HETEROCYCLES

Paper | Special issue | Vol. 82, No. 2, 2011, pp. 1503-1514
Received, 10th August, 2010, Accepted, 1st October, 2010, Published online, 5th October, 2010.
DOI: 10.3987/COM-10-S(E)104

■ Unusual Oxidation in the Course of Synthesis of N-Confused Nickel Tetrahydrobilins

Jan-Erik Damke, Torben König, Gerold Haake, Lechosław Latos-Grażyński, and Franz-Peter Montforts*

Institut für Organische Chemie des FB 2, Universität Bremen, Leobener Strasse,NW 2-C, D-28359 Bremen, Germany

Abstract

N-confused Tetrahydrobilins rac-16 and rac-17 were prepared to investigate their cyclization directed to the formation of N-confused chlorins. For achieving the desired cyclization the 5´-position of rac-16 respectively rac-17 was activated by an electron withdrawing cyano function and their 2´-positions were blocked by a methyl group. In addition, the insertion of Ni(II) was accomplished for exercising a template effect during the cyclization process, but the formed nickel complexes rac-18 and rac-19 underwent oxidation to yield oxo-tetrahydrobilins rac-20 and rac-21.

INTRODUCTION
Since the pioneering work of A.W. Johnson1 and A. Eschenmoser2 the cyclization of bilin type tetra(hydro)pyrroles became an important synthetic concept for the construction of macrocyclic porphyrinoid and corrinoid structures.
In our laboratory cyclization of tetrahydrobilins rac-2 were investigated with regard to the construction of hexahydrocorrins rac-13 or dihydroporphyrins (chlorins) 3.4 Depending on functional groups or/and substituents at the cyclization positions the tetrahydrobilins rac-2 show different modes of reaction.
Electron withdrawing groups (X = Hal, CN, CO2R) favour the formation of chlorins 3 whereas the 1-unsubstituted bilin (X = H) rac-2 forms the corrin structure rac-1 (Scheme 1).1
In the course of investigations directed to synthesis of chlorins like 4 with nitrogen turned to the periphery of the chromophore (N-confused chlorins) we aimed on the preparation of the tetrahydrobilins rac-16 and rac-17 with cyano groups at the 5´-positions and methyl groups at the 2´-positions.

RESULTS AND DISCUSSION
Synthesis of tetrahydrobilins rac-16 and rac-17 should be achieved starting from the known nickel complex rac-154 to which pyrrol building blocks 8 and 14 should be attached to form the tetrapyrrolic systems. Pyrrole carbaldehyde 8 could be obtained along two different routes (Scheme 2) adopting literature procedures.5a,b Methylpyrrole carbonitrile 7 could be obtained5b directly by reaction of acetamido cyanoacetate 5 and 1,4-dichlorobutyne 6 forming the pyrrole cycle. Alternatively the aldehyde function of known pyrrole 95a was transformed into the cyano group of 7. Expected regioselective formylation yielded pyrrole building block 8.

Pyrrole carbaldehyde 14 was prepared by Knorr’s pyrrole synthesis6 and subsequent Vilsmeier formylation (Scheme 3).

Tetrahydrobilins rac-16 and rac-17 were obtained from nickel complex rac-154 and pyrroles 8 and 14 (Scheme 4). Alkaline hydrolysis of the ester function of the nickel complex rac-15, followed by acid-induced condensation with decarboxylation and decomplexation with the pyrrole carbaldehydes 8 and 14 furnished the tetracyclic bilins rac-16 and rac-17 respectively.
Both tetrahydrobilins rac-16 and rac-17 should be recomplexed with nickel acetate to give the nickel tetrahydrobilins rac-18 and rac-19.

Interestingly however, apart of complexation of the macrocycles the methine bridges underwent oxidation to ketofunctions to form the very stable compounds rac-20 and rac-21.
To achieve the required cyclization for chlorin formation the Ni tetrahydrobilins rac-20 and rac-21 were simply heated in trichlorobenzene. It could be seen that the primary required eliminations of HCN from C-11 gave tetrahydrobilins rac-22 and rac-23 respectively. But the formed exocyclic enamine double bonds (Scheme 5) did not undergo the desired cyclization reactions.

