The first use of porphyrins as catalysts in cross-coupling reactions: a water-soluble palladium complex with a porphyrin ligand as an efficient catalyst precursor for the Suzuki-Miyaura reaction in aqueous media under aerobic conditions

Article abstract of DOI:10.1016/j.tetlet.2007.07.141

For the first time, a palladium complex with a porphyrin ligand is used as a catalyst precursor for cross-coupling reactions. The synthesis of a palladium complex with a phosphine-free and water-soluble potassium carboxylate salt of a porphyrin, and its e

Full text of DOI:10.1016/j.tetlet.2007.07.141

Tetrahedron Letters 48 (2007) 6688–6691
The first use of porphyrins as catalysts in cross-coupling reactions:
a water-soluble palladium complex with a porphyrin ligand as an
efficient catalyst precursor for the Suzuki–Miyaura reaction in
aqueous media under aerobic conditions
b,
b
Ioannis D. Kostas,a,* Athanassios G. Coutsolelos, Georgios Charalambidis and
*
Aggeliki Skondrab
aNational Hellenic Research Foundation, Institute of Organic and Pharmaceutical Chemistry, Vas. Constantinou 48,
116 35 Athens, Greece
bLaboratory of BioInorganic Chemistry, Department of Chemistry, University of Crete, PO Box 2208, Voutes, 710 03,
Heraklion, Crete, Greece
Received 2 May 2007; revised 10 July 2007; accepted 19 July 2007
Available online 27 July 2007
Abstract—For the first time, a palladium complex with a porphyrin ligand is used as a catalyst precursor for cross-coupling reac-
tions. The synthesis of a palladium complex with a phosphine-free and water-soluble potassium carboxylate salt of a porphyrin, and
its evaluation in the Suzuki–Miyaura reaction of phenylboronic acid with aryl bromides (from electron-rich to electron-poor), in
neat water, under aerobic conditions is described. Catalysis is performed at 100 ꢀC for 4 h, using K2CO3 as base, and a substrate
to catalyst molar ratio of 1000:1, leading to yields of coupling products in the range of 80–100%. The catalyst can be recycled
and reused, but unfortunately, with a loss in activity.
ꢁ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
ligands for the cross-coupling reactions in aqueous
media,5 but in recent years, other hydrophilic phos-
phine-free systems, such as CNC-pincer palladium
complexes,6 have also been found to be highly efficient
catalysts for this transformation.
Homogeneous palladium catalysis has become an essen-
tial tool for synthetic organic chemists in carbon–carbon
bond formation.1 The coupling of aryl halides with
organoboronic acids, the Suzuki–Miyaura reaction, is
one of the most important palladium-catalyzed cross-
coupling reactions.1,2 The replacement of organic
solvents by water in transition metal homogeneous
catalysis has received remarkable attention, as water is
inexpensive, non-toxic, non-flammable, environmentally
sustainable, and allows simple separation and reuse of
the catalyst.3 For these reasons, intensive research
efforts are being directed to perform the Suzuki–Miyaura
coupling either via aqueous biphasic catalysis or in neat
water.4 Initially, water-soluble phosphines were used as
Palladium porphyrins are of great interest owing to their
high yield of intersystem crossing and long lifetime of
the resulting triplet state in diverse media.7 Palladium
porphyrins have found applications as luminescent
markers,8 oxygen sensors,9 sensitizers for singlet oxygen
formation,10 and photo-induced protein cross-linking
agents.11 Additionally, bis-zinc(II) porphyrin building
blocks have been used to assemble monodentate phos-
phorus ligands as an approach to prepare supramole-
cular bidentate chelating ligands for rhodium and
palladium catalysis.12 Our groups have contributed
towards the synthesis of new metalloporphyrin deriva-
tives,13 mainly as biomimetic complexes, and have
reported the application of new phosphines14a as well
as air-stable phosphine-free ligands14b–e for palladium-
catalyzed coupling reactions, having the advantage of
performing the reactions under aerobic conditions. In
Keywords: Porphyrin; Aqueous catalysis; Green chemistry; Suzuki–
Miyaura cross-coupling; C–C bond formation; Homogeneous
catalysis.
