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vinyl group, the propionic ester side chain and the exocyclic anhydride
ring system. In their attempts to achieve the optimal in vivo activity of
18 type photosensitizers, Pandey et al.137 modified the molecule by
introducing substituents at different position(s) on the parent molecule.
C. CHEMICAL MODIFICATION OF PURPURIN-18
Smith and coworkers have shown that amide derivatives of purpurin-18
(obtained by cleavage of the cyclic anhydride ring by amines) can form
related imide derivatives in minor quantity if the reaction mixture is
left at room temperature for several weeks.138 Zheng and Pandey139
developed an efficient method for the preparation of such compounds with
variable lipophilic characteristics. In their approach, purpurin-18
methyl ester 17 was reacted with various alkylamines at room temperature
to give the corresponding amides in high yield (95%), as a mixture of 20
and 21 in a ratio of 6 to 1. The structures for the minor and the major
Scheme 6. Formation of purpurin isoimides by the DCC method.
\S ' Ma
23 (696 nm) slow moving band
C02Me *ii152 Î
Me CONH-R C02H 20
24 (690 nm) fast moving band
Pandey and Zheng
products were assigned as 21 (15-amide) and 20 (13-amide), respectively.
Attempts to convert the amides 20 and 21 into the corresponding imides 22
by following the methods used in other aromatic systems gave mainly
decomposition products. Leaving the amide solution in CH2C12 or in THF at
room temperature for a week gave a mixture of purpurins with the cyclic
anhydride 17 (699 nm), and the cyclic imide 22 (705 nm) in minor amounts
and the starting material as the major product. Refluxing the reaction
mixture at elevated temperature slightly improved the yield of purpurin
anhydride without formation of any desired imide analogue. Interestingly,
reaction of the mixture of amides 20 and 21 with Montmorillonite K-10
clay using CH2C12 as the solvent again gave a mixture of cyclic imide 22
as a minor product (12%) and the anhydride analogue 17 as the major
product (85%). The formation of
the undesirable cyclic anhydride was avoided by following two different
approaches. In the first approach, reaction of purpurin amides 20 and 21
with dicyclohexylcarbodiimide (DCC) afforded a mixture of purpurin
isoimides 23 and 24 as isomers in a ratio of 6:1, in 96% overall yield.
This can be separated into individual isomers by column chromatography
(Scheme 6). Treatment of this isomeric mixture with DBU/toluene at 60 °C
produced imide 22 in 60% yield. Interestingly, replacing DBU with
stronger bases such as methanolic KOH at room temperature gave the
desired purpurin imide in 85% yield.
Possible mechanisms for the formation of N-alkyl-isoimide (e.g., 23)
by the dehydration of the intermediate amide with DCC, as well as its
final conversion into the imide, are shown in Scheme 7. Donation of a
proton from the amide 21 to DCC could lead to intermediate 25, which
Scheme 7. Possible mechanisms for the formation of isoimide and its
conversion to the corresponding imide ring system.
43/Porphyrins as Photosensitizers in Photodynamic Therapy
Scheme 8. Mechanism of imide formation via intermediate amide 28.
C4 C = 0
.. " // OCH3 I
Me02C 0 NHR
, Ñ Ñ = Î
Scheme 9. Formation of purpurin-18 imides and isoimides.
22 purpurin 18 imide
23 (696 nm) purpurin 18 isoimide
could decompose via the indicated quasi-six-member-ring transition state
26 into N-substituted cyclic isoimides 23. It can also be postulated that
reaction of DCC with purpurin amide first generates the unstable DCC
derivative 27, which, upon intramolecular cyclization, produces the
unstable isoimide that eventually affords the desired isoimide 23 and
dicyclohexylurea as a byproduct. Such transformation via quasi-six-
member-ring systems has also been proposed in other aromatic systems.140
Finally, treatment with base would cleave the isoimide, and the resulting
intermediate amide after the indicated intramolecular cyclization will
form the desired imide 22.
In the second approach, the intermediate amide mixture was converted
into the corresponding methyl esters 28 by reacting with diazomethane;
upon brief methanolic KOH
treatment these intermediates produced the desired imide analogue in the
excellent yield (Schemes 8 and 9). Because of the difficulty of removing