Octanuclear Cu(I)-dithiophosphates: An efficient catalyst system for N-arylation of azoles, amines, and amides

Article abstract of DOI:10.1002/jccs.201100592

The formation of a C-N bond via the cross-couplings of aryl iodides with azoles, aryl amine, and amides can be successfully achieved in decent yield by the utilization of both [Cu₈(H){S₂P(OiPr) ₂}₆]⁺ and [Cu₈{S₂P(OEt) ₂}₆]²⁺ as the pre-catalysts.

Full text of DOI:10.1002/jccs.201100592

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Communication
Octanuclear Cu(I)-dithiophosphates: An Efficient Catalyst System for N-Arylation of
Azoles, Amines, and Amides
Cheng-Chieh Wu, Bo-Han Lee, Ping-Kuei Liao, Ching-Shiang Fang and C. W. Liu*
Department of Chemistry, National Dong Hwa University, Hualien, Taiwan 97401, R.O.C.
(Received: Oct. 7, 2011; Accepted: Jan. 12, 2012; Published Online: Mar. 6, 2012; DOI: 10.1002/jccs.201100592)
The formation of a C-N bond via the cross-couplings of aryl iodides with azoles, aryl amine, and amides
can be successfully achieved in decent yield by the utilization of both [Cu8(H){S2P(OiPr)2}6]+ and
[Cu8{S2P(OEt)2}6]2+ as the pre-catalysts.
Keywords: Copper; S-donor ligands; N-arylation; Cross-coupling.
Catalytic C-N bond formation reactions are highly
valuable in organic synthesis because the yielded products,
aromatic amines/amides, are important classes of com-
pounds as those are ubiquitous in a multitude of bioactive
natural products,1 and pharmaceuticals.2 Though palla-
dium-catalyzed N-arylation is an effective but expensive
method with limited functional group tolerance,3 yet cen-
tury old Ullmann-type reaction has been limited due to its
harsh reaction conditions despite lower cost.4 Neverthe-
less, several efforts have been made in past decades to
overcome these limitations with the use of various copper
sources, additives, and bases to achieve the couplings of
aryl halides with amines/amides,5 which have shown a high
functional group tolerance.6 It is generally agreed that the
deprotonated amine/amide acts as a nucleophile followed
by the oxidative addition of aryl halide to copper, then the
reductive elimination to yield the coupling products in the
N-arylation reaction.7 The ligands used as additives might
facilitate the copper salts to dissolve in common laboratory
organic solvents, avoid the metal aggregation, lower the re-
action energy barrier, and thus enhance the activities.8
Normally 5-10 mol% of copper salts and 10-20 mol%
of ligands as additives are utilized in a typical catalytic
N-arylation.9 In addition well defined copper complexes
supported by N-donor ligands and exhibited a 1:1 Cu/L ra-
tio are also effective to perform the N-arylation of 2-pyr-
rolidinone.10 Thus a cluster with eight Cu(I) centers held
together by six ligand units, which is highly soluble in com-
mon organic solvents, must be cost effective in terms of the
amount of the Cu/L ratio used. Inspired by the successful
coupling reaction of aryl iodides with alcohols catalyzed
by copper clusters of the type [Cu8(Cl){S2P(OR)2}6]+,11a
accordingly the potentials of [Cu8{S2P(OEt)2}6]2+ and
[Cu8(H){S2P(OiPr)2}6]+ synthesized solely from our
group12 as the precatalyst for N-arylations were tested.
Herein we report the structure of [Cu8{S2P(OEt)2}6-
(MeCN)2](PF6)2 (A), and catalytic activities of both
[Cu8(H){S2P(OiPr)2}6](PF6) (B) and (A) in the Ullmann-
Goldberg type coupling of aryl halides with nitrogen-con-
taining heterocycles, aryl amines, and amides. To our
knowledge, this is the first report of N-arylation by utilizing
copper dithiolato clusters as the precatalyst.
Only recently we have reported the synthesis of
empty, octanuclear CuI8 cluster involving six dichalco-
phosphate ligands despite of its high tendency to incorpo-
rate an anion at the center even from solvent impurities.12,13
Now we could successfully grow single crystals of its sul-
fur analogue [Cu8{S2P(OEt)2}6(MeCN)2] (PF6)2 (A), which
was synthesized simply by mixing of [Cu(MeCN)4](PF6)
and dithiophosphate (dtp) ligand in a 4:3 ratio in THF fol-
lowed by the re-crystallization in MeCN. The avoidance of
any chlorinated impurities existed in the common labora-
tory solvent is crucial for the isolation of the empty Cu8
cube.
The di-cationic cluster of octanuclear Cu(I) species
contains a distorted Cu8 cubic core supported by six dtp lig-
ands which coordinate through S atoms in a tetraconnec-
tive-tetrametallic (m2, m2) bridging mode (Figure 1).14 The
molecule contains a centre of inversion. Each of the Cu at-
oms is coordinated by three S atoms from three dtp units.
Thus three-coordinated Cu1, Cu2, Cu4 and their symme-
try-related atoms remain in trigonal planar geometry with
averaged S-Cu-S angles of 119.43(9)°. In addition, both
Cu3 and Cu3A are further connected to a N atom from a
* Corresponding author. Fax: +886-3-8633570; E-mail: chenwei@mail.ndhu.edu.tw
† Electronic Supplementary Information (ESI) available: Tables S1, S2, and spectroscopy data (1H, 13C NMR) are available.
480
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J. Chin. Chem. Soc. 2012, 59, 480-484

