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Synthesis 2010(10): 1707-1711  
DOI: 10.1055/s-0029-1218735
PAPER
© Georg Thieme Verlag Stuttgart ˙ New York

The Meldrum’s Acid Route to Prodigiosin Analogues

Gordon A. Hunter, Hamish McNab*, Kirsti Withell
School of Chemistry, The University of Edinburgh, West Mains Road, Edinburgh EH9 3JJ, UK
Fax: +44(131)6504743; e-Mail: H.McNab@ed.ac.uk;

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Publication History

Received 15 February 2010
Publication Date:
09 April 2010 (online)

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Abstract

3-Methoxy-5-(2-thienyl)thiophene-2-carboxaldehyde and 3-methoxy-l-methyl-5-(2-thienyl)pyrrole-2-carboxaldehyde were prepared from the appropriate 3-hydroxypyrrole or 3-hydroxy­thiophene by regioselective O-alkylation and formylation. Condensation of these aldehydes with activated pyrroles in the presence of phosphoryl chloride provides analogues of prodigiosin, which differ from the natural products in the nature of the heteroatoms.

Key words

gas-phase reactions - heterocycles - pyrroles - prodigiosins

There has been much interest in the synthesis of the prodigiosin family of antibiotics 1, originally isolated from the microorganism Serratia marcescens, because of their antibacterial, cytotoxic, and immunosuppressive activities (Figure  [¹] ). [¹] A number of classic total syntheses have been reported, [²] but the problem of routine, scaleable formation of the central alkoxypyrrole ring was not solved until 1996 by a cross-coupling strategy. [³] Some years ago, we used our pyrolytic route to 3-hydroxypyrroles [4] and 3-hydroxythiophenes [5] to create prodigiosin analogues in which the pyrrole (ring A) was replaced by a thiophene moiety and in which the alkoxypyrrole (ring B) was replaced by an N-substituted alkoxypyrrole or by an alkoxy­thiophene moiety. [6] These modifications significantly alter the hydrogen-bonding regime of the prodigiosins and since our original communication, [6] few further examples of such structural types have been reported. [7] In this paper, we provide full experimental details of our original work and report extensions to other ring C analogues of the natural products.

Figure 1 General structure of prodigiosins

The Meldrum’s acid route to prodigiosin analogues involves a four- or five-step synthesis starting from the known [5] methylthio compound 2 (Scheme  [¹] ). The thiophenone 4K (3-hydroxythiophene 4E) was readily generated as a stable, crystalline solid, by flash vacuum pyrolysis (FVP) of 2 at 625 ˚C (76%). [5] Alternatively, treatment of 2 with dimethylamine to give 3 followed by FVP (625 ˚C) provided the N-methylpyrrolone 5K (3-hydroxypyrrole 5E) (ca. 70%). This compound was very reactive, either in solution or as the neat material, and was O-alkylated without purification. Conditions for highly regioselective O-alkylation of N-substituted 3-hydroxypyrroles have been previously established [8] and were applied successfully to 5 and to the 3-hydroxythiophene 4 to provide 7 and 6 (both 90%), respectively. Once again, the pyrrole system 7 was air sensitive and was taken on to the next step without purification. The regioselectivity of electrophilic substitution reactions of 3-hydroxy- and 3-alkoxypyrroles has also been established [9] and was found to be applicable to Vilsmeier formylation conditions; the 2-carboxaldehydes 8 and 9 were obtained as the only regioisomers, in 75% yield.

Scheme 1

A simplified version of the methoxypyrrole lacking ring A, compound 10 was prepared by photochemical ring contraction of 4-methoxypyridine N-oxide as previously reported by Streith and co-workers. [¹0]

The range of ‘ring C’ pyrroles within the natural products structures is extensive, and many are of formidable complexity. [¹] In order to establish the methodology, our initial reactions focused on commercially available kryptopyrrole (2,4-dimethyl-3-ethylpyrrole) 11 with only one vacant carbon ring position. N-Alkylation provided the tetrasubstituted pyrrole 12 (Figure  [²] ). 2-Undecylpyrrole (13), present as ring C in undecylprodigiosin was synthesized by a literature method. [¹¹]

Figure 2 Pyrroles 10-13, thiophene 17, and pyrazole 18

2-Methyl-3-pentylpyrrole (16), found in prodigiosin itself, was made in two steps, by photochemical ring contraction of 4-pentylpyridine N-oxide (14) in the presence of copper(II) ions [¹0] followed by Wolff-Kischner reduction of the formyl group of 15 (Scheme  [²] ). Although this route is reasonably concise, [¹²] the ring contraction step occurred in very low yield (20%) and was not amenable to scale-up. The final Wolff-Kischner step was also less efficient than expected. 3-Methoxythiophene (17) and 3-aminopyrazole (18) were also used as ring C analogues, on account of their complementary hydrogen-bonding properties.

