Three Different Reactions, One Catalyst: A Cu(I) PNP Pincer Complex as Catalyst for C-C and C-N Cross-Couplings

Article abstract of DOI:10.1021/acs.orglett.7b00857

An air-stable, thermally robust, and well-defined Cu(I) PNP pincer complex based on the 2,6-diaminopyridine scaffold is described. This complex is an active catalyst for the cross-couplings of a range of aryl and heteroaryl (including benzoxazole, thiazole, pyridine, and thiophene) halides with different organomagnesium reagents, alkynes, and aryl-amines giving excellent to good isolated yields.

Full text of DOI:10.1021/acs.orglett.7b00857

Letter
pubs.acs.org/OrgLett
Three Different Reactions, One Catalyst: A Cu(I) PNP Pincer Complex
as Catalyst for C−C and C−N Cross-Couplings
Matthias Mastalir,† Ernst Pittenauer,‡ Berthold Stoger,‡ Gunter Allmaier,‡ and Karl Kirchner*,†
̈
̈
†Institute of Applied Synthetic Chemistry and ‡Institute of Chemical Technologies and Analytics, Vienna University of Technology,
Getreidemarkt 9/163-AC, A-1060 Wien, Austria
S
* Supporting Information
ABSTRACT: An air-stable, thermally robust, and well-defined
Cu(I) PNP pincer complex based on the 2,6-diaminopyridine
scaffold is described. This complex is an active catalyst for the
cross-couplings of a range of aryl and heteroaryl (including
benzoxazole, thiazole, pyridine, and thiophene) halides with
different organomagnesium reagents, alkynes, and aryl-amines
giving excellent to good isolated yields.
C−C and C−heteroatom bonds in synthetic organic chemistry.
ross-coupling reactions have become one of the most
Cimportant and prevalent methods for the construction of They comprise a wide array of synthetic targets, ranging from
manufacturing of materials and pharmaceuticals to the synthesis
of building blocks and natural products. Although palladium
cross coupling catalysts still dominate the field,1 copper was
actually the first metal used for C−C and C−N coupling
reactions known as Glaser,2 Goldberg,3 Ullmann,4 Cadiot−
Chodkiewicz,5 and Castro−Stephens6 reactions. In fact, the
Glaser reaction, a copper-promoted homocoupling of metallic
acetylides, was described as early as 1869.2 In terms of
sustainability and economic viability, copper is more abundant,
less expensive, and less toxic as compared to palladium, and the
use of copper catalysts for cross coupling reactions is thus
rapidly growing.7,8 In fact, copper catalyst are highly efficient
for the formation of C−C and C−heteroatom bonds and deal
with a wide range of halides and pseudo halides (mesylates,
tosylates, triflates, and pivalates).7,8
Scheme 1. Cross-Coupling Reactions Catalyzed by the Cu(I)
PNP Complex [Cu(PNPMe-iPr)Br]·(A)
In this letter, we report on an air-stable and well-defined
Cu(I) PNP pincer complexes based on the 2,6-diaminopyridine
scaffold, which is an efficient catalyst for the coupling of several
aromatic and aliphatic halides and triflates with different
organomagnesium reagents, alkynes, and aromatic amines
(Scheme 1). This type of PNP ligand was recently also
successfully used in combination with the nonprecious metals
Mn, Fe, and Ni as catalysts for dehydrogenations and C−C and
C−N coupling reactions.9 It has to be noted that PNP pincer
complexes have been rarely used in copper chemistry and
catalysis.10,11
Scheme 2. Synthesis of [Cu(PNPMe-iPr)Br]·(A) and
Structural View of [Cu(PNPMe-iPr)Br]·C4H8O2 (A·C4H8O2)
Showing 50% Thermal Ellipsoids (H Atoms Omitted for
a
Clarity)
The neutral Cu(I) PNP complex [Cu(PNPMe-iPr)Br]·(A)
was obtained by treatment of CuBr(Me2S) with the ligand
PNPMe-iPr in 93% isolated yield (Scheme 2). The molecular
structure of A was determined by single-crystal X-ray
a
Selected bond lengths (Å) and angles (deg): Cu1−Br1 2.4492(3),
Cu1−P1 2.2693(6), Cu1−P2 2.2635(6), Cu1−N1 2.102(2), Br1−
Cu1−N1 118.02(4), P1−Cu1−P2 141.88(2), P1−Cu1−N1 80.64(5),
P2−Cu1−N1 81.87(4).
