Copper- and palladium-containing perovskites: Catalysts for the Ullmann and Sonogashira reactions

Article abstract of DOI:10.1055/s-2005-865233

The utility of perovskite-based materials in organic synthesis is explored through examination of a series of copper- and palladium-containing perovskites in Ullmann and Sonogashira type reactions. La_0.9Ce _0.1Co_0.6Cu_0.4O₃ is identified as an effective catalyst for the synthesis of a range of biaryl ether and thioether functionalities, whilst a Cu- and Pd-containing perovskite is effective in the Sonogashira reaction. These results suggest that perovskites may be useful leads in the search for new catalysts and reagents for organic synthesis.

Full text of DOI:10.1055/s-2005-865233

LETTER
1291
Copper- and Palladium-Containing Perovskites: Catalysts for the Ullmann
and Sonogashira Reactions
Catalysts for
t
o
U
llmann a
p
nd Sonogash
h
ira Reaction
i
s
e Lohmann,a Stephen P. Andrews,a Brenda J. Burke,a Martin D. Smith,a J. Paul Attfield,b Hirohisa Tanaka,c
Kimiyoshi Kaneko,d Steven V. Ley*a
a
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK
Fax +44(1223)336442; E-mail: svl1000@cam.ac.uk
b
School of Chemistry, CSEC, The University of Edinburgh, Erskine Williamson Building, The King’s Buildings, Mayfield Road,
Edinburgh, EH9 3JZ, UK
c
Materials R&D Division, Technical Centre, Daihatsu Motor Co. Ltd. Ryuo, Gamo-gun, Shiga 520-2593, Japan
d
Hokko Chemical Industry Co., Ltd., Fine Chemicals Research Laboratories, 2165, Toda, Atsugi-shi, Kanagawa-ken 243-0023, Japan
Received 3 February 2005
and elements such as S, F, and Cl have been incorporated
Abstract: The utility of perovskite-based materials in organic syn-
in place of oxygen, adding further points of diversity. Us-
ing these principles, a large number of perovskites is at-
tainable and it may be possible to favorably alter their
thesis is explored through examination of a series of copper- and
palladium-containing perovskites in Ullmann and Sonogashira type
reactions. La0.9Ce0.1Co0.6Cu0.4O3 is identified as an effective catalyst
for the synthesis of a range of biaryl ether and thioether functional- properties by changing the sizes and relative amounts of
ities, whilst a Cu- and Pd-containing perovskite is effective in the
their constituent elements. In this manner, large numbers
Sonogashira reaction. These results suggest that perovskites may be
of catalysts may be generated and screened for their appli-
useful leads in the search for new catalysts and reagents for organic
cation to organic transformations, with the aim of improv-
synthesis.
ing and extending existing methodologies and identifying
and exploiting new processes.
Key words: perovskite, catalyst, Ullmann, cross-coupling, Sono-
gashira
Ullmann-Type Condensations: Biaryl Ethers
Since the discovery of calcium titanate ‘perovskite’, a
large number of natural and synthetic materials with the
same crystal structure (now generally known as perovs-
kites) have been discovered. Many perovskites display
useful catalytic and magnetic properties1–3 but until re-
cently, there were no reports of the use of perovskites in
organic synthesis. It has been demonstrated that the palla-
dium-containing perovskite LaFe0.57Co0.38Pd0.05O3, origi-
nally reported to be a self-regenerative catalyst for
application to automotive emissions control,4 was found
to be an effective material for mediating the Suzuki cross-
coupling of an aryl halide with an organoboron reagent.5
LaFe0.57Co0.38Pd0.05O3 was found to be active with low
palladium loadings (typically 0.05 mol%) and could be re-
used five times without apparent loss of activity. More re-
cently, a series of seven Pd-containing perovskites was
assessed for its utility in the Suzuki reaction.6 However,
the application of perovskites to organic synthesis should
not be limited to this reaction, nor should it be limited to
the chemistry of palladium. In order to illustrate this tenet,
copper- and palladium-containing perovskites have been
examined for their utility in organic chemistry.
Table 1 Screening of Copper-Containing Perovskites as Catalysts
for the Ullmann Reaction
Cl
MeO
I
2.5 mol% perovskite
O
1.4 equiv Cs2CO3,
+
5 mol%, EtOAc
PhMe, 110 °C,
Cl
48 h
HO
OMe
Perovskite
Isolated yield (%)
La0.9Ce0.1Co0.6Cu0.4O3
YBa2Cu3O7
82
73
65
0
LaFe0.57Cu0.38Pd0.05O3
LaFeO3
Biaryl ether, thioether and amine moieties are important
features of many natural and pharmaceutical products.
