The dithianyl group as a synthon in porphyrin chemistry: Condensation reactions and preparation of formylporphyrins under basic conditions

Article abstract of DOI:10.1021/ja045223u

Vilsmeier formylation is one of the most widely used substitution reactions for the functionalization of porphyrins. However, its utility is limited by the electrophilic/acidic reaction conditions, deactivation of the aromatic system and regiochemical pro

Full text of DOI:10.1021/ja045223u

Published on Web 10/05/2004
The Dithianyl Group as a Synthon in Porphyrin Chemistry: Condensation
Reactions and Preparation of Formylporphyrins under Basic Conditions
Mathias O. Senge,*,† Sabine S. Hatscher,† Arno Wiehe,‡ Katja Dahms,† and Andrea Kelling†
Institut fu¨r Chemie, UniVersita¨t Potsdam, Karl-Liebknecht-Str. 24-25, D-14476 Golm, Germany, and
Institut fu¨r Chemie, Organische Chemie, Freie UniVersita¨t Berlin, Takustr. 3, D-14495 Berlin, Germany
Received August 7, 2004; E-mail: mosenge@chem.uni-potsdam.de
Scheme 1. Synthesis of 1,3-Dithianylporphyrins via Condensation
Despite an increasing number of technical, biomedicinal, and
chemical applications of porphyrins, only few methods exist to
introduce functional groups at the meso positions of the macrocycle.1a
Newer developments are transition metal-catalyzed coupling reac-
tions requiring use of halogenoporphyrins1b and SNAr reactions
using strong nucleophiles.1c Historically, SEAr reactions have been
used widely, notably Vilsmeier formylation and related reactions.2
Formylporphyrins are excellent precursors for subsequent trans-
formations; however, their utility is rather limited, as formylation
requires use of acidic conditions and works well only with NiII or
CuII complexes and introduction of a CHO group deactivates the
system toward further formylations. Thus, no practical methods
exists for meso-polyformylporphyrins.3 To overcome these limita-
tions we have developed a new synthetic concept for functionalized
porphyrins using the 1,3-dithianyl residue as a synthon in porphyrin
chemistry.
Reactionsa
Current progress1a toward unsymmetrically substituted tetra-
pyrroles, both with condensation or substitution methods, offers
the possibility to introduce functional groups in a strategic and
regiochemical manner provided that appropriate synthons are
available.4 A classic synthon is the 1,3-dithiane-2-yl residue
developed by Seebach and Corey.5 Derivatives thereof are useful
acyl anion equivalents and were used both as a functional and
protected formyl group.6 Thus, the lithio derivative of 1 offers the
possibility to introduce latent formyl groups under nucleophilic
instead of electrophilic conditions.
The dithianyl synthon can be used in two different strategies for
the preparation of novel porphyrins.7 First, reaction of 1 with DMF
yields the aldehyde 2,8 which we have used as a key building block
for porphyrins via condensation reactions (Scheme 1).9 Aldehyde
2 can be converted in quantitative yield into the dipyrromethane
3,10a which in turn is a useful building block for various condensa-
tions. Depending on the other reactants or the reaction conditions,
2 was used to prepare porphyrins with two to four dithianyl residues.
For example, a 3 + 1 condensation gave the 5,10-disubstituted
derivative 4 in low yield,10b while the 5,15-derivative 5 was obtained
by reaction with dipyrromethane and TFA catalysis in 16%.
More complicated were reactions aimed at the preparation of
the seemingly simple 5,10,15,20-tetrasubstituted porphyrin 7.