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
N-Arylation Catalyzed by Copper-sulfur Clusters
solvated MeCN and hence these two 4-coordinated Cu at-
oms adopt pyramidal geometry. Cu…Cu distances are ir-
regular, 3.596(2) ~ 3.125(2) Å, which are at least 0.3 Å lon-
ger than those anion-encapsulated Cu8 cubes surrounded
by six dtp ligands.11 Thus the structural characteristic of a
copper framework contraction in the diselenophopshate
ligand system,13 which is induced by the encapsulated ha-
lide and/or chalogenide, is nicely demonstrated in the anal-
ogous S-donor ligands. Cu-S distances are in the range of
2.222(3) ~ 2.303(3) Å, which are comparable to
[Cu8(S2PPh2)6]2+,15 and Cu(3)-N distance is 2.139(9) Å.
Initially the coupling reaction of tolyl iodide and
pyrrole was examined by using K2CO3 as the base (Table
S1), but only a trace amount of product was produced.
Later the use of Cs2CO3 yielded a fair result where the reac-
tion temperature could be kept as low as 90 °C to produce
74% yield of the N-arylated product (entry 7, Table S1).
However, the optimized condition was chosen as listed in
entry 4 with 83% yield at 105 °C for 24 h. Finally the opti-
mum amount of the catalysts used was screened by using
the pyrrole and iodotoluene as the protocol listed in Table
S2 from which 0.8 mol % of the catalyst was chosen for all
the reactions.
In a typical reaction 1 mmol of iodotoluene and 0.8
mol% of catalyst were charged in a glass tube followed by
the addition of 1.5 mL of pyrrole. The reaction is then car-
ried out at elevated temperature with stirring as mentioned
in Table 1. Thus in this reaction, pyrroles acts as a solvent.
Similar reactions performed on 4-bromotoluene, the use of
catalyst (A) produced a 63% yield while catalyst (B) could
make it up to 75% yield (entry a3, a4). However the reac-
tion of pyrrole with 4-chlorotoluene could only result in
trace amount of the coupling product even at an elevated
temperature up to 120 °C (entry a5, a6). In addition, the re-
actions of both 3,5-dimethyliodobenzene and 4-methoxy-
iodobenzene with pyrrole produced the coupling products
in high yield in the presence of either catalyst (entry a7-
a10). The electron-donating substituent on the aryl iodide
is thus enhancing the catalytic activity. On the other hand,
no coupling products were afforded at all between 4-nitro-
iodobenzene (or 4-acyliodobenzene) and pyrrole even at
Fig. 1. (a) Perspective view of the cationic part in A
(ethyl groups have been omitted for clarity).
Cu1-S1 2.228(3), Cu1-S4 2.233(2), Cu1-S2
2.237(3), Cu2-S5 2.235(3), Cu2-S3 2.239(3),
Cu2-S4 2.244(2), Cu3-S6 2.220(2), Cu3-S5
2.230(2), Cu3-S2 2.240(2), Cu4-S3 2.277(2),
Cu4-S6 2.292(3), Cu4-S1 2.315(3), Cu3-N1
¼
2.139(9), Cu Cu 3.125(2) ~ 3.596(2), S-P
2.005(4) ~ 2.027(4). (b) Schematic diagram of
the cationic part in A. Only four dtp ligands are
shown in diagram for clarity.
J. Chin. Chem. Soc. 2012, 59, 480-484
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481