Classical Ullmann-type condensations8 may be used to
prepare these compounds but generally employ high tem-
peratures and stoichiometric amounts of metals.
The perovskite structure tolerates a wide range of metals,
and modified perovskites are obtainable either by ex-
changing metals in existing cubic perovskites with others
of similar size, or by creating layered or distorted perovs-
kites by substituting with different sized metals.7 The lev-
el of oxygenation in these structures may also be altered
Despite these factors, the Ullmann reaction is tolerant of
many spectator functional groups in both components,
and can be performed by coupling a variety of substrates
such as arylboronic acids and aryl iodonium salts with
phenols, thiophenols or anilines. Recently, great advances
have been made in the development of milder methods
that are catalytic in copper.9,10 In a test case, three copper-
SYNLETT 2005, No. 8, pp 1291–1295
1
7.
0
5.
2
0
0
5
Advanced online publication: 21.04.2005
DOI: 10.1055/s-2005-865233; Art ID: D03505ST
© Georg Thieme Verlag Stuttgart · New York

1292
S. Lohmann et al.
LETTER
Table 2 1H NMR Conversions for the Solvent and Base Screening
of La0.9Ce0.1Co0.6Cu0.4O3-Catalyzed Ullmann Reactions
containing
perovskites
(La0.9Ce0.1Co0.6Cu0.4O3,
YBa2Cu3O7 and LaFe0.57Cu0.38Pd0.05O3) were screened for
catalytic activity in an Ullmann reaction of 4-chloroiodo-
benzene with 2-methoxynapth-7-ol and compared to a
control reaction with a copper-deficient perovskite,
LaFeO3, using conditions originally reported to be effec-
tive when used with (CuOTf)2·PhH as the source of
copper11 (Table 1).
Cl
MeO
2.5 mol%
La0.9Ce0.1Co0.6Cu0.4O3
I
O
1.4 equiv base,
+
5 mol% EtOAc
solvent, 110 °C,
Cl
48 h
HO
After 48 hours, La0.9Ce0.1Co0.6Cu0.4O3 (LaCu*) was
shown to give the highest isolated yield of those catalysts
tested, with the layered perovskite superconductor
YBa2Cu3O7 and LaFe0.57Cu0.38Pd0.05O3 showing potential
in this unoptimized screen. In the copper-deficient control
reaction, no coupling product was observed.
OMe
Base
PhMe
DMSO
MeOH–THF
(3:1, v/v)
Cs2CO3
K2CO3
K3PO4
KF
86%
Nil
Nil
Nil
Nil
Nil
Nil
26%
Nil
Nil
51%
40%
59%
Nil
Using the lead catalyst, LaCu*, solvents and bases were
screened in order to obtain the optimal set of reaction
conditions (Table 2).12 Of the combinations investigated,
it was found that those initially tested (refluxing toluene
and Cs2CO3) gave the highest isolated yields. The ethyl
acetate additive is believed to aid solubility of catalytic
NaOMe
Nil
Table 3 Substrate Scope for the La0.9Ce0.1Co0.6Cu0.4O3-Catalyzed Ullmann Reactions with Phenols
R1
R2
2.5 mol% La0.9Fe0.1Co0.6Cu0.4O3
R1
O
R2
OH
+
X
1.4 equiv Cs2CO3, 5 mol% EtOAc
PhMe, 110 °C, 48 h
Aryl halide
Phenol
Isolated yield (%) Aryl halide
88
Phenol
Isolated yield (%)
72
Br
Br
Cl
HO
HO
HO
HO
F3C
I
90
86a,b
Cl
F3C
O
78
74
I
Br
N
HO
HO
HO
MeO
71c
78b
Br
Cl
Cl
HO
HO
MeO
I
82
0
0
OMe
Cl
N
I
I
OH
46
81
Cl
H
N
F3C
HO
HO
HO
O2N
S
Br
89
71
Br
I
HO
HO
O2N
F
Br
F
a 25% Isolated yield in absence of EtOAc.
b Control reactions in absence of catalyst gave no conversion.
c Double catalyst loading (5 mol% perovskite) showed identical conversion.
Synlett 2005, No. 8, 1291–1295 © Thieme Stuttgart · New York

LETTER
Catalysts for the Ullmann and Sonogashira Reactions
1293
copper species and significant decreases in isolated yields to their ability to coordinate the copper catalyst.14,15 In the
were observed in its absence (Table 3).13
coupling of D-phenylalanine with 4-chloroiodobenzene,
an isolated yield of 4% was achieved when the reaction
was performed with K2CO3 in DMF and catalyzed by
La0.9Ce0.1Co0.6Cu0.4O3.
