Diels-alder reactions of protoporphyrin ix dimethyl ester

Terrahedron

Vol. 3.5. No. 42, pp. 1603-7606, 1995 Elsevier Science Ltd Printed in Great Britain oc40-4039m $9.50+0.00

L&err,

CKMO-4039(95)01633-3

Diels-Alder

Reactions of Protoporphyrin

IX Dimethyl

Ester

Alan R. Morgan and Dilmeet H. Kohli* Department of Chemistry, The Umversity of Toledo, Toledo, OH 43606.

Abstract: The reaction of a divmyl porphyrin (protoporphyrin IX dimethyl ester) with a number of azo dienophiles was studied. In all cases where reaction occurred and the product could be isolated, the expected [4+2] addition product was observed. In most cases, [4+2]@+2] adducts were also identified.

Currently, there is much mtercst m Diels-Alder reactions of porphyrins.1 In fact, a Diels-Alder adduct (Benzoporphynn derivative - mono acid) has been targeted as a second-generation photosensitizer

for

photodynamtc therapy (an evolvmg modality for the treatment of certain solid human neoplasms) and clinical evaluation is ongomg.2 This article describes the reactions of protoporphyrin IX dimethyl ester (1) with a number of azo dienophilcs. The aim was to extend the scope of Diels-Alder reactions of porphyrins by identifying new dienophiles and characterizing the products. Cyclic diacyl dumides and similar azo compounds have in fact found utility in Diels-Alder reactions. 3 A report of a [4+2] addition product with [i.e. 4-phcnylurazine (Za)] as dienophile.4 protoporphynn IX involves 4-phenyl-1 ,?,4-tnazoline-3.S-dtone Although the product of the reaction was not charactenLcd, the change m the visible spectrum of protoporphyrin IX followmg addition of the ura/.ole derivpative suggested that cycloaddition had occurred. This suggested that the evaluation of a series of iuo compounds lbr dienophile activity may be useful. In the present study therefore, the following dienophiles were investigated for then reaction with protoporphyrin IX dimethyl ester (I).

cm$-p-&

II) II 3-C’

N=N \

II 0

CO,WH,),

The -CO-N=N-CO- functionality is gencrall) quite reactive and consequently, when required, is derived through oxidation of the dihydro analog (the ura~olc). A II oxidations of umzoles to generate umzmes m this study, used rerr-butyl hypxhlonte as oxidant. In a typical procedure, the oxidant was added 7607

7604

to the umzole in ethyl acetate under a nitrogen atmosphere, at room tempemture.5 Forty minutes following completion of addition the resulting solution was used for cycloaddition studies. In the case of preparation of 4aminourazine, solubility problems precluded the use of ethyl acetate and dimethyl formamide was substituted. 3,6-Pyridazinedione (3) was prepared from 1,2-dihydro-3,6-pyridazinedione by a similar procedure as the umzines. Di-rerr-butyl azodicarboxylate (4) was purchased in its reactive form from Aldrich. The reactive dienophile, generated as described above, was slowly added to a stirred solution of the porphyrin in dry tetrahydrofuran, at room temperature under a nitrogen atmosphere. Reaction was monitored spectrophotometrically, by following the increase in ratio between the 656 nm absorption typical of porphyrin Diels-Alder adducts and the 630 nm absorption of the reactant porphyrin. After 25 minutes no further increase in intensity of this band was observed. The solvent was removed under reduced pressure, the residue chromatographed on a silica-gel column and the major products were examined spectroscopically after recrystalhzation. The reaction occurred with all the urazine dienophiles and the expected [4t2] addition products were isolated. In most cases, [4+2]/[2+2] adducts were also identified as shown in Scheme 1.

H3c02c

5

(4tZ]B

&02CH3

\

w

2

H3C02d 8 5-8

( a. R=C6H5

; b R=C(CH3h

; c. R=C2Hs.

d. R=CH3

5-6

)

[4+2]/[2+2]A

(e. R=NH2

02CH3

; I-. R=H)

