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Dec. 1, 2004  Vol.6 No.12 P.86 Copyright cij17logo.gif (917 bytes)

Efficient synthesis of dipyrromethanes and their use in the preparation of porphyrins

Huang Dan, Tian Shu
(College of Chemistry and Chemical Enfineering of Nantong University, Nantong 226007, Jiangsu, China)

Received  Jul. 1, 2004; Financial assistance from Education Department of Jiangsu Province (No. 01KJD150005).

Abstract Ceric ammonium nitrate efficiently catalyzes the reaction of pyrrole with various aldehydes to afford the corresponding dipyrromethane in good yield and they are used in the preparation of porphyrins.
Keywords Ceric ammonium nitrate, pyrrole, dipyrromethane, porphyrin

1 INTRODUCTION
meso-Substituted dipyrromethanes are important precursors for the synthesis of meso-substituted porphyrins,[1] expanded porphyrins, and porphyrin analogues.[2] Several one-flask methods have been reported for the synthesis of meso-substituted dipyrromethanes by the condensation of an aldehyde and pyrrole using various combinations of acids and solvents,[3-15] such as p-Toluenesulfonic acid, propionic acid, trifluoroacetic acid (TFA) and BF3·etherate in the presencet of menthol, dichloromethane or in the absence of any other solvent, etc. These methods have afforded meso-substituted dipyrromethanes bearing many types of functional groups. However, among the above catalysts used in condensation reaction, some are expensive, some are inconvenient to use and some are of lower yield of reaction.
    In recent years, ceric ammonium nitrate (CAN) has been exploited extensively in organic reactions such as oxidation, oxidative addition, nitration, photooxidation, deprotection, and graft polymerization, etc.[16] Recently Ji reported the use of CAN as a catalyst in Michael addition of indole to a,b-unsaturated ketones.[17] However, the use of CAN as a catalyst in the synthesis of dipyrromethanes under neutral conditions has not been reported. In this report we describe a condensation reaction of pyrrole with aldehydes using a catalytic amount of ceric ammonium nitrate at room temperature in the absence of any other solvent, which provides an efficient route to the synthesis of 5-substituted dipyrromethanes.

2 EXPERIMENTAL
2.1 Reagents and instruments
Pyrrole and Benzaldehyde were freshly distilled before use. CH2Cl2, ClCH2CH2Cl was distilled from CaH2. All other chemicals are reagent grade. The Flash column chromatography was carried out on Merck Silica gel (230-400 mesh). Melting points were recorded on an Electrothermal digital melting point apparatus and were uncorrected. 1H NMR spectra were recorded on a Varian Mercury 400 MHz spectrometer as solutions in d3-chloroform. Chemical shifts in 1H NMR spectra are reported in parts per million (ppm, d) downfield from the internal standard Me4Si (TMS). High-resolution mass spectra were obtained with a GCT-TOF instrument. Elemental analyses were performed on a Carlo-Erba EA1110 CNNO-S analyzer.
2.2 Experimental procedure
Pyrrole (25 equiv) and the aldehyde (1.0 equiv) were added to a dry round-bottomed flask and degassed with a stream of Ar for 5 min. CAN (0.10 equiv) was then added, and the solution was stirred under Ar at room temperature until the disappearance of the starting aldehyde (5-20 min, checked by TLC) and then quenched with 0.1 M NaOH. Ethyl acetate was then added. The organic phase was washed with water and dried (Na2SO4), and after the solvent was evaporated under vacuum, the crude product was purified by flash column chromatography ( petroleum ether : ethyl acetate : triethylamine, 80 : 20 : 1, V/V). Removal of the solvent under vacuum gave a solid that was recrystallized two times from ethanol or ethanol/water to give pure dipyrromethane as a crystalline solid. Reaction is showed in Scheme 1.

Sheme 1

3 RESULTS AND DISCUSSION
3.1 Preparation of meso-substituted dipyrromethanes            
To optimize the formation of the dipyrromethane, we initially examined the reaction of benzaldehyde with pyrrole in the presence of 10% CAN at room temperature using different solvents. The reaction in CH2Cl2, ClCH2CH2Cl and absolute methanol, even with a large excess of pyrrole, gives a mixture in which the dipyrromethane is not the major product, and the yields are < 10%. In the contrast, the condensation yield is 45% when reaction of benzaldehyde and pyrrole (1:20) in absentce of any other solvent.
    Next, we examined the effect of changing the pyrrole: benzaldehyde ratio on the yield. As the pyrrole:benzaldehyde ratio increases the amount of dipyrromethane increased for the presence of CAN.
    Dipyrromethanes 3a-k were prepared by condensation of the aldehyde and pyrrole (1: 25) using 10% CAN, as shown in Table 1. The crude reaction mixture after removal of pyrrole was purified by chromatography (petroleum ether: ethyl acetate: triethylamine = 80:20:1). Triethylamine (-1%) is essential to prevent deposition of the dipyrromethane on silica columns, which are slightly acidic. Finally, all of the dipyrromethanes (3a-k) were recrystallized, achieving highly pure dipyrromethane which is to be used in the synthesis of substituted porphyrins.