Corresponding authors. Tel.: +30 210 7273878; fax: +30 210 7273831
(I.D.K.); tel.: +30 2810 545045 (A.G.C.); e-mail addresses:
ikostas@eie.gr; coutsole@chemistry.uoc.gr
*
0040-4039/$ - see front matter ꢁ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.07.141

I. D. Kostas et al. / Tetrahedron Letters 48 (2007) 6688–6691
6689
the present work, we report the synthesis of a palladium
complex with a phosphine-free and water-soluble potas-
sium carboxylate salt of a porphyrin, which was success-
fully applied in the Suzuki–Miyaura reaction of
phenylboronic acid with aryl bromides, in neat water,
under aerobic conditions. Although palladium-catalyzed
coupling reactions have been used extensively for the
synthesis of porphyrins,15 this Letter represents the first
study concerning the evaluation of a porphyrin ligand as
a precatalyst in cross-coupling reactions.
and 559 nm). These features are characteristic of palla-
dium insertion in a porphyrin system. Moreover, the
absence of negative chemical shifts in the 1H NMR
spectrum of porphyrin 5 was also an indicative that
porphyrin 5 had been metallated. Finally, complex 6
was obtained, almost quantitatively, by saponification
using a large excess of KOH in THF/MeOH mixture.
Complex 6, as the potassium carboxylate salt displayed
complete solubility in water.
Palladium-porphyrin complex 6, as a stock solution in
water (1 mM), was used as catalyst in the Suzuki–Miya-
ura reaction of phenylboronic acid with representative
aryl bromides (electron-rich and electron-poor) at
100 ꢀC, using K2CO3 as base, and a substrate to catalyst
molar ratio of 1000:1 (Scheme 2, Table 1). All the reac-
tions were performed in air, and water was the only sol-
vent used. As expected, the catalytic activity depended
on the halide, while electron-withdrawing groups on
the aryl ring increased the reaction rate. After 4 h reac-
tion time, the GC yield of the coupling product was
found to be 80% for deactivated 4-bromoanisole (entry
1), 83% for non-activated bromobenzene (entry 2), and
100% for activated 4-bromobenzonitrile (entry 3). For
activated substrates, the yield was very high even after
1–2 h (entries 4 and 5). The feasibility of recycling and
reusing the catalyst was also examined taking the cou-
pling of phenylboronic acid with 4-bromobenzonitrile
as a model (entry 3; cycles 1–3). After the first cycle,
extraction with hexane allowed a simple separation of
the coupling product from the water-soluble catalyst 6.
The resulting aqueous phase was reused, simply by the
2. Results and discussion
The synthesis of the water-soluble palladium porphyrin
6 is outlined in Scheme 1. Functionalized benzaldehyde
3 was obtained in 95% yield by the alkylation of 4-
hydroxybenzaldehyde (1) with ethyl 4-bromobutyrate
(2) in the presence of K2CO3, in DMF at 80 ꢀC. Porphy-
rin 4 was prepared in 10% yield following the classical
method of Adler and Longo,16 via the reaction of the
aldehyde 3 with pyrrole in refluxing propionic acid.
Palladium insertion was carried out by the addition of
palladium chloride to the free base 4 in refluxing benzo-
nitrile,17 leading to porphyrin 5 in 90% yield. Metal
insertion was confirmed by the characteristic changes
in the UV–vis spectrum of the metallated porphyrin 5
1
compared to 4, and by H NMR spectroscopy. The vis-
ible absorption spectra of porphyrin 4 had a Soret band
at 422 nm and four Q-bands (519, 555, 589 and 651 nm).
In the metallated compound 5, the Soret shift occurred
at 420 nm and the Q-bands were reduced to two (525
O
O
O
H
N
O
O
H
H
O
O
O
O
O
NH
N
N
O
O
K2CO3
DMF, 80 o
95%
O
O
+
Br
O
C
Propionic Acid
reflux
3
HN
O
HO
2
10%
1
O
KO
O
O
O
PdCl2
Benzonitrile
reflux
90%
O
O
O
O
4
OK
O
O
O
KO
O
O
0.5 M KOH
THF / MeOH
N
N
N
N
N
N
N
O
O
O
Pd
O
Pd
O
97%
N
O
O
O
OK
O
O
6
5
Scheme 1.

