meso-Pyrimidinyl-substituted A2B-corroles

Article abstract of DOI:10.1021/ol071226a

meso-Pyrimidinyl-substituted A₂B-corroles were synthesized in good yields by condensation of 5-mesityldipyrromethane and 2-substituted 4,6-dichloropyrimidine-5-carbaldehydes. A simple reduction of the amount of Lewis acid (BF₃-OEt

Full text of DOI:10.1021/ol071226a

ORGANIC
LETTERS
2007
Vol. 9, No. 16
3165-3168
meso-Pyrimidinyl-Substituted
A2B-Corroles
Wouter Maes, Thien H. Ngo, Jeroen Vanderhaeghen, and Wim Dehaen*
Molecular Design and Synthesis, Department of Chemistry, Katholieke UniVersiteit
LeuVen, Celestijnenlaan 200F, 3001 LeuVen, Belgium
wim.dehaen@chem.kuleuVen.be
Received May 24, 2007
ABSTRACT
meso-Pyrimidinyl-substituted A2B-corroles were synthesized in good yields by condensation of 5-mesityldipyrromethane and 2-substituted
4,6-dichloropyrimidine-5-carbaldehydes. A simple reduction of the amount of Lewis acid (BF3 OEt2) resulted in the formation of A2B-corroles,
‚
which was optimized to maximize the corrole yield. Nucleophilic aromatic substitution, Suzuki, and Stille cross-coupling reactions were performed
on the Cu-metalated pyrimidinylcorroles to obtain sterically encumbered triarylcorroles, while the substitution pattern at the 2-position of the
pyrimidinyl substituent was altered through Liebeskind−Srogl cross-couplings.
Corroles, contracted porphyrin analogues lacking one meso-
carbon, have long been rather rare compounds due to their
challenging synthesis.1 Since 1999, however, novel one-step
synthetic pathways toward meso-triarylcorroles, and the
discovery that these macrocycles stabilize unusually high
metal oxidation states, have caused a revival of corrole
chemistry.2 Nowadays, a number of well-established syn-
thetic protocols are available for the preparation of substituted
triarylcorroles and therefore an increasing amount of effort
is devoted to the study of their properties and applications.2,3
Further investigations into synthetic pathways toward novel
more sophisticated functional corroles are, however, still
required to fully elucidate and exploit the potential of these
macrocycles in a number of promising applications, e.g.,
catalysis,4 sensors,5 and photodynamic therapy.6,7
Synthetic pyrimidine chemistry is a well-studied part of
organic chemistry since the versatile pyrimidine skeleton is
commonly found in pharmaceutical drugs, fungicides, and
herbicides.8a Dihalopyrimidines have been used extensively
(3) Some recent reviews on synthetic corrole chemistry: (a) Gryko, D.
T. Eur. J. Org. Chem. 2002, 1735. (b) Gryko, D. T.; Fox, J. P.; Goldberg,
D. P. J. Porphyrins Phthalocyanines 2004, 8, 1091. (c) Ghosh, A. Angew.
Chem., Int. Ed. 2004, 43, 1918. (d) Nardis, S.; Monti, D.; Paolesse, R.
Mini-ReV. Org. Chem. 2005, 2, 355.
(4) (a) Gross, Z.; Gray, H. B. AdV. Synth. Catal. 2004, 346, 165. (b)
Mahammed, A.; Gross, Z. J. Am. Chem. Soc. 2005, 127, 2883. (c) Aviv, I.;
Gross, Z. Synlett 2006, 951. (d) Luobeznova, I.; Raizman, M.; Goldberg,
I.; Gross, Z. Inorg. Chem. 2006, 45, 386.
(5) (a) Barbe, J.-M.; Canard, G.; Brande`s, S.; Je´roˆme, F.; Dubois, G.;
Guilard, R. Dalton Trans. 2004, 1208. (b) Barbe, J.-M.; Canard, G.; Brande`s,
S.; Guilard, R. Angew. Chem., Int. Ed. 2005, 44, 3103. (c) Li, C.-Y.; Zhang,
X.-B.; Han, Z.-X.; Akermark, B.; Sun, L.; Shen, G.-L.; Yu, R.-Q. Analyst
2006, 131, 388. (d) Barbe, J.-M.; Canard, G.; Brande`s, S.; Guilard, R. Chem.