Table 1 Synthesis of dipyrromethanes

entry

R

Product

Yield(%)a

1

3a

53.23

2

3b

76.45

3

3c

54.37

4

3d

55.68

5

3e

57.43

6

3f

54.57

7

3g

65.78

9

3h

38.12

10

3i

79.83

10

3j

55.32

a The reactions were carried out with 1 (25 mmol) and 2a-2j (1mmol ) at room temperature, employing 10 mol% CAN. b Isolated yield after column chromatography and all products are determined by 1H NMR, HRMS and mp etc.

    Most of the dipyrromethanes are indefinitely stable in the purified form upon storage at 0oC in the absence of light.

3.2 Characteristics results
meso-Phenyldipyrromethane (3a): (53%) as pale yellow crystals; mp: 100-101ºC; 1H NMR (CDCl3): d 5.48 (s, 1 H), 5.92 (s, 2 H,), 6.16 (q, J=2.8 Hz, 2 H), 6.70 (d, J=1.2 Hz, 2 H), 7.21-7.32 (m, 5 H), 7.92 (br s, 2 H); HRMS: m/z cacld for C15H14N2: 222.1157, found: 222.1190. Anal. Calcd. for C15H14N2: C, 81.05; H, 6.35; N, 12.60. Found: C, 80.10; H, 6.32; N, 12.48.
    meso -(p-tolyl)dipyrromethane (3b). (76.45%) as tan solid: mp 110-111ºC; 1H NMR (CDCl3) d 2.35 (s, 3 H), 5.46 (s, 1 H), 5.94 (s, 2 H) 6.17 (q, J= 3.2 Hz, 2 H), 6.70 (q, J= 2.8 Hz, 2 H), 7.15 (dd, J= 2.8 Hz and 3.6 Hz, 4 H), 7.92(br s, 2H); HRMS (EI+) cacld for C16H16N2: 236.1313, found 236.1336. Anal. Calcd. for C16H16N2: C, 81.32; H, 6.82; N, 11.85. Found: C, 81.40; H, 6.89; N, 11.71.
    meso -(p-chlorophenyl)dipyrromethane (3c). (54.37%) as light yellow solid: mp 112-113ºC; 1H NMR (CDCl3) d 5.44 (s, 1 H), 5.88 (s, 2 H), 6.16 (q, J=2.8 Hz, 2 H), 6.70 (d, J=1.2 Hz, 2 H), 7.09-7.14 (m, 2 H), 7.24-7.29(m, 2 H), 7.93 (br s, 2 H); HRMS (EI+) cacld for C15H13N2Cl: 256.0767, found 256.0795. Anal. Calcd. for C15H13N2Cl: C, 70.18; H, 5.10; N, 10.91. Found: C, 70.06; H, 5.15; N, 10.86.
    meso -(p-bromophenyl)dipyrromethane (3d). (55.68%) as white solid: mp 125-126ºC; 1H NMR (CDCl3) d 5.43 (s, 1 H), 5.86(d, 2 H), 6.15 (q, J= 2.8 Hz, 2 H), 6.68 (d, J= 1.6 Hz, 2 H), 7.10 (m, 2 H), 7.24(m, 2H), 7.92 (br s, 2 H); HRMS (EI+) cacld for C15H13N2Br 300.0262 ,found 300.0289. Anal. Calcd. for C15H13N2Br: C, 59.82; H, 4.35; N, 9.30. Found: C, 59.84; H, 4.30; N, 9.38.
    meso -(p-iodophenyl)dipyrromethane (3e). (54.37%) as light tan solid: mp 145-147 ºC; 1H NMR (CDCl3) d 5.42 (s, 1 H), 5.86 (s, 2 H), 6.14 (q, J= 2.8 Hz, 2 H), 6.65 (d, J= 1.8 Hz, 2 H), 6.99 (m, 2 H), 7.58(m, 2 H), 8.42 (br s, 2 H); HRMS (EI+) cacld. C15H13N2I 348.0123, found 348.0101. Anal.Calcd. for C15H13N2I: C, 51.74; H, 3.76; N, 8.05. Found: C, 51.79; H, 3.80; N, 8.06.
