Diethyl 2,7-dibromo-4H,5H-thieno[3,2-b:4,5-b′]dipyrrole-3,6- dicarboxylate: A key intermediate for a diversity oriented synthesis of 2,7,12,17-tetraarylporphycenes

Article abstract of DOI:10.1021/ol052913+

A new Suzuki-based strategy for the synthesis of 4,4′-diaryl (or heteroaryl)-substituted 2,2′-bipyrroles (10), precursors of 2,7,12,17-tetraaryl (or heteroaryl)-substituted porphycenes, is described. Bromination of the previously described diethyl 4H,5H-t

Full text of DOI:10.1021/ol052913+

ORGANIC
LETTERS
2006
Vol. 8, No. 5
847-850
Diethyl 2,7-Dibromo-4H,5H-
thieno[3,2-b:4,5-b ]dipyrrole-3,6-
′
dicarboxylate: A Key Intermediate for a
Diversity Oriented Synthesis of
2,7,12,17-Tetraarylporphycenes
Ofir Arad, Jordi Morros, Xavier Batllori, Jordi Teixido´, Santiago Nonell, and
Jose´ I. Borrell*
Grup d’Enginyeria Molecular, Institut Qu´ımic de Sarria`, UniVersitat Ramon Llull, Via
Augusta, 390, E-08017 Barcelona, Spain
j.i.borrell@iqs.url.edu
Received December 1, 2005
ABSTRACT
A new Suzuki-based strategy for the synthesis of 4,4′-diaryl (or heteroaryl)-substituted 2,2′-bipyrroles (10), precursors of 2,7,12,17-tetraaryl (or
heteroaryl)-substituted porphycenes, is described. Bromination of the previously described diethyl 4H,5H-thieno[3,2-b:4,5-b
dicarboxylate afforded dibromo compound 19, which is the key intermediate of such strategy.
′]dipyrrole-3,6-
Porphycenes (1) are porphyrin isomers with much higher
absorption coefficients above 630 nm, which is the spectral
region of interest for photodynamic therapy of cancer (PDT).
In fact, studies of cell photoinactivation have demonstrated
their usefulness as PDT photosensitizers.1 However, since
the synthesis by Vogel and co-workers of the parent
nonsubstituted compound 1{1} in 1986,2 only a few variants
of the initial synthetic methodology have been described.3-5
All of them are based on an Ullmann dimerization of a
preformed pyrrole which carries the R susbstituent present
in the resulting porphycene (Figure 1).
(1) (a) Guardiano, M.; Biolo, R.; Jori, G.; Schaffner, K. Cancer Lett.
1989, 44, 1. (b) Milanesi, C.; Biolo, R.; Jori, G.; Schaffner, K. Laser Med.
Sci. 1991, 6, 437. (c) Richert, C.; Wessels, J. M.; Muller, M.; Kisters, M.;
Benninghaus, T.; Goetz, A. E. J. Med. Chem. 1994, 37, 2797. (d) Aicher,
A.; Miller, K.; Reich E.; Hautmann, R. Urol. Res. 1994, 22, 25. (e)
Villanueva, A.; Can˜ete, M.; Nonell, S.; Borrell, J. I.; Teixido´, J.; Juarranz,
A. Anti-Cancer Drug Des. 1996, 11, 89. (f) Can˜ete, M.; Lapen˜a, M.;
Juarranz, A.; Vendrell, V.; Borrell, J. I.; Teixido´, J.; Nonell, S.; Villanueva,
A. Anti-Cancer Drug Des. 1997, 12, 543. (g) Karrer, S.; Abels, C.; Szeimies,
R.-M.; Baumler, W.; Dellian, M.; Hohenleutner, U.; Goetz, A. E.;
Landthaler, M. Arch. Dermatol. Res. 1997, 289, 132. (h) Karrer, S.;
Szeimies, R.-M.; Ebert, A.; Fickweiler, S.; Abels, C.; Ba¨umler W.;
Landthaler, M. Laser Med. Sci. 1997, 12, 307. (i) Can˜ete, M.; Ortiz, A.;
Juarranz, A.; Villanueva, A.; Nonell, S.; Borrell, J. I.; Teixido´ J.; Stockert,
J. C. Anti-Cancer Drug Des. 2000, 15, 143. (j) Can˜ete, M.; Ortega, C.;
Gavalda`, A.; Cristo´bal, J.; Juarranz, A.; Nonell, S.; Teixido´, J.; Borrell, J.