Scheme 2

In most cases, the final step to give the prodigiosin analogue was a phosphoryl chloride catalyzed condensation of the aldehydes 8 and 9 with a 2-unsubstituted pyrrole under published conditions [¹³] (Scheme  [³] ) and provided the three-ring systems 19-24 (68-97%). The final products were isolated and characterized as their dichlorophosphate salts, which were either crystalline solids or thick purple oils and were characterized by NMR and by FAB mass spectrometry. The salts were generally reasonably stable, with the exception of the ring C thiophene derivative 23, which decomposed within 72 hours of formation, even when stored at -20 ˚C.

Scheme 3

The X-ray crystal structure of the N-methyl derivative 24 showed hydrogen bonding between the NH of the pyrrole of ring C and the methoxy group, [6] within an essentially coplanar framework. This corresponds to the β-form of prodigiosin free base, [¹4] but very different hydrogen-bonding regimes are observed when rings A and/or B have a free NH. [¹4]

Condensation of 3-methoxypyrrole-2-carboxaldehyde (10) with kryptopyrrole gave the prodigiosin analogue 25 lacking ring A, but with the B-C hydrogen-bonding regime found in the natural products. The free base 25′ of this product was also isolated. Condensation of 8 with 3-aminopyrazole (18) provided the base 26 (Figure  [³] ); the exocyclic nitrogen atom also occurs in the tambjamine natural products. [¹]

Figure 3 Compounds 25 and 26

In conclusion, a range of prodigiosin analogues has been synthesized, in which the key steps are (i) synthesis of the ring A-ring B section as a hydroxypyrrole or hydroxy­thiophene by FVP of an appropriate methylene Meldrum’s acid derivative, (ii) regioselective O-alkylation and C-formylation, and (iii) coupling of the aldehyde with an appropriate pyrrole or activated thiophene derivative. We have recently reported that certain N-unsubstituted 3-hydroxypyrroles are available by the Meldrum’s acid route, [¹5] which could broaden the scope of the approach used in the present work.

¹H and ¹³C NMR spectra were recorded at 250 MHz and 63 MHz respectively unless otherwise stated. Chemical shifts are given in ppm relative to TMS. Mass spectra were recorded under electron impact conditions unless otherwise stated.

5-(l-Dimethylamino-l-thienylmethylene)-2,2-dimethyl-l,3-dioxane-4,6-dione (3)

Treatment of 2 [5] with an excess of Me2NH in MeCN gave 3 (65%); mp 205-207 ˚C (dec.).

¹H NMR (CDCl3): δ = 7.66 (d, ³ J = 5.0 Hz, 1 H), 7.39 (d, ³ J = 3.8 Hz, 1 H), 7.12 (dd, ³ J = 3.8, 5.0 Hz, 1 H), 3.34 (s, 6 H), 1.67 (s, 6 H).

¹³C NMR (CDCl3): δ = 167.66 (Cq), 162.29 (Cq), 136.93 (Cq), 133.90, 133.75, 128.23, 102.33 (Cq), 84.59 (Cq), 46.69, 44.26, 26.57 (2 C), (one Cq overlapping).

MS: m/z (%) = 281 (M+, 13), 224 (14), 223 (36), 179 (85), 178 (50), 150 (27), 135 (38), 109 (33), 108 (100), 95 (33), 82 (88), 69 (18), 63 (16).

Anal. Calcd for C13H15NO4S: C, 55.5; H, 5.35; N, 5.0. Found: C, 55.6; H, 5.45; N, 4.95.

1-Methyl-5-(2-thienyl)pyrrol-3(2 H )-one (5)

Compound 3 (2.81 g, 10 mmol) was distilled at 160 ˚C/0.001 Torr through an electrically heated silica furnace tube (35 × 2.5 cm) at 625 ˚C over 3 h under typical FVP conditions. [4] Product 5 (1.25 g, 70%) condensed in a liquid N2 trap situated at the exit point of the furnace. This compound was an air sensitive viscous oil, which could not be purified. It was normally used in its crude form by washing it directly from the trap with the reaction solvent.