A possible interpretation of the observed oxidation during complexation of tetrahydrobilins rac-16 and rac-17 with nickel acetate is summarized in scheme 6. It can be assumed that the primary formed products rac-18 and rac-19 undergo nucleophilic addition of water at the electrophilic C(3´´)-methylidene positions. The C(3´´)-methylidene positions of rac-18 or rac-19 are activated as parts of azafulvene structures and the additional electron-withdrawing cyano functions.
Aerial oxidation of the allylic alcohol functions of intermediates rac-24 and rac-25 yields the nickel ketobilins rac-20 and rac-21. The keto functions are ideal ligands for coordinating the central nickel ion.

Semiempirical PM3-calculations and NOESY experiments indicate the planarity of the metallo complex core of rac-20 and rac-21. The central nickel ion is in planar square coordination by the three nitrogen atoms of the ABC part and by the carbonyl function of the 3´´-bridge of the extra pyrrole ring D (Figure 1).

The rigidity of the structure was confirmed experimentally by two-dimensional NOESY experiments which showed distances of ca. 3.6 Å between the C(1) methyl groups of rings A and C(2´) methyl substitutents of rings D (Figure 2). The whole Ring D moieties are tilted against the coordination plane.

Also the comparison of the UV/Vis-spectra (Figure 3) of the tricyclic nickel complex rac-15 and of the tetracyclic nickel complex rac-20 containing the extra pyrrole ring shows striking similarities of the spectra thus confirming NMR experiments and calculations. The extra pyrrole ring of rac-20 causes only a moderate bathochromic shift on the tricyclic metallo complex part of rac-20 thus indicating twisting of the D ring against the chromophoric system.

EXPERIMENTAL
General. Starting materials were either prepared according to literature procedures or were purchased from Fluka, Merck, or Aldrich and used without further purification. All solvents were purified and dried by standard methods. All reactions were carried out under argon. Column chromatography (CC): silica gel 60 Å, 32-63µm (ICN Biomedicals). Thin layer chromatography (TLC): precoated silica gel Kieselgel 60 F254 (Riedel de Haen) plates.
1H-NMR Spectra: Bruker DPX-200 Avance spectrometer; δ in ppm rel. to SiMe4 as internal standard, J in Hz; δ(H) from spectra in CDCl3 at 23 °C, if not otherwise noted. MS and HR-MS: Finnigan MAT 8200, Finnigan MAT 95 or Esquire- spectrometer [EI (70 eV, direct inlet) and ESI]; in m/z (rel. %). IR Spectra (KBr, cm-1): Perkin-Elmer Paragon 500 FT-IR spectrometer. UV/Vis Spectra: Varian Cary 50 spectrophotometer, λmax (relative intensity) in nm. Melting points are uncorrected and were determined on a Reichert Thermovar hot-stage apparatus or on Gallenkamp apparatus.

5-Methyl-1H-pyrrole-2-carbonitrile (7)
(Method A) 1.24 g (11.4 mmol) of 5-methyl-1H-pyrrole-2-carbaldehyde5a (9) were dissolved in 30 mL of MeOH and then sodium acetate (5.4 g) followed by hydroxylamine hydrochloride (3.8 g, 55 mmol) were added at room temperature. The immediately formed colorless suspension was stirred for 30 min at room temperature. The mixture was transferred with 150 mL of CH2Cl2 into a separatory funnel containing 100 mL of brine.
The product was exhaustively extracted with CH2Cl2 and the combined organic extracts were filtered through oven dried cotton wool to remove water. The solvent was evaporated. The crude oximino pyrrole was dissolved under an Ar atmosphere in 40 mL of dry CHCl3 and then N,N-carbonyldiimidazole (3.4 g, 21.0 mmol) was added in small portions. For completion of the reaction the mixture was stirred at room temperature for 16 h. The solvent was evaporated and the residue was purified by flash chromatography (Matrex silicagel, CH2Cl2/EtOAc, 9+1). After removal of the solvent 1.18 g (11.1 mmol, 98%) of a colorless oil of 7 was obtained. For analytical characterization the sample was crystallized from CHCl3/n-pentane.

