Microwave-assisted solvent- and ligand-free copper-catalysed cross-coupling between halopyridines and nitrogen nucleophiles

Article abstract of DOI:10.1039/c0gc00296h

N-Heteroarylated products are obtained in good yields by microwave-assisted solvent- and ligand-free copper-catalysed amination of halopyridines with nitrogen nucleophiles.

Full text of DOI:10.1039/c0gc00296h

View Article Online / Journal Homepage / Table of Contents for this issue
Dynamic Article Links
Green Chemistry
Cite this: Green Chem., 2011, 13, 42
www.rsc.org/greenchem
COMMUNICATION
Microwave-assisted solvent- and ligand-free copper-catalysed
cross-coupling between halopyridines and nitrogen nucleophiles†
Zhen-Jiang Liu,a Jean-Pierre Vors,b Ernst R. F. Gesing*c and Carsten Bolm*a
Received 7th July 2010, Accepted 21st October 2010
DOI: 10.1039/c0gc00296h
Table 1 Screening of bases and copper sources in the N-arylation of
pyrazolea
N-Heteroarylated products are obtained in good yields
by microwave-assisted solvent- and ligand-free copper-
catalysed amination of halopyridines with nitrogen nucle-
ophiles.
Substituted N-heterocycles are prevalent in biologically active
compounds. Pyridine derivatives such as N-pyridinylpyrazoles,
-imidazoles, -pyrroles, -indoles and -amides have attracted
particular attention, and several of those compounds have found
use in the biological, pharmaceutical and material sciences.1 Fur-
thermore, they proved promising as ligands in metal catalysis.2
The required core structures can generally be assembled in
a straightforward manner by copper-catalysed Ullmann-type
reactions. However, the classical versions of this cross-coupling3
have several drawbacks, which greatly restrict their applications
in industry. For example, they often require stoichiometric
amounts of a copper reagent, a high reaction temperature and
a polar solvent. Consequently, great efforts have been made to
improve the efficiency of Ullmann-type reactions.4 Although
many copper/ligand combinations are known to perform these
transformations under comparatively mild conditions, there is
still a need to find even simpler catalyst systems.4a,5 Ideally,
they should be ligand-free6 and proceed in “green” solvents or
even be solvent-free.7,8 Also microwave irradiation is of great
importance in the context of green synthesis and sustainable
chemistry,9 and it is also known to accelerate copper-mediated
C–N coupling.6i,7b–c,10 In 2004, Gawley and co-workers reported
SNAr reactions of halopyridines with pyrrolidine and piperidine
deriv◦atives under microwave irradiation, but a high temperature
(130 C) was required, and 3-halopyridines did not react at all.7b
More recently, Liu and co-workers described copper-promoted
amination reactions using microwave techniques.6i This method,
however, needs stoichiometric amounts of copper reagents. In
Entry
Cu source
Base
Yield of 3a (%)b
1
2
3
4
5
6
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
CuI
Cs2CO3
K2CO3
Na2CO3
t-BuOK
t-BuONa
K3PO4
K3PO4·H2O
K3PO4·H2O
K3PO4·H2O
K3PO4·H2O
K3PO4·H2O
—
83
70
10
39
69
76
91
61
66
77
Traces
0
7
8c
9
10
11
12
CuBr
—
—
a Reaction conditions: 3-iodopyridine (1a, 0.5 mmol), pyrazole (2a,
0.65 mmol), copper source (0.05 mmol), base (1.0 mmol), 100 ◦C,
MW (50 W), 0.5 h. b Referring to the amount of product isolated by
chromatography. c Use of 0.65 mmol of 1a and 0.5 mmol of 2a.
a continuation of our search for simple and environmentally
friendly catalyst systems for C–N couplings,6b we herein dis-
close our findings on microwave-assisted solvent- and ligand-
free copper-catalysed amination of halopyridines with various
nitrogen nucleophiles leading to pyridinyl-substituted pyrazoles,
imidazoles, pyrroles, indoles and amides.11
To establish the most efficient solvent- and ligand-free catalyst
system under microwave irradiation conditions, various bases
and copper sources were screened using the coupling of 3-
iodopyridine (1a) with pyrazole (2a) as a model reaction.