Eur. J. 2007, 13, 2118.
(6) (a) Aviezer, D.; Cotton, S.; David, M.; Segev, A.; Khaselev, N.; Galili,
N.; Gross, Z.; Yayon, A. Cancer Res. 2000, 60, 2973. (b) Agadjanian, H.;
Weaver, J. J.; Mahammed, A.; Rentendorj, A.; Bass, S.; Kim, J.; Dmo-
chowski, I. J.; Margalit, R.; Gray, H. B.; Gross, Z.; Medina-Kauwe, L. K.
Pharm. Res. 2006, 23, 367.
(1) Synthetic corrole chemistry up to 1999: Paolesse, R. In The Porphyrin
Handbook; Kadish, K. M., Smith, K. M., Guilard, R., Eds.; Academic
Press: San Diego, CA, 2000; Vol. 2, Chapter 11, p 201.
(2) (a) Vogel, E.; Will, S.; Shulze-Tilling, A.; Neumann, L.; Lex, J.;
Bill, E.; Trautwein, A. X.; Wieghardt, A. Angew. Chem., Int. Ed. 1994, 33,
731. (b) Gross, Z.; Galili, N.; Saltsman, I. Angew. Chem., Int. Ed. 1999,
38, 1427. (c) Gross, Z.; Galili, N.; Simkhovich, L.; Saltsman, I.; Botos-
hansky, M.; Bla¨ser, D.; Boese, R.; Goldberg, I. Org. Lett. 1999, 1, 599. (d)
Paolesse, R.; Jaquinod, L.; Nurco, D. J.; Mini, S.; Sagone, F.; Boschi, T.;
Smith, K. M. Chem. Commun. 1999, 1307. (e) Paolesse, R.; Nardis, S.;
Sagone, F.; Khoury, R. G. J. Org. Chem. 2001, 66, 550. (f) Gryko, D. T.
Chem. Commun. 2000, 2243. (g) Gryko, D. T.; Jadach, K. J. Org. Chem.
2001, 66, 4267. (h) Gryko, D. T.; Koszarna, B. Org. Biomol. Chem. 2003,
1, 350. (i) Koszarna, B.; Gryko, D. T. J. Org. Chem. 2006, 71, 3707.
(7) Aviv, I.; Gross, Z. Chem. Commun. 2007, 1987.
10.1021/ol071226a CCC: $37.00
© 2007 American Chemical Society
Published on Web 07/14/2007

by Lehn et al. for the synthesis of multitopic ligands suitable
for the preparation of grid-type metal ion architectures.8b In
previous work we have been studying the synthesis and
reactivity of 4,6-dichloropyrimidines as structural compo-
nents of meso-pyrimidinyl-substituted porphyrinoids,9
heteracalixarenes,10 and dendrimers.11 The major advantage
concerning the introduction of dichloropyrimidinyl moieties
on the meso-positions of oligopyrrolic macrocycles is the
fact that these pyrimidinyl substituents allow a variety of
post-macrocyclization synthetic modifications. Earlier work
on pyrimidinylporphyrins pointed out that the chlorine atoms
on the pyrimidine group(s) can easily be substituted by
nucleophilic aromatic substitution (SNAr)9b,f or Suzuki cross-
coupling9d reactions. Similar reactions on pyrimidinylcorroles
hence could give access to a diversity of functional corroles
that is unprecedented in synthetic corrole chemistry. To date,
the majority of corrole functionalizations involve simple
functional group transformations on the (limited amount of)
meso-aryl groups, or introduction of functions on the
â-pyrrolic positions, e.g., via bromination, hydroformylation,
nitration, and chlorosulfonation.3 Another unique feature of
meso-pyrimidinylcorroles is the fact that the substituents are
introduced at the ortho,ortho′-positions, and hence are located
above and below the corrole macrocycle, which could be
advantageous regarding energy transfer properties and ste-
reoselective catalysis.12
In 2001, our group presented the synthesis of sterically
encumbered triarylcorroles starting from aryldipyrromethanes
and aromatic aldehydes.9c Lewis acid-catalyzed (BF3‚OEt2)