Standard condensations, for example, reaction of 3 with 2 or
reaction of 2 with pyrrole under BF3‚OEt2 catalysis, afforded the
5,10,15-trisubstituted porphyrin 6 in 56% yield, each. Presumably,
the target compound 7 is rather unstable. Related fragmentation
reactions for nonporphyrinic systems have thus far been observed
only in mass spectrometric studies.11 However, 7 is accessible from
2 and pyrrole by using traces of BF3 followed by neutralization
with NEt3 to afford the 5,10,15,20-tetrakis(1,3-dithianyl)-porphy-
rinogen in 53% yield. Subsequent oxidation with DDQ followed
a Conditions: (a) n-BuLi, THF, -78 °C, 1 h; then -10 °C, DMF, 2 h;
then 0 °C, 16 h; then ice, 85%. (b) Pyrrole, BF3‚OEt2, rt, 40 min, then
NaOH, 96%. (c) CH2Cl2, tripyrrane, pyrrole, 45 min, rt; then TFA, rt, 16
h; then DDQ; then NEt3, 3%. (d) CH2Cl2, dipyrromethane, TFA, 14 h, rt;
then DDQ, 10 min, reflux, 16%. (e) CH2Cl2, pyrrole, BF3‚OEt2, 1 h, rt;
then NEt3, DDQ, 4 min, 15%. (f) CH2Cl2, pyrrole, BF3‚OEt2, 1 h, rt; then
excess DDQ, 1 h, 46%. (g) CHCl3, 8 equiv of bis(trifluoroacetoxy)iodo-
benzene (BTIB), 45 °C, 30 min, 62%. (h) CHCl3, 4 equiv of BTIB, rt, 30
min, 30%.
by rapid workup gave 7 in 15% yield with respect to 2. Isolated 7
rapidly decomposed in solution in the presence of traces of acid
and air under intermediary formation of 6.12
Porphyrins with both meso alkyl/aryl and dithianyl groups are
much more stable. For example, standard 2 + 2 condensation
reactions gave porphyrin 12 with two dithianyl residues ac-
companied by 10 (due to scrambling) in low yields (Scheme 2).
These compounds and those having not more than two dithianyl
groups are reasonably stable toward chemical transformations. For
example, 10 could be metalated with zinc acetate at room
temperature in 60% yield and demetalated with BBr3 in 50% yield.14
Our initial results on the dethioacetylation15 reactions mimic these
stabilities. While 10 and 12 could be quickly and quantitatively
converted into the formylporphyrins 11 and 13 using DDQ,16a all
attempts with 6 or 7 gave only partial deprotection and complex
† Universita¨t Potsdam.
‡ Freie Universita¨t Berlin.
9
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J. AM. CHEM. SOC. 2004, 126, 13634-13635
10.1021/ja045223u CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2. 2 + 2 Condensation Reactionsa
and substitution reactions. This opens a new access to formylpor-
phyrins under either mildly acidic or basic reaction conditions and
offers the potential to prepare all possible homologues and
regioisomers of poly-meso-formylporphyrins. Currently, we are
optimizing the reactions described herein and trying to develop
methods for the deprotection of 6 and 7. Additionally, the possibility
to use derivatives of 1 as photocleavable linkers in supramolecular
multiporphyrin systems exists, as the photolytic cleavage of
dithianyl derivatives has been described.20
Acknowledgment. We thank the DFG (Se543/6-2 and /5-2) for
their generous financial support and Bernd Lu¨bcke for technical
assistance.
a Conditions: (a) CH2Cl2, 5-phenyldipyrromethane, catalytic TFA, 16
h, rt; then DDQ, 45 min, 10 3%, 12 2%. (b) CH2Cl2, benzaldehyde, catalytic
TFA, 16 h, rt; then DDQ, 45 min, 10 2%, 12 4%. (c) CH2Cl2, DDQ,
BF3‚OEt2, rt, 10 min, 97%.
Supporting Information Available: Selected experimental pro-
cedures and compound characterization data (PDF) and full crystal-
lographic data for 12 (CIF-file). This material is available free of charge
via the Internet at http://pubs.acs.org.
Scheme 3. Synthesis of Formylporphyrins via SNAr Reactionsa
References
(1) (a) Vicente, M. G. H. In The Porphyrin Handbook; Kadish, K. M., Smith,
K. M., Guilard, R., Eds.; Academic Press: New York, 2000; Vol. 1, pp
149-199. (b) Burrell, A. K.; Officer, D. L.; Plieger, P. G.; Reid, D. C.
W. Chem. ReV. 2001, 101, 2751-2796. (c) Senge, M. O.; Kalisch, W.
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(4) Classic formylation reactions would result in the formation of product
mixtures: Morgan, A. R.; Rampersaud, A.; Garbo, G. M.; Keck, R. W.;
Selman, S. H. J. Med. Chem. 1989, 32, 904-908. Torpin, J. W.; Ortiz de
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(7) For use of 4-(1,3-dithiolan-2-yl)pyrrole for â-formylporphyrins, see:
Fumoto, Y.; Uno, H.; Murashima, T.; Ono, N. Heterocycles 2000, 54,
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(8) Meyers, A. I.; Strickland, R. C. J. Org. Chem. 1972, 37, 2579-2583.