The results are summarised in Table 1. With reference to our
previous report on ligand-free copper-catalysed N-arylation,6b
all experiments were initially performed with 10 mol% of Cu2O
and 2.0 equiv. of base under microwave irradiation at 100 ◦C
for 0.5 h (Table 1, entries 1–8).12 Several bases proved applicable
furnishing the coupling product, N-pyridinylpyrazole (3a), in
yields ranging from 10–91%. Use of Cs2CO3 and K3PO4·H2O
gave the best results affording the coupling product in 83 and
91% yield, respectively (entries 1 and 7). Using an excess of 3-
iodopyridine resulted in a decrease in yield (entry 8). Also other
aInstitute of Organic Chemistry, RWTH Aachen University, Landoltweg
1, D-52056, Aachen, Germany.
E-mail: Carsten.Bolm@oc.rwth-aachen.de
bBayer CropScience S, Centre de Recherche de La Dagoire 14–20, Rue
Pierre Baizet, 69009, Lyon, France
cBayer CropScience AG, BCS-R-I-CI, Building 6550,
Alfred-Nobel-Strasse 50, D-40789, Monheim am Rhein, Germany.
E-mail: ernst-rudolf.gesing@bayer.com
† Electronic supplementary information (ESI) available: Further exper-
imental details. See DOI: 10.1039/c0gc00296h
42 | Green Chem., 2011, 13, 42–45
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
Table 2 Coupling of 3-iodopyridine (1a) with various nitrogen nucle-
ophiles under microwave-assisted solvent- and ligand-free conditions
Table 3 N-Heteroarylation of pyrazole with various halopyridines
under microwave-assisted solvent- and ligand-free conditions
Entry
1
RR¢NH
Product
Yield (%)a
91
Entry
1
Halopyridine
Product
Yield (%)a
3a
3b
3c
3d
3a
91 (X = I)
2
87
50
64
2
3
4
5
6
60 (X = Br)
7 (X = Cl)
10 (X = F)
0 (X = OTf)
86 (X = I)
3b
4b
4
5b
3e
90
7b
8b
9b
10
42 (X = Br)
58 (X = Cl)
47 (X = F)
80 (X = I)
5
6
3f
74
55
11
12
13
74 (X = Br)
22 (X = Cl)
50 (X = F)
7b
3g
a Referring to the amount of product isolated by chromatography.
b Starting from hydrochloride of the halo pyridine and using 3.0 equiv.
of K3PO4·H2O.
8
9
3h
3i
0 (12)c
0
products in 90 and 74% yields, respectively (entries 5 and 6). The
N-heteroarylation of phenylmethyl sulfoximine14 gave product
3g in 55% yield (entry 7).15 Alkyl and aromatic amines did not
react with 1a under these conditions (entries 8 and 9). However,
when the temperature was raised to 130 ◦C and Cs2CO3 was used
instead of K3PO4·H2O the coupling between 3-iodopyridine
(1a) and benzylamine led to 3h albeit only in 12% yield
(entry 8).
a Referring to the amount of product isolated by chromatography.
b Cs2CO3 was used instead of K3PO4·H2O. c In parentheses: reaction
performed at 130 ◦C.
copper sources such as CuI and CuBr catalysed the coupling
reaction, but the yields of 3a were slightly lower than with
Cu2O (entries 9 and 10). Control experiments confirmed that
neither with the base alone (entry 11) nor in the absence of
copper and base (entry 12) was the heteroarylated product
formed. Thus, the cross-coupling did not proceed by a SNAr
mechanism.13
Encouraged by the results of the reaction between 1a and
2a, the substrate scope of the microwave-assisted solvent- and
ligand-free coupling was investigated. As shown in Table 2, the
reactions between 3-iodopyridine (1a) and various heterocycles
such as pyrazole, imidazole, pyrrole and indole proceeded well.