Received: March 22, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00857
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Cu(I) Catalyzed Cross-Couplings of Aryl Halides
and Alkyl Triflates with Phenyl- and Alkynyl Magnesium
Bromides
Table 2. Efficiency of Aryl-Alkyne Cross-Couplings
a
entry
solvent
base
yield [%]
1
2
3
3
4
5
6
7
toluene
THF
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
Cs2CO3
TEA
traces
89
DMF
DME
dioxane
THF
0
81
69
62
THF
traces
traces
traces
THF
DIPA
b
8
THF
t-BuOK
a
Isolated yields after purification with silica column chromatography.
CuBr(Me2S) as catalyst.
b
Table 3. Cu(I) Catalyzed Aryl-Alkyne Cross-Couplings
a
Isolated yields after purification with silica column chromatography.
Alkyne mixed with i-PrMgBr.
b
diffraction. A structural view is depicted in Scheme 2 with
selected bond distances given in the caption.
The first reactions we investigated were Kumada−Corriu1
and Castro−Stephens type6 cross-couplings of aryl halides and
alkyl triflates with phenyl- and alkynyl magnesium bromides.
For the latter, i-PrMgCl was added to prepare the organo-
magnesium compound in situ. All reactions were performed in
THF with 1 mol % of the catalyst at 50 °C for 16 h without
further optimizations. The results of these coupling reactions
are summarized in Table 1. In general, good to excellent
isolated yields were observed for all substrates. Also heteroaryl
halides (based on benzoxazole, thiazole, pyridine, and
a
Isolated yields after purification with silica column chromatography.
Cs2CO3 was used as base at 130 °C.
b
thiophene) afforded good yields (Table 1, entries 3−7).
Moreover, we tested the reactivity of nonactivated primary
and secondary aliphatic triflates for the cross coupling with
B
DOI: 10.1021/acs.orglett.7b00857
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 4. Efficiency of Aryl-Amine Cross-Couplings
Table 5. Cu(I) PNP Catalyzed Aryl-Amine Cross-Coupling
a
entry
solvent
base
yield [%]
1
2
3
4
5
6
toluene
THF
THF
THF
THF
DME
THF
t-BuOK
t-BuOK
t-BuONa
K2CO3
20
91
93
44
Cs2CO3
t-BuOK
t-BuOK
87
78
b
7
traces
a
Isolated yields after purification with silica column chromatography.
CuBr(Me2S) as catalyst.
b
PhMgBr (Table 3, entries 8−10). These reactions proceeded in
good to excellent isolated yields (47−94%). It has to be noted
that CuBr(Me2S) itself was catalytically poorly active. Under
identical reaction conditions the coupling of 4-bromotoluene
with PhMgBr afforded 1 in only 11% isolated yield as compared
to 84% with catalyst A (Table 1, entry 1).
Next we investigated the reaction of aromatic halides with
phenyl acetylene. Coupling reactions between alkynes and sp2
systems are well-known as Sonogashira reaction with copper as
additive, while palladium-free reactions are described less
commonly in the literature.12 The reaction of iodobenzene
and phenyl acetylene was chosen to identify the optimal
reaction conditions for this process (Table 2). The best results
were achieved in THF at 110 °C for 16 h with t-BuOK (1.2.
equiv) as base and a catalyst loading of 5 mol %. CuBr(Me2S)
was catalytically inactive (Table 2, entry 8). To explore the
scope of catalyst A we evaluated the coupling of various aryl
and heteroaryl halides with phenyl acetylene. The results of the
couplings are given in Table 3. Both aryl heteroaryl halides
(based on pyridine, thiophene, and thiazole) afforded good to
excellent yields. In the case 4-iodobenzonitrile, the reaction
temperature was 130 °C, and Cs2CO3 (1.2. equiv) was used as
base in order to obtain a high isolated yield (Table 3, entry 4).