Scheme 1 Yield Data ‘?A (5t6) % (7+8) (5+6)/(7+8)

a

b

c

d

e

f

10 3 3.3

50 17 2.9

63 2 315

48 8 6

33

12

7605

The initial reaction studied was of 4phenylurazine (2s) with protoporphyrin IX dimethyl ester (1). The eluent used for column chromatography was methylene chloride-hexane-tetrhydtofuran (19:3: 1 v/v). The first fraction was identified spectroscopically as the unreacted protoporphyrin IX dimethyl ester (1). The visible spectrum of fraction 2 had an intense absorption band at 6.56 nm, suggesting that reaction had occurred. TLC analysis showed that two components were present in the product. After rechromatographing the mixture on silica column with dichloromethane-hexane-tetrahydrofuran (157: 1 v/v) as eluent and spectroscopic analysis of each fraction, it was confirmed that these components corresponded to ring A and ring B isomers of the mono-cyclic adduct. This was in agreement with previous studies using protoporphyrin IX dimethyl ester (1). The faster moving band had a large absorption band at 656 nm. The 1~ NMR spectrum included resonances attributable to only one vinyl group, thus indicating reaction at only one site. Resonances due to phenyl and exocyclic ring protons confirmed the presence of the urazole moiety. One upfield singlet was assigned to the protons of the aliphatic methyl group. The faster and the slower moving bands showed similar spectroscopic data which confirmed their assignment as mono [4+2] cycloaddition products. Other studies with derivatives of 1 have shown that ring B isomer; are more mobile than their ring A counterparts on a silica column. lb, 2a Based on this observation, the faster moving adduct described above was tentatively assigned the B isomer 5a and the slower moving band, the A isomer 6a (Scheme 1). tH NMR spectrum of the third fraction was absent of resonances attributable to a vinyl group. The spectrum indicated addition of the dienophile to both vinyl groups, and the presence of only one aliphatic methyl group. Based on the visible, lH NMR and mass spectral data, the third fraction was formulated as a mixture of ring A and ring B [4+2]/[2+2] cycle adduct 7a, Sa (Scheme 1). The reaction of 3,6-pyridazinedione (3) with protoporphyrin IX dimethyl ester (1) was carried out in methylene chloride and did occur, as shown by an absorption band at 692 nm in the visible spectrum, however thin layer chromatography revealed numerous bands which were difficult to separate and characterize due to low yields. The reaction of di-terr-butyl azodicarboxylate (4) with protoporphyrin IX dimethyl ester (1) was carried out in dry tetrahydrofuran. No reaction was observed even on increasing dienophile content or on refluxing the reaction mixture for 10 hours. Starting material was recovered and identified by 1H NMR spectroscopy and mass spectrometry. The dienophile probably does not undergo Diels-Alder reaction in this case because of its steric bulk and tmns configuration. In fact, it has been reported that when the 1,4 position of the diene is highly substituted, there is steric hindrance towards 1,4 addition, particularly if the dienophile has a trans configuration.6 Although, no [2+2] adduct was isolated in any of the above reactions, the identification

of

[4+2]/[2+2] adducts demonstrates that dipolar additions of urazines to the vinyl group of (1) occur, which suggests that the mechanism for the formation of the [4+2] adduct is similar to that reported for the reaction of tetracyanoethylene with protoporphyrin IX dimethyl ester. lb In that case, mono [2+2] adducts were shown to rearrange to the corresponding [4+2] adducts, indicating that a dipolar addition of the dienophile to the porphyrin vinyl moiety occurred as a first step. In this project, the number of dienophiles which undergo addition reactions with protoporphyrin IX dimethyl ester have been extended to include a series of azo derivatives. The distance of the R-substituent from the reactive azo center suggests that functionality could be built up at this site if desired. Further modification of [4+2] adducts, following literature precedents could result in a new series of dihydroporphyrins having spectroscopic properties compatible with their use as sensitizers for a number of different applications.7

ACKNOWLEDGEMENT:

We thank The University of Toledo for financial support for this project.

