LETTER 1291

Copper- and Palladium-Containing Perovskites: Catalysts for the Ullmann

and Sonogashira Reactions
at lyst fortheUlman andSonogashiraReactions Lohmann,a Stephen P. Andrews,a Brenda J. Burke,a Martin D. Smith,a J. Paul Attfield,b Hirohisa Tanaka,c
CSophie
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-
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-
ities, 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.
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
properties by changing the sizes and relative amounts of
their constituent elements. In this manner, large numbers
of catalysts may be generated and screened for their appli-
cation to organic transformations, with the aim of improv-
ing and extending existing methodologies and identifying

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Key words: perovskite, catalyst, Ullmann, cross-coupling, Sono- and exploiting new processes.
gashira

Ullmann-Type Condensations: Biaryl Ethers

Since the discovery of calcium titanate ‘perovskite’, a
large number of natural and synthetic materials with the Table 1 Screening of Copper-Containing Perovskites as Catalysts
same crystal structure (now generally known as perovs- for the Ullmann Reaction
kites) have been discovered. Many perovskites display Cl
useful catalytic and magnetic properties1–3 but until re- I
MeO
cently, there were no reports of the use of perovskites in 2.5 mol% perovskite
O
1.4 equiv Cs2CO3,
organic synthesis. It has been demonstrated that the palla-
+
dium-containing perovskite LaFe0.57Co0.38Pd0.05O3, origi- 5 mol%, EtOAc
nally reported to be a self-regenerative catalyst for PhMe, 110 °C,
Cl 48 h
application to automotive emissions control,4 was found HO
OMe
to be an effective material for mediating the Suzuki cross-
coupling of an aryl halide with an organoboron reagent.5 Perovskite Isolated yield (%)
LaFe0.57Co0.38Pd0.05O3 was found to be active with low
palladium loadings (typically 0.05 mol%) and could be re- La0.9Ce0.1Co0.6Cu0.4O3 82
used five times without apparent loss of activity. More re- YBa2Cu3O7 73
cently, a series of seven Pd-containing perovskites was
assessed for its utility in the Suzuki reaction.6 However, LaFe0.57Cu0.38Pd0.05O3 65
the application of perovskites to organic synthesis should LaFeO3 0
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 Biaryl ether, thioether and amine moieties are important
examined for their utility in organic chemistry. features of many natural and pharmaceutical products.
Classical Ullmann-type condensations8 may be used to
The perovskite structure tolerates a wide range of metals,
prepare these compounds but generally employ high tem-
and modified perovskites are obtainable either by ex-
peratures and stoichiometric amounts of metals.
changing metals in existing cubic perovskites with others
of similar size, or by creating layered or distorted perovs- Despite these factors, the Ullmann reaction is tolerant of
kites by substituting with different sized metals.7 The lev- many spectator functional groups in both components,
el of oxygenation in these structures may also be altered and can be performed by coupling a variety of substrates
such as arylboronic acids and aryl iodonium salts with
SYNLETT 2005, No. 8, pp 1291–129517.05205 phenols, thiophenols or anilines. Recently, great advances
Advanced online publication: 21.04.2005 have been made in the development of milder methods
DOI: 10.1055/s-2005-865233; Art ID: D03505ST that are catalytic in copper.9,10 In a test case, three copper-
© Georg Thieme Verlag Stuttgart · New York
1292 S. Lohmann et al. LETTER