¹H NMR (CDCl3): δ (tautomers 5E and 5K both present - data for 5K quoted) = 7.54 (dd, ³ J = 5.0 Hz, 4 J = 1.2 Hz, 1 H), 7.38 (dd, ³ J = 3.7 Hz, 4 J = 1.2 Hz, 1 H), 7.12 (dd, ³ J = 5.0, 3.7 Hz, 1 H), 5.34 (s, 1 H), 3.90 (s, 2 H), 3.19 (s, 3 H).

¹³C NMR (CDCl3): δ = (non-Cq signals only) 130.21, 129.91, 127.84, 100.95, 62.65, 35.54.

MS: m/z (%) = 179 (M+, 71), 178 (100), 164 (8), 150 (9), 109 (6), 108 (6), 82 (8), 71 (6), 69 (12), 65 (11), 63 (10), 58 (7).

HRMS: m/z calcd for C9H9NOS (M+): 179.0405; found: 179.0407.

O - Alkylation of 3-Hydroxypyrrole 5 and 3-Hydroxythiophene 4; General Procedure

The reported method for regioselective O-alkylation of 3-hydroxypyrroles was used. [8] To a stirred suspension of NaH (80% dispersion in oil, 0.288 g, ca. 6 mmol, washed 3 times with n-hexane and dried at 0.1 Torr) in dimethylimidazolidinone (20 mL) was added a solution of the hydroxypyrrole 5 or hydroxythiophene 4 (2 mmol) in dimethylimidazolidinone (5 mL) under a stream of N2. A solution of methyl p-toluenesulfonate (0.372 g, 2 mmol) in dimethylimidazolidinone (4 mL) was added dropwise and the resulting mixture was stirred overnight at r.t. The reaction mixture was quenched with EtOH-H2O (40 mL, 1:1) and extracted with Et2O (3 × 50 mL). The combined organic layers were back-extracted with H2O (5 × 100 mL), dried (MgSO4), and the solvent was removed under reduced pressure.

3-Methoxy-5-(2-thienyl)thiophene (6)

Compound 4 gave 6 (90%); bp 122-124 ˚C/0.2 Torr.

¹H NMR (CDCl3): δ = 7.20 (dd, ³ J = 5.0 Hz, 4 J = 1.2 Hz, 1 H), 7.16 (dd, ³ J = 3.6 Hz, 4 J = 1.2 Hz, 1 H), 7.00 (dd, ³ J = 5.0, 3.6 Hz, 1 H), 6.86 (d, 4 J = 1.6 Hz, 1 H), 6.14 (d, 4 J = 1.6 Hz, 1 H), 3.81 (s, 3 H).

¹³C NMR (CDCl3): δ = 158.14 (Cq), 137.38 (Cq), 135.95 (Cq), 127.61, 124.45, 123.45, 115.70, 95.63, 57.07.

MS: m/z (%) = 196 (M+, 100), 167 (11), 153 (44), 109 (20), 108 (13), 69 (15), 45 (49).

HRMS: m/z calcd for C9H8OS2 (M+): 196.0017; found: 196.0022.

3-Methoxy-l-methyl-5-(2-thienyl)pyrrole (7)

Compound 5 gave 7 (90% crude yield), an air-sensitive compound, which could not be purified.

¹H NMR (CDCl3): δ = 7.24 (dd, ³ J = 4.9 Hz, 4 J = 1.2 Hz, 1 H), 7.09-7.02 (m, 2 H), 6.32 (d, 4 J = 1.1 Hz, 1 H), 6.12 (d, 4 J = 1.1 Hz, 1 H), 3.76 (s, 3 H), 3.62 (s, 3 H).

¹³C NMR (CDCl3): δ = 147.77 (Cq), 134.31 (Cq), 126.84, 124.36, 124.33 (Cq), 123.86, 105.80, 97.71, 57.08, 34.34.

MS: m/z (%) = 193 (M+, 100), 178 (59), 137 (10), 109 (9), 108 (8).

HRMS: m/z calcd for C10H11NOS (M+): 193.0561; found: 193.0560.

Formylation of 3-Methoxypyrrole 7 and 3-Methoxythiophene 6; General Procedure

POCl3 (1 mL) was added to DMF (10 mL) followed by a solution of the methoxythiophene 6 or the methoxypyrrole 7 (1 mmol) in DMF (10 mL). The reaction was continued for the temperature and time stated. When reaction was complete, the mixture was added to H2O (50 mL) and then NaOH (2 M, 50 mL) was added with stirring. The resulting solution was extracted with Et2O (4 × 50 mL). The combined organic layers were washed with H2O (2 × 100 mL), dried (MgSO4), and the solvent was removed under reduced pressure to give the crude product.