In all cases the corresponding N-3-pyridinyl-substituted hetero-
cycles were obtained, and the yields were moderate to excellent
(up to 91%, Table 2, entries 1–4). Furthermore, 2-pyrrolidinone
and acetamide coupled well with 1a affording the corresponding
To compare relative reactivity, coupling between pyrazole
(2a) and substituted pyridines having various leaving groups
in 2,- 3- or 4-position was examined. The data are shown in
Table 3. The best results were achieved in coupling of the iodo-
substituted pyridines leading to the corresponding products
in up to 91% (entries 1, 6, and 10). Also bromo derivatives
coupled, but the yields are lower (up to 74%; entries 2, 7,
and 11). 3-Chloro- and 3-fluoropyridine showed a very low
reactivity, and the corresponding product was obtained in only
7 and 10% yield, respectively (entries 3 and 4). The coupling
of pyrazole with 2-fluoropyridine and the hydrochlorides of 4-
chloro- and 4-fluoropyridine afforded the products in moderate
yields (entries 8, 9 and 13), and those reactions probably involved
a SNAr mechanisms. Low yields were observed in coupling of
2-chloropyridine (entry 12) and 3-substituted chloro- fluoro-
and trifluoromethylsulfonyl pyridines (entries 3–5). Overall the
This journal is
The Royal Society of Chemistry 2011
Green Chem., 2011, 13, 42–45 | 43
©

View Article Online
following reactivity order could be inferred: I > Br ꢀ Cl ª F ꢀ
OTf.13
1450; (c) S. V. Ley and A. W. Thomas, Angew. Chem. Int. Ed., 2003,
42, 5400; (d) K. Kunz, U. Scholz and D. Ganzer, Synlett, 2003, 2428;
(e) I. P. Beletskaya and A. V. Cheprakov, Coord. Chem. Rev., 2004,
248, 2337; (f) J.-P. Corbet and G. Mignani, Chem. Rev., 2006, 106,
2651; (g) M. Carril, R. SanMartin and E. Dom´ınguez, Chem. Soc.
Rev., 2008, 37, 639.
In summary, copper-catalysed coupling reaction of halo
pyridines with various nitrogen nucleophiles can be performed
under microwave-assisted solvent- and ligand-free conditions
providing the corresponding coupling products in moderate to
high yields. Further studies to find alternative and “greener”
catalyst systems and to expand the substrate scope are currently
in progress in our laboratories.
5 F. Monnier and M. Taillefer, Angew. Chem. Int. Ed., 2008, 47,
3096.
6 For examples of ligand-free catalyst systems, see: (a) M. Taillefer, N.
Xia and A. Oualli, Angew. Chem. Int. Ed., 2007, 46, 934; (b) A. Correa
and C. Bolm, Adv. Synth. Catal., 2007, 349, 2673; (c) E. Sperotto, J.
G. de Vries, G. P. M. van Klink and G. van Koten, Tetrahedron Lett.,
2007, 48, 7366; (d) T. Kubo, C. Katoh, K. Yamada, K. Okano, H.
Tokuyama and T. Fukuyama, Tetrahedron, 2008, 64, 11230; (e) J. L.
Bolliger and C. M. Frech, Tetrahedron, 2009, 65, 1180; (f) X.-M. Wu
and Y. Wang, J. Chem. Res., 2009, 555; (g) L. Zhu, P. Guo, G. Li,
J. Lan, R. Xie and J. You, J. Org. Chem., 2007, 72, 8535; (h) J. W.
W. Chang, X. Xu and P. W. H. Chan, Tetrahedron Lett., 2007, 48,
245; (i) H. Huang, X. Yan, W. Zhu, H. Liu, H. Jiang and K. Chen,
J. Comb. Chem., 2008, 10, 617.
7 For examples of solvent-free catalyst systems, see: (a) F. Y. Kwong
and S. L. Buchwald, Org. Lett., 2003, 5, 793; (b) S. Narayan, T.
Seelhammer and R. E. Gawley, Tetrahedron Lett., 2004, 45, 757;
(c) W. S. Chow and T. H. Chan, Tetrahedron Lett., 2009, 50, 1286;
(d) general review: P. J. Walsh, H. Li and C. Anaya de Parrodi, Chem.
Rev., 2007, 107, 2503.
8 It should be, however, noted that solvent-free exothermic reactions
can be problematic because a thermal buffer is missing. For a related
study, see: L. Balland, N. Mouhab, J.-M. Cosmao and L. Estel, Chem.
Eng. Proc., 2002, 41, 395.
9 (a) Microwave Methods in Organic Synthesis, ed. M. Larhed and K.
Olofsson, Springer-Verlag, Berlin, 2006; (b) Microwaves in Organic
Synthesis, 2nd edition, ed. A. Loupy, Wiley-VCH, Weinheim, 2006;
(c) C. O. Kappe and A. Stadler, Microwaves in Organic and Medicinal
Chemistry, Wiley-VCH, Weinheim, 2005.