(Method B5b) 8.5 g (50 mmol) of ethyl 2-acetamido-2-cyanacetate (5) were added to a stirred solution of 250 mL 1M NaOEt/EtOH. The reaction mixture was refluxed and 1,4-dichloro-2-butyne (6) ( 4.9 mL, 50 mmol) was added at once. The solution was stirred for 1 h before adding another 4.9 mL (50 mmol) of 1,4-dichloro-2-butyne. Stirring was continued for another hour. After cooling to room temperature the solvent was evaporated and the precipitate was dissolved in 175 mL of EtOAc. Water (175 mL) was added to the redish mixture, the organic phase was separated, and the water phase was exhaustively extracted with EtOAc. The combined organic extracts were washed with sat. aq. NaHCO3, 1N HCl and sat. aq. NaCl-solutions and dried by filtration through oven dried cotton wool. The solvent was evaporated and the crude product was purified by column chromatography (silicagel, CH2Cl2/EtOAc, 9+1). After removal of the solvent 2.31 g (21.7 mmol, 43.5%) of solid 7 was obtained, which was recrystallized from CHCl3/n-pentane.

5-Methyl-1H-pyrrole-2-carbonitrile (7)
Colorless crystals, mp 54 °C, (lit.,5c mp 54-56 °C). TLC (SiO2, CH2Cl2/AcOEt 9+1): Rf = 0.62. IR (KBr): ν = 3300 (NH), 3150, 2985 (CH), 2925 (CH) 2820 (w), 2210 (s, ν CN), 1575 (m), 1480 (s), 1395 (m), 1290 (m), 1270 (m), 1190 (s), 1050 (s), 995 (w), 785 (s) cm-1. MS (EI) m/z (%): 107 (M+, 13C, 4), 106 (M+, 53), 105 (100), 78 (19), 64 (5). 1H-NMR (360 MHz, CDCl3): 2.27 (3H, s, 5C-CH3), 5.95 (1H, ddq, 3J = 3.6, 4J = 2.71, 4J = 0,87, H-C(4)), 6.49 (1H, dd, 3J = 3.62, 4J = 2.65, H-C(3)), 8.23 (1H, s, br, NH). HRMS m/z: C6H6N2+ calcd. 106.05310, found 106.05329.

4-Formyl-5-methyl-1H-pyrrole-2-carbonitrile (8)
To a suspension of AlCl3 (1.20 g, 8.99 mmol) in 6 mL of dry CH2Cl2 were added under an Ar atmosphere at room temperature nitromethane (640 µL) and then 316 mg (2.99 mmol) of pyrrolecarbonitrile 7. The solution was cooled to 0 °C and dichloromethyl methyl ether (666 µL, 7.47 mmol) was added by a syringe. The mixture was stirred for 5 min at 0 °C and 15 min at room temperature. 20 mL of water was cautiously added and the mixture was stirred for additional 15 min at room temperature. The mixture was exhaustively extracted with EtOAc (total ca. 50 mL), the combined organic extracts were dried by filtration through oven dried cotton wool and the solvent was evaporated. The crude product was purified by flash chromatography (Matrex silicagel, CH2Cl2/MeOH, 9+1) and crystallization from EtOAc. Yield 296 mg (2.21 mmol, 74%) 8 as colorless crystals.

4-Formyl-5-methyl-1H-pyrrole-2-carbonitrile (8)
74% yield, colorless crystals, mp 179 °C. TLC (SiO2, CH2Cl2/MeOH 9+1): Rf = 0.32. IR (KBr): ν = 3100 (NH), 3050 (s), 2975 (m), 2925 (m), 2820 (m), 2210 (s, (CN)), 1650 (s, (C=O)-formyl), 1575 (m), 1495 (s), 1450 (m), 1405 (m), 1395 (m), 1370 (s), 1340 (m), 1155 (m), 1130 (s), 1045 (w), 1005 (w), 980 (w), 860 (m), 840 (m). 810 (w). MS (EI) m/z (%): 135 (M+, 13C, 6), 134 (M+, 84), 133 (100), 108 (M+-CN, 6), 105 (M+-CHO, 22), 78 (13), 53 (14). 1H-NMR (200 MHz, CDCl3): 2.81 (3H, s, CH3-C(2)), 6.98 (1H, d, 4J = 2.0, H-C(4)), 9.64 (1H, s, CHO-C(5)), 11.08 (1H, s, br, NH). HRMS m/z: C7H6N2O+ calcd. 134.04801, found 134.04796.