3-Methoxy-5-(2-thienyl)thiophene-2-carboxaldehyde (8)

Compound 6 (40 ˚C, 1 h) gave 8 (75%); mp 106.5-108.5 ˚C (EtOH).

¹H NMR (CDCl3): δ = 9.92 (s, 1 H), 7.36-7.30 (m, 2 H), 7.04 (dd, ³ J = 3.8 Hz, 5.0 Hz, 1 H), 6.88 (s, 1 H), 3.98 (s, 3 H).

¹³C NMR (CDCl3): δ = 180.29, 164.69 (Cq), 145.98 (Cq), 136.23 (Cq), 128.22, 127.17, 125.85, 119.30 (Cq), 111.26, 58.71.

MS: m/z (%) = 224 (M+, 100), 223 (38) 195 (13), 167 (22), 153 (17), 121 (15), 109 (16), 108 (34), 69 (20).

Anal. Calcd for C10H8O2S2: C, 53.6, H, 3.55. Found: C, 54.1; H, 3.6.

3-Methoxy-l-methyl-5-(2-thienyl)pyrrole-2-carboxaldehyde (9)

Compound 7 (20 ˚C, 30 min) gave 9 (75%); bp 175-177 ˚C/0.2 Torr.

¹H NMR (CDCl3): δ = 9.54 (s, 1 H), 7.31 (dd, ³ J = 5.0 Hz, 4 J = 1.2 Hz, 1 H), 7.09 (dd, ³ J = 3.6 Hz, 4 J = 1.2 Hz, 1 H), 7.01 (dd, ³ J = 5.0 Hz, 3.6 Hz, 1 H), 5.85 (s, 1 H), 3.86 (s, 3 H), 3.74 (s, 3 H).

¹³C NMR (CDCl3): δ = 175.28, 158.82 (Cq), 134.80 (Cq), 131.80 (Cq), 127.62, 127.44, 126.99, 118.63 (Cq), 94.81, 57.53, 33.99.

MS: m/z (%) = 221 (M+, 100), 220 (21), 206 (16), 204 (13), 192 (12), 109 (14), 108 (23), 70 (12), 69 (10).

Anal. Calcd for C11H11NO2S: C, 59.7; H, 5.0; N, 6.35. Found: C, 61.0; H, 5.35; N, 6.4.

3-Ethyl-1,2,4-trimethylpyrrole (12)

The general method of Heaney and Ley was used. [¹6] Anhyd DMSO (10 mL) was added to crushed KOH pellets (1.12 g, 0.02 mol) and the mixture was stirred for 5 min. 2,4-Dimethyl-3-ethylpyrrole (0.616 g, 0.005 mol) was added and the mixture was stirred for 45 min. The mixture was cooled in ice and MeI (1.42 g, 0.01 mol) was added dropwise with stirring and the stirring was continued for 45 min at r.t. H2O (10 mL) was added and the mixture was extracted with Et2O (3 × 50 mL). The combined organic extracts were washed with H2O (3 × 25 mL), dried (MgSO4), and the solvent was removed under reduced pressure to give 12, which was purified by Kugelrohr distillation (0.418 g, 61%); bp 75 ˚C/0.2 Torr.

¹H NMR (CDCl3): δ = 6.32 (s, 1 H), 3.47 (s, 3 H), 2.42 (q, ³ J = 7.3 Hz, 2 H), 2.14 (s, 3 H), 2.05 (d, 4 J = 0.7 Hz, 3 H), 1.10 (t, ³ J = 7.3 Hz, 3 H), consistent with reported data. [¹7]

¹³C NMR (CDCl3): δ = 127.13 (Cq), 124.34 (Cq), 120.66 (Cq), 117.48, 33.05, 17.67, 15.72, 9.80, 9.26.