6690
I. D. Kostas et al. / Tetrahedron Letters 48 (2007) 6688–6691
DMF (15 mL). Ethyl 4-bromobutyrate (7.62 g,
Br
B(OH)2
Pd cat. (0.1 mol%)
39 mmol) was added dropwise and the mixture was
heated at 80 ꢀC for 2 h. After cooling, the salts were fil-
tered. DMF was evaporated to dryness, and the reaction
mixture was re-dissolved in CH2C12 (100 mL) and
washed with 4 · 50 mL distilled water. Drying over
sodium sulfate, filtration and evaporation of the solvent
afforded benzaldehyde 3 as a pale yellow oil (7.09 g,
95%). The reaction product was used without any fur-
+
R
K2CO3, H2O
100°C, 4 h
air
R
R = OMe, H, CN, NO2
Scheme 2.
Table 1. Suzuki–Miyaura cross-coupling in water, catalyzed by
palladium-porphyrin complex 6 under aerobic conditions
1
ther purification. H NMR (500 MHz, CDCl3): d 9.86
Entry
R
Time (h)
GC yielda (%)
(s, 1H, CHO), 7.81 (d, J = 8.5 Hz, 2H, Ar), 6.98 (d,
J = 8.5 Hz, 2H, Ar), 4.13 (q, J = 7.0 Hz, 2H, CH2),
4.09 (t, J = 6.5 Hz, 2H, CH2), 2.51 (t, J = 7.0 Hz, 2H,
CH2), 2.14 (sextet, J = 6.5 Hz, 2H, CH2), 1.24 (t,
J = 7.0 Hz, 3H, CH3). 13C NMR (75 MHz, CDCl3): d
191.2 (CO), 173.4 (CO), 164.3 (C), 132.4 (Ar), 130.4
(C), 115.1 (Ar), 67.5 (CH2), 60.9 (CH2), 31.0 (CH2),
24.8 (CH2), 14.6 (CH3). HRMS (ES+) Calcd for
C13H16O4 (M)+: 236.1049. Found: 236.1042.
1
2
3
OMe
H
CN
4
4
4
80
83
Cycle-1: 100
Cycle-2: 76
Cycle-3: 53
99
4
5
CN
NO2
2
1
93
Reagents and conditions: ArBr (1.0 mmol), PhB(OH)2 (1.5 mmol),
K2CO3 (2.0 mmol), Pd complex 6 in H2O (1 mM, 1 mL), 100 ꢀC.
a Yield of coupled product R–C6H4–Ph, based on aryl bromide (GC).
4.2. Porphyrin 4
addition of the substrate and base. The reaction was
repeated at 100 ꢀC for 4 h, for up to three cycles, but
unfortunately, the catalyst exhibited a loss in activity,
perhaps due to the decreased stability of complex 6
under the reaction conditions. Palladium leaching from
the aqueous phase can be excluded due to the negligible
catalytic activity of the organic phase after the extrac-
tion of the coupling products. In order to investigate
this, the organic extracts derived from the reaction of
phenylboronic acid with 4-bromoanisole were evapo-
rated to dryness, water (2 mL) was added, and the
mixture was filtered. The aqueous phase was mixed with
4-bromobenzonitrile, phenylboronic acid and K2CO3
using the same molar ratio as in the previous experi-
ments, and refluxed in air. Even after 24 h, no coupling
product was detected, indicating that no leaching had
occurred.