Finally, we tested the reactivity of catalyst A for the coupling
of aromatic halides with anilines (Ullman, Goldberg, and
Buchwald-Hartwig13 type reactions). The reaction of iodoben-
zene and phenyl aniline was investigated to identify the most
efficient conditions for the aryl-amine coupling as depicted in
Table 4. The best results were again obtained in THF at 110 °C
with t-BuOK (1.2. equiv) as base for 16 h and 3 mol % of
catalyst. CuBr(Me2S) again was catalytically inactive (Table 4,
entry 7). The scope of catalyst A was studied for the coupling
of various aryl and heteroaryl halides with anilines. These
results are summarized in Table 5. In all cases good to excellent
isolated yields were observed. In the case of 1-chloro-2-
nitrobenzene, Cs2CO3 (1.2. equiv) was used as base (Table 5,
entry 4). With 2-chlorobenzoxazole, the reaction time could be
reduced to 3 h (Table 5, entry 8). Unactivated chloro
compounds did not react under these conditions.
a
Isolated yields after purification with silica column chromatography.
Cs2CO3 was used as base at 130 °C. Reaction time 3 h.
b
c
isolated products are obtained. This is particularly interesting in
the case of heterocycles due their coordinating properties. This
palladium-free application of a Cu(I) catalyst constitutes an
environmentally benign processes and is an excellent alternative
for various sp, sp2, and sp3 coupling reactions revealing a broad
functional group tolerance.
In conclusion, we described the synthesis and catalytic
applications of a thermally robust and well-defined Cu(I) PNP
pincer complex based on the 2,6-diaminopyridine scaffold. We
have developed different protocols for the coupling of aryl and
heteroaryl halides with a wide range of aryl amines, alkynes, and
organomagnesium reagents. The catalyst works well with a
wide variety of substrate, and in most cases, high yields of
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b00857.
C
DOI: 10.1021/acs.orglett.7b00857
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Crystallographic data for A (CCDC entry 1522968)
Letter
(12) (a) Tsai, W.-T.; Lin, Y.-Y.; Chen, Y.-A.; Lee, C.-F. Synlett 2014,
25, 443. (b) Dewan, A.; Sarmah, M.; Bora, U.; Thakur, A. J.
Tetrahedron Lett. 2016, 57, 3760. (c) Monnier, F.; Turtaut, F.;
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B.; Beckers, J.; Rothenberg. Green Chem. 2004, 6, 215. (e) Biffis, A.;
Scattolin, E.; Ravasio, N.; Zaccheria, F. Tetrahedron Lett. 2007, 48,
8761. (f) Probst, N. P.; Deprez, B.; Willand, N. Tetrahedron Lett. 2016,
57, 1066. (g) Tambade, P. J.; Patil, Y. P.; Nandurkar, N. S.; Bhanage,
B. M. Synlett 2008, 6, 886. (h) Moegling, J.; Benischke, A. D.;
Hammann, J. M.; Veprek, N. A.; Zoller, F.; Rendenbach, B.;
Hoffmann, A.; Sievers, H.; Schuster, M.; Knochel, P.; Herres-Pawlis,
S. Eur. J. Org. Chem. 2015, 2015, 7475.
(CIF)
1
Synthetic procedures, H, 13C{1H}, and 31P{1H} NMR
spectra of A and all organic products (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: kkirch@mail.tuwien.ac.at.
ORCID
(13) (a) Hartwig, J. F. Angew. Chem., Int. Ed. 1998, 37, 2046.
(b) Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L. Acc. Chem.
Res. 1998, 31, 805. (c) Yang, B. H.; Buchwald, S. L. J. Organomet.
Chem. 1999, 576, 125.
Matthias Mastalir: 0000-0002-8969-7902
Ernst Pittenauer: 0000-0002-8409-802X
Berthold Stoger: 0000-0002-0087-474X
̈
Gunter Allmaier: 0000-0002-1438-9462
̈
Karl Kirchner: 0000-0003-0872-6159
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
M.M. and K.K. gratefully acknowledge the financial support by
the Austrian Science Fund (FWF) (Project No. P28866-N34).
The X-ray center of the Vienna University of Technology is
acknowledged for financial support and for providing access to
the single-crystal diffractometer.
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DOI: 10.1021/acs.orglett.7b00857
Org. Lett. XXXX, XXX, XXX−XXX