2-Methyl-3-pentylpyrrole (16)

4-Pentylpyridine-N-oxide ( 14 ): To a solution of 4-pentylpyridine [¹8] (19.5 g, 0.131 mol) in glacial AcOH (85 mL) was added H2O2 (27.5% solution, 16.0 mL). The mixture was heated with stirring, at 75 ˚C for 4 h and then cooled to r.t. before a further addition of H2O2 (27.5% solution, 16.0 mL). The mixture was heated for a further 48 h at 75 ˚C and then concentrated to ca. 30 mL (keeping the water-bath below 40 ˚C and taking the relevant safety precautions). H2O (30 mL) was added, the mixture again concentrated to ca. 30 mL (again taking the necessary precautions) and the residue was dissolved in CHCl3 (90 mL). The solution was added to a K2CO3 paste (100 g K2CO3 in 100 mL H2O) with stirring, the mixture was filtered, and the organic layer of the filtrate was separated and dried (MgSO4). The solvent was removed under reduced pressure to give 14 as a pale brown oil (20.17 g, 93%); bp 105 ˚C/0.30 Torr.

¹H NMR (CDCl3): δ = 7.98-7.86 (m, 2 H), 6.94-6.81 (m, 2 H), 2.37 (t, ³ J = 7.7 Hz, 2 H), 1.44-1.32 (m, 2 H), 1.18-0.99 (m, 4 H), 0.65 (t, ³ J = 6.6 Hz, 3 H).

¹³C NMR (CDCl3): δ = 148.92 (Cq), 138.11, 125.46, 33.70, 30.53, 29.24, 21.77, 13.35.

MS: m/z (%) = 165 (M+, 30), 109 (24), 108 (100), 93 (46), 92 (24), 91 (17), 65 (17).

HRMS: m/z calcd for C10H15NO (M+): 165.1154; found: 165.1158.

2-Formyl-3-pentylpyrrole ( 15 ): Using the method provided in ref. 10, 4-pentylpyridine-N-oxide (14; 0.5 g, 3 mmol) was added to a solution of CuSO4˙5H2O (7.49 g, 0.03 mol) in deionized H2O (600 mL). The mixture was degassed for 30 min and then irradiated for 6 h using a 400 W Hg lamp. During irradiation a gentle stream of N2 was maintained through the solution. NaCl (150 g) was added to the reaction mixture with stirring, and then the solution was continuously extracted with CH2Cl2 overnight. The organic layer was separated and dried thoroughly (MgSO4) and the solvent was removed under reduced pressure. The residue was subjected to dry flash chromatography using n-hexane and EtOAc as eluents to give 15 as a cream solid (0.099 g, 20%); bp 150-155 ˚C/0.30 Torr.

¹H NMR (CDCl3): δ = 9.81 (br s, 1 H), 9.61 (s, 1 H), 7.03 (t, ³ J = 2.5 Hz, 1 H), 6.15 (t, ³ J = 2.5 Hz, 1 H), 2.75 (t, ³ J = 7.6 Hz, 2 H), 1.61 (m, 2 H), 1.47-1.28 (m, 4 H), 0.90 (t, ³ J = 6.8 Hz, 3 H).

¹³C NMR (CDCl3): δ = 177.44, 138.31 (Cq), 129.05 (Cq), 126.00, 111.40, 31.35, 31.26, 25.13, 22.32, 13.86.

MS: m/z (%) = 165 (M+, 23), 122 (42), 109 (23), 108 (35), 86 (64), 84 (100), 80 (31).

HRMS: m/z calcd for C10H15NO (M+): 165.1154; found: 165.1158.

Wolff-Kischner Reduction of 15 to 2-Methyl-3-pentylpyrrole ( 16 ): To a stirred mixture of crushed KOH pellets (0.28 g) and hydrazine hydrate (0.21 mL) in ethylene glycol (2.8 mL) was added 2-formyl-3-pentylpyrrole (15; 0.232 g, 1.4 mmol). The mixture was heated under reflux for 15 min and allowed to cool to r.t. H2O (20 mL) was added and the solution was extracted with Et2O (3 × 30 mL). The combined organic layers were washed with H2O (5 × 30 mL), dried (MgSO4), and the solvent was removed under reduced pressure to give 16 as a brown oil (0.049 g, 23%); bp 60 ˚C/0.5 Τorr (Lit. [²a] bp 95-99 ˚C/4 Torr).

¹H NMR (CDCl3): δ = 7.82 (br s, 1 H), 6.60 (m, 1 H), 6.04 (m, 1 H), 2.41 (t, ³ J = 7.6 Hz, 2 H), 2.20 (s, 3 H), 1.63-1.50 (m, 2 H), 1.48-1.30 (m, 4 H), 0.93 (t, ³ J = 7.0 Hz, 3 H); data compatible with reported [¹9] spectrum.

