Cycloaddition reactions of porphyrins

Adequately substituted porphyrins can participate in pericyclic reactions as dienes, dienophiles, dipolarophiles and as 1,3-dipoles. They also show interesting dipolar 1,5-electrocyclizations and cheletropic reactions with carbenes. All these different types of reactivity have been exploited in order to synthesize new potential biologically active porphyrin derivatives, mainly chlorins and bacteriochlorins. This paper reviews the most recent works where porphyrins have participated in pericyclic reactions

Amongst natural heterocycles the porphyrin-type compounds have a prominent position in Nature.It is known for a long time that certain vital functions, like respiration, photosynthesis, drug detoxification, and others depend on the action of some porphyrin-type metal complexes.Life without such compounds would be totally different from what it is on Earth.It was early recognised 1 that there is a close relationship between protoheme, the respiratory enzymes' prosthetic group, and chlorophyll a, a photosynthetic green pigment in plants.A great deal of work has been put since then on the establishment of synthetic routes leading to porphyrin derivatives.Two landmarks have to be mentioned: the synthesis of protoporphyrin-IX (1) by Fischer in 1929, 2 and the synthesis of chlorophyll a (2) by Woodward and his seventeen postdoctoral colleagues in 1960. 3Research has also been centred on physical chemistry and biochemical aspects of such macrocycles. 4,5More recently several groups have reported promising applications for porphyrin derivatives.Mimicking the cytochrome P 450 activity, several metalloporphyrins can be used as oxidative catalysts. 6On the biological side it is known that such compounds can be used in the diagnosis and treatment of neoplastic diseases. 7Certain types of cancer are being treated in several countries by using a formulation containing a purified derivative of hematoporphyrin (Photofrin ® ), the technique being known as Photodynamic Therapy (PDT).Bactericidal and virucidal activities are also known for some porphyrins. 8More recently, the age-related macular degeneration is being treated by, using a chlorin (a dihydrotype porphyrin) derivative (3). 7Other derivatives, such as bacteriochlorins (tetrahydro-type porphyrins) are being tested in PDT.Due to their intense absorption in the red region of the spectrum, chlorins and bacteriochlorins might play a key role against cancer and other diseases.How can such types of porphyrin derivatives be made?Certainly by total chemical synthesis.However many steps may be involved with the synthesis of several intermediates.A better alternative can be the chemical modification of simple porphyrins, namely via cycloaddition transformations.For instance, if a porphyrin macrocycle is substituted with a vinyl group, then the latter and a peripheral double bond of the macrocycle can act as a diene system.In such way the macrocycle can react with dienophiles to yield Diels-Alder adducts.Our group has shown that meso-tetraarylsubstitued porphyrins can also participate as dienophiles or as dipolarophiles, increasing the possibilities of using these compounds in other types of cycloadditions.New derivatives of the porphyrin, chlorin and bacteriochlorin types have been obtained in good yields using such types of transformations.