I.; Villanueva, A.; Rello S.; Stockert, J. C. Int. J. Oncol. 2004, 24, 1221.
Figure 1. 2,7,12,17-Substituted porphycenes (1{1-5}).
Thus, the original methodology3 starts from a diethyl
2-methylpyrrole-3,5-dicarboxylate (2, R1 ) Et) bearing the
10.1021/ol052913+ CCC: $33.50
© 2006 American Chemical Society
Published on Web 01/31/2006

Scheme 1. Described Methodologies for the Synthesis of 2,7,12,17-Tetrasubstituted Porphycenes 1
desired R substituent (Scheme 1). Compound 2 is oxidized
recently by Hayashi et al. to obtain the first fluorine-
to the corresponding carboxylic acid 3 (R1 ) Et) which, in
turn, is converted to the iodo derivative 4 (R1 ) Et). This
later undergoes de-halogen coupling to the tetraester 5 (R1
) Et), which is hydrolyzed to the tetraacid 6. Sublimation
of 6 yields the unstable bipyrroles 7 that underwent formy-
lation to give the corresponding diformyl derivative 8. This
latter compound is transformed to the desired porphycene
(1) by a McMurry coupling. Such a procedure has been used
for the synthesis of several alkyl-substituted porphycenes
such as 1{2} (R ) Me), 1{3} (R ) C2H5), and 1{4} (R )
C3H7).6
containing porphycenes.5
All of the preceding methods present two major draw-
backs: (a) A change of substituent R, to improve the
drugability and photochemical properties of the final por-
phycene, forces the development of a de novo synthesis, and
(b) such methodologies are far from being of general
applicability.
Thus, the nature of R greatly influences the performance
of the reactions precluding the synthesis of some target
compounds. This was the case, for instance, of the 2,7,12,17-
tetra(pyridin-4-yl)porphycene 5{6} (R ) C6H4N), which
failed in our hands in the steps previous to the Ullmann
coupling.
All of these synthetic limitations combined with our
interest in 2,7,12,17-tetraaryl-substituted porphycenes, due
to the interesting photophysical properties7 and biological
activity1e,i,j found in 2,7,12,17-tetraphenylporphycene (1{5},
R ) Ph), impelled us to develop a synthetic route for such
porphycenes in which the aryl (or heteroaryl) R substituents
will be introduced on a preformed 2,2′-bipyrrole in the later
stages of the itinerary. Such a concept was used by our group
in 2003 to obtain 2,7,12,17-tetraaryl-3,6,13,16-tetraazapor-
phycenes (13) from a dibromo-substituted biimidazole (12)
(Figure 2).8
A literature search carried out revealed 4,4′-dibromo-1,1′-
bis(trimethylsilyl)bipyrrole (14)9 as a possible starting mate-
rial for our purpose. However, the very low yield (10%) in
the formation of the starting 1,1′-bis(trimethylsilyl)bipyrrole
precluded its use.
Our group described in 1995 the synthesis of 2,7,12,17-
tetraphenylporphycene (1{5}, R ) Ph) by a slight variation
of the aforementioned methodology by which the tetraester
5{5} (R1 ) Et, R ) Ph) is directly transformed into the 5,5′-
diformyl-2,2′-bipyrrole 8{5} (R ) Ph), avoiding the inter-
mediate sublimation.3
More recently, we reported a non-tetradecarboxylative
method to obtain 1{5} (R ) Ph) that avoids passing through
the unstable intermediate 7{5} (R ) Ph).4 We started from
a pyrrole 2{5} (R ) Ph, R1 ) Bn) bearing two orthogonal
ester groups, which was transformed to the corresponding
bipyrrole 5{5} (R ) Ph, R1 ) Bn). The benzyl ester groups
were selectively removed to afford diacid 9{5} (R ) Ph)
that was subsequently decarboxylated to diester 10{5} (R
) Ph). 10{5} was converted in dialdehyde 8{5} (R ) Ph),
precursor of tetraphenyl porphycene 1{5}, using the Mc-
Fadyen-Stevens reaction. A similar concept has been used
(2) Vogel, E.; Ko¨cher, M.; Schmickler, H.; Lex, J. Angew. Chem., Int.
