-coupling protocol that proceeds at
low temperature in aqueous media is important.
Previously, we reported a protocol for the cross-coupling of
azoles with aryl iodides using an MnCl2Á4H2O/trans-1,2-diamino-
cyclohexane catalytic system.16 However, the use of aryl iodides
and high reaction temperatures was necessary to achieve good
yields of the products. Based on this precedent and as part of our
continuing endeavors to develop environmentally friendly proto-
cols that operate efficiently under mild conditions, herein we re-
port the manganese/copper co-catalyzed C–N cross-coupling
reactions between nitrogen heterocycles and aryl/heteroaryl ha-
lides in water. This novel system constitutes a rare example of effi-
cient bimetallic catalysis and the first involving both manganese
and copper reagents that operate in water at low temperature.
In our initial study, iodobenzene (1) and pyrazole (2) were cho-
sen as model substrates. A preliminary reaction was carried out
using a combination of MnCl2, trans-1,2-diaminocyclohexane and
K3PO4 at 60 °C in water. However, no conversion of iodobenzene
The application of bimetallic catalysis for the Ullmann conden-
sation has been relatively unexplored. Taillefer et al. first reported
an efficient Fe(acac)3/CuO co-catalytic system for the arylation of
nitrogen heterocycles with aryl halides.11 Fu and co-workers re-
ported a FeCl3/CuO bimetallic catalyst that promoted the arylation
of aliphatic/aryl amines and phenols in the presence of rac-BINOL
⇑
Corresponding author. Tel.: +65 6790 3846; fax: +65 6896 9414.
E-mail address: yongchua.teo@nie.edu.sg (Y.-C. Teo).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.10.128

7172
Y.-C. Teo et al. / Tetrahedron Letters 52 (2011) 7171–7174
into product 3a was observed, even after prolonged stirring (Table
1, entry 1). A control reaction carried out using CuI, but in the ab-
sence of the Mn additive only gave the product in a poor yield of 9%
(entry 2). To our delight, the coupling of pyrazole with iodoben-
zene gave a moderate yield of 51% in the presence of catalytic
amounts of both MnCl2 and CuI (entry 3). This co-catalyzed N-ary-
lation result prompted us to further evaluate the efficiency of other
metal salts and bases for the N-arylation process (entries 4–10).
Optimized conditions were achieved using MnF2 (30 mol %), CuI
(10 mol %), trans-1,2-diaminocyclohexane (20 mol %) and KOH
(2 equiv) in water at 60 °C for 24 h which afforded the arylated
product in a good yield of 88% (entry 10). A control experiment car-
ried out in the absence of Mn additive using KOH as the base gave a
poor yield of 24% (entry 11). This indicates the necessity for the Mn
salt together with the copper salt as a bimetallic catalyst for this
reaction. Attempts to lower the reaction temperature (40 °C) or de-
crease the Mn catalyst loading (10 mol %) led to traces or lower
yields of the product (entries 12 and 13). Interestingly, we also
found that the reaction proceeded efficiently in water only; lower
yields of 50% and 54% were obtained when either DMF or toluene
was employed as the solvent. This method is attractive for several
reasons: (i) it employs a sustainable and environmentally-friendly
catalytic system that is a combination of MnF2/CuI which are inex-
pensive and readily available; (ii) it avoids the time consuming and
uneconomical transformations associated with the synthesis of
specially designed ligands; (iii) it offers experimental simplicity
and mild conditions which exclude the need for an inert atmo-
sphere and anhydrous solvent; (iv) it uses water as the reaction
medium which is abundant, cheap and environmentally benign.