    meso -(o-nitrophenyl)dipyrromethane (3f). (57.57%) as yellow solid: mp 145-147ºC; 1H NMR (CDCl3) d 5.86 (s, 2 H), 6.15 (q, J= 2.8 Hz, 2 H), 6.20 (s, 1 H), 6.71 (d, J= 1.6 Hz, 2 H), 7.26 (dd, J= 3.2 Hz and 6.8 Hz, 1 H), 7.36-7.40 (m, 1 H ), 7.49-7.52 (m, 1H), 7.86 (dd, J= 0.8 Hz and 0.4 Hz, 1H), 8.16 (br s, 2 H); HRMS (EI+) cacld. C15H13N3O2 :267.1008, found 267.1029. Anal. Calcd. for C15H13N3O2: C, 67.40; H, 4.90; N, 15.72 Found: C, 67.53; H, 4.72; N, 15.64.
    meso -(p-nitrophenyl)dipyrromethane (3g). (65.78%) as green solid: mp 159-160ºC; 1H NMR (CDCl3) d 5.58 (s, 1 H), 5.87 (s, 2 H), 6.17 (q, J= 2.4 Hz, 2 H), 6.75 (d, J= 1.8 Hz, 2 H), 7.37 (d, J= 8.4 Hz 2 H), 8.02 (br s, 2 H), 8.17(d, J= 8.8 Hz, 2 H); HRMS (EI+) cacld. C15H13N3O2 :267.1008, found 267.1030. Anal. Calcd. for C15H13N3O2: C, 67.40; H, 4.90; N, 15.72 Found: C, 67.25; H, 4.95; N, 15.58.
    meso -(p-tert-butyphenyl)dipyrromethane (3h). (38.12%) as pale yellow crystals: mp 160-161ºC; 1H NMR (CDCl3) d 1.31 (s, 9 H), 5.47 (s, 1 H), 5.92 (m, 2 H), 6.15 (q, J= 3.2 Hz, 2 H), 6.70 (m, 2 H), 7.12 (m, 2 H), 7.32(m, 2 H), 7.92 (br s, 2 H); HRMS (EI+) cacld. C19H22N2:278.1783, found 278.1798. Anal. Calcd. for C19H22N2: C, 81.97; H, 7.97; N, 10.06. Found: C, 81.93; H, 7.95; N, 10.12.
    meso -(p-methoxyphenyl)dipyrromethane (3i). (68.83%) as colorless solid: mp 99-100ºC; 1H NMR (CDCl3) d 3.79 (s, 3 H), 5.42 (s, 1 H), 5.91 (m, 2 H), 6.15 (q, J=2.8 Hz, 2 H ), 6.68 (m, 2 H), 6.85 (m, 2 H), 7.12 (m, 2 H), 7.91 (br s, 2 H); HRMS (EI+) cacld. C16H16N2O :252.1263, found 252.1238. Anal. Calcd. for C15H12N2O2: C, 76.16; H, 6.39; N, 11.10. Found: C, 76.20; H, 6.35; N, 11.00.
    meso -(mesityl)dipyrromethane (3j). (55.32%) as pale yellow solid: mp 171-172ºC; 1H NMR (CDCl3) d 2.04 (s, 6 H), 2.27 (s, 3 H), 5.92 (s, 1 H), 6.03 (m, 2 H), 6.17 (m, 2 H), 6.65 (m, 2 H), 6.86(s, 2 H), 7.95 (br s, 2 H); HRMS (EI+) cacld. C18H20N2 :264.1626, found 264.1604. Anal. Calcd. for C15H13N3O2: C, 81.78; H, 7.62; N, 10.60 Found: C, 81.80; H, 7.66; N, 10.54.
3.3 Preparation of trans-substituted porphyrin from dipyrromethanes
A dipyrromethane can be condensed with an aldehyde to afford the trans-substituted prophyrin (Scheme 2). Results are summarized in Table 2.

Scheme 2

Table 2 Synthesis of porphyrins

Entry

R

product

Yield (%)a

1

4a

30

2

4b

35

3

4c

32

a Isolated yield after column chromatography and all products.

4 CONCLUSION            
In summary, we have developed a refined synthetic method of dipyrromethanes. The procedure is based on condensation of an aldehyde with large excess pyrrole catalyzed by CAN. The reaction provided 5-substituted dipyrromethanes in moderate yields. Further study of the scope of the reaction and application in the synthesis of porphyrins are under way.

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