An investigation of a palladium catalysed biaryl synthesis of pyrrolophenanthridine derivatives. Extension of the Heck reaction

Article

An Investigation of a Palladium Catalysed Biaryl Synthesis of Pyrrolophenanthridine Derivatives. Extension of the Heck Reaction.

Simon J. Garden^*, José C. Torres and Angelo C. Pinto

Instituto de Química, Departamento de Química Orgânica, Bloco A,

Universidade Federal do Rio de Janeiro, 21945-970, Rio de Janeiro - RJ, Brazil.

Derivados halogenados de N-benzilisatinas ciclizaram facilmente, com eliminação de haletos de hidrogênio, numa reação de síntese de biarilas sob catálise por paládio, na ausência de ligantes fosfinas, levando às oxopirrolo[3,2,1-de]fenantridinas correspondentes.

N-Benzylisatin derivatives have been found to readily undergo cyclisation via hydrogen halide elimination in a biaryl synthesis reaction when using palladium catalysts, in the absence of phosphine ligands, to yield oxopyrrolo[3,2,1-de]phenanthridine derivatives.

Keywords: Heck reaction (Jeffery's conditions), benzylisatins, pyrrolophenanthridines, biaryl coupling

Introduction

The pyrrolo[3,2,1-de]phenanthridine skeleton has been found in a large number of natural products from the plants of almost all of the genera of the family Amaryllidaceae. Examples of these compounds include assoanine¹ (1), oxoassoanine² (2), hippadine³ (3) and ungeremine⁴ (4) amongst others⁵. These compounds (Figure 1) are of interest as synthetic targets not only for the development of synthetic methodology but also for their biological activities⁶. An important feature of the pyrrolo[3,2,1-de]phenanthridine skeleton is the biaryl linkage and this has often been a central subject of the synthetic methodology employed for the construction of these, and a diverse range of phenanthridine or benzophenanthridine derivatives⁷.

The Heck reaction⁸ is a versatile methodology for the formation of new C-C bonds, particularly for the coupling of an aromatic halide with an olefin⁹. The corresponding biaryl synthesis where hydrogen halide is eliminated from the two aromatic components is a recent extension of the Heck reaction¹⁰, whereas the corresponding biaryl synthesis using an oxidative addition reaction with stoichiometric quantities of palladium salts has been more extensively studied¹¹.

Results and Discussion

In a general approach for the construction of pyrrolophenanthridine alkaloids an appropriately substituted N-benzylisatin derivative (5), that contained the entire carbon framework, was envisaged as a suitable precursor for the obtention of these natural products and their analogs (Scheme 1).

Subsequent reduction of the cyclised isatin derivatives to indoles would yield, for example, dehydroanhydrolycorine¹² (6). Successful cyclization would also furnish substrates to further on going investigations of the use of BH₃.THF for the reduction of isatin derivatives to indoles¹³. Strategically, oxidation of the derivatives of compound 6 could present problems due to oxidation of the indolic double bond. However, Gribble reduction¹⁴ of the indolic double bond and subsequent oxidation of the indoline would seem to be a viable route for the synthesis of, for example, anhydrolycorin-7-one (7) and hippadine (3), Scheme 1.

The appropriate N-benzylisatin derivatives 5 for investigation of the synthesis of the pyrrolphenanthridines were readily prepared by benzylation of substituted isatin derivatives¹⁵8 using basic conditions (Scheme 2).

Initial experiments to determine conditions for the formation of the biaryl linkage focused upon the attempted cyclisations of 7-bromo- and 7-iodo-5-methyl-N-benzylisatin (5a and 5b) using 10 mol% Pd(OAc)₂ in the presence of 20 mol% of triphenylphosphine in aceto-nitrile¹⁶. Substantial substrate consumption was observed but no defined product could be isolated upon workup. It was therefore questioned as to whether the cis dicarbonyl system could possibly interfere in the coupling reaction. An inspection of the isatin literature revealed a study by Martinez and Naarmann that reported the Suzuki couplings of a number of heteroarylboronates with 5-bromo- and 5-iodo- isatin using tetrakis-triphenylphosphine palladium as the catalyst, albeit in very modest yields¹⁷. A plausible explanation for the modest yields obtained by Martinez and Naarmann and the poor mass balance in our reactions, where the substrate was recovered in 52-62% yield, was encountered in the work of Lathourakis and Litinas¹⁸, where these authors have shown that PPh₃ reacts with isatin to yield a phosphoranylidene that can undergo Wittig reactions. Therefore, to eliminate this source of interference the ketone was transformed into the corresponding ketal (9a-i) using conventional methodology (Scheme 2).