Coupling of Aldehydes with Activated Heterocycles; General Procedure

The procedure of Koeveringe and Lugtenburg was used. [¹³] The 2-carbaldehyde 8-10 (1 mmol) and the respective ring C compound 11-13, 16, 17 (1 mmol) were dissolved in n-pentane (15 mL) containing the minimum amount of CH2Cl2 (ca. 5 drops) required for solubility. The solution was then cooled to 0 ˚C and POCl3 (0.155 g, 1 mmol) was added with stirring over 1 min and the stirring was continued for the time stated. The reaction mixture immediately became red. If a solid formed, it was collected by filtration and washed with n-pentane. If the product did not precipitate, the solvent was removed under reduced pressure to give the product as a thick, intensely colored oil. Compounds of this class may be sternutatory.

3,5-Dimethyl-4-ethyl-2-[3-methoxy-5-(2-thienyl)thienyl-2-methylene]-2 H -pyrrolium Dichlorophosphate (19)

Compound 8 and kryptopyrrole 11 (1 min) gave 19 (72%); mp 180 ˚C (dec.) (EtOH).

¹H NMR (CDCl3): δ = 7.87 (d, ³ J = 3.3 Hz, 1 H), 7.63 (s, 1 H), 7.43 (d, ³ J = 4.4 Hz, 1 H), 7.07 (dd, ³ J = 4.4 Hz, 3.3 Hz, 1 H), 6.97 (s, 1 H), 4.12 (s, 3 H), 2.78 (s, 3 H), 2.41 (q, ³ J = 7.5 Hz, 2 H), 2.25 (s, 3 H), 1.06 (t, ³ J = 7.5 Hz, 3 H).

¹³C NMR (CDCl3): δ = 168.73 (Cq), 163.96 (Cq), 154.67 (Cq), 144.85 (Cq), 135.41 (Cq), 134.10 (Cq), 131.34 (Cq), 129.96, 129.81, 129.25, 124.87, 115.67 (Cq), 109.88, 59.92, 17.17, 13.89, 13.78, 10.06.

MS (FAB): m/z = 330 (M+).

Anal. Calcd for C18H20C12NO3PS2: C, 46.4; H, 4.3; N, 3.0. Found: C, 46.5; H, 4.3; N, 3.05.

4-Ethyl-1,3,5-trimethyl-2-[3-methoxy-5-(2-thienyl)thienyl-2-methylene]-2 H -pyrrolium Dichlorophosphate (20)

Compound 8 and 3-ethyl-1,2,4-trimethylpyrrole (12; 15 min) gave 20 (93%).

¹H NMR (CDCl3): δ = 8.13 (br s, 1 H), 7.65 (br s, 1 H), 7.53 (m, 1 H), 7.14 (m, 2 H), 4.20 (s, 3 H), 3.87 (br s, 3 H), 2.69-2.44 (m, 8 H), 1.06 (t, ³ J = 7.7 Hz, 3 H).

¹³C NMR (CDCl3): δ = 170.48 (Cq), 158.00 (Cq), 154.04 (Cq), 145.10 (Cq), 135.14 (Cq), 133.97 (Cq), 131.37 (Cq), 130.86, 130.14, 129.35, 125.94, 114.04 (Cq), 110.77, 60.73, 30.81, 17.61, 14.14, 13.97, 13.17.

MS (FAB): m/z = 344 (M+).

HRMS (FAB): m/z calcd for C19H22NOS2 (M+): 344.1143; found: 344.1122.

5-Undecyl-2-[3-methoxy-5-(2-thienyl)thienyl-2-methylene]-2 H -pyrrolium Dichlorophosphate (21)

Compound 8 and 2-undecylpyrrole (13; [¹¹] 15 min) gave 21 (97%).

¹H NMR (CDCl3): δ = 13.67 (br s, 1 H), 8.40 (s, 1 H), 7.60-7.52 (m, 2 H), 7.52 (m, 1 H), 7.17 (m, 1 H), 6.99 (s, 1 H), 6.62 (m, 1 H), 4.16 (s, 3 H), 2.86 (t, ³ J = 7.7 Hz, 2 H), 1.75 (m, 2 H), 1.38-1.16 (m, 16 H), 0.86 (t, ³ J = 6.6 Hz, 3 H).