Table 2 1H NMR Conversions for the Solvent and Base Screening containing perovskites (La0.9Ce0.1Co0.6Cu0.4O3,
of La0.9Ce0.1Co0.6Cu0.4O3-Catalyzed Ullmann Reactions YBa2Cu3O7 and LaFe0.57Cu0.38Pd0.05O3) were screened for
Cl catalytic activity in an Ullmann reaction of 4-chloroiodo-
MeO benzene with 2-methoxynapth-7-ol and compared to a
I 2.5 mol%
La0.9Ce0.1Co0.6Cu0.4O3 O control reaction with a copper-deficient perovskite,
1.4 equiv base, LaFeO3, using conditions originally reported to be effec-
+
5 mol% EtOAc tive when used with (CuOTf)2·PhH as the source of
Cl
solvent, 110 °C, copper11 (Table 1).
HO 48 h
OMe
After 48 hours, La0.9Ce0.1Co0.6Cu0.4O3 (LaCu*) was
shown to give the highest isolated yield of those catalysts
Base PhMe DMSO MeOH–THF tested, with the layered perovskite superconductor
(3:1, v/v) YBa2Cu3O7 and LaFe0.57Cu0.38Pd0.05O3 showing potential
Cs2CO3 86% Nil 51% in this unoptimized screen. In the copper-deficient control
reaction, no coupling product was observed.
K2CO3 Nil Nil 40%
Using the lead catalyst, LaCu*, solvents and bases were
K3PO4 Nil 26% 59% screened in order to obtain the optimal set of reaction
conditions (Table 2).12 Of the combinations investigated,
KF Nil Nil Nil
it was found that those initially tested (refluxing toluene
NaOMe Nil Nil Nil and Cs2CO3) gave the highest isolated yields. The ethyl
acetate additive is believed to aid solubility of catalytic
Table 3 Substrate Scope for the La0.9Ce0.1Co0.6Cu0.4O3-Catalyzed Ullmann Reactions with Phenols

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2.5 mol% La0.9Fe0.1Co0.6Cu0.4O3 R1 R2
R2 R1 O
OH + X 1.4 equiv Cs2CO3, 5 mol% EtOAc
PhMe, 110 °C, 48 h

Aryl halide Phenol Isolated yield (%) Aryl halide Phenol Isolated yield (%)

Cl 88 Br 72

I HO F3C HO

Cl 90 Br 86a,b

F3C HO HO

O
I 78 Br 74
N

MeO HO HO

Cl 71c Br 78b

I HO MeO HO

Cl HO OMe 82 Cl 0

I I N
OH
H 0 Cl 46
N
F3C
S HO O2N HO
Br
Br 89 I 81

O2N HO F HO

Br 71

F HO

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,
Using these conditions with perovskite LaCu* in catalytic an isolated yield of 4% was achieved when the reaction
quantities (1 mol% Cu), a range of phenols have success- was performed with K2CO3 in DMF and catalyzed by
fully been coupled with aryl halides in good to excellent La0.9Ce0.1Co0.6Cu0.4O3.
yields (Table 3). The reaction has been performed with
I
electron-poor aryl chlorides and a range of aryl bromides
and iodides (electron-rich or electron-poor) and shows
Cl 5 mol% LaCu*,
tolerance towards N heteroatoms as exemplified by the 110 °C, 48 h
+ Cl
coupling of 3-bromopyridine with 3,4-dimethylphenol.
Control reactions in which no transition metals were add- a) DMF, K2CO3
or b) PhMe, Cs2CO3 HO2C N
ed were also performed and confirmed that a copper-con- H
taining perovskite is required for the transformation to
occur (Table 3). HO2C NH2

Figure 1 Ullmann condensation with D-phenylalanine

Ullmann Reactions: Synthesis of Thioethers
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
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.

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also tolerant of heteroatoms (S and N) within the coupling
partners (Table 4).
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
Perovskite-Catalyzed Sonogashira Couplings
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
2.5 mol% LaCu*, R1 S R2
R1 R2
SH + X 2 equiv NaOtBu, 10 mol% neocuproine
PhMe, 110 °C, 48 h

Aryl halide Thiophenol Isolated yield (%) Aryl halide Thiophenol Isolated yield (%)

Cl SH 91a Cl 89
SH
I I

I SH 90 I 94
SH

MeO F

SH 64 N 78
I
Br SH
S S

I 100b Cl 46
SH SH
F O2N

Br 99 Cl 100
SH SH

O2N
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
I R2
aryl halide–alkyne pairs were reacted with 2.5 mol% of
2.5 mol%
perovskite one of the three palladium-containing perovskites (0.125
R1 mol% Pd) and 4 equivalents Et3N in a solvent mixture of
+ heating
R2 or 5% H2O in dimethylformamide (DMF) or dimethylacet-
MW heating amide (DMA) at 120 °C. The highest isolated yields of the
R1 Sonogashira products along with the perovskite employed
are shown (Table 6). Although there are literature reports
Reactants Isolated yield (%) of Sonogashira type couplings in the absence of any
1 2
transition metals;26–28 under the conditions described, no
R R LaPdCu* NdPdCu* LaPd* coupling was observed in the absence of the catalyst. 4-
Cl H 75 a
57 a
28a Acetyl phenyl triflate and 4-ethynyl anisole were not con-
verted to the corresponding Sonogashira product under
COMe NH2 84b 92b 82b any of the conditions examined.
COMe OMe 86b 82b 96b
a
1 Equiv aryl iodide, 2.5 mol% perovskite, 2.2 equiv alkyne, 2 equiv Conclusion
Na2CO3, 1 equiv TBAB, MW 175 °C, 20 min.
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-
palladium,22,23 and other metals.24,25 The ability of three kites are genuinely useful catalysts for organic chemistry.
palladium-containing perovskites (LaFe0.57Cu0.38Pd0.05O3 A range of perovskites is generated on an industrial scale

