Synthesis of meso-substituted dihydro-1,3-oxazinoporphyrins

Summary Novel dihydro-1,3-oxazinoporphyrins and naphtho[e]bis(dihydro-1,3-oxazinoporphyrin) derivatives, in which the porphyrin macrocycle is covalently linked to the dihydro-1,3-oxazine ring system were successfully synthesized from 5-(4-aminophenyl)-10,15,20-triphenylporphyrin in good yields. The structures of the target products were established on the basis of spectral data and elemental analyses.


Introduction
Porphyrin macrocycles are of crucial interest for their potential applications in diverse fields such as biomimetic models for photosynthesis [1,2], electronic materials [3], catalysis [4] and medicine [5,6]. In the past few decades, the synthesis of porphyrin derivatives has emerged as one of the major areas of research due to the success of these molecules for the eradication of malignant cells by photodynamic therapy (PDT) after their selective accumulation [7][8][9][10] in neoplastic tissues. In addition, the low dark-toxicity profile, easy removal from the tissue, and efficiency in generating reactive oxygen species by the absorption of photons in the visible or near IR region make them ideal candidates for developing effective photodynamic agents. These findings have encouraged researchers to design and synthesize potential targeting anticancer drugs derived from porphyrins [11,12]. Previously, a large number of these molecules have been synthesized by the coupling of diverse pharma-ceutically important moieties, such as carbohydrates [13][14][15], amino acid residues [16][17][18][19], steroids [20,21], glycosides [22][23][24], nitroxyl derivatives [25], pyrrolidinone [26], pyrrolidine [27] and piperazine [28], to the porphyrin periphery. In addition, many porphyrin dimers and trimers have displayed significant biological efficacy [29] and some of these are used as photosensitizers in PDT applications for the treatment of various types of cancers [30].
Thorough literature search revealed that heterocycles containing a dihydro-1,3-oxazine ring system exhibit a wide spectrum of pharmacological activities, for example, acting as antimicrobial [31][32][33], anti-HIV [34], antimalarial [35] or antitumor agents [36,37]. By considering the anticancer significance of these two classes of molecules, it was contemplated to construct new dihydro-1,3-oxazinoporphyrins combining the porphyrin and Scheme 1: Synthesis of dihydro-1,3-benzoxazinoporphyrins. dihydro-1,3-oxazine moieties in a single molecular framework. Such hybrid compounds may prove useful for pharmacological studies or in the development of new phototherapeutic agents. Therefore, in continuation of our efforts towards the synthesis of diverse porphyrin analogues [38][39][40][41] through peripheral functionalization of easily accessible meso-tetraarylporphyrins, we now report herein the first synthesis and spectroscopic characterization of a novel series of dihydro-1,3-oxazinoporphyrins.
The newly synthesized porphyrins were characterized on the basis of 1 H NMR, IR, mass and UV-vis data. The 1 H NMR spectra of all the free-base porphyrins showed a singlet around δ −2.7 ppm corresponding to the internal NH protons. Iminoporphyrins 2 and 3 showed the OH and N=CH protons as singlets around 13.4 and 8.9 ppm, respectively. For the aminoporphyrins 4 and 5, the hydroxy group and NH protons appeared as broad singlets at 8.4 ppm and 4.3 ppm, respective-ly. The protons of the CH 2 group appeared as a singlet at 4.6 ppm. The two characteristic peaks for the dihydro-1,3oxazinoporphyrins 6, 7, 10, 11 and 14-20 corresponding to N-CH 2 -Ar and N-CH 2 -O groups appeared as two singlets between 4 and 6 ppm. In contrast, the proton NMR spectra of dihydro-1,3-oxazinoporphyrins 8, 9, 12 and 13 showed two doublets between 4 and 5 ppm corresponding to one proton each with a coupling constant of 16.5 Hz due to the coupling between two geminal protons of the N-CH 2 -Ar group, and a characteristic singlet around 6-7 ppm for the N-CH-O proton of the oxazine ring. The IR spectra of the porphyrins 2-5 showed a peak around 3400 cm −1 corresponding to the hydroxy group. Further, the disappearance of the hydroxy peak in the IR spectra of porphyrins 6-13 confirmed the formation of the oxazine ring. Further, the electronic absorption and emission data of all the synthesized porphyrins are presented in Table 1.
The electronic absorption spectra of all the free-base dihydro-1,3-oxazinoporphyrins exhibited a typical Soret band at 421 nm and four weaker Q bands at ~518, 553, 592 and 648 nm. In contrast, the zinc(II) dihydro-1,3-oxazinoporphyrins showed the Soret band at 426 nm and two Q bands at ~555 and 597 nm. In addition, the newly prepared free-base porphyrins displayed

Conclusion
In summary, we have developed a convenient synthetic protocol for the construction of a new series of dihydro-1,3-oxazinoporphyrins in moderate to good yields. These novel porphyrindihydro-1,3-oxazine hybrids may be considered as potential candidates not only for biological evaluations but also for the development of newer π-conjugated molecules for various material applications.