A solution of benzaldehyde 3 (3.00 g, 13 mmol) in pro-
pionic acid (150 mL) was heated to 100 ꢀC and pyrrole
(0.97 mL, 14 mmol) was added dropwise. The mixture
was refluxed for 2 h, and then the crude product was
evaporated to dryness under vacuum. Filtration through
a silica gel pad with CH2Cl2/MeOH (95:5, v/v) as eluent
was performed to remove the tar. The resulting crude
product was purified by chromatography on silica gel,
and the product was eluted with CH2Cl2/EtOH 97:3 to
1
give compound 4 as a purple solid (0.37 g, 10%). H
NMR (500 MHz, CDCl3): d 8.87 (s, 8H, Ar), 8.12 (d,
J = 8 Hz, 8H, Ar), 7.26 (d, J = 8.5 Hz, 8H, Ar), 4.30
(t, J = 6.0 Hz, 8H, CH2), 4.26 (q, J = 7.0 Hz, 8H,
CH2), 2.70 (t, J = 7.0 Hz, 8H, CH2), 2.32 (m, 8H,
CH2), 1.36 (t, J = 7 Hz, 12H, CH3), À2.73 (s, 2H,
NH). 13C NMR (75 MHz, CDCl3): d 173.7 (CO),
159.1 (C), 136.0 (Ar), 135.2 (C), 131.4 (Ar), 120.2 (C),
113.2 (Ar), 67.5 (CH2), 61.0 (CH2), 31.5 (CH2), 25.3
(CH2), 14.8 (CH3). UV–vis: kabs (CH2Cl2) (e,
mMÀ1 cmÀ1) 422 (389.4), 519 (16.5), 555 (12.2), 589
(6.0), 651 (7.8). HRMS (ES+) Calcd for C68H71N4O12
(M+H)+: 1135.5068. Found: 1135.4997.
3. Conclusions
In summary, we have synthesized a palladium complex
of a phosphine-free and water-soluble potassium carb-
oxylate salt of a porphyrin, which can serve as an effi-
cient precatalyst for the Suzuki–Miyaura cross-coupling
of aryl bromides with phenylboronic acid under mild
reaction conditions, in neat water, in air. The catalyst
could be easily recycled and reused, but unfortunately,
with a loss in activity. This first study of the application
of porphyrins to cross-coupling reactions provides
important information on the catalytic activity of these
systems. The development of analogous water-soluble
porphyrins displaying higher stability under the reaction
conditions for palladium-catalyzed reactions is currently
in progress.
4.3. Porphyrin 5
Porphyrin 4 (65 mg, 0.057 mmol) was dissolved in ben-
zonitrile (70 mL) and PdCl2 (20.4 mg, 0.115 mmol) was
added. The solution was refluxed for 3 h, cooled, and
then reduced to dryness under vacuum. Then, CH2Cl2
(40 mL) was added, and the mixture was washed with
aqueous NaCl (2 · 30 mL). The organic layer was dried
over sodium sulfate, filtered, concentrated, and the resi-
due was chromatographed on a silica gel column
(CH2Cl2/MeOH, 97:3) to obtain 5 as an orange solid
1
(63 mg, 90%). H NMR (500 MHz, CDCl3): d 8.83 (s,
4. Experimental
4.1. Aldehyde 3
8H, Ar), 8.03 (d, J = 8.5 Hz, 8H, Ar), 7.20 (d, J =
8.5 Hz, 8H, Ar), 4.24 (m, 16H, CH2), 2.67 (t,
J = 7.0 Hz, 8H, CH2), 2.28 (q, J = 6.5 Hz, 8H, CH2),
1.35 (t, J = 7.0 Hz, 12H, CH3). 13C NMR (75 MHz,
CDCl3): d 173.7 (CO), 159.1 (C), 142.3 (C), 135.5 (Ar),
134.7 (C), 131.3 (Ar), 121.8 (C), 113.2 (Ar), 67.5
A mixture of 4-hydroxybenzaldehyde (4.00 g, 33 mmol)
and K2CO3 (5.40 g, 39 mmol) was stirred in anhydrous

I. D. Kostas et al. / Tetrahedron Letters 48 (2007) 6688–6691
6691
Chem. 2002, 219, 11–59; (f) Littke, A. F.; Fu, G. C.
Angew. Chem., Int. Ed. 2002, 41, 4176–4211; (g) Bedford,
R. B.; Cazin, C. S. J.; Holder, D. Coord. Chem. Rev. 2004,
248, 2283–2321; (h) Bellina, F.; Carpita, A.; Rossi, R.
Synthesis 2004, 2419–2440; (i) Frisch, A. C.; Beller, M.
Angew. Chem., Int. Ed. 2005, 44, 674–688.
(CH2), 61.0 (CH2), 31.4 (CH2), 25.3 (CH2), 14.7 (CH3).