Using these conditions with perovskite LaCu* in catalytic
quantities (1 mol% Cu), a range of phenols have success-
fully been coupled with aryl halides in good to excellent
yields (Table 3). The reaction has been performed with
electron-poor aryl chlorides and a range of aryl bromides
and iodides (electron-rich or electron-poor) and shows
tolerance towards N heteroatoms as exemplified by the
coupling of 3-bromopyridine with 3,4-dimethylphenol.
Control reactions in which no transition metals were add-
ed were also performed and confirmed that a copper-con-
taining perovskite is required for the transformation to
occur (Table 3).
I
5 mol% LaCu*,
110 °C, 48 h
Cl
+
Cl
a) DMF, K2CO3
or b) PhMe, Cs2CO3
HO2C
N
H
HO2C
NH2
Figure 1 Ullmann condensation with D-phenylalanine
Ullmann Reactions: Synthesis of Thioethers
Encouragingly, the isolated yield was increased to 22% by
changing the solvent to toluene and the base to Cs2CO3,
highlighting the potential to increase the efficacy of the
procedure and extend its applications.
As with the phenolic couplings, it was found that the reac-
tion with thiophenols could be performed with electron-
poor aryl chlorides as well as electron-rich or electron-
poor aryl bromides and iodides and that the reaction is
also tolerant of heteroatoms (S and N) within the coupling
partners (Table 4).
Perovskite-Catalyzed Sonogashira Couplings
Preliminary studies of Ullmann couplings with aryl ha-
lides and amines have shown that La0.9Ce0.1Co0.6Cu0.4O3
can catalyze the reaction, though further optimization of
the process is still required. It has been demonstrated that
amino acids are good substrates for Ullmann reactions due
The utility of LaCu* in the Ullmann reaction encouraged
us to investigate other processes that may be mediated by
copper, such as the Sonogashira reaction.16–18 Recent ad-
vances have disclosed mild conditions for Sonogashira-
type couplings19 that are catalytic in both copper,20,21
Table 4 Substrate Scope for the La0.9Ce0.1Co0.6Cu0.4O3-Catalyzed Ullmann Reactions with Thiophenols
R1
R2
2.5 mol% LaCu*,
S
R2
R1
SH
Cl
+
X
2 equiv NaOtBu, 10 mol% neocuproine
PhMe, 110 °C, 48 h
Aryl halide
Thiophenol
Isolated yield (%) Aryl halide
Thiophenol
Isolated yield (%)
89
91a
SH
Cl
SH
SH
SH
SH
SH
I
I
90
94
78
I
SH
SH
I
F
MeO
64
N
S
I
Br
Cl
S
100b
99
46
I
SH
SH
F
O2N
O2N
100
Br
Cl
O
a Control reaction in absence of catalyst gave no conversion.
b No conversion in absence of neocuproine.
Synlett 2005, No. 8, 1291–1295 © Thieme Stuttgart · New York

1294
S. Lohmann et al.
LETTER
Table 5 Catalyst Screening: Sonogashira Reactions
pair of reacting partners. Following this principle, several
aryl halide–alkyne pairs were reacted with 2.5 mol% of
one of the three palladium-containing perovskites (0.125
mol% Pd) and 4 equivalents Et3N in a solvent mixture of
5% H2O in dimethylformamide (DMF) or dimethylacet-
amide (DMA) at 120 °C. The highest isolated yields of the
Sonogashira products along with the perovskite employed
are shown (Table 6). Although there are literature reports
of Sonogashira type couplings in the absence of any
transition metals;26–28 under the conditions described, no
coupling was observed in the absence of the catalyst. 4-
Acetyl phenyl triflate and 4-ethynyl anisole were not con-
verted to the corresponding Sonogashira product under
any of the conditions examined.
R2
I
2.5 mol%
perovskite
R1
heating
+
R2
or
MW heating
R1
Reactants
R1
Isolated yield (%)
R2
LaPdCu*
75a
NdPdCu*
LaPd*
28a
Cl
H
57a
92b
82b
COMe
COMe
NH2
OMe
84b
82b
86b
96b
a 1 Equiv aryl iodide, 2.5 mol% perovskite, 2.2 equiv alkyne, 2 equiv
Na2CO3, 1 equiv TBAB, MW 175 °C, 20 min.
Conclusion
b 1 Equiv aryl iodide, 2.5 mol% perovskite, 1.1 equiv alkyne, 4 equiv
Et3N, 5% H2O in DMF, 120 °C, 16 h.