Ed. Engl. 1986, 25, 257.
(3) Nonell, S.; Bou, N.; Borrell, J. I.; Teixido´, J.; Villanueva, A.; Juarranz,
A.; Can˜ete, M. Tetrahedron Lett. 1995, 36, 3405.
Consequently, we focused on structure 15, described by
Farnier et al. in 1976,10 as a possible precursor of 2,7,12,17-
(4) Gavalda`, A.; Borrell, J. I.; Teixido´, J.; Nonell, S.; Arad, O.; Grau,
R.; Can˜ete, M.; Juarranz, A.; Villanueva, A.; Stockert, J. C. J. Porphyrins
Phthalocyanines 2001, 5, 846.
(5) Hayashi, T.; Nakashima, Y.; Ito, K.; Ikegami, T.; Aritome, I.; Suzuki,
Hisaeda, Y. Org. Lett. 2003, 5, 2845.
(6) Vogel, E.; Balci, M.; Pramod, K.; Koch, P.; Lex, J.; Ermer, O. Angew.
Chem., Int. Ed. Engl. 1987, 26, 928.
(7) Rubio, N.; Prat, F.; Bou, N.; Borrell, J. I.; Teixido´, J.; Villanueva,
A.; Juarranz, A.; Can˜ete, M.; Stockert, J. C.; Nonell, S. New J. Chem. 2005,
29, 378.
(8) Nonell, S.; Borrell, J. I.; Borro´s, S.; Colominas, C.; Rey, O.; Rubio,
N.; Sa´nchez-Garc´ıa, D.; Teixido, J. Eur. J. Org. Chem. 2003, 1635.
(9) Benincori, T.; Brenna, E.; Sannicolo`, F.; Zotti, G.; Zecchin, S.;
Schiavon, G.; Gatti, C.; Frigerio, G. Chem. Mater. 2000, 12, 1480.
848
Org. Lett., Vol. 8, No. 5, 2006

for the next steps without further purification. Once the
dibromo compound was obtained, we faced the key step of
our synthetic strategy: the introduction of the R-substituent
by a Suzuki reaction.
We treated 19 with phenylboronic acid (RB(OH)2, R )
Ph) using a wide range of reaction conditions which include
the following: Pd(PPh3)4, PdCl2(dppf) or Pd(OAc)2 and
Buchwald ligand14 as catalysts; Na2CO3, K3PO4 or CsF as
bases; DMF, dimethoxyethane, or 1,4-dioxane as solvents;
the use of conventional or microwave heating. However, the
desired diphenyl-substituted derivative was not formed in
any case. These results are in agreement with literature
reports, indicating that, in some cases, the Suzuki coupling
does not proceed on unprotected pyrroles.15
Figure 2.
Consequently, we decided to protect both nitrogen atoms
of dibromothienodipyrrole 19. Treatment with methyl chlo-
roformate using NaH as base and anhydrous THF as solvent
afforded the monoprotected derivative 23 in 60% yield. All
efforts carried out to achieve diprotection failed. Thus, when
19 was treated with MeOCOCl/K2CO3/TBAI (tetrabutylam-
monium iodide) in DMF,16 the N,N′-dimethyl-substituted
thienodipyrrole 24 was surprisingly obtained (Figure 3).
tetraarylporphycenes. This compound fulfills the require-
ments needed for our synthetic approach: (i) The pyrrole
rings of 15 only present free those positions in which we
want to introduce the bromine atoms; (ii) the sulfur bridge,
easily removable with Raney nickel according to Farnier,11
blocks the two inner positions of the bipyrrolic system
present in 15 avoiding further substitution there, which would
compromise planarity of the resulting porphycene;5 and (iii)
15 contains two ester groups easily transformable into the
required aldehydes by using the aforesaid McFadyen-
Stevens protocol.4
The thieno[3,2-b:4,5-b′]dipyrrole (15) is obtained (Scheme
2) starting from the commercially available thiophene-2,5-
dicarboxaldehyde (16), also accessible from thiophene,12 by
treatment with ethyl azidoacetate (17) in NaOEt/EtOH to
afford bis(azido-2′-ethoxycarbonyl-2′-vinyl)-2,5-thiophene
(18) in 54% yield. Compound 18 is transformed in the
desired thienodipyrrole 15 by heating in xylene at reflux
(85% yield). This optimized procedure allows us to obtain
15 in 100 g scale.13
Bromination of 15 was first assayed by using N-bromo-
succinimide or 1,3-dibromo-5,5-dimethylhydantoin, typical
brominating agents for pyrroles, in a wide range of organic
solvents, but in no case was compound 19 even detected.