Communication
Wu et al.
120 °C, which could be due to the electron withdrawing ni-
tro (or acyl) group on the aryl halide. Despite the elec-
tron-withdrawing chloro substituent on the aryl iodide (en-
try a11, a12), the coupling reaction with pyrrole did
achieve in good yield presumably the resonance effects in-
crease the negative charge of the C atom connected to io-
dide, which assists the subsequent oxidative addition reac-
tion of the aryl iodide.
The coupling reaction of indole with equimolar
amount of 4-iodotoluene was carried out initially in toluene
in the presence of catalyst A (0.8 mol%) at 105 °C, which
produced only 40% yield of the coupling product, but the
same reaction could yield 94% products in DMF. Obvi-
ously the polar DMF made the aryl iodide polarizable and
easier to perform the oxidative addition reaction. The reac-
tions of indole with 4-methoxyiodobenzene proceed al-
most quantitatively (entry a15, a16). On the other hand,
catalytic reactions of 4-nitroiodobenzene (or 4-acyliodo-
benzene) with indole do not yield any coupling products at
all.
tentially hinder the oxidative addition reaction of iodo-
toluene, either diethyl- or cyclohexylamine is definitely a
better nucleophile than aniline as evidenced by their Kb
values.17 These reactions suggest that the nucleophilicity of
amines cannot be too strong in the reaction media. Other-
wise the cleavage of the Cu-N bond will not be possible to
afford the reductive-elimination product.
The change of amine from pyrrole to pyrazole having
an extra N atom showed a better reactivity while coupled
with 4-iodotoluene (entry a19, a20). Surprisingly the reac-
tion of imidazole with iodotoluene did not produce any
coupling products after the addition of either catalyst. It
should be noted that color changes from brown to blue-
green in the reaction media were observed. In order to ex-
plore the probable reaction intermediates which failed to
yield any coupling products, the reation of forty equiva-
lents of imidazole with A was performed under a normal
catalytic reaction condition. Surprisingly a Cu-imidazole
complex where five N atoms of imidazoles coordinated to a
copper atom in a square pyramidal fashion was isolated and
characterized structurally.16 Thus the unsuccessful reaction
can be foreseen by the formation of five Cu-N bonds, which
block the potential coordination sites around the copper
center, hence the impedance of catalytic activities, for the
follow-up oxidative addition of aryl halides to produce the
coupling products. On the other hand, the coupling of 4-
iodotoluene with aniline, a weaker nucleophile than azole,
in the presence of A in DMF took place with 61% yield
even at 140 °C (entry b1, Table 2), the catalyst B showed a
better catalytic activity on this reaction (86% yield, 120 °C)
(entry b2). However, no coupling reactions between di-
phenyl-, cyclohexyl-, and diethylamine with 4-iodotoluene
were observed. Whereas the bulky phenyl groups of the
diphenylamine after coordinated to copper center could po-
Both clusters were also tested for their ability to cata-
lyze the coupling of aryl halides with amides and also
found positive results. For example, A facilitates the reac-
tion of 4-iodotoluene with benzamide in 76% yield at 140
°C (86% yield at 160 °C) while B shows a far better activity
to 89% yield just at 120 °C (entry c1-c4, Table 3). Unfortu-
nately the same product could not be synthesized using 4-
bromotoluene. A similar activity trend between A and B is
observed for the coupling of acetamide with 4-iodotoluene
(entry c10-c13). The presence of electron-donating group
on aryl halide displays a better reactivity while coupling
with amide. Thus ~80% yield is achieved in the reaction of
benzamide with both 3,5-dimethyliodobenzene and 4-
methoxyiodobenzene in the presence of A at 140 °C (entry
c5, c7) and 90% yield at 120 °C by using B as the catalyst
(entry c6, c8). A similar reactivity trend is also identified in
the reaction of acetamide and 4-methoxyiodobenzene (en-
try c14, c15).
The di-cationic cluster A, which is more electroposi-
tive and thus electrophilic, does not display better catalytic
activities toward N-arylations than those of B, a mono-
cationic cluster. Thus the in-situ generated chloride-cen-
tered Cu8 clusters, [Cu8(Cl){S2P(OEt)2}6]+, from A could
be the factor to reduce its electrophilicity. Indeed almost
the same amount of coupling products from the reaction of
482
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JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
N-Arylation Catalyzed by Copper-sulfur Clusters
dithiophosphates (A, B) toward N-arylations. The catalysts
can work at mild conditions to couple azoles, aryl amine,
and amides with aryl iodide. They have shown better per-
formance in the case of azoles, which can also be coupled
to aryl bromide. Coupling of amide requires slightly higher
temperature, however. When the aryl iodide contains an
electron-releasing group as the substituent, the catalysts
work with high efficiency to produce ~90% yield of N-
arylated products. In addition, the strength of nucleophil-
icity to which the amine exhibits is critical to the formation
of a N-C bond catalyzed by either clusters A or B. Prelimi-
nary results indicate that B is also an efficient catalyst for
the Sonogashira C-C coupling reaction.
ACKNOWLEDGEMENTS
This study was supported by the Grants (100-2113-
M-259-003-MY3) from the National Science Council of
Taiwan.
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J. Chin. Chem. Soc. 2012, 59, 480-484
© 2012 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.jccs.wiley-vch.de
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J. Chin. Chem. Soc. 2012, 59, 480-484