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(10) Reaction conditions modified from: (a) Littler, B. J.; Ciringh, Y.; Lindsey,
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Tetrahedron Lett. 2003, 44, 157-160.
(11) Sturaro, A.; Traldi, P. Org. Mass Spectrom. 1986, 21, 335-341.
(12) 5,10,15,20-Tetraalkylporphyrins with similar steric bulk have been shown
to undergo atypical side reactions.13 Additionally, all dithianyl-containing
porphyrins showed significant line broadening for the â-protons neighbor-
ing these groups, indicating hindered rotation. A single-crystal X-ray
structure determination of 12 shows the S-S vector in each dithianyl
residue to be orthogonal to the mean plane of the macrocycle ( 91.3°).
The macrocycle exhibits a minor waV distortion and some core elongation.
(13) Ema, T.; Senge, M. O.; Nelson, N. Y.; Ogoshi, H.; Smith, K. M. Angew.
Chem., Int. Ed. Engl. 1994, 33, 1879-1881. Senge, M. O.; Bischoff, I.;
Nelson, N. Y.; Smith, K. M. J. Porphyrins Phthalocyanines 1999, 3, 99-
116.
(14) During preparation of the manuscript, the synthesis of 11 and related
systems using acetal groups via multistep syntheses was reported:
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a Conditions: (a) n-BuLi, THF, -40 °C, 2 h, 100%. (b) THF, -78 °C,
TMED, 15 min; then rt, H2O, 15 min; then DDQ, rt, 15 min, 15a 54%,
15b 47%, 15c 53%, 15d 4%, 15e 50%, 15f 10%. (c) CH2Cl2, DDQ, then
BF3‚OEt2, rt, 45 min, 96-100%.
mixtures. A variety of different oxidants were tested with 5, and
reproducibleresultswereobtainedsofaronlywithbis(trifluoroacetoxy)-
iodobenzene.16b17 Use of 4 equiv at 50 °C or 8 equiv at room
temperature resulted in formation of the monoformylporphyrin 818
in 60% yield, while 4 equiv gave the dimethoxy derivative 9.
Second, a potentially more useful strategy involves direct use
of the lithio derivative of 1 as a nucleophile for the substitution of
porphyrins. We have shown that various alkyl and aryllithium
reagents can be used for the direct meso substitution of unactivated
porphyrins in high yield.1c These reactions are regioselective and
may be used for the substitution of all four meso positions, allowing
the synthesis of ABCD porphyrins. Indeed, conversion of 1 into
the lithio nucleophile and reaction with either NiII or free base
porphyrins gave promising results.
As shown in Scheme 3, both meso aryl or alkyl NiII porphyrins
and 5,15-diphenylporphyrin 14b could be substituted in about 50%
yield (unoptimized). Substitution of other free bases (e.g., 14d19
and 14f) is possible but requires further optimization. All respective
formylporphyrins 16, including the free bases, were easily obtained
with DDQ/BF3‚OEt2 in quantitative yield.
(16) (a) Collman, J. P.; Tyvoll, D. A.; Chng, L. L.; Fish, H. T. J. Org. Chem.
1995, 60, 1926-1931. (b) Stork, G.; Zhao, K. Tetrahedron Lett. 1989,
30, 287-290.
(17) Most oxidants, ammonia salts, or reductants gave no reaction at all; DDQ
resulted in degradation.
(18) Schlo¨zer, R.; Fuhrhop, J.-H. Angew. Chem., Int. Ed. Engl. 1975, 14, 363-
364.
(19) Wiehe, A.; Simonenko, E. J., Senge, M. O.; Ro¨der, B. J. Porphyrins
Phthalocyanines 2001, 5, 758-761.
(20) Mitkin, O. D.; Wan, Y., Kurchan, A. N.; Kutateladze, A. G. Synthesis
2001, 8, 1133-1142.
In conclusion, we have shown the dithianyl residue to be a
convenient synthon in porphyrin chemistry, both for condensation
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