condensation of 5-(2,6-dichlorophenyl)dipyrromethane (1a)
and electron deficient aromatic aldehydes in CH2Cl2, fol-
lowed by cyclization and oxidation in propionitrile or
CH2Cl2, in the presence of DDQ or p-chloranil, gave corroles
in good yields. One particular aldehyde used, 4,6-dichloro-
pyrimidine-5-carbaldehyde (2a), afforded a novel meso-
pyrimidinylcorrole 3 (20% yield) on condensation with
dipyrromethane 1a (Scheme 1). On the other hand, conden-
sation of pyrimidinecarbaldehyde 2a with 5-mesityldipyr-
romethane (1b) did not result in the formation of any corrole,
only the A2B2-porphyrin analogue was obtained in a very
high yield (53%). These prior observations and the potential
of pyrimidinylcorroles toward preparation of particular
functional corroles have been investigated in detail.13
As part of a project to prepare porphyrin derivatives of
4,6-dichloropyrimidine-5-carbaldehydes, and the use of such
Scheme 1. Synthesis of A2B-Triarylcorrole 3
porphyrins for the construction of multiporphyrin dendrimers,9f
it was discovered that a slight modification of the reaction
conditions, as optimized for porphyrins, opens a more general
synthetic pathway toward meso-pyrimidinyl-substituted A2B-
corroles.14 On using a tenfold decreased amount of boron-
trifluoride catalyst (0.085 equiv) in the condensation of 4,6-
dichloropyrimidine-5-carbaldehyde (2a) and 5-mesityldipyrro-
methane (1b), in a 1-1 ratio,15 we obtained, besides the
expected A2B2-porphyrin 5a (25%), pyrimidinylcorrole 4a
in 18% yield (Scheme 2).
5-Mesityldipyrromethane (1b) was easily synthesized via
the recently reported method in water,16 while 4,6-dichlo-
ropyrimidine-5-carbaldehyde (2a) was prepared by chloro-
formylation of 4,6-dihydroxypyrimidine.17 The pyrimidine
building block could be varied by introduction of substituents
on the vacant 2-position. 4,6-Dichloro-2-phenylpyrimidine-
5-carbaldehyde (2b) and 4,6-dichloro-2-(p-methoxyphenyl)-
pyrimidine-5-carbaldehyde (2c) were prepared by similar
chloroformylation of the dihydroxypyrimidine precursors,
which in their turn were prepared by condensation of the
corresponding benzamidines with diethyl malonate.18 4,6-
Dichloro-2-methylsulfanylpyrimidine-5-carbaldehyde (2d)
could be obtained through methylation and subsequent
chloroformylation of thiobarbituric acid.19 Flash chromato-
graphic purification of the obtained pyrimidinecarbaldehydes
proved to be essential to obtain satisfactory yields for the
tetrapyrrolic macrocycles. Pyrimidinylcorroles 4b-d were
synthesized easily and in relatively good yields (13% for
(8) (a) von Angerer, S. In Science of Synthesis; Yamamoto, Y., Ed.; Georg
Thieme Verlag: Stuttgart, Germany, 2004; Vol. 16, p 379, and references
cited therein. (b) Ruben, M.; Rojo, J.; Romero-Salguero, F. J.; Uppadine,
L. H.; Lehn, J.-M. Angew. Chem., Int. Ed. 2004, 43, 3644.
(9) (a) Motmans, F.; Ceulemans, E.; Smeets, S.; Dehaen, W. Tetrahedron
Lett. 1999, 40, 7545. (b) Smeets, S.; Asokan, C. V.; Motmans, F.; Dehaen,
W. J. Org. Chem. 2000, 65, 5882. (c) Asokan, C. V.; Smeets, S.; Dehaen,
W. Tetrahedron Lett. 2001, 42, 4483. (d) Maes, W.; Dehaen, W. Synlett
2003, 79. (e) Maes, W.; Vanderhaeghen, J.; Dehaen, W. Chem. Commun.
