3-Hydroxy-1H-pyrrole

Abstract

Flash vacuum pyrolysis (FVP) of tert-butyl {[(2,2-di­methyl-4,6-dioxo-1,3-dioxan-5-ylidene)methyl]amino}acetate at 600 ˚C gives the unstable 3-hydroxy-1H-pyrrole in ca. 55% yield as the only significant product. It exists as the enol tautomer in di­methyl sulfoxide solution, and predominantly as the keto tautomer in water. 3-Hydroxy-1H-pyrrole reacts readily with mild electrophiles, exclusively at the 2-position. FVP of the product obtained from one such reaction with methoxymethylene-substituted ­Meldrum’s acid gives pyrano[3,2-b]pyrrol-5(1H)-one in 77% yield.

Pyrroles with oxygen-containing functionalities are of interest in opto-electronic applications because of their highly electron-rich nature. [¹] The parent 3-hydroxy-1H-pyrrole (1E) [1H-pyrrol-3(2H)-one (1K)] has been reported only once, [²] generated by a multistep sequence culminating in hydrogenolysis, decarboxylation, and in situ silylation of benzyl 3-hydroxy-1H-pyrrole-2-carboxylate. The silyl protecting group was removed by treatment with methanol to give 1E in ca. 1% overall yield from commercially available precursors. Spectroscopic details and rate and equilibrium studies of ketonisation of 1E were reported (Figure  [¹] ), [²] but nothing is known of the chemical properties of this compound.

In the previous paper, [³] we have shown that the ‘normal’ 1,3-H shift of N-unsubstituted methyleneketenes [4] 3 [generated by flash vacuum pyrolysis (FVP) of aminomethylene derivatives of Meldrum’s acid 2] leading to imidoylketenes 4 can be circumvented when an electron-withdrawing group (X) is present in the α-position of the side chain. [³] In such cases, a 1,4-H shift takes place, leading to azomethine ylides 5 which collapse to N-unsubstituted 1,2-dihydropyrrol-3-ones (3-hydroxypyrroles when Y = H) 6 (Scheme  [¹] ). This is the normal thermal behaviour of the corresponding N,N-disubstituted amino­methylene Meldrum’s acid derivatives. [4] [5] In this paper, we show how this strategy can be extended to provide a convenient two-step route to 3-hydroxypyrrole 1E itself, and report the first studies of its chemical properties.

In order to fulfil these requirements, a group X (Scheme  [¹] ) is required that can be thermally eliminated under the conditions of the pyrolysis. In principle, any ester group (X = CO₂R) in which the group R bears a β-hydrogen atom, should be capable of retro-ene elimination [6] to provide the 2-carboxylic acid; it is well known that ­decarboxylation of 3-hydroxypyrrole-2-carboxylic acids takes place under very mild conditions (Scheme  [²] ). [7]

In practice, the aminomethylene Meldrum’s acid derivatives 2a and 2b derived respectively from glycine ethyl ester [³] and glycine tert-butyl ester (89%) were readily made from methoxymethylene-substituted Meldrum’s acid 7 under standard conditions (Scheme  [³] ). [8] FVP of the ethyl ester 2a at 850 ˚C gave some 3-hydroxypyrrole 1E, but many impurities were present. However, FVP of the tert-butyl ester 2B at 600 ˚C gave a clean sample of 1E (55%) whose ^¹H NMR spectrum in DMSO-d ₆ is consistent with the published data of the hydroxy tautomer [Figure  [²] (a)]. [²] HSQC extension to the carbon dimension gives the data shown in Figure  [²] (b); assignments are consistent with those of 1-substituted 3-hydroxypyrroles previously reported. [9]

3-Hydroxypyrrole 1E is reported to ‘resinify very rapidly’ [²] and, in our hands, it cannot be purified by distillation or chromatography. It is best generated immediately before reactions. In polar organic solvents (e.g., DMSO), it exists exclusively as the hydroxy tautomer, as found for 1-substituted analogues; [¹0] in aqueous solution it is present in the keto form. [²] 3-Hydroxypyrrole 1E is moderately stable in acid solution (e.g., TFA) for a few hours, where it is quantitatively protonated at the 2-position; [¹¹] in trifluoroacetic acid-d, rapid deuterium exchange takes place at the 2- and 4-positions.