REFERENCES: 1. (a) Grigg, R.; Johnson, A. W.; Sweeney, A. C/rem. Common. 1968,697. (b) DiNeIlo, R. K.; Dolphm, D. J. Org. Chem. 1980,45,5196. 2. (a) Scherrer-Pangka, V.; Morgan, A. R.; Dolphin, D. J. Org. Chem. 1986.51, 1094. (b) Richter, A. M.; Waterfield, E.; Jain, A. K.; Canaan, A. J.; Allison, B. A.; Levy, J. G. Phorochem. Photobiol. 1993,57, 1ooO. 3. (a) Clement, R. A. J. Org. Chem. 1%2,27, 1115. (b) Cookson, R. C.; Gilani, S. S. H.; Stevens, I. D. R. Tetrahedron L&t. 1962, 14,615. (c) Gillis, B. T.; Hagarty, J. D. J. Org. Chem. 1%7,32,330. 4. Maguire, G. Ph.D. Dissertation; Paisley College of Technology. 1988. 5. Cookson, R. C.; Gupte, S. S.; Stevens, I. D. R.; Watts, C. T. Organic Synthesis. 51, 121. 6. Gillis, B. T.; Beck, P. E. J. Org. Chem. 1962,27, 1947. Waldemar, A.; Arias, L. A.; De Lucchi, 0. Synthesis 1981,543. 7. SPECTROSCOPIC DATA: 5a tH NMR (CDC13): 6 10.96,9.89,9.79,9.26 (4 s, 4H, meso m, 8.19 (dd, lH, vinyl CH, Jcis=12 Hz, Jtmns=18Hz), 7.77 (d, 2H, ortho II, phenyl), 7.64 (dd, 2H, meta II, phenyl), 7.52 (t, lH, para II, phenyl), 6.93 (t, lH, C=CII, exocychc ring), 6.37 (dd, lH, vinyl C&, Jtr dns=18Hz, Jgem=1.25Hz), 6.17 (dd, lH, vmyl Cb, Jcis=l’Hz, Jgem=l.25Hz), 5.12 (dd, lH, CI& exocychc nng, Jgem=3.2Hz, Jvic=l@Iz), 4.59 (dd, lH, C& exocyclic nng, Jgem=3.3Hz, Jvic=18Hz), 4.33,4.18 (2 t, 4H, CHzC&CO$H3), 3.65.3.64, 3.58,3.52,3.41 (5 s, 15H, 2 x CO2C&, 3 x ring C&), 3.18,3.16 (2 overlapping t, 4H, CI&CH2CO$H3. 2.10 (s, 3H, aliphatic C&), -2.78 (s, 2H, N&). UViVis (CH2Cl2): 658,630,602, 534, 500,402. FAB Mass: Calc. m/e=766.3353 (for MH+); Found, m/e=766.3326 6a tH NMR (CDCI3): 6 11.06,9.86,9.74,9.23 (4 s, 4H, meso II-)), 8.25 (dd, lH, vinyl C& Jcis=12 Hz, Jtrans=18Hz), 7.78 (d, 2H, ortho 51, phenyl), 7.62 (dd, 2H, meta II, phenyl), 7.50 (t, lH, para& phenyl), 6.98 (t, lH, C=CII, exocyclic nng), 6.41 (dd, lH, vinyl C&, Jtmns=18Hz), 6.10 (dd, lH, vinyl CI&, Jcis=12Hz), 5.13 (dd, lH, C& exocycllc ring, J gem=?.XHL, Jvic=18Hz), 4.62 (dd, lH, CI& exocyclic ring, Jgem=2.8Hz, Jvic=lt(Hi),

4.34,4.19

(2 t, 4H, CH2CbC02CH3),

3.66,3.65,3.63,3.50,3.43

(5s 15H, 2 x

C@C&. 3 x ring CI&), 3.21,3.16 (2 overlapping t, 4H, CI&CH$O$H3), 2.09 (s, 3H, aliphatic CI&), -2.82 (s, lH, Nm. UViVis (CH2Cl2): 656,630,602.534,500,402. FAB Mass: Calc. m/e=766.3353 (for MH+); Found, m/e=766.3348. 7a + 8a ‘H NMR (CDCl3): 6 10.17, 10.16. 9.34,8.52 (4 s, 4H, meso II, major isomer), 10.09, 10.00,9.24, 8.41(4 s, 4H, meso H, minor isomer), 7.71 (m, 4H, ortho H, phenyl*), 7.59 (m, 4H, metaH, phenyl*), 7.50 (m, 2H, para H, phenyl*), 7.04 (t, lH, C=CH, exocychc nng, maJor isomer), 7.02 (t, lH, C=C& exocyclic nng, minor isomer), 6.88 (t, lH, CII, cyclobutane methmc, maJor isomer), 6.78 (t, lH, CH, cyclobutane methine, minor isomer), 5.03,4.54 (2 m, 8H, 2xCH2, cyclobutane. , 3- x C=CH-CI& exocyclic ring*), 4.09 (m, 8H, CH$Z&CO$H3*), 3.60,3.59,3.58,3.57,3.23,3.21,3.18,3.17 (8s, 30H, 4 x CO2C&, 6 x ring CI-&*), 3.08 (m, 8H, CI&CH2C02CH3*) , 2.05 (s, 3H, aliphatic C&, maJor isomer), 2.02 (s, 3H, aliphatic C&, minor isomer), -2.82 (s, 2H. NH*), *resonances for both isomers. UViVis (CH2Cl2): 646,5%,540, 506,426,394. FAB Mass: Calc. m/e=940.36_56 (Ior M+); Found, miez940.3636.

(Received in USA 30 June 1995; revised 15 August 1995: nccepted I6 August 1995)