2005, 2612. (f) Maes, W.; Vanderhaeghen, J.; Smeets, S.; Asokan, C. V.;
Van Renterghem, L. M.; Du Prez, F. E.; Smet, M.; Dehaen, W. J. Org.
Chem. 2006, 71, 2987.
(10) Maes, W.; Van Rossom, W.; Van Hecke, K.; Van Meervelt, L.;
Dehaen, W. Org. Lett. 2006, 8, 4161.
(11) (a) Maes, W.; Amabilino, D. B.; Dehaen, W. Tetrahedron 2003,
59, 3937. (b) Chavan, S. A.; Maes, W.; Gevers, L. E. M.; Wahlen, J.;
Vankelecom, I. F. J.; Jacobs, P. A.; Dehaen, W.; De Vos, D. E. Chem.
Eur. J. 2005, 11, 6754.
(12) Collman, J. P.; Decre´au, R. A. Org. Lett. 2005, 7, 975.
(13) Collman prepared the meso-pyrimidinyl-substituted A3-corrole
analogue using either conventional or microwave heating: Collman, J. P.;
Decre´au, R. A. Tetrahedron Lett. 2003, 44, 1207.
(14) meso-Pyrimidinyl-substituted expanded porphyrins could also be
prepared by a slight modification of the Rothemund-Lindsey conditions
optimized for porphyrin synthesis (ref 9e).
(15) On using the stoichiometric 1-2 ratio, corrole 4a was obtained in
only 4% yield (23% porphyrin 5a).
(16) Rohand, T.; Dolusic, E.; Ngo, T. H.; Maes, W.; Dehaen, W.
ARKIVOC 2007, 307.
(17) Klo¨tzer, W.; Herberz, M. Monatsh. Chem. 1965, 96, 1567.
(18) (a) Hendry, J. A.; Homer, R. F. J. Chem. Soc. 1952, 328. (b) Kim,
D. H.; Santilli, W. A.; Santilli, A. A. U.S. Patent 3,631,045, 1971.
(19) Santilli, A. A.; Kim, D. H.; Wanser, S. V. J. Heterocycl. Chem.
1971, 8, 445.
3166
Org. Lett., Vol. 9, No. 16, 2007

the A2B-corrole and the A2B2-porphyrin were formed, and
the maximum corrole yield was observed on adding 0.043
equiv of Lewis acid.21 Under these conditions, the desired
corrole 4a was obtained, after column chromatographic
purification, in as much as 35% yield, which is among the
highest yields ever reported for corroles. On applying this
optimized amount of BF3‚OEt2 to the synthesis of corroles
4b and 4d, the yield for 4b could be increased to 22%, while
the yield for 4d dropped to 14%. The highest yield (27%)
for corrole 4d was obtained on using 0.068 equiv of catalyst.
The optimum Lewis acid concentration hence seems to be
strongly dependent on the substitution pattern of the pyri-
midinecarbaldehyde.22
Scheme 2. Synthesis of meso-Pyrimidinyl A2B-Corroles 4a-d
The meso-dichloropyrimidinyl moiety allows easy func-
tionalization of the corrole macrocycle, e.g., via SNAr and
Pd-catalyzed cross-coupling reactions. Due to the inherent
lower stability of free-base (Fb) corroles, as compared to
the porphyrin analogues, it was preferred to perform the
functionalization study for the pyrimidinylcorroles on the
more stable metallocorrole derivatives. For this purpose, Cu
was chosen as the preferred metal, due to its easy insertion,
absence of axial ligands, and the diamagnetic ground
state.2a,23,24 Cu-corroles 6a-d were obtained in high yields
(78-95%) from the Fb corroles on stirring them with
Cu(OAc)2 in pyridine at ambient temperature for 10 min
(Scheme 2).23c SNAr of phenols on meso-pyrimidinyl-
substituted porphyrins proceeds smoothly at 90 °C in DMF
with K2CO3 base (for 48 h).9b,f However, on applying these
conditions to the substitution of A2B-corrole 6a with 4-tert-
butylphenol (4 equiv), monosubstituted A2B-corrole 7a was
observed as the only product in 87% yield. Disubstitution
could only be achieved on using harsh substitution condi-
tions; DMSO, K2CO3, 6 equiv of 4-tert-butylphenol, 175 °C
(microwave irradiation), 1 h. In this way the desired
disubstituted A2B-corrole 7b was obtained in 85% yield
(Scheme 3).25
4b and 4c, 20% for 4d) from these substituted building
blocks under the same reaction conditions (Scheme 2).