3,5-Dimethyl-1H-pyrrole-2-carbonitrile (13)6
4 g (40 mmol, 4.1 mL) of acetylacetone 12 and 5.12 g (40 mmol) of 2-cyano-2-oximino acetic acid methyl ester 11 were dissolved in 80 mL of 50% aq. acetic acid and the mixture was heated to 80 °C. During 45 min 10 g (154 mmol) of zinc dust were added in portions so that the temperature could be kept between 75 to 85 °C. Subsequently the mixture was heated for 30 min to 80 °C. The mixture was poured on 400 mL of ice water. The pyrrole carbonitrile 13 precipitated on standing overnight and it was filtered off. The residue was dissolved in CH2Cl2 and zinc residues were filtered off. After evaporation of the solvent the residue was purified by column chromatography (SiO2, CH2Cl2/EtOAc, 9+1) to afford after crystallization from dichloromethane/n-pentane 3.03 g (25.2 mmol, 63%) of pyrrolecarbonitrile 13 as colorless crystals.

3,5-Dimethyl-1H-pyrrole-2-carbonitrile (13)
63% yield, colorless crystals, mp 76 °C. TLC (SiO2, CH2Cl2/AcOEt 9+1): Rf = 0.61. IR (KBr): ν = 3270 (NH), 3160, 3070 (m, C=CH), 2915 (m, CH), 2845 (m), 2760 (m), 2525 (m), 2210 (s, (CN)), 1585 (m, (C=C)), 1500 (m), 1440 (m), 1380 (m), 1300 (m), 1265 (m), 1165 (w), 1145 (w), 1040 (w), 985 (m), 980 (w), 800 (s), 725 (w), 645 (w), 610 (m), 545 (w), 495 (w). 1H-NMR (200 MHz, CDCl3): 2.20 (3H, s, CH3-C(5)), 2.26 (3H, s, CH3-C(3)) 5.81 (1H, s, H-C(4)), 8.06 (1H, s, br, NH). MS (EI) m/z (%): 120 (M+, 58), 119 (100), 105 (14), 92 (5), 65 (7), 39 (7). HRMS m/z: C7H8N2+ calcd.120.06875, found 120.06854.

3,5-Dimethy-4-formyl-1H-pyrrole-2-carbonitrile (14)
364 μL (3.98 mmol) POCl3 was added to 636 µL of dry DMF at 0 °C under an argon atmosphere and the mixture was stirred for 15 min. To a solution of 159.8 mg (1.33 mmol, 3 eq.) of 3,5-dimethyl-1H-pyrrole-2-carbonitrile 13 in 10 mL of dry DMF cooled to 10 °C the previously prepared Vilsmeier reagent was added dropwise under an argon atmosphere and the solution was then heated for 2.5 h at 60 °C. The reaction was quenched by addition of 20 mL of saturated sodium-acetate solution and stirred for further 20 min at 60 °C. The reaction mixture was diluted with 20 mL of water, extracted four times with CH2Cl2 and dried by filtration through oven dried cotton wool. After removal of CH2Cl2 in a rotary evaporator, DMF was evaporated by a Kugelrohr distillation apparatus under a reduced pressure. The residue was purified by column chromatography (SiO2, CH2Cl2/EtOAc, 15+1) to afford 143.9 mg (0.971 mmol, 73.0%) of pyrrolecarbonitrile 14 as a colourless solid.