The findings of this preliminary study to probe the utility
of perovskites in synthesis serve to illustrate that perovs-
kites are genuinely useful catalysts for organic chemistry.
A range of perovskites is generated on an industrial scale
and it has now been demonstrated that screening of just a
few of these compounds has allowed rapid optimization of
well-established organic transformations. It is hoped that
in the future, ever increasing numbers of perovskites will
be available for evaluation as new catalysts and reagents
for organic synthesis with the aim of defining new pro-
cesses and new applications.
palladium,22,23 and other metals.24,25 The ability of three
palladium-containing perovskites (LaFe0.57Cu0.38Pd0.05O3
[LaPdCu*],
LaFe0.57Co0.38Pd0.05O3
[LaPd*]
and
Nd2.04Cu0.95Pd0.05O4 [NdPdCu*]) to promote Sonogashira
couplings was examined under microwave and conven-
tional heating conditions (Table 5).
The range of isolated yields indicated that the desired
Sonogashira product could be achieved in optimal
amounts by modification of the perovskite catalyst rather
than applying a standard set of reaction conditions to each
General Procedure for La0.9Ce0.1Co0.6Cu0.4O3-Catalyzed
Ullmann Couplings of Phenols
Table 6 Substrate Scope of Perovskite-Promoted Sonogashira Cou-
plings
La0.9Ce0.1Co0.6Cu0.4O3 (4.4 mg, 5 mol%) was added to a mixture of
aryl halide (0.71 mmol), phenol (1.00 mmol), Cs2CO3 (325 mg, 1.00
mmol) and 1 drop of EtOAc in toluene (1 mL) in a microwave vial.
The tube was flushed with argon, sealed and heated in an oil bath at
110 °C for 48 h. The reaction mixture was filtered through a Chem
Elut CE1005 drying column, eluting with Et2O (3 × 10 mL). Com-
bined filtrates were concentrated in vacuo and purified by column
chromatography to afford the desired product.
X
R1
R2
2.5 mol%
perovskite
+
4 equiv Et3N
5% H2O/DMA or DMF
120 °C
R2
R1
General Procedure for LaCu*-Catalyzed Ullmann Couplings of
Thiophenols
R1
X
R2
Perovskite
LaPdCu*
LaPdCu*
LaPd*
Yield (%)
71a,b
96a,b
96b
Procedure A: La0.9Ce0.1Co0.6Cu0.4O3 (4.4 mg, 5 mol%) was added
to a mixture of NaOt-Bu (136 mg, 1.42 mmol), neocuproine (14 mg,
0.07 mmol), aryl halide (0.71 mmol), thiophenol (1.00 mmol) and
toluene (1 mL) in a microwave vial. The reaction tube was flushed
with argon, sealed and heated in an oil bath at 110 °C for 48 h. The
reaction mixture was filtered through a Chem Elut CE1005 drying
column, eluting with Et2O (3 × 10 mL). Combined filtrates were
concentrated in vacuo and purified by column chromatography to
afford the coupled product.
p-Cl
I
OMe
OMe
OMe
OMe
OMe
NH2
OMe
OMe
p-NO2
I
p-COMe
p-OMe
p-NO2
I
I
LaPdCu*
LaPdCu*
NdCuPd*
LaPdCu*
47c
Br
71c
Procedure B: La0.9Ce0.1Co0.6Cu0.4O3 (4.4 mg, 5 mol%) was added
to a mixture of aryl halide (0.71 mmol), thiophenol (1.00 mmol),
Cs2CO3 (325 mg, 1.00 mmol) and 1 drop of EtOAc in toluene (1
mL) in a microwave vial. The reaction tube was flushed with argon,
sealed and heated in a oil bath at 110 °C for 48 h. The reaction
mixture was filtered through a Chem Elut CE1005 drying column,
eluting with Et2O (3 × 10 mL). Combined filtrates were concen-
trated in vacuo and purified by column chromatography to afford
the coupled product.
p-COMe
o-CO2H
p-COMe
I
92b
I
52b
OTf
LaPdCu*or NdCuPd* 0b
a Control reaction in absence of catalyst gave no conversion.
b Reaction was performed in DMF.
c Reaction was performed in DMA.
Synlett 2005, No. 8, 1291–1295 © Thieme Stuttgart · New York

LETTER
Catalysts for the Ullmann and Sonogashira Reactions
1295
General Procedure for Perovskite-Catalyzed Sonogashira Re-
action
(8) Ullmann, F. Chem. Ber. 1903, 2389.
(9) Ley, S. V.; Thomas, A. W. Angew. Chem. Int. Ed. 2003, 42,
5400.
(10) Nelson, T. D.; Crouch, R. D. Org. React. 2004, 63, 265.