Since the content of borontrifluoride catalyst appeared to
be a crucial parameter to obtain either the meso-pyrimidinyl
A2B-corrole or the A2B2-porphyrin as the major product, an
optimization study of the amount of Lewis acid was
performed to maximize the corrole yield (Table 1).20 The
Table 1. Optimization of the Yield for A2B-Corrole 4aa
BF3‚OEt2
corrole 4ab
porphyrin 5ab
(equiv)
(%)
(%)
0.850
0.102
0.085
0.068
0.054
0.043
0.034
0.027
0
9
50
35
25
17
10
6
Pd-catalyzed Suzuki cross-coupling reactions were already
performed on 5,15-bis(4,6-dichloropyrimidin-5-yl)porphyrin
5a with a number of arylboronic acids.9d Extension of this
method to meso-pyrimidinylcorroles would enable the prepa-
ration of unique highly sterically shielded corroles. A simple
Suzuki reaction with phenylboronic acid was performed on
Cu-corrole 6a under standard reaction conditions,9d and the
desired disubstituted A2B-corrole 8 was obtained in 75%
yield (Scheme 3).26 The method could also be extended to
18
25
29
35
27
15
3
2
a General conditions: (1) [1b] ) [2a] ) 2.8 mM, BF3‚OEt2, CH2Cl2, rt,
Ar, 1 h; (2) p-chloranil (1 equiv), CH2Cl2, reflux, 1 h. b Isolated yield.
optimization was performed for corrole 4a and a 1-1 ratio
of dipyrromethane 1b and pyrimidinecarbaldehyde 2a was
used, rather than the stoichiometric 2-1 ratio. The excess
of pyrimidinecarbaldehyde could, however, easily be reco-
vered on chromatographic purification of the corrole. On
using 0.85 equiv of BF3‚OEt2, only A2B2-porphyrin 5a was
formed in a very high yield (50%), and the porphyrin amount
gradually decreased when less catalyst was used. For a
BF3‚OEt2 content ranging from 0.027 up to 0.102 equiv, both
(21) A similar optimization study of the amount of Lewis acid is currently
being explored for the stoichiometric 2-1 ratio.
(22) See the Supporting Information for more details.
(23) (a) Wasbotten, I. H.; Wondimagegn, T.; Ghosh, A. J. Am. Chem.
Soc. 2002, 124, 8104. (b) Bru¨ckner, C.; Brinas, R. P.; Krause Bauer, J. A.
Inorg. Chem. 2003, 42, 4495. (c) Steene, E.; Dey, A.; Ghosh, A. J. Am.
Chem. Soc. 2003, 125, 16300.
(24) The electronic ground state of Cu-corroles has been revisited
recently: Bro¨ring, M.; Bre´gier, F.; Consul Tejero, E.; Hell, C.; Holthausen,
M. C. Angew. Chem., Int. Ed. 2007, 46, 445.
(25) In tris(pentafluorophenyl)corrole, the most studied corrole derivative
to date, the p-fluorine substituents can also be replaced by SNAr, as was
demonstrated in the reaction with o-pyridyllithium (1 h at -78 °C in THF,
35% yield, ref 2b).
(26) Both SNAr and Suzuki reactions were also successful on Fb corrole
4a, but the obtained yields are significantly lower due to the (oxidative)
lability of the corroles.