Porphyrins as Dienes
It was recognized more than thirty years ago that vinyl porphyrins can react as dienes 9,10 and since then this has been the subject of several studies.In 1969 the formation of photoproducts such as 6, obtained in the reaction of protoporphyrin-IX dimethyl ester 4 with singlet oxygen, was explained via the intermediate [4+2] adduct 5 (Scheme 1). 9 The cycloaddition was referred to occur in either pyrrolic unit but not in both.During the same period, the reactivity of protoporphyrin-IX dimethyl ester with tetracyanoethylene (TCNE) and dimethyl acetylenedicarboxylate (DMAD) was reported to afford isobacteriochlorins (bis-adducts). 10Subsequent reinvestigation of the reaction of protoporphyrin-IX di(t-butyl) ester with TCNE has reported a more complex situation. 11Monoadducts (7-9) and bis-adducts (10-13) from [2+2] and [4+2] cycloadditions were obtained; the expected isobacteriochlorin 13 was only isolated in minor amount.The reaction of protoporphyrin-IX with DMAD was also revised. 12Only monoadducts were obtained (e.g. 14); the elimination of the angular methyl group was described to afford monobenzoporphyrins 15.A direct access to benzoporphyrins was also reported by the same group using a Diels-Alder reaction of a β-unsubstituted-β`-vinylporphyrin with an excess of DMAD. 13The reaction of protoporphyrin-IX with other dienophiles (e.g.β−phenylsulphonylpropiolate, β-phenylsulphonylacrylonitrile) has also been reported. 12 N Me 14 The possibility of β-vinyl-meso-tetraarylporphyrins 16 to act as dienes in Diels-Alder reaction was also investigated. 14With TCNE both the [4+2] and [2+2] adducts, respectively 17 and 18, are obtained (Scheme 2).NMR studies showed that the [2+2] adduct can be obtained by rearrangement of the [4+2] chlorin.The vinylporphyrin 16 (Ar = Ph) also reacts with DMAD to yield chlorin 19 and the benzoporphyrin 20. 15 Compound 20 can be obtained in quantitative yield by oxidation of 19 with DDQ.Later, the reaction of 16 with DMAD and with other dienophiles was reinvestigated but the results are identical to those already published. 16These reactions give different yields when carried out at normal or at high pressure.The same type of approach was also used to synthesize new chlorins, bacteriochlorins and benzoporphyrins from protoporphyrin-IX or other divinylporphyrins, chlorophylls and analogues, in order to evaluate their potential applications in PDT. 17

Scheme 3
The reaction of porphyrins with heterodienophiles was also explored.For instance, protoporphyrin-IX dimethyl ester reacts with substituted nitrosobenzenes to yield the Diels-Alder adducts. 19However, even with the more reactive ones (with electron-withdrawing substituents) only the monoadducts 24a and 25a are obtained.In the presence of an excess of the dienophile the formyl-monoadducts 24b and 25b are also obtained.

Scheme 6
Porphyrin ortho-quinodimethanes can be generated by mild thermal extrusion of SO 2 from porphyrin-fused 3-sulfolenes and trapped with a range of dienophiles. 22As an example, when 33 is heated in the presence of dienophiles the Diels-Alder adducts 35  Pyrrolo[3,4-b]porphyrins 37 24 and 39 25 give Diels-Alder reactions with acetylenedicarboxylates at the exocyclic pyrrole unit (Scheme 8).Upon prolonged heating in refluxing toluene, derivative 40 is converted into benzoporphyrins. 25

Scheme 8
Porphyrins with exocyclic dienic systems have also been used in Diels-Alder reactions with several dienophiles.Compounds 41 26 and 44 27

Porphyrins as Dienophiles
We have shown for the first time that the peripheric double bonds of the porphyrins can participate in [4+2] cycloadditions, as the 2π electrons component.Porphyrins 52a-e react with ortho-benzoquinodimethane 54 (a highly reactive diene generated in situ by, for example, the thermal extrusion of SO 2 from sulfone 53) to give chlorins 55 in moderate yields (Scheme 11). 31hen porphyrins 52a-c are used, together with the expected chlorins 55a-c, two other products are obtained in each case.These are the porphyrins 56 and 57, obtained by dehydrogenation of the corresponding chlorins.However, when meso-tetrakis(pentafluorophenyl)porphyrin 52d is used as dienophile, porphyrins of types 56 and 57 are not formed.The dehydrogenation of the chlorin 55d (Ar = C 6 F 5 ) to 56d and 57d only occurs when it is heated in refluxing toluene in the presence of DDQ.32 In the reaction with 52d, together with chlorin 55d, two stereoisomeric bacteriochlorins 58 (cis and trans) are obtained.These bacteriochlorins have very interesting UV-vis absorption properties with strong bands at 747 and 761 nm; this is an important feature to be fulfilled by a good PDT photosensitizer.