With the optimized conditions in hand, we next investigated
the scope of the process with respect to aryl halides. The coupling
reactions of pyrazole as the model heterocycle with differently
substituted aryl halides were carried out. In general, the corre-
sponding N-arylation products were obtained in moderate to good
yields. The steric effect was significant as ortho-substituents ham-
pered the reaction and led to traces or lower yields of the products
(Table 2, entries 2–4). The protocol was tolerant of both electron-
donating and electron-withdrawing groups as good yields were ob-
tained regardless of the electronic nature of the substituent. No
significant electronic effects were observed for both meta-and
para-substituted aryl iodides (entries 5–13). Although aryl iodides
are interesting substrates, we extended the protocol to aryl bro-
mides as the electrophilic counterpart as these are of much greater
interest for industrial applications. In most cases, good yields were
obtained when the reactions were carried out at 100 °C (entries
14–21).
In a second set of experiments, the scope of the process was
tested with a series of nitrogen heterocycles and aryl iodides. The
arylated azoles were obtained in moderate to good yields from
the cross-couplings of 7-azaindole and indazole (Table 3, entries
1–6). Lower yields were observed for indole, imidazole and pyrrole
under the standard conditions, but elevating the reaction temper-
ature to 100 °C led to an improvement in yields (entries 7–15).
Moreover, the arylation of a representative substituted pyrazole,
3-methylpyrazole also gave the corresponding N-phenyl deriva-
tives in good yields (entries 16–18).
Finally, we were successful in extending the system to include
heteroaryl iodides as coupling partners, which are important phar-
maceutical intermediates. Our catalytic system promoted effi-
ciently the cross-coupling reactions between 7-azaindole and
indole with 3-iodopyridine and 3-iodothiophene and pyrazole with
2-iodopyridine and 3-iodothiophene (Table 4, entries 1–6).
In summary, we have developed an original example of cooper-
ative bimetallic catalysis based on Mn and Cu reagents in water.
The N-arylation of various nitrogen heterocycles with differently
substituted aryl iodides proceeded effectively in water at 60 °C in
most instances. The low cost and readily available Mn and Cu salts,
the operational simplicity, and mild reaction conditions render this
transformation as an attractive alternative for the assembly of N-
arylated products and should be applicable to custom synthesis
Table 2
Mn/Cu co-catalyzed N-arylation of pyrazole (2) with various substituted aryl halides
in watera
MnF2 (30 mol%)
CuI (10 mol%)
R
R
Table 1
+
N
X
HN
Optimization studies on Mn/Cu catalytic systems for the N-arylation of pyrazole (2) in
2 equiv KOH
N
N
watera
H2O, 60 oC, 24h
3a-l
[Mn] cat. (30 mol%)
CuI (10 mol%)
trans-1,2-diamino-
cyclohexane (20 mol%)
PhI
+
NH
N
Entry
X
R
Product
Yieldb (%)
N
2 equiv base
N
H2O, 60 oC, 24 h
1
I
H
3a
88
trans-1,2-diamino-
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
I
I
I
I
I
I
I
I
I
I
I
I
Br
Br
Br
Br
Br
Br
Br
Br
2-OMe
2-Me
2-Cl
3-Me
3-Cl
3-CF3
3-NO2
4-OMe
4-F
3b
—
—
3c
3d
3e
3f
3g
3h
3i
30
1
2
3a
cyclohexane (20 mol%)
Trace
Trace
75
77
80
70
75
62
80
Entry
[Mn] cat. (0.3 equiv)
Base
Yieldb (%)
1
2
3
4
5
6
7
8
MnCl2
—
MnCl2
MnF2
Mn(OAc)2
Mn(acac)2
Mn(ClO4)2
MnO2
MnF2
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
Cs2CO3
KOH
0c
9d
51
60
41
17
30
trace
17
4-Cl
4-Br
3j
50
76
4-CF3
H
3-OMe
3-Me
3-Cl
3-CF3
4-OMe
4-F
3k
3a
3l
3c
3d
3e
3g
3h
3i
71c
70c
84c
75c
70c
65c
64c
70c
9
10
11
12
13
MnF2
88
—
KOH
KOH
KOH
24d
tracee
55f
MnF2
MnF2
a
Reactions and conditions: pyrazole (1.47 mmol), iodobenzene (2.21 mmol),
base (2.94 mmol), CuI (10 mol %), [Mn] source (30 mol %), trans-1,2-diaminocyclo-
hexane (20 mol %), H2O (0.75 mL), 60 °C, 24 h.