3,5-Dimethy-4-formyl-1H-pyrrole-2-carbonitrile (14)
73% yield, colourless solid, mp 154 °C. TLC (SiO2, CH2Cl2/AcOEt 15+1): Rf = 0.38. ν = 3230 (s, NH), 2965, 2940 (m, CH), 2690 (w), 2480 (w), 2210 (s, (CN)), 1670 (s, (C=O)), 1460 (m), 1430 (w), 1375 (m), 1320 (m), 1240 (s), 1200 (m), 1185 (m), 1120 (s), 1070 (w), 1020 (w), 960 (w), 910 (w), 850 (m), 730 (m), 720 (w). 1H-NMR (200 MHz, CDCl3): 2.93 (3H, s, CH3-C(2)), 3.01 (3H, s, CH3-C(2)), 8,08 (1H, s, CHO-C(4)), 8.91 (1H, s, br, NH). MS (EI) m/z (%):149 (M+, 13C, 5), 148 (M+, 60), 147 (100), 119 (M+-CHO, 6), 105 (1), 92 (3), 65 (5). HRMS m/z: C8H8N2O+ calcd. 148.06366, found 148.06330.

General procedure for preparation of tetrahydrobilins rac-20 and rac-21
A 5N solution of potassium hydroxide in MeOH/H2O 9:1 (4 mL) was added to a solution of 13.0 mg (27.2 μmol) 1-Cyano-14-ethoxycarbonyl-1,2,3,17-tetrahydro-1,2,2,7,8,12,13-heptamethyl-15H-tripyrrin-nickel (II) (rac-15) in dry THF (5 mL). The mixture was heated at 80 °C for 45 min under an argon atmosphere. After cooling, the reaction mixture was diluted with CH2Cl2 (20 mL) and washed with a aq. NaHCO3 solution (20 mL). The aqueous layer was vigorously extracted with CH2Cl2 (4 x 30 mL), the combined organic layers were dried by filtration through oven dried cotton wool and concentrated in vacuo to afford the free carboxylic acid of rac-15. Degassed solutions of pyrroles 6.9 mg 8 or 7.7 mg 14 (51.7 μmol) in dry CHCl3 (6 mL) and 0.4N p-toluenesulfonic acid in CHCl3 (0.68 mL, 272 μmol, 10 eq.) were successively added by a syringe through a septum to the degassed solution of carboxylic acid under an argon atmosphere. The mixture was refluxed with stirring for 20 min. The green reaction mixture was diluted with CH2Cl2 (20 mL), poured into a separatory funnel containing water (30 mL) and it was vigorously extracted with CH2Cl2 (3 x 20 mL). The combined organic layers were dried by filtration through oven dried cotton wool and concentrated in vacuo. The metal free bilins rac-16 or rac-17 were used without further purification for the next reaction step. Therefore, a solution of 24.1 mg of dry Ni(OAc)2 (136 μmol) and NaOAc (11.2 mg) in dry MeOH (3 mL) was added to solutions of rac-16 or rac-17 in dry CH2Cl2 (6 mL). The mixture was reacted at room temperature for 30 min under an argon atmosphere. The reaction mixture was transferred into a separatory funnel containing water (20 mL) and it was vigorously extracted with CH2Cl2 (3 x 20 mL). The organic layers were dried by filtration through oven dried cotton wool and concentrated under a reduced pressure. The residue was purified by column chromatography (SiO2, CH2Cl2/EtOAc, 15:1) to yield rac-20 or rac-21 as dark red-purple solids.

[1-Cyano-14-(5´cyano-2´-methyl-1´H-pyrrole-3´-carbonyl)-1,2,3,17-tetrahydro-1,2,2,7,8,12,13-heptamethyl-15H-tripyrrinato] nickel(II) (rac-20). 35% yield (5.1 mg, 9.5 µmol), dark red-purple solid. TLC (SiO2, CH2Cl2/MeOH AcOEt 99+1): Rf = 0.70. UV-VIS (CH2Cl2): λmax (c = 1.25∙10-5 M) = 572 (11744), 360 (17680 cm2∙mmol-1). 1H-NMR (200 MHz, CDCl3): 1.21 (3H, s, CH3-C(2) trans rel. NC-C(1)), 1.29 (3H, s, CH3-C(2) cis rel. NC-C(1)), 2.13 (3H, s, CH3-C(7)), 2.17 (3H, s, CH3-C(13)), 2.24 (3H, s, CH3-C(12)), 2.27 (3H, s, CH3-C(8)), 2.52 (3H, s, CH3-C(2´)), 2.82, 2.93 (2H, AB, J = 16,6 Hz, 2H-C(3)), 5.78, (1H, s, H-C(5)), 6.70, (1H, s, H-C(10)), 7.16, (1H, s, H-C(4´)), 8.74, (1H, s, H-N(1´)). MS (EI) m/z (%): 536 (M+, 58Ni, 36), 509 (M-HCN+, 58Ni, 12). HRMS m/z: C29H30N6O58Ni+ calcd. 536.18346, found 536.18268.