In reactions of 3-hydroxypyrrole 1E, the yield is quoted for the two steps from 2b. Thus, 3-hydroxypyrrole 1E is readily acylated with acetyl chloride in the presence of triethylamine to provide the O-acetoxy compound 8 (49%). 3-Hydroxypyrrole 1E reacts rapidly with soft electrophiles at the 2-position (Scheme  [4] ). For example, coupling with diazonium salts provides the hydrazone 9 (56%) [¹²] and reaction with methoxymethylene-substituted Meldrum’s acid 7 gives 10 (61%). Compound 10 is transformed into the previously unknown parent member 11 of the rare pyrano[3,2-b]pyrrol-5(1H)-one ring system by FVP at 600 ˚C in 77% yield. [¹³] As found previously, [¹³] the alternative cyclisation onto the nitrogen atom to provide a pyrrolizin-3-one is not observed. Treatment of 1 with dimethyl acetylenedicarboxylate gives the conjugate addition product 12 (41%) which adopts the tautomer shown exclusively. The analogous tautomer is obtained when dimethyl acetylenedicarboxylate is reacted with indoxyl, [¹4] but an alternative tautomer is formed when dimethyl acetylenedicarboxylate is reacted with 1-substituted 3-hydroxypyrroles. [¹5]

In conclusion, 3-hydroxypyrrole 1E can now be made reproducibly in 49% overall yield by a two-step method; the key step is an FVP-mediated, one-pass cyclisation, dealkylation, and decarboxylation. 3-Hydroxypyrrole 1E is highly reactive; it can be O-acylated under basic conditions and reacts readily with soft electrophiles at the 2-position.

^¹H and ^¹³C NMR spectra were recorded at 250 MHz and 63 MHz respectively unless otherwise stated. Chemical shifts are given relative to TMS. Mass spectra were recorded under electron impact conditions. UV/Vis gives ε in dm^³ mol^-¹ cm^-¹.

Flash vacuum pyrolysis (FVP) reactions were carried out by distillation of the substrate in vacuo through an electrically heated silica furnace tube (35 × 2.5 cm). Products were trapped in a U-tube situated at the exit point of the furnace and cooled with liquid N₂. Pyrolysis conditions are quoted as follows: substrate, quantity (w), furnace temperature (T _f ), inlet temperature (T _i ), pressure range (P), pyrolysis time (t), and product(s).

tert -Butyl {[(2,2-Dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)-­methyl]amino}acetate (2b)

Et₃N (0.70 mL) was added to a soln of glycine tert-butyl ester hydrochloride (0.419 g, 2.5 mmol) in MeCN (40 mL). Methoxymethylene-substituted Meldrum’s acid 7 (0.465 g, 2.5 mmol) was added and the soln was stirred at r.t. for 2.5 h. The solvent was removed and the residue was dissolved in CH₂Cl₂ and washed with 2 M HCl. The organic layer was dried (MgSO₄) and the solvent removed to give 2b (0.634 g, 89%) as a yellow solid; mp 135-136 ˚C (EtOH).

^¹H NMR (CDCl₃): δ = 9.61 (br m, 1 H), 8.07 (d, ^³ J = 14.6 Hz, 1 H), 4.09 (d, ^³ J = 5.8 Hz, 2 H), 1.70 (s, 6 H), 1.49 (s, 9 H).

^¹³C NMR (CDCl₃): δ = 166.07 (q), 165.07 (q), 165.53 (q), 159.94, 104.61 (q), 85.72 (q), 83.65 (q), 56.61 (CH₂), 27.74 (3 CH₃), 26.71 (2 CH₃).

MS: m/z (%) = 285 (M⁺, 29), 229 (14), 184 (23), 172 (32), 126 (100).

Anal. Calcd for C₁₃H₁₉NO₆: C, 54.75; H, 6.65; N, 4.9. Found: C, 54.95; H, 6.65; N, 4.95.

3-Hydroxy-1 H -pyrrole (1E)

FVP of 2b (w 0.0988 g, T _f 600 ˚C, T _i 200 ˚C, P 2.6-2.8 × 10^-² Torr, t 5 min) gave 3-hydroxypyrrole 1E ^² (ca. 55%; NMR yield based on a cyclohexane standard) as an orange-brown oil.

^¹H NMR (360 MHz, DMSO-d ₆): δ (enol tautomer 1E) = 9.95 (br s, 1 H), 7.79 (br s, 1 H), 6.43 (td, ^³ J = 2.7 Hz, ⁴ J = 1.7 Hz, 1 H), 6.16 (td, ^³ J = 2.7 Hz, ^³ J = 2.4 Hz, 1 H), 5.61 (td, ^³ J = 2.4 Hz, ⁴ J = 1.7 Hz, 1 H); data consistent with literature values. [²]

^¹³C NMR (90 MHz, DMSO-d ₆): δ (enol tautomer 1E) = 143.72 (q), 114.99, 100.51, 98.19.