Submission of 9 (a and b) or N-benzyl-5-methyl-7-iodo-2-oxindole, obtained by reduction of 5b with hydrazine hydrate¹⁹, to the same reaction conditions¹⁶ as used in the first experiments also yielded no defined products but the substrates were recovered in 87-91% yield. The reaction conditions¹⁶ were subsequently modified by replacing acetonitrile with DMF to allow an increased reaction temperature. When 9b was submitted to the new conditions, the formation of defined products could be observed upon TLC analysis. ¹H NMR analysis of the crude product after workup of the reaction revealed the conversion of the reaction to be low, 29% (96% mass balance), and the major product was identified as the reduced N-benzyl-5-methylisatin ethylene ketal (25%) from comparison of spectral data with an authentic sample²⁰. The structure of the minor component (4%) was suspected to be the desired cyclised product 10a; this suspicion being latter confirmed, vide infra. Subsequent investigations of the reaction conditions were based upon experimental work first reported by Jeffery²¹. Similarly to the initial experiments using the substrates 5a and 5b under Heck conditions, substrate consumption was observed but no defined products could be detected by TLC or upon workup of the reaction. Attention was then focused upon the ketal substrate 9a, which in the presence of 10% Pd(OAc)₂ (0.1mol L^-1 DMF), 1 mole equivalent of Bu₄NBr, and 5.5 mole equivalents of KOAc at 100^oC (bath temp.) resulted in the formation of a single product at 56% conversion of the substrate, Table 1, entry 1 (95% mass balance). This product had the same NMR features as the minor product observed in the previous experiment using this substrate, vide supra. In a similar experiment where PdCl₂ was used as the catalyst (table entry 2) a comparable result was obtained with a 98% mass balance. In contrast to the bromide 9a, the iodide 9b readily furnished the same product as the previous experiments. Isolation and characterisation of this product identified it as the oxopyrrolophenanthridine 10a. Investigation of the catalyst loading revealed a reaction time dependance upon the reaction (table entries 4-7). The ortho-iodobenzyl derivative 9c cyclised under similar conditions to yield the parent ring system 10b (table entry 8). Further evidence for halogen positional versatility can be seen in table entries 9 and 10 where the oxopyrrolophenanthridine derivative 10c was obtained in 77-78% yield from either substrate 9d or 9e. The iodides were found to be superior to the bromides giving better yields and shorter reaction times (compare table entries 1 and 2 with 5, 10 with 11, and 12 with 13). The presence of a nitro group either on the halogenated aromatic ring or the aromatic ring to be attacked by the intermediate organopalladium species significantly accelerated the reaction giving increased yields in reduced reaction times (compare table entries 1, 2 and 3 with 9 and 10). Little difference in reaction time or yield was observed in the cyclisations of the unsubstituted 9c and the methylenedioxy substituted 9h (table entries 8 and 13). However, the dimethoxy substituted 9i required a signifcantly longer reaction time to attain an almost equally good yield (table entry 14).

In all successful reactions initiation of the reaction was evidenced by a darkening of the reaction mixture which normally had an onset temperature greater than 80^oC (bath temp.). Both aromatic iodides and bromides have been cyclised successfully in the absence of phosphine ligands, though the experiments revealed that the iodides are better substrates²². No special precautions are required for performing these cyclisations which have been routinely performed exposed to the laboratory atmosphere.

The reaction offers a unique opportunity to investigate structural requirements and substituent effects as it has been found to be tolerant to both activation and deactivation of the aromatic nuclei and therefore, mechanistically relevant information can be delineated. These studies as well as the application of this methodology to the synthesis of a number of natural products are currently being investigated.

Experimental

General

¹H and ¹³C NMR spectra were recorded using 300 MHz and 200 MHz (¹H) Bruker spectrometers and are referenced to TMS. Coupling constants are quoted in Hz. Mass spectra were recorded at NPPN (Nucleo de Pesquisa de Produtos Naturais, Universidade Federal do Rio de Janeiro) using a Hewlett-Packard GC-MS or by direct insertion using a VG Autospec. Infra-red spectra were recorded using a Perkin Elmer 1600 FT-IR (error ± 4cm^-1) as KBr discs. Melting points were recorded on a hotstage microscope and/or using a MelTemp II capillary apparatus and are reported as uncorrected values. DMF was used as supplied without further treatment.