(11) Marcoux, J. F.; Doye, S.; Buchwald, S. L. J. Am. Chem. Soc.
1997, 119, 10539.
(12) Kwong, F. Y.; Buchwald, S. L. Org. Lett. 2002, 4, 3517.
(13) Capdevielle, P.; Maumy, M. Tetrahedron Lett. 1993, 34,
1007.
The appropriate perovskite (0.008 mmol, 2.5 mol%) was added to a
mixture of aryl halide (0.315 mmol, 1.0 equiv), alkyne (0.346
mmol, 1.1 equiv), Et3N (1.26 mmol, 4.0 equiv) and 5% H2O in DMF
or DMA (1.1 mL). The reaction tube was flushed with argon, fitted
with a reflux condenser and heated at 120 °C for 6–24 h. The reac-
tion mixture was diluted with Et2O (2 mL) and poured into 10% aq
LiCl (15 mL). The aqueous phase was separated and extracted with
Et2O (3 × 10 mL). Combined organic phases were concentrated in
vacuo and purified by silica gel chromatography to afford the cou-
pled product.
(14) Ma, D. W.; Xia, C. F. Org. Lett. 2001, 3, 2583.
(15) Ma, D. W.; Zhang, Y. D.; Yao, J. C.; Wu, S. H.; Tao, F. G.
J. Am. Chem. Soc. 1998, 120, 12459.
(16) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.
1975, 4467.
(17) Cassar, L. J. Organomet. Chem. 1975, 93, 253.
(18) Dieck, H. A.; Heck, F. R. J. Organomet. Chem. 1975, 93,
259.
(19) Soheili, A.; Albaneze-Walker, J.; Murry, J. A.; Dormer, P.
G.; Hughes, D. L. Org. Lett. 2003, 5, 4191.
(20) Chouzier, S.; Gruber, M.; Djakovitch, L. J. Mol. Catal. A:
Chem. 2004, 212, 43.
(21) Saphier, M.; Masarwa, A.; Cohen, H.; Meyerstein, D. Eur. J.
Inorg. Chem. 2002, 1226.
Acknowledgment
The authors would like to thank Daihatsu Motor Co. Ltd. and Hok-
ko Chemical Industry Co. Ltd. for their kind gift of perovskites, the
Novartis Research Fellowship (to SVL), The Royal Society for a
URF (to MDS), GlaxoSmithKline and Insight Faraday for a CASE
award (to SPA) and the French Foreign Office for a Lavoisier fel-
lowship (to SL).
(22) Park, S. B.; Alper, H. Chem. Commun. 2004, 1306.
(23) Novak, Z.; Szabo, A.; Repasi, J.; Kotschy, A. J. Org. Chem.
2003, 68, 3327.
(24) Wang, L.; Li, P. H.; Zhang, Y. C. Chem. Commun. 2004,
514.
(25) Son, S. U.; Jang, Y.; Park, J.; Na, H. B.; Park, H. M.; Yun,
H. J.; Lee, J.; Hyeon, T. J. Am. Chem. Soc. 2004, 126, 5026.
(26) Leadbeater, N. E.; Marco, M.; Tominack, B. J. Org. Lett.
2003, 5, 3919.
(27) Thathagar, M. B.; Beckers, J.; Rothenberg, G. Green Chem.
2004, 6, 215.
References
(1) Attfield, J. P. Int. J. Inorg. Mater. 2001, 3, 1147.
(2) Cava, R. J. J. Am. Ceram. Soc. 2000, 83, 5.
(3) Ramirez, A. P. J. Phys.: Condens. Mat. 1997, 9, 8171.
(4) Nishihata, Y.; Mizuki, J.; Akao, T.; Tanaka, H.; Uenishi, M.;
Kimura, M.; Okamoto, T.; Hamada, N. Nature 2002, 418,
164.
(5) Smith, M. D.; Stepan, A. F.; Ramarao, C.; Brennan, P. E.;
Ley, S. V. Chem. Commun. 2003, 2652.
(6) Andrews, S. P.; Stepan, A. F.; Ley, S. V.; Tanaka, H.; Smith,
M. D. Adv. Synth. Catal. 2005, in press.
(28) Appukkuttan, P.; Dehaen, W.; Van der Eycken, E. Eur. J.
Org. Chem. 2003, 4713.
(7) Raveau, B.; Rao, C. N. R. Transition Metal Oxides:
Structure, Properties and Synthesis of Ceramic Oxides; John
Wiley & Sons: Oxford, 1998.
Synlett 2005, No. 8, 1291–1295 © Thieme Stuttgart · New York