4-Cl
b
a
Yield of isolated product.
Without Cu source.
Without Mn source.
Reaction stirred at 40 °C.
Reactions and conditions: pyrazole (1.47 mmol), aryl halide (2.21 mmol), KOH
(2.94 mmol), CuI (10 mol %), MnF2 (30 mol %), trans-1,2-diaminocyclohexane
(20 mol %), H2O (0.75 mL), 60 °C, 24 h.
c
d
e
b
Yield of isolated product.
Reaction temperature: 100 °C.
f
c
Catalyst: MnF2 (10 mol %) and CuI (10 mol %).

Y.-C. Teo et al. / Tetrahedron Letters 52 (2011) 7171–7174
7173
Table 3
Table 4
Mn/Cu co-catalyzedN-arylation ofazoles withvarious substitutedarylhalides inwatera
Mn/Cu co-catalyzed N-arylation of azoles with various substituted heteroaryl halides
in watera
MnF2 (30 mol%)
CuI (10 mol%)
R
R
MnF2 (30 mol%)
CuI (10 mol%)
NH
+
N
I
2 equiv KOH
NH
+
Het-ArX
N Ar-Het
H2O, 60 oC, 24 h
4-9
2 equiv KOH
trans-1,2-diamino-
H2O, 100 oC, 48 h
cyclohexane (20 mol%)
10-12
Yield (%)b
trans-1,2-diamino-
Entry
NuH
Product
Yieldb (%)
93
cyclohexane (20 mol%)
Entry
1
NuH
Het-ArX
Product
N
1
2
3
4a
4b
4c
N
N
N
N
N
I
I
94
92
78
70
N
10a
85
75
N
H
N
N
Me
N
N
S
S
2
3
4
N
H
N
Cl
N
10b
N
N
N
N
N
N
N
N
I
I
N
H
N
4
5
6
5a
5b
5c
84
94
91
11a
S
N
N
S
N
H
Me
11b
N
N
N
N
N
I
I
N
N
N
N
Cl
N
H
5
6
94
57
12a
N
N
S
S
7
8
6a
6b
82c
78c
12b
a
Reactions and conditions: N-nucleophile (1.47 mmol), heteroaryl iodide
(2.21 mmol), KOH (2.94 mmol), CuI (10 mol %), MnF2 (30 mol %), trans-1,2-diami-
nocyclohexane (20 mol %), H2O, 100 °C, 24 h.
N
H
Me
b
Yield of isolated product.
Cl
9
6c
7a
7b
82c
63c
60c
and industrial processes. In addition, the use of water as the sol-
vent greatly enhances the economical and environmental friendli-
ness of this catalytic system. Further work to broaden the scope of
this system to other cross-coupling reactions is in progress.
N
N
10
11
N
N
N
N
H
Me
Cl
N
Acknowledgements
12
13
N
7c
8a
65c
57c
The authors would like to thank the National Institute of Educa-
tion and Nanyang Technological University for generous financial
support.
N
N
14
15
8b
8c
53c
62c
Me
N
H
Supplementary data
N
Cl
Supplementary data (experimental procedures and compound
characterization data) associated with this article can be found,
in the online version, at doi:10.1016/j.tetlet.2011.10.128.