Thus, we treated 15 with Br2 in a 2:5 AcOH/AcOEt mixture
to yield the desired dibromo derivative 19 in 89% yield as
a white precipitate of high purity that can be directly used
Figure 3.
Fortunately, treatment of 19 with trimethylsilylethoxy-
methyl chloride (SEM-Cl) with NaH in THF yielded the
N,N′-di(SEM) protected thienodipirrole 20 (G ) SEM) in
94% yield (Scheme 2).17
The Suzuki coupling between 20 and RB(OH)2 (R ) Ph)
in the presence of Pd(PPh3)4 and Na2CO3 in 1,4-dioxane gave
the diphenyl-substituted thienodipyrrole 21{5} (R ) Ph) in
quantitative yield. Similarly obtained were the di(pyridin-
4-yl)-substituted derivative 21{6} (R ) C6H4N) and the di-
Scheme 2
Org. Lett., Vol. 8, No. 5, 2006
849

(p-methoxyphenyl)-substituted one 21{7} (R ) p-MeOC6H4),
in 95% and 100% yield, respectively, upon treatment of 20
with the corresponding boronic acids.
Desulfurization of 21{5}, 21{6}, and 21{7} was carried
out by treatment with Raney Ni in ethanol to afford
bipyrroles 22{5} (R ) Ph) and 22{6} (R ) C6H4N) in
quantitative yield, while bipyrrole 22{7} (R ) p-MeOC6H4)
was obtained in 94% yield (Scheme 2).
During the removal of the SEM protecting groups of
22{5}, 22{6}, and 22{7}, we found problems similar to those
described by Rawal and Cava.18 Finally, the reaction was
achieved by using TBAF in 1,4-dioxane at reflux to yield
10{5} (R ) Ph), 10{6} (R ) C6H4N), and 10{7} (R )
p-MeOC6H4) in 93%, 89%, and 91% yield, respectively
(Scheme 2), proving the general applicability of this synthetic
approach.
synthesis of 2,7,12,17-tetraphenylporphycene (1{5}, R ) Ph)
(see Scheme 1) and, on the other, opens a new general route
for the synthesis of 2,7,12,17-tetraaryl (or heteroaryl)-
substituted porphycenes.
An application of such methodology to the production of
porphycene libraries is currently underway.
Acknowledgment. Financial support by the Spanish
MCyT is gratefully acknowledged (Grant No. SAF2002-
04034-C02-02). O.A. thanks Fundacio´ Patronal Institut
Qu´ımic de Sarria` for a predoctoral fellowship.
Supporting Information Available: Detailed synthetic
procedures and spectroscopic characterization of compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL052913+
The preparation of 10{5} (R ) Ph), 10{6} (R ) C6H4N),
and 10{7} (R ) p-MeOC6H4) completes, in one side, a new
(16) Handy, S. T.; Sabatini, J. J.; Zhang, Y.; Vulfova, I. Tetrahedron
Lett. 2004, 45, 5057.
(10) Farnier, M.; Soth, S.; Fournari, P. Can. J. Chem. 1976, 54, 1074.
(11) Farnier, M.; Soth, S.; Fournari, P. Can. J. Chem. 1976, 54, 1083.
(12) Feringa, B. L.; Hulst, R.; Rikers, R.; Brandsma, L. Synthesis 1988,
316.
(17) Diethyl 2,7-Dibromo-4H,5H-bis(trimethylsilylethoxymethyl)-
thieno[3,2-b:4,5-b′]dipyrrole-3,6-dicarboxylate (20). NaH (2.1 g, 60% in
mineral oil) was added portionwise to a suspension of 11 g (24 mmol) of
19 in 50 mL of anhydrous THF under Ar atmosphere. The resulting mixture
was stirred for 15 min at room temperature. Then, 15 mL of trimethylsi-
lylethoxymethyl chloride (SEM-Cl) was added dropwise, and the resulting
solution was stirred for 1 h at room temperature. Crushed ice (100g) was
added, and the resulting mixture was stirred until a precipitate appeared.