UV–vis: kabs (CH2Cl2) (e, mMÀ1 cmÀ1) 420 (402.3), 525
(29.2), 559 (3.5). HRMS (ES+) Calcd for
C68H69N4O12Pd
1239.3864.
(M+H)+:
1239.3947.
Found:
3. Cornils, B.; Herrmann, W. A. In Aqueous-Phase Catalysis
in Multiphase Homogeneous Catalysis; Cornils, B., Herr-
4.4. Porphyrin 6
´
mann, W. A., Horvath, I. T., Leitner, W., Mecking, S.,
Palladium porphyrin 5 (29 mg, 23 lmol) was dissolved
in a solution of THF (45 mL), methanol (18 mL) and
0.5 M KOH (19 mL). The reaction was monitored by
thin layer chromatography (CH2Cl2/MeOH, 9:1). After
stirring at room temperature for 24 h, the solution was
evaporated to dryness to afford compound 6 as a dark
red solid (28 mg, 97%). UV–vis: kabs (MeOH) (e,
mMÀ1 cmÀ1) 417 (395.2), 524 (33.3), 558 (5.0).
Olivier-Bourbigou, H., Vogt, D., Eds.; Wiley-VCH: Wein-
heim, 2005; Vol. 1, pp 25–308.
4. Recent selected monographs and reviews: (a) Herrmann,
W. A.; Reisinger, C.-P.; Ha¨rter, P. Heck and Other C–C
Coupling Reactions in Ref. 3; Vol. 1, pp 230–238; (b) Li,
C.-J. Chem Rev. 2005, 105, 3095–3165; (c) Scho¨nfelder, D.;
Nuyken, O.; Weberskirch, R. J. Organomet. Chem. 2005,
690, 4648–4655; (d) Shaughnessy, K. H.; DeVasher, R. B.
Curr. Org. Chem. 2005, 9, 585–604; (e) Shaughnessy, K. H.
Eur. J. Org. Chem. 2006, 1827–1835.
4.5. General experimental procedure for the Suzuki–
Miyaura coupling
5. For the first report on palladium-catalyzed alkylations in
aqueous media, see: Casalnuovo, A. L.; Calabrese, J. C. J.
Am. Chem. Soc. 1990, 112, 4324–4330.
´
6. Churruca, F.; SanMartin, R.; Ines, B.; Tellitu, I.;
A round bottom flask equipped with a reflux condenser,
was charged in air with aryl bromide (1.0 mmol), phen-
ylboronic acid (0.183 g, 1.5 mmol), K2CO3 (0.276 g,
2.0 mmol), and a stock solution of complex 6 in H2O
(1 mM, 1 mL, 0.001 mmol). The mixture was stirred in
a preheated 100 ꢀC oil bath for 4 h, and then allowed
to cool to room temperature. After the addition of water
(1 mL) and extraction with hexane (4 · 10 mL), the
organic phase was dried over Na2SO4, filtered, passed
through Celite and analyzed by GC and GC–MS. For
the reuse of the catalyst, the flask, containing the
aqueous solution of the complex, was charged with aryl
bromide (1.0 mmol), phenylboronic acid (0.183 g,
1.5 mmol), and K2CO3 (0.276 g, 2.0 mmol), and the
mixture was stirred at 100 ꢀC for 4 h. On each occasion,
after cooling and extraction with hexane, the combined
organic extracts were dried over Na2SO4, filtered, passed
through Celite and analyzed by GC and GC–MS.
Dichloromethane was used as the extracting solvent
for the coupling product of 1-bromo-4-nitrobenzene
with phenylboronic acid. All the biaryls prepared are
known compounds.14c
´
Domınguez, E. Adv. Synth. Catal. 2006, 348, 1836–1840,
and references cited therein.
7. (a) Eastwood, D.; Gouterman, M. J. Mol. Spectrosc. 1970,
35, 359–375; (b) Callis, J. B.; Gouterman, M.; Jones, Y.
M.; Henderson, B. H. J. Mol. Spectrosc. 1971, 39, 410–
420.
8. Papkovsky, D. B.; O’Riordan, T.; Soini, A. Biochem. Soc.
Trans. 2000, 28, 74–77.
9. Borisov, S. M.; Vasil’ev, V. V. J. Anal. Chem. 2004, 59,
155–159.