Experimental section
Procedure for N-heteroarylations of nitrogen nucleophiles
(example: synthesis of 3-(1H-pyrazol-1-yl)pyridine (3a)
After cooling of an oven-dried tube to room temperature
under argon, it was charged with 3-iodopyridine (1a, 102.5 mg,
0.5 mmol), pyrazole (2a, 45 mg, 0.65 mmol), Cu2O (7.2 mg,
0.05 mmol) and K3PO4·H2O (231 mg, 1.0 mmol). The tube was
sealed under argon and placed into a CEM Discover microwave
apparatus. Initially, an irradiation power of 50 W was applied.
When the temperature reached 100 ◦C, the instrument automat-
ically adjusted the power to maintain a constant temperature.
After a total heating time of 1 h, the reaction mixture was cooled
to room temperature and diluted with ethyl acetate (10 mL; use
of less solvent can reduce the yield.) The resulting solution was
filtered through a pad of silica gel and concentrated to give
the crude product. Purification by silica gel chromatography
(1 : 1 pentane/ethyl acetate) gave 3-(1H-pyrazol-1-yl)pyridine
(3a, 66 mg, 91%) as a yellowish oil. The identity and purity of
10 (a) L. Shi, M. Wang, C.-A. Fan, F.-M. Zhang and Y.-Q. Tu, Org.
Lett., 2003, 5, 3515; (b) M. Meciarova´, J. Podlesna´ and S. Toma,
Monatsh. Chem., 2004, 135, 419; (c) S.-Y. Chen, H. Huang, X.-J. Liu,
J.-K. Shen, H.-L. Jiang and H. Liu, J. Comb. Chem., 2008, 10, 358;
(d) M. Poirier, S. Goudreau, J. Poulin, J. Savoie and P. L. Beauliu,
Org. Lett., 2010, 12, 2334.
1
the product was confirmed by H and 13C NMR spectroscopic
analysis. See the ESI† for full details.
11 For other copper-catalysed N-heteroarylations of nitrogen nucle-
ophiles with heteroaryl halides, see: (a) D. Cheng, F. Gan, W. Qian
and W. Bao, Green Chem., 2008, 10, 171; (b) F. Li and T. S. A. Hor,
Chem. Eur. J., 2009, 15, 10585; (c) Z. Zhang, J. Mao, D. Zhu, F. Wu,
H. Chen and B. Wan, Tetrahedron, 2006, 62, 4435; (d) D. Zhu, R.
Wang, J. Mao, L. Xu, F. Wu and B. Wan, J. Mol. Catal. A: Chem.,
2006, 256, 256; (e) Z. Xi, F. Liu, Y. Zhou and W. Chen, Tetrahedron,
2008, 64, 4254; (f) P. Vera-Luque, R. Alajar´ın, J. Alvarez-Builla and
J. J. Vaquero, Org. Lett., 2006, 8, 415; (g) M. A. Khan and J. B.
Polya, J. Chem. Soc. (C), 1970, 85; (h) J. Baffoe, M. Y. Hoe and B. B.
Toure´, Org. Lett., 2010, 12, 1532; (i) F. Lang, D. Zewge, I. N. Houpis
and R. P. Volante, Tetrahedron Lett., 2001, 42, 3251; (j) X. Han,
Tetrahedron Lett., 2010, 51, 360; (k) V. S. C. Yeh and P. E. Wiedeman,
Tetrahedron Lett., 2006, 47, 6011; (l) H. Zhang, Q. Cai and D. Ma, J.
Org. Chem., 2005, 70, 5164; (m) J. B. Arterburn, M. Pannala and A.
M. Gonzalez, Tetrahedron Lett., 2001, 42, 1475; (n) J. C. Antilla, A.
Klapars and S. L. Buchwald, J. Am. Chem. Soc., 2002, 124, 11684;
(o) H.-J. Cristau, P. P. Cellier, J.-F. Spindler and M. Taillefer, Eur.
J. Org. Chem., 2004, 695; (p) A. Shafir and S. L. Buchwald, J. Am.
Chem. Soc., 2006, 128, 8742; (q) X. Han, Tetrahedron Lett., 2010, 51,
360.
12 In the MW experiments, the temperature was measured by an
internal thermocouple. The setting power of the MW instrument
was 50 W during the entire reaction time. When the temperature
reached 100 ◦C, the instrument automatically adjusted the power to
maintain this temperature.
13 For recent mechanistic studies on copper-catalysed cross-couplings,
see: (a) E. R. Strieter, B. Bhayana and S. L. Buchwald, J. Am.