The solid was filtered, washed with MeOH until it became white, and dried
over P2O5 in vacuo (50 °C) to yield 13.4 g (18 mmol, 77%) of 20. The
mother liquor was extracted with hexane, washed (MgSO4), and concentrated
in vacuo to yield an extra crop of 3.0 g (4 mmol, 17%) of 20: mp 127-
129 °C; IR (KBr) νmax 2952, 2902, 1705, 1382, 1319, 1228, 1088, 920,
(13) Diethyl 2,7-Dibromo-4H,5H-thieno[3,2-b:4,5-b′]dipyrrole-3,6-di-
carboxylate (19). A solution of 3 mL of Br2 in 45 mL of AcOH was added
dropwise to a suspension of 3.0 g (9.7 mmol) of 15 in a mixture of 250 mL
of AcOEt and 100 mL of AcOH. The resulting mixture was stirred for 8 h
at room temperature. The resulting precipitate was filtered, washed with 3
× 50 mL of an aqueous NaHCO3 solution, and dried over P2O5 in vacuo
(50 °C) to yield 4.1 g (8.7 mmol, 89%) of 19 as a white solid: mp > 290
°C dec; IR (KBr) νmax 3417, 3327, 2924, 2853, 1686, 1649, 1375, 1230
cm-1; 1H NMR (DMSO-d6) δ 11.52 (s, 2H, NH), 4.34 (q, 4H, J ) 7.2 Hz,
O-CH2CH3), 1.35 (t, 6H, J ) 7.2 Hz, O-CH2CH3); 13C NMR (DMSO-d6)
δ 158.9, 127.7, 125.2, 121.9, 96, 1, 60, 6, 14.3; MS (70 eV) m/z 463.6 ([M
+ 2H]+), 419.6, 371.6, 264.7; HRMS calcd for C14H12Br2N2O4S 461.8884,
found 461.8892. Anal. Calcd for C14H12Br2N2O4S: C, 36.23; H, 2.61; N,
6.04; S, 6.91. Found: C, 36.11; H, 2.54; N, 5.98; S, 6.59.
1
859, 835 cm-1; H NMR (CDCl3) δ 6.27 (s, 4H, N.-CH2), 4.41 (q, 4H, J
) 7.2 Hz, O-CH2CH3), 3.51 (t, 4H, J ) 8.4 Hz, O-CH2), 1.45 (t, 6H, J )
7.2 Hz, O-CH2CH3), 0.83 (t, 4H, J ) 8.4 Hz, Si-CH2), -0.07 (s, 18H,
Si-(CH3)3); 13C NMR (CDCl3) δ 160.5, 130.7, 128.5, 123.9, 99.6, 75.0,
65.9, 61.1, 17.9, 14.4, -1.4; MS (ESI-TOF) m/z ) 747.0 ([M + Na +
2H]+), 337.3, 236.1, 218.2, 163.0; HRMS (MALDI-TOF) calcd for C26H40-
Br2N2O6SSi2 + Na 745.041, found 745.040. Anal. Calcd for C26H40Br2N2O6-
SSi2: C, 43.09; H, 5.56; N, 3.87; S, 4.42. Found: C, 43.25; H, 5.37; N,
3.64; S, 4.21.
(14) Walker, S. D.; Barder, T. E.; Martinelli, J. R.; Buchwald, S. L.
Angew. Chem. Int. Ed. 2004, 43, 1871.
(15) (a) Ghosez L.; Franc C.; Denonne F.; Cuisinier C.; Touillaux R.
Can. J. Chem. 2001, 79, 1827. (b) Handy, S. T.; Bregman, H.; Lewis, J.;
Zhang, X.; Zhang, Y. Tetrahedron Lett. 2003, 44, 427.
(18) Rawal, V. H.; Cava, M. P. J. Am. Chem. Soc. 1986, 108 (8), 2110.
850
Org. Lett., Vol. 8, No. 5, 2006