(20) The effect of the BF3‚OEt2 content was somewhat underestimated
in our previous work (ref 9b,c). The importance of the concentration of
TFA as an acid catalyst in corrole synthesis was recognized and extensively
investigated by Gryko et al. (ref 2f-h).
Org. Lett., Vol. 9, No. 16, 2007
3167

Scheme 3. Functionalization of meso-Pyrimidinyl-Substituted
Corroles via SNAr or Pd-Catalyzed Suzuki/Stille Reactions
Scheme 4. Functionalization of meso-Pyrimidinyl-Substituted
Corroles via Liebeskind-Srogl Cross-Coupling
Stille cross-couplings. Reaction of 2-(tributylstannyl)thio-
phene with 6a in the presence of CsF afforded o,o′-dithienyl-
substituted pyrimidinylcorrole 9 in 73% yield (Scheme 3).
The substituent at the 2-position of the meso-pyrimidinyl
group can be introduced at the pyrimidinecarbaldehyde stage.
This implies, however, that a number of synthetic steps have
to be performed in order to obtain each of the pyrimidine-
carbaldehyde precursors individually. Therefore, an alterna-
tive strategy was developed that enables introduction of
functional moieties at the corrole stage by Pd-catalyzed
Liebeskind-Srogl27 cross-coupling reactions on thiomethyl
functionalized corrole 6d. This is particularly useful if the
pyrimidinecarbaldehyde precursor is hard to obtain. Reac-
tion of 6d with 4-cyanophenylboronic acid in the presence
of copper(I) thiophene-2-carboxylate (CuTC) afforded
Cu-corrole 10 in 61% yield (Scheme 4). On reaction of Fb
corrole 4d with phenylboronic acid in the presence of
Pd(PPh3)4 and a small excess of CuTC (1.2 equiv), only
metalation of the corrole was observed. On addition of a
fresh amount of CuTC (2 equiv), the desired phenyl-
substituted corrole 6b was obtained in 80% yield, essentially
without any Suzuki-type reaction at the chlorine substituents.
In summary, novel meso-pyrimidinyl-substituted A2B-
corroles have been synthesized in high yields by condensa-
tion of 5-mesityldipyrromethane and 2-substituted 4,6-
dichloropyrimidine-5-carbaldehydes, in a 1-1 ratio, catalyzed
by BF3‚OEt2. The borontrifluoride content was optimized
to maximize the corrole yield (up to 35%) and reduce the
porphyrin formation. The presented corroles are very attrac-
tive scaffolds for the preparation of sophisticated functional
corroles (useful toward applications, e.g., catalysis or cancer
therapy) due to the ease and broad scope of functionalization
of the dichloropyrimidinyl moiety. The o,o′-chlorine groups
on the pyrimidine substituent can easily be exchanged via
SNAr and Pd-catalyzed Suzuki or Stille cross-couplings,
affording sterically shielded “double picket fence” corroles
in high yields. On the other hand, the 2-pyrimidinyl position
can be equipped with various substituents ready for further
elaboration of the corrole macrocycle, either by introduction
on the pyrimidinecarbaldehyde building blocks or by intro-
duction at the corrole stage via Liebeskind-Srogl reactions.
Further exploration of the synthesis and functionalization of
various types of meso-pyrimidinyl-substituted (metallo)-
corroles will be reported in due course.
Acknowledgment. The authors thank the Fund for
Scientific Research-Flanders (FWO) for financial support
and a postdoctoral fellowship to W.M., and the Katholieke
Universiteit Leuven for continuing financial support.
Supporting Information Available: Experimental pro-
cedures, characterization data, 1H and 13C NMR and
selected UV-vis spectra for the novel A2B-corroles, and
some details regarding the optimization of the corrole yield.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(27) (a) Liebeskind, L. S.; Srogl, J. Org. Lett. 2002, 4, 979. (b) Kusturin,
C.; Liebeskind, L. S.; Rahman, H.; Sample, K.; Schweitzer, B.; Srogl, J.;
Neumann, W. L. Org. Lett. 2003, 5, 4349.
OL071226A
3168
Org. Lett., Vol. 9, No. 16, 2007