[1-Cyano-14-(5´-cyano-2´,4´-dimethyl-1´H-pyrrol-3´-carbonyl)-1,2,3,17-tetrahydro-1,2,2,7,8,12,13-heptamethyl-15H-tripyrrinato] nickel(II) (rac-21). 39% yield (5.8 mg, 10.6 µmol), dark red-purple solid. TLC (SiO2, CH2Cl2/MeOH 99+1): Rf = 0.74. UV-VIS (CH2Cl2): λmax (relative intensity) = 572 (0.68), 538 (0.40, sh), 360 (1). 1H-NMR (200 MHz, CDCl3): 1.20 (3H, s, CH3-C(2) trans rel. NC-C(1)), 1.30 (3H, s, CH3-C(2) cis rel. NC-C(1)), 2.14 (3H, s, CH3-C(7)), 2.19 (3H, s, CH3-C(13)), 2.25 (3H, s, CH3-C(12)), 2.27 (3H, s, CH3-C(8)), 2.40, (3H, s, CH3-C(4´)), 2.53 (3H, s, CH3-C(2´)), 2.82, 2.93 (2H, AB, J = 16,6 Hz, 2H-C(3)), 5.78, (1H, s, H-C(5)), 6.71, (1H, s, H-C(10)), 8.74, (1H, s, H-N(1´)). MS (EI) m/z (%): 550 (M+, 58Ni, 100), 535 (M-CH3+, 58Ni, 11) 523 (M-HCN+, 58Ni, 60). HRMS m/z: C30H32N6O58Ni+ calcd. 550.19911, found: 550.19921.

ACKNOWLEDGEMENTS
We thank Johannes Stelten (Institute of Organic Chemistry, University of Bremen) for NMR measurements, Dr. Thomas Dülcks and Dorit Kemken (Institute of Organic Chemistry, University of Bremen) for MS measurements and Dr. Tobias Borrmann (Institute of Organic Chemistry, University of Bremen) for helpful assistance in the preparation of theoretical calculations. Prof. Dr. Lechosław Latos-Grażyński thanks the Alexander von Humboldt-Foundation (Bonn, Germany) for granting him the Alexander von Humboldt-Award.

References

1. (a) A. W. Johnson, Chem. in Britain, 1967, 3, 253; (b) A. W. Johnson, Chem. Soc. Rev., 1975, 4, 1; CrossRef A. W. Johnson, Chem. Soc. Rev., 1980, 9, 125; CrossRef (c) K. M. Smith in ‘The Porphyrin Handbook’, Eds. K. M. Kadish, K. M. Smith and R. Guilard, Academic Press, San Diego, US, 2000, Vol. 1, pp. 119-148.
2. (a) A. Eschenmoser and C. E. Winter, Science, 1977, 196, 1410; CrossRef (b) A. Eschenmoser, Angew. Chem., 1988, 100, 5. CrossRef
3. (a) F.-P. Montforts and J. W. Bats, Helv. Chim. Acta, 1987, 70, 402; CrossRef (b) F.-P. Montforts and J. W. Bats, Angew. Chem., 1982, 94, 208; CrossRef ibid. Suppl., 1982, 499.
4. (a) F.-P. Montforts, Angew. Chem., 1981, 93, 795; CrossRef (b) F.-P. Montforts and U. M. Schwartz, Liebigs Ann. Chem., 1985, 1228. CrossRef
5. (a) J. M. Muchowski and P. Hess, Tetrahedron Lett., 1988, 29, 777; CrossRef (b) T. Curran, J. Org. Chem. 1996, 61, 9068; CrossRef (c) L. F. Elsom and R. A. Jones, J. Chem. Soc. (B), 1970, 79. CrossRef
6. (a) C. Lingjiang and D. A. Lightner, Synthesis, 1999, 46; CrossRef (b) T. Könekamp, Diploma Thesis, Universität Bremen, 2004.