Experimental procedure

The appropriate isatin derivative (1.00 mmol), Pd(OAc)₂ (0.10 mmol), Bu₄NBr (1.10 mmol), KOAc (5.50 mmol) and DMF (10 mL) were added to a round bottom flask. The reaction mixture was heated on an oil bath (100 ± 5^oC, bath temp.) and the reaction accompanied by TLC. On complete reaction, distilled water (50ml) or aqueous HCl (0.2mol L^-1, 50mL) was added to the reaction mixture and the mixture was extracted with ethyl acetate (3 x 15 mL). The organic phase was dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was then chromatographed on a silica gel column using hexane/ethyl acetate (4:1, V/V) as eluent. Physical and spectroscopic data of compounds 10 follow:

spiro-4-(ethylenedioxy)-2-methyl-7-hydropyrrolo[3,2,1-de] phenanthridin-5-one (10 a)

mp. 190-193^oC; IR n_max/cm^-1 3058, 2975, 2889, 1719, 1636, 1449, 1349, 1204, 1029, 1000, 948, 864, 773, 741 (KBr), Mass [m/z (abun.)] 293(33%), 264(100), 220(29), 193(27), 178(4), 165(17), 110(31), 96(29), 96(29), 82(28); ¹H NMR (300 MHz, CDCl₃) d 2.34 (s, 3H, CH₃), 4.29-4.34 (m, 2H, CH₂), 4.56-4.61 (m, 2H, CH₂), 4.88 (s, 2H, CH₂), 7.06 (d, 1H, CH, J 0.6 Hz), 7.10 (dd, 1H, CH, J 0.9, 6.3 Hz), 7.24 (dt, 1H, CH, J 1.4, 7.4, 7.4 Hz), 7.26 (dt, 1H, CH, J 0.7, 7.4, 7.4 Hz), 7.43 (s, 1H, CH), 7.67 (d, 1H, CH, J 7.5 Hz); ¹³C NMR PENDANT (75 MHz, CDCl₃) d 21.6 (CH₃), 44.5 (CH₂), 66.0 (CH₂), 103.4 (C), 117.2 (C), 122.4 (CH), 122.7 (C), 124.6 (CH), 125.1 (CH), 127.8 (CH), 128.1 (CH), 128.2 (C), 128.5 (CH), 128.9 (C), 133.3 (C), 137.1 (C), 172.9 (C=O). Found: C, 73.23; H, 5.04; N, 4.62. Calc. for C₁₈H₁₅NO₃: C, 73.71; H, 5.15; N, 4.76%.

spiro-4-(ethylenedioxy)-7-hydropyrrolo[3,2,1- de] phenanthridin-5-one (10 b)

mp. 161-162^oC, IR n_max/cm^-1 3060, 2986, 2903, 1721, 1633, 1489, 1440, 1367, 1312, 1283, 1194, 1148, 1002, 950, 756; Mass [m/z (abun.)] 279(32%), 250(100), 220(3), 206(53), 190(4), 178(37), 151(36), 126(6), 103(28), 89(62), 76(71), 63(19); ¹H NMR (300 MHz, CDCl₃) d 4.31-4.39 (m, 2H, CH₂), 4.57-4.62 (m, 2H, CH₂), 4.93 (s, 2H, CH₂), 7.04 (t, 1H, CH, J 7.7), 7.13 (d, 1H, CH, J 7.2 Hz), 7.22-7.31 (m, 3H, CH), 7.65 (dd, 1H, CH, J 0.6, 8.0 Hz), 7.73 (dd, 1H, CH, J 1.4, 7.3 Hz); ¹³C NMR PENDANT (75 MHz, CDCl₃) d 42.3 (CH₂), 65.8 (CH₂), 103.1 (C), 117.4 (C), 122.4 (CH), 122.7 (C), 123.5 (CH), 124.1 (CH), 124.3 (CH), 127.6 (CH), 127.7 (C), 128.0 (C), 128.0 (CH), 128.5 (CH), 139.3 (C), 172.8 (C=O). Found: C, 73.03; H, 4.42; N, 5.08. Calc. for C₁₇H₁₃NO₃: C, 72.94; H, 4.64; N, 5.01%.

spiro-4-(ethylenedioxy)-2-nitro-7-hydropyrrolo[3,2,1-de] phenanthridin-5-one (10 c)

mp. 238-240^oC (decomp.); IR n_max/cm^-1 3083, 2971, 2909, 1739, 1613, 1527, 1493, 1339, 1252, 1175, 1031, 946, 781, 753, 729; Mass [m/z (abun.)] 324(24%), 295(100), 251(39), 224(16), 205(26), 177(45), 150(32), 126(5), 103(16), 86(66), 75(79), 63(16); ¹H NMR (200 MHz, CDCl₃/DMSO-d₆) d 4.16-4.22 (m, 2H, CH₂), 4.35-4.41 (m, 2H, CH₂), 4.81 (s, 2H, CH₂), 7.02 (d, 1H, CH, J 5.3 Hz), 7.20 (m, 2H, CH), 7.67 (d, 1H, CH, J 5.4 Hz), 7.91 (s, 1H, CH), 8.42 (s, 1H, CH); ¹³C NMR PENDANT (50 MHz, CDCl₃/DMSO-d₆) d 42.1 (CH₂), 65.9 (CH₂), 101.5 (C), 117.7 (C), 119.4 (CH), 119.9 (CH), 122.7 (CH), 123.2 (C), 125.6 (C), 127.6 (CH), 128.2 (C], 128.4 (CH], 129.8 (CH), 144.2 (C), 144.6 (C), 172.9 (C=O]*. Found: C, 63.13; H, 3.45; N, 8.81. Calc. for C₁₇H₁₂N₂O₅ : C, 62.94; H, 3.55; N, 8.86%. *Signal observed in the normal ¹H decoupled ¹³C spectrum recorded in C₆D₆/CDCl₃.