10. Wiehe, A.; Stollberg, H.; Runge, S.; Paul, A.; Senge, M.
O.; Ro¨der, B. J. Porphyrins Phthalocyanines 2001, 5, 853–
860.
11. Kim, K.; Fancy, D. A.; Carney, D.; Kodadek, T. J. Am.
Chem. Soc. 1999, 121, 11896–11897.
12. Slagt, V. F.; van Leeuwen, P. W. N. M.; Reek, J. N. H.
Dalton Trans. 2007, 2302–2310, and references cited therein.
13. Recent selected papers: (a) Spyroulias, G. A.; Despoto-
poulos, A. P.; Raptopoulou, C. P.; Terzis, A.; de Mon-
tauzon, D.; Poilblanc, R.; Coutsolelos, A. G. Inorg. Chem.
2002, 41, 2648–2659; (b) Davoras, E. M.; Coutsolelos, A.
G. J. Inorg. Biochem. 2003, 94, 161–170; (c) Daphnomili,
´
D.; Raptopoulou, C.; Agondanou, J.-H.; Benazeth, S.;
Terzis, A.; Coutsolelos, A. G. Inorg. Chem. 2004, 43,
4363–4371; (d) Ladomenou, K.; Charalambidis, G.;
Coutsolelos, A. G. Tetrahedron 2007, 63, 2882–2887.
14. Recent selected papers: (a) Kostas, I. D.; Steele, B. R.;
Terzis, A.; Amosova, S. V. Tetrahedron 2003, 59, 3467–
3473; (b) Kovala-Demertzi, D.; Yadav, P. N.; Demertzis,
M. A.; Jasinski, J. P.; Andreadaki, F. J.; Kostas, I. D.
Tetrahedron Lett. 2004, 45, 2923–2926; (c) Kostas, I. D.;
Andreadaki, F. J.; Kovala-Demertzi, D.; Prentjas, C.;
Demertzis, M. A. Tetrahedron Lett. 2005, 46, 1967–1970;
(d) Kostas, I. D.; Heropoulos, G. A.; Kovala-Demertzi,
D.; Yadav, P. N.; Jasinski, J. P.; Demertzis, M. A.;
Andreadaki, F. J.; Vo-Thanh, G.; Petit, A.; Loupy, A.
Tetrahedron Lett. 2006, 47, 4403–4407; (e) Kostas, I. D.;
Steele, B. R.; Terzis, A.; Amosova, S. V.; Martynov, A. V.;
Makhaeva, N. A. Eur. J. Inorg. Chem. 2006, 2642–2646.
15. For a recent selected review, see: Setsune, J.-I. J. Porphy-
rins Phthalocyanines 2004, 8, 93–102.
Acknowledgement
The investigation was funded by the General Secretariat
of Research and Technology of Greece.
References and notes
1. Recent selected books and monographs: (a) Tsuji, J.
Palladium Reagents and Catalysts; John Wiley & Sons:
Chichester, 1995; (b) Diederich, F.; Stang, P. J. Metal-
Catalyzed Cross-Coupling Reactions; Wiley-VCH: Wein-
heim, 1998; (c) Reetz, M. T. In Transition Metal Catalysed
Reactions; Davies, S. G., Murahashi, S.-I., Eds.; Blackwell
Science: Oxford, 1999; (d) Miyaura, N. Cross-Coupling
Reaction; Springer: Berlin, 2002.
16. Adler, A. D.; Longo, F. R.; Finarelli, J. D.; Goldmacher,
J.; Assour, J.; Korsakoff, L. J. Org. Chem. 1967, 32, 476-
476.
17. Buchler, J. W.; Puppe, L. Liebigs Ann. Chem. 1974, 1046–
1062.
2. Recent selected reviews: (a) Miyaura, N.; Suzuki, A.
Chem. Rev. 1995, 95, 2457–2483; (b) Stanforth, S. P.
Tetrahedron 1998, 54, 263–303; (c) Suzuki, A. J. Organo-
met. Chem. 1999, 576, 147–168; (d) Suzuki, A. J. Orga-
nomet. Chem. 2002, 653, 83–90; (e) Miyaura, N. Top. Curr.