N
N
Me
16
9a
63
Me
N
N
N
References and notes
17
18
9b
9c
81
60
N
H
N
N
Me
Me
Me
Cl
1. (a) Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem. Rev. 2002, 102, 1731; (b) Muci, A. R.;
Buchwald, S. L. Top. Curr. Chem. 2002, 219, 131; (c) Metal-Catalyzed Cross-
Coupling Reactions; Diederich, F., Meijere, A., Eds.; Wiley-VCH: Weinheim,
2004; (d) Campeau, L.-C.; Fagnou, K. Chem. Commun. 2005, 1253; (e) Daugulis,
O.; Zaitsev, V. G.; Shabashou, D.; Pham, Q.-N.; Lazareva, A. Synlett 2006, 3382;
(f) Godula, K.; Sames, S. Science 2006, 312, 67; (g) Dick, A. R.; Sanford, M. S.
Tetrahedron 2006, 62, 2439; (h) Hartwig, J. F. Synlett 2006, 1283; (i) Alberico, D.;
Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107, 174; (j) Seregin, I. V.; Gevorgyan,
V. Chem. Soc. Rev. 2007, 36, 1173; (k) Davies, H. M. L.; Manning, J. R. Nature
2008, 451, 417.
a
Reactions and conditions: N-nucleophile (1.47 mmol), aryl iodide (2.21 mmol),
KOH (2.94 mmol), CuI (10 mol %), MnF2 (30 mol %), trans-1,2-diaminocyclohexane
(20 mol %), H2O (0.75 mL), 60 °C, 24 h.
b
Yield of isolated product.
Reaction temperature: 100 °C.
c

7174
Y.-C. Teo et al. / Tetrahedron Letters 52 (2011) 7171–7174
2. (a) Buckingham, J. B. Dictionary of Natural Products; CRC Press, 1994. Vol. 1; (b)
Oshiro, Y.; Sato, S.; Kurahashi, N.; Tanaka, T.; Kikuchi, T.; Tottori, K.; Uwahodo,
Y.; Nishi, T. J. Med. Chem. 1998, 41, 658; (c) Belfield, A. J.; Brown, G. R.;
Foubister, A. J. Tetrahedron 1999, 55, 11399; Lawrence, S. A. Amines Synthesis
Properties and Application; Cambridge University Press: Cambridge, 2004.
3. (a) Ullmann, F. Ber. Deutsch. Chem. Ges. 1903, 36, 2382; For a review, see: (b)
Schnürcg, M.; Flasik, R.; Khan, A. F.; Spina, M.; Mihovilovic, M. D.; Stanetty, P.
Eur. J. Org. Chem. 2006, 3283; (c) Larsson, P.-F.; Correa, A.; Carril, M.; Norrby, P.-
O.; Bolm, C. Angew. Chem., Int. Ed. 2009, 48, 5691.
4. Reviews: (a) Ley, S. V.; Thomas, A. W. Angew. Chem. Int. Ed. 2003, 42, 5400; (b)
Kunz, K.; Scholtz, U.; Ganzer, D. Synlett 2003, 2428; (c) Beletskaya, I. P.;
Cheprakov, A. V. Coord. Chem. Rev. 2004, 248, 2337; (d) Corbert, J.-P.; Mignani,
G. Chem. Rev. 2006, 106, 2651.
5. For diamines as the ligands in Cu-catalysed C–N coupling, see: (a) Klapars, A.;
Antila, J. C.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123, 7727; (b)
Antila, J. C.; Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 11684; (c)
Klapars, A.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 7421; (d)
Antila, J. C.; Baskin, J. M.; Barder, T. E.; Buchwald, S. L. J. Org. Chem. 2004, 69,
5578; (e) Rao, R. K.; Naidu, A. B.; Jaseer, E. A.; Sekar, G. Tetrahedron 2009, 65,
4619.
2849; (e) Lu, Z.; Twieg, R. J. Tetrahedron 2005, 61, 903; (f) Cai, Q.; Zhu, W.;
Zhang, H.; Zhang, Y.; Ma, D. Synthesis 2005, 496; (g) Zhang, H.; Cai, Q.; Ma, D. J.
Org. Chem. 2005, 70, 5164; (h) Kim, J.; Chang, S. Chem. Commun. 2008, 3052.