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[LaPdCu*], LaFe0.57Co0.38Pd0.05O3 [LaPd*] and and it has now been demonstrated that screening of just a
Nd2.04Cu0.95Pd0.05O4 [NdPdCu*]) to promote Sonogashira few of these compounds has allowed rapid optimization of
couplings was examined under microwave and conven- well-established organic transformations. It is hoped that
tional heating conditions (Table 5). in the future, ever increasing numbers of perovskites will
be available for evaluation as new catalysts and reagents
The range of isolated yields indicated that the desired for organic synthesis with the aim of defining new pro-
Sonogashira product could be achieved in optimal cesses and new applications.
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-
La0.9Ce0.1Co0.6Cu0.4O3 (4.4 mg, 5 mol%) was added to a mixture of
plings
aryl halide (0.71 mmol), phenol (1.00 mmol), Cs2CO3 (325 mg, 1.00
X mmol) and 1 drop of EtOAc in toluene (1 mL) in a microwave vial.
R1 2.5 mol% R2 The tube was flushed with argon, sealed and heated in an oil bath at
perovskite 110 °C for 48 h. The reaction mixture was filtered through a Chem
+ 4 equiv Et3N
Elut CE1005 drying column, eluting with Et2O (3 × 10 mL). Com-
R2 5% H2O/DMA or DMF bined filtrates were concentrated in vacuo and purified by column
120 °C
R1
chromatography to afford the desired product.

General Procedure for LaCu*-Catalyzed Ullmann Couplings of

1 2 Thiophenols
R X R Perovskite Yield (%)
Procedure A: La0.9Ce0.1Co0.6Cu0.4O3 (4.4 mg, 5 mol%) was added
p-Cl I OMe LaPdCu* 71a,b 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
p-NO2 I OMe LaPdCu* 96a,b 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
p-COMe I OMe LaPd* 96b reaction mixture was filtered through a Chem Elut CE1005 drying
column, eluting with Et2O (3 × 10 mL). Combined filtrates were
p-OMe I OMe LaPdCu* 47c
concentrated in vacuo and purified by column chromatography to
p-NO2 Br OMe LaPdCu* 71c afford the coupled product.
Procedure B: La0.9Ce0.1Co0.6Cu0.4O3 (4.4 mg, 5 mol%) was added
p-COMe I NH2 NdCuPd* 92b to a mixture of aryl halide (0.71 mmol), thiophenol (1.00 mmol),
o-CO2H I OMe LaPdCu* 52b
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,
p-COMe OTf OMe LaPdCu*or NdCuPd* 0b 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,
a
Control reaction in absence of catalyst gave no conversion. eluting with Et2O (3 × 10 mL). Combined filtrates were concen-
b
Reaction was performed in DMF. trated in vacuo and purified by column chromatography to afford
c
Reaction was performed in DMA. the coupled product.

Synlett 2005, No. 8, 1291–1295 © Thieme Stuttgart · New York

LETTER
General Procedure for Perovskite-Catalyzed Sonogashira Re-
action
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.
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).
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.
(7) Raveau, B.; Rao, C. N. R. Transition Metal Oxides:
Structure, Properties and Synthesis of Ceramic Oxides; John
Wiley & Sons: Oxford, 1998.
Catalysts for the Ullmann and Sonogashira Reactions 1295
(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.
(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.
(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.
Downloaded by: University of Pittsburgh. Copyrighted material.
(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.
(28) Appukkuttan, P.; Dehaen, W.; Van der Eycken, E. Eur. J.
Org. Chem. 2003, 4713.
Synlett 2005, No. 8, 1291–1295 © Thieme Stuttgart · New York