Chem. Soc., 2009, 131, 78; (b) G. O. Jones, P. Liu, K. N. Houk
and S. L. Buchwald, J. Am. Chem. Soc., 2010, 132, 6205; (c) P.-
F. Larsson, C. Bolm and P.-O. Norrby, Chem. Eur. J. accepted for
publication.
Acknowledgements
We are grateful to the Fonds der Chemischen Industrie for finan-
cial support. ZJL thanks Bayer CropScience for postdoctoral
funding.
Notes and references
1 (a) T. T. Denton, X. Zhang and J. R. Cashman, J. Med. Chem., 2005,
48, 224; (b) H.-C. Zhang, C. K. Derian, D. F. McComsey, K. B. White,
H. Ye, L. R. Hecker, J. Li, M. F. Addo, D. Croll, A. J. Eckardt, C.
E. Smith, Q. Li, W.-M. Cheung, B. R. Conway, S. Emanuel, K. T.
Demarest, P. Andrade-Gorden, B. P. Damiano and B. E. Maryanoff,
J. Med. Chem., 2005, 48, 1725; (c) J. Roppe, N. D. Smith, D. Huang,
L. Tehrani, B. Wang, J. Anderson, J. Brodkin, J. Chung, X. Jiang, C.
King, B. Munoz, M. A. Varney, P. Prasit and N. D. P. Cosford, J.
Med. Chem., 2004, 47, 4645; (d) Y. Wang, Y. Li and B. Wang, Int. J.
Mol. Sci., 2007, 8, 166; (e) N. P. Buu-Hoi, R. Rips and R. Cavier, J.
Med. Chem., 1960, 2, 335; (f) A. M. Crider, R. Lamey, H. G. Floss
and J. M. Cassady, J. Med. Chem., 1980, 23, 848; (g) L. He, L. Duan,
J. Qiao, R. Wang, P. Wei, L. Wang and Y. Qiu, Adv. Funct. Mater.,
2008, 18, 2123.
2 (a) K. H. Sugiyarto and H. A. Goodwin, Aust. J. Chem., 1988, 41,
1645; (b) J. Elguero, A. Fruchier, A. de la Hoz, F. A. Jalo´n, B. R.
Manzano, A. Otero and F. Go´mez-de la Torre, Chem. Ber., 1996,
129, 589; (c) J. A. A. W. Elemans, E. J. A. Bijsterveld, A. E. Rowan
and R. J. M. Nolte, Eur. J. Org. Chem., 2007, 751.
3 (a) F. Ullmann, Ber. Dtsch. Chem. Ges., 1903, 36, 2382; (b) F.
Ullmann, Ber. Dtsch. Chem. Ges., 1904, 37, 853.
14 Sulfoximines have been found to be effective chiral ligands in several
catalytic asymmetric reactions by our group. For recent examples,
4 For reviews, see: (a) F. Monnier and M. Taillefer, Angew. Chem. Int.
Ed., 2009, 48, 6954; (b) D. Ma and Q. Cai, Acc. Chem. Res., 2008, 41,
44 | Green Chem., 2011, 13, 42–45
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
see: (a) M. Frings, I. Atodiresei, J. Runsink, G. Raabe and C. Bolm,
Chem. Eur. J., 2009, 15, 1566; (b) M. Frings and C. Bolm, Eur. J. Org.
Chem., 2009, 4085; (c) S.-M. Lu and C. Bolm, Chem. Eur. J., 2008,
14, 7513; (d) S.-M. Lu and C. Bolm, Adv. Synth. Catal., 2008, 350,
1101; (e) M. Langner and C. Bolm, Angew. Chem., Int. Ed., 2004,
43, 5984; (f) M. Langner, P. Re´my and C. Bolm, Chem. Eur. J., 2005,
11, 6254; (g) P. Re´my, M. Langner and C. Bolm, Org. Lett., 2006, 6,
1209; (h) C. Moessner and C. Bolm, Angew. Chem. Int. Ed., 2005, 44,
7564.
15 The optimised solvent- and ligand-free conditions [10 mol% of
Cu2O, 2.0 equiv. of Cs2CO3, 100 ◦C, MW (50 W), 1 h] can also
be applied in the coupling between phenyl iodide and S-methyl-S-
phenylsulfoximine to give the corresponding N-arylated product in
72% yield.
This journal is
The Royal Society of Chemistry 2011
Green Chem., 2011, 13, 42–45 | 45
©