8. For oxime phosphines as the ligands in Cu-catalysed C–N coupling, see: (a) Xu,
L.; Mao, J.; Zhu, D.; Wu, F.; Wang, R.; Wan, B. Tetrahedron 2006, 61, 6553; (b)
Zhu, D.; Xu, L.; Wu, F.; Wan, B. Tetrahedron Lett. 2006, 47, 5781.
9. For salicylaldoximes as the ligands in Cu-catalysed C–N coupling, see: (a)
Kwong, F. Y.; Buchwald, S. L. Org. Lett. 2003, 5, 793; (b) Cristau, H.-J.; Cellier, P.
P.; Spindler, J.-F.; Taillefer, M. Chem. Eur. J. 2004, 10, 5607; (c) Cristau, H.-J.;
Cellier, P. P.; Spindler, J.-F.; Taillefer, M. Eur. J. Org. Chem. 2004, 695; (d) Jiang,
Q.; Jiang, D.; Jiang, Y.; Fu, H.; Zhao, Y. Synlett 2007, 1836.
10. For b-diketones and b-keto esters as the ligands in Cu-catalysed C–N coupling,
see: (a) Shafir, A.; Buchwald, S. L. J. Am. Chem. Soc. 2006, 128, 8742; (b) de
Lange, B.; Lambers-Verstappen, M. H.; de Vondervoort, L. S.; Sereinig, N.; de
Rijk, R.; de Vries, A. H. M.; de Vries, J. G. Synlett 2006, 3105; (c) Shafir, A.;
Lichtor, P. A.; Buchwald, S. L. J. Am. Chem. Soc. 2007, 129, 3490; (d) Lv, X.; Bao,
W. J. Org. Chem. 2007, 72, 3863; (e) Xia, N.; Taillefer, M. Angew. Chem., Int. Ed.
2009, 48, 337; (f) Wang, D.; Ding, K. Chem. Commun. 2009, 1891.
11. Taillefer, M.; Xia, N.; Ouali, A. Angew. Chem., Int. Ed. 2007, 46, 934.
12. Wang, Z.; Fu, H.; Jiang, Y.; Zhao, Y. Synlett 2008, 2540.
6. For diols as the ligands in Cu-catalysed C–N coupling, see: (a) Kwong, F. Y.;
Klapars, A.; Buchwald, S. L. Org. Lett. 2002, 4, 581; (b) Job, G. E.; Buchwald, S. L.
Org. Lett. 2002, 4, 3703; (c) Jiang, D.; Fu, H.; Jiang, Y.; Zhao, Y. J. Org. Chem. 2007,
72, 672.
7. For amino acids and amino alcohols as the ligands in Cu-catalysed C–N
coupling, see: (a) Ma, D.; Zhang, Y.; Yao, J.; Wu, S.; Tao, F. J. Am. Chem. Soc. 1998,
120, 12459; (b) Ma, D.; Xia, C. Org. Lett. 2001, 3, 2583; (c) Ma, D.; Cai, Q.; Zhang,
H. Org. Lett. 2003, 5, 2453; (d) Wang, Z.; Bao, W.; Jiang, Y. Chem. Commun. 2005,
13. Guo, D.; Huang, H.; Zhou, Y.; Xu, J.; Jiang, H.; Chen, K.; Liu, H. Green Chem. 2010,
12, 276.
14. (a) Grieco, P. A. Organic Synthesis in Water; Blackie Academic & Professional:
London, 1998; (b) Lindstrom, U. M. Chem. Rev. 2002, 102, 2751; (c) Li, C. J. Chem.
Rev. 2005, 105, 3095.
15. Sinou, D. Adv. Synth. Catal. 2002, 344, 221.
16. Teo, Y.-C.; Yong, F.-F.; Poh, C.-Y.; Yan, Y.-K.; Chua, G.-L. Chem. Commun. 2009,
6258.