¹³C NMR (CDCl3): δ = 171.92 (Cq), 161.49 (Cq), 156.34 (Cq), 135.11 (Cq), 132.73 (Cq), 132.45, 131.85, 129.80, 129.44, 128.84, 121.64, 117.11 (Cq), 110.74, 60.49, 31.73, 29.43, 29.39, 29.31, 29.25, 29.17, 29.08, 28.84, 27.79, 22.51, 13.97.

MS (FAB): m/z = 428 (M+).

HRMS (FAB): m/z calcd for C25H34NOS2 (M+): 428.2082; found: 428.2095.

4-Pentyl-5-methyl-2-[3-methoxy-5-(2-thienyl)thienyl-2-methylene]-2 H -pyrrolium Dichlorophosphate (22)

Compound 8 and 2-methyl-3-pentylpyrrole (16; 30 min) gave 22 (77%).

¹H NMR (CDCl3): δ = 14.15 (br s, 1 H), 8.13 (s, 1 H), 7.61-7.48 (m, 2 H), 7.18-7.07 (m, 3 H), 4.15 (s, 3 H), 2.45 (s, 3 H), 2.39 (t, ³ J = 7.7 Hz, 2 H), 1.60-1.48 (m, 3 H), 1.44-1.29 (m, 3 H), 0.91 (t, ³ J = 6.4 Hz, 3 H).

¹³C NMR (CDCl3): δ = 170.11 (Cq), 158.64 (Cq), 152.97 (Cq), 138.96 (Cq), 135.42 (Cq), 132.90 (Cq), 130.49, 130.27, 129.06, 128.61, 125.51, 116.25 (Cq), 111.17, 60.12, 31.32, 28.77, 25.95, 22.26, 13.87, 13.29.

MS (FAB): m/z = 358 (M+).

HRMS (FAB): m/z calcd for C20H24NOS2 (M+): 358.1299; found: 358.1330.

3-Methoxy-2-[3-methoxy-5-(2-thienyl)thienyl-2-methylene]-2 H -thiophenium Dichlorophosphate (23)

Compound 8 and 3-methoxythiophene (17; 15 min) gave 23 (84%).

¹H NMR (acetone-d 6): δ = 7.79 (s, 1 H), 7.36 (dd. ³ J = 5.1 Hz, 4 J = 1.1 Hz, 1 H), 7.18 (m, 2 H), 7.09 (s, 1 H), 7.04 (dd, ³ J = 5.1 Hz, 3.6 Hz, 1 H), 6.92 (d, ³ J = 5.5 Hz, 1 H), 3.78 (s, 3 H), 3.71 (s, 3 H).

MS (FAB): m/z = 321 (M+).

HRMS (FAB): m/z calcd for C15H13O3S2 (M+): 321.0078; found: 321.0068.

3,5-Dimethyl-4-ethyl-2-[3-methoxy-l-methyl- 5-(2-thienyl)pyrrolyl-2-methylene]-2 H -pyrrolium Dichlorophosphate (24)

Compound 9 and kryptopyrrole 11 (1 min) gave 24 (68%); mp 133.5 ˚C (dec.) (EtOH).

¹H NMR (CDCl3): δ = 11.26 (br s, 1 H), 7.57 (d, ³ J = 4.9 Hz, 1 H), 7.51 (br m, 1 H), 7.26 (br s, 1 H), 7.18 (m, 1 H), 6.27 (br s, 1 H), 4.22 (br s, 3 H), 3.90 (br s, 3 H), 2.55 (s, 3 H), 2.40 (q, ³ J = 7.6 Hz, 2 H), 2.32 (s, 3 H), 1.04 (t, ³ J = 7.6 Hz, 3 H).

¹³C NMR (CDCl3): δ = 159.14 (Cq), 153.28 (Cq), 144.50 (Cq), 142.40 (Cq), 131.99 (Cq), 130.99, 130.51 (Cq), 130.25, 128.73, 128.41 (Cq), 122.17 (Cq), 119.40, 97.91, 60.09, 33.18, 17.28, 14.11, 13.54, 10.27.

MS (FAB): m/z = 327 (M+).

Anal. Calcd for C19H23Cl2N2O3PS: C, 49.5; H, 5.0; N, 6.05. Found: C, 49.9; H, 5.2; N, 6.3.

3,5-Dimethyl-4-ethyl-2-(3-methoxypyrrolyl-2-methylene)-2 H -pyrrolium Dichlorophosphate (25)

2-Formyl-3-methoxypyrrole (10; [¹0] 0.037 g, 0.3 mmol) and kryptopyrrole 11 (0.3 mmol) (60 min) gave 25 (86%).