spiro-4-(ethylenedioxy)-9,10-(methylenedioxy)-7-hydro -pyrrolo[3,2,1-de] phenanthridin-5-one (10 d)

mp. 226-228^oC (decomp.); IR n_max/cm^-1 3047, 2969, 2900, 1716, 1638, 1508, 1475, 1369, 1238, 1188, 1153, 1042, 939, 787, 744; Mass [m/z (abun.)] 323(42%), 294(100), 264(25), 250(37), 223(27), 164(23), 138(14), 124(30), 110(14), 96(43), 82(39), 69(25), 63(14); ¹H NMR (300 MHz, CDCl₃) d 4.31-4.39 (m, 2H, CH₂), 4.54-4.61 (m, 2H, CH₂), 4.88 (s; 2H, CH₂), 6.00 (s, 2H, CH₂), 6.61 (s, 1H, CH), 7.03 (t, 1H, CH, J 7.5 Hz), 7.18 (s, 1H, CH), 7.19 (dd, 1H, CH, J 0.7, 7.5 Hz), 7.50 (d, 1H, CH, J 7.5 Hz); ¹³C NMR (75 MHz, CDCl₃) d 42.9 (CH₂), 66.0 (CH₂), 101.8 (CH₂), 102.9 (CH), 103.5 (C), 107.8 (CH), 117.8 (C), 122.3 (C), 122.6 (C), 122.7 (C), 123.7 (CH), 123.8 (2 x CH), 139.0 (C), 148.1 (C), 148.3 (C), 173.1 (C=O).

spiro-4-(ethylenedioxy)-9,10-dimethoxy-7- hydropyrro-lo[3,2,1-de] phenanthridin-5-one (10 e)

mp. 188-190^oC; IR n_max/cm^-1 3067, 2966, 2839, 1719, 1635, 1467, 1358, 1217, 1185, 1149, 1048, 1002, 940, 854, 780, 737; Mass [m/z (abun.)] 339(42%), 310(100), 266(21), 239(28), 153(8), 134(8), 126(5), 63(3); ¹H NMR (300 MHz, CDCl₃) d 3.89 (s, 3H, CH₃), 3.95 (s, 3H, CH₃), 4.31-4.35 (m, 2H, CH₂), 4.57-4-62 (m, 2H, CH₂), 4.88 (s, 2H, CH₂), 6.60 (s, 1H, CH), 7.03 (t, 1H, CH, J 7.4 Hz), 7.16 (s, 1H, CH), 7.19 (d, 1H, CH, J 7.4 Hz), 7.53 (d, 1H, CH, J 7.4Hz); ¹³C NMR (75 MHz, CDCl₃) d 42.0 (CH₂), 55.9 (2 x CH₃), 65.7 (CH₂), 101.2 (C), 105.1 (CH), 109.9 (CH), 117.5 (C), 120.5 (C), 121.0 (CH), 122.3 (C), 123.2 (CH), 123.2 (CH), 123.4 (CH), 138.4 (C), 148.6 (C), 149.3 (C), 172.8 (C=O); HRMS. Found: 339.1107. Calc. for C₁₉H₁₇NO₅: 339.1107.

Acknowledgements

The authors thank CNPq, the PRONEX program and FAPERJ for financial support. SJG also thanks the Fundação Oswaldo Cruz, Farmanguinhos, Rio de Janeiro for support from the PAPES II program. The following are gratefully acknowledged: Prof. Marcos N. Eberlin (UNICAMP, São Paulo) for the HRMS and the Instituto de Química, USP, São Paulo, and CENPES, Rio de Janeiro, for the elemental analyses.

References

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16. A typical experiment involved refluxing an CH₃CN solution (0.05mol L^-1) of the substrate in the presence of 10 mole% Pd(OAc)₂, 20 mole% Ph₃P and 2 equivalents of Et₃N.

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20. Prepared by reaction of the known N-benzylisatin (see reference 15) with ethylene glycol in the presence of H₂SO₄.

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Received: January 21, 2000

Published on the web: August 31, 2000

Publication Dates

• Publication in this collection
  15 Jan 2001
• Date of issue
  Oct 2000

History

• Accepted
  31 Aug 2000
• Received
  21 Jan 2000