58-cis 58-trans
The formation of chlorins of type 55 is also observed when 5,15-disubstituted arylporphyrins are used.For instance, chlorin 55e is the main product from the reaction of 52e with obenzoquinodimethane 54.
Porphyrins also give Diels-Alder reactions with heterocyclic o-quinodimethanes.For instance, the quinazoline-fused chlorin 59, 32 the quinoxaline-fused chlorin 60, 33 and the isoindole-fused chlorin 61 34  We have also shown that porphyrins react with "stable" dienes like the commercially available polycyclic hydrocarbon pentacene.When a mixture of this compound and a porphyrin 64 in 1,2,4-trichlorobenzene is heated at ca 200ºC, under nitrogen atmosphere, the corresponding Diels-Alder adduct 65 (Scheme 14) is obtained in moderate to good yield (22-87%). 36Using meso-mono-(64a), meso-di-(64b,c) and meso-tetraarylporphyrins (64d-f) as dienophiles a range of novel chlorins with an interesting and unusual three-dimensional structure can be obtained.As expected, with porphyrin 64a two regioisomeric chlorins are obtained.All chlorins 65 show strong absorption bands at ca 650 nm in their UV-vis spectra.Other aminoacids can be used successfully as precursors of different azomethine ylides.As an example, the diasterioisomeric chlorins 72 (35%) and 73 (30%) are obtained from the reaction of porphyrin 52d with the 1,3-dipole generated in situ from proline and paraformaldehyde. 39N-Unsubstituted amino acids can also be used.The reaction of porphyrin 52d with glycine and paraformaldehyde in refluxing toluene gives the expected chlorin 74 (47%) and the isobacteriochlorin (less than 1%). 39he reaction of porphyrins with nitrones also gives the expected monoadducts and, in some cases, bis-adducts of the bacteriochlorin type can also be isolated and characterized.As an example, meso-tetrakis(pentafluorophenyl)porphyrin reacts with nitrone 75 (generated in situ) to give the isoxazolidine-fused chlorin 76 (Scheme 17) in 72% yield (based on consumed starting porphyrin). 39,40Similarly, chlorin derivatives 78a-d (Scheme 17) are obtained in moderate to good yields from the reaction of same porphyrin with the sugar nitrones 77a-d. 41 N N HN

Scheme 17
Porphyrins react with diazomethane to yield pyrazoline-fused chlorins.For instance, β-nitromeso-tetraphenylporphyrin 79 reacts with diazomethane, at room temperature, to afford the pyrazoline-fused chlorin 80 (41% yield) as the main product. 42The pyrazole-fused porphyrin 81 (7% yield) and the methanochlorin 82 (3% yield) are also isolated from the reaction mixture (Scheme 18).The pyrazoline 80 is the precursor of these two minor products: it can be converted easily into 81 by elimination of nitrous acid with DBU or into 82 by thermal extrusion of N 2 in refluxing toluene.Quite similar results are obtained from the reaction of diazomethane with meso- tetrakis(pentafluorophenyl)porphyrin (Scheme 19). 43Both thermal (refluxing mesitylene) or photochemical extrusion of N 2 from the pyrazoline derivative 83 gives the methanochlorin 84 in almost quantitative yield.

Scheme 25
The reaction of with nitrenes follows a different mechanism than the one with carbenes.Addition of ethoxycarbonylnitrene to octaethylporphyrin yields the ring-expanded meso-homoazaporphyrin 102, resulting from attack at a meso-double bond.Heating this derivative in the solid state or in solution causes ring contraction to the meso- ethoxycarbonylaminoporphyrin 103 (Scheme 26). 51Ring contraction of 102 to the metal complex of 103 occurs rapidly, at room temperature, in the presence of copper or zinc acetate.The reaction of the Cu or Zn complexes of octaethylporphyrin with ethoxycarbonylnitrene gives the corresponding metal complex of 103 directly.