¹H NMR (CDCl3): δ = 11.76 (br s, 2 H), 7.53 (br s, 1 H), 7.24 (s, 1 H), 5.97 (s, 1 H), 3.96 (s, 3 H), 2.46 (s, 3 H), 2.44 (q, ³ J = 7.4 Hz, 2 H), 2.24 (s, 3 H), 1.05 (t, ³ J = 7.4 Hz, 3 H).

¹³C NMR (CDCl3): δ = 165.02 (Cq), 154.45 (Cq), 143.33 (Cq), 139.72, 131.13 (Cq), 126.60 (Cq), 118.31, 117.59 (Cq), 96.24, 58.84, 17.02, 14.10, 12.67, 9.85.

MS (FAB): m/z = 231 (M+).

HRMS (FAB): m/z calcd for C14H19N2O (M+): 231.1497; found: 231.1505.

3,5-Dimethyl-4-ethyl-2-(3-methoxypyrrolyl-2-methylene)-2 H -pyrrole (25′)

Compound 25 (0.109 g, 0.3 mmol, was dissolved in CH2Cl2 (30 mL) and washed with aq 2 M NaOH (3 × 30 mL). The organic layer was dried (MgSO4) and the solvent was removed to give the corresponding base 25′ (0.055 g, 80%); bp 220 ˚C/1.0 Torr.

¹H NMR (CDCl3): δ = 13.46 (br. s, 1 H), 7.53 (br. s, 1 H), 7.23 (m, 1 H), 5.85 (m, 1 H), 3.92 (s, 3 H), 2.56 (s, 3 H), 2.38 (q, ³ J = 7.6 Hz, 2 H), 2.22 (s, 3 H), 1.03 (t, ³ J = 7.6 Hz, 3 H).

¹³C NMR (CDCl3): δ = 164.24 (Cq), 155.37 (Cq), 142.16 (Cq), 138.99, 130.90 (Cq), 126.60 (Cq), 118.28, 117.31 (Cq), 95.22, 58.44, 17.06, 14.15, 12.70, 9.74.

MS: m/z (%) = 230 (M+, 29), 199 (27), 155 (31), 149 (49), 141 (40), 136 (29), 123 (32), 111 (40), 109 (35), 97 (67), 95 (55), 84 (56), 83 (40), 81 (78), 73 (56), 71 (71), 69 (100).

HRMS: m/z calcd for C14H18N2O (M+): 230.1419; found: 230.1428.

3-{ N -[3-methoxy-5-(2-thienyl)thienyl-2-methylene]}amino­pyrazole (26)

To a solution of 8 (0.135 g, 0.6 mmol) in propan-2-ol (25 mL) was added 3-aminopyrazole (18; 0.051 g, 0.6 mmol). The mixture was heated under reflux for 24 h, the solvent was removed under reduced pressure, and the crude product 26 was recrystallized (0.109 g, 63%); mp 130-131 ˚C (hexane-EtOAc).

¹H NMR (DMSO-d 6): δ = 12.63 (br s, 1 H), 8.84 (s, 1 H), 7.63 (m, 2 H), 7.51 (m, 1 H), 7.37 (s, 1 H), 7.15 (m, 1 H), 6.32 (m, 1 H), 3.99 (s, 3 H).

¹³C NMR (DMSO-d 6): δ = 161.04 (Cq), 158.25 (Cq), 148.83, 139.63 (br, Cq), 136.51, 130.44 (br, Cq), 128.87, 127.51, 125.78, 117.38 (Cq), 113.53, 96.48 (br), 59.20.

MS: m/z (%) = 289 (M+, 100), 260 (14), 258 (22), 209 (14), 208 (17), 207 (88), 179 (27), 135 (14), 108 (19), 94 (20).

Anal. Calcd for C13H11N3OS2: C, 53.95; H, 3.85; N, 14.5. Found: C, 54.2; H, 4.05; N, 14.35.

Acknowledgment

We are grateful to The University of Edinburgh for the award of the Colin and Ethel Gordon Scholarship (to G.A.H.), the Engineering and Physical Sciences Research Council (UK) for a Research Studentship (to K.W.) and Lonza Ltd. for a generous gift of Meldrum’s acid.

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Figure 1 General structure of prodigiosins

Scheme 1

Figure 2 Pyrroles 10-13, thiophene 17, and pyrazole 18

Scheme 2

Scheme 3

Figure 3 Compounds 25 and 26