^¹H NMR (500 MHz, H₂O + D₂O): δ (keto tautomer 1K) = 8.27 (m, 1 H), 5.20 (d, ^³ J = 2.9 Hz, 1 H) 3.94 (d, ⁴ J = 1.4 Hz, 2 H).

^¹³C NMR (125 MHz, H₂O + D₂O): δ (keto tautomer 1K) = 204.21 (q), 170.83, 99.23, 55.55 (CH₂).

Protonation of 3-Hydroxypyrrole 1E

A freshly prepared sample of 3-hydroxypyrrole 1E was dissolved in TFA and the NMR spectra recorded.

^¹H NMR (500 MHz, TFA): δ = 8.92 (s, 1 H), 6.34 (d, ^³ J = 2.0 Hz, 1 H), 5.03 (d, ^³ J = 2.0 Hz, 2 H); signals at δ = 6.34 and 5.03 were not observed when 1 was dissolved in TFA-d.

^¹³C NMR (125 MHz, TFA): δ = 189.23 (q), 173.17, 100.17, 54.83 (CH₂).

3-Acetoxy-1 H -pyrrole (8)

The product 1E from FVP of 2b (w 0.208 g, T _f 600 ˚C, T _i 200 ˚C, P 2.9-3.2 × 10^-² Torr, t 17 min) was dissolved in DMF (2.5 mL). Et₃N (0.5 mL) and AcCl (0.4 mL) were added and the mixture was stirred at r.t. for 1 h. The mixture was diluted with H₂O, acidified, and extracted with EtOAc (3 × 20). The combined organic fractions were washed with 2 M HCl and sat. NaHCO₃ (2 × 20) and then dried (MgSO₄) and the soln concentrated to give the crude material as a brown oil. The oil was purified by Kugelrohr distillation to give 8 (0.045 g, 49%) as an orange oil; bp 88-90 ˚C/0.5 Torr).

^¹H NMR (360 MHz, CDCl₃): δ = 8.03 (br s, 1 H), 6.82 (m, 1 H), 6.63 (td, ^³ J = 3.0 Hz, ^³ J = 2.3 Hz, 1 H), 6.09 (ddd, ^³ J = 3.0 Hz, ⁴ J = 1.6 Hz, 1 H), 2.24 (s, 3 H).

^¹³C NMR (90 MHz, CDCl₃): δ = 168.90 (q), 137.40 (q), 115.68, 107.01, 101.14, 20.90 (CH₃).

MS: m/z (%) = 125 (M⁺, 37), 83 (100).

HRMS: m/z [M]⁺ calcd for C₆H₇NO₂: 125.04713; found; 125.04709.

2-(4-Tolylhydrazono)-1,2-dihydro pyrrol-3-one (9)

The pyrolysate 1E from FVP of 2b (w 0.094 g, T _f 600 ˚C, T _i 200 ˚C, P 2.3-2.4 × 10^-² Torr, t 13 min) was dissolved in DMF (2.5 mL). 4-Tolyldiazonium tetrafluoroborate (0.062 g, 0.33 mmol) was added and the resulting deep red soln was stirred for 20 min. The soln was diluted with H₂O and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with NaHCO₃ (2 × 20 mL) and brine (20 mL) and dried (MgSO₄); the solvent was removed to give a brown solid. Purification by dry flash chromatography (hexane-EtOAc, 3:2) gave 9 (0.039 g, 56%) as an orange-red solid; mp 188-190 ˚C.

^¹H NMR (360 MHz, CDCl₃): δ = 7.66 (t, ^³ J = 3.6 Hz, 1 H), 7.26-7.12 (m, 4 H), 5.53 (d, ^³ J = 3.6 Hz, 1 H), 2.32 (s, 3 H).

^¹³C NMR (90 MHz, CDCl₃): δ = 177.88 (q), 147.93, 140.10 (q), 133.52 (q), 132.60 (q), 129.85 (2 CH), 114.12 (2 CH), 101.45, 29.58 (CH₃).

UV/Vis (MeOH): λ_max (ε) = 456 (11,100), 373.0 (7,750), 260.0 nm (6,400).

MS: m/z (%) = 201 (M⁺, 100), 106 (26).

HRMS: m/z [M]⁺ calcd for C₁₁H₁₁N₃O: 201.08966; found: 201.08964.

5-(3-Hydroxy-1 H -pyrrol-2-ylmethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (10)

FVP of 2b (w 0.108 g, T _f 600, T _i 200 ˚C, P 2.3-2.5 × 10^-² Torr, t 23 min) gave an orange-brown oil, which was dissolved in a mixture of DMF and Et₃N (10:1, 4 mL). Methoxymethylene-substituted Meldrum’s acid 7 (0.067 g, 0.36 mmol) was added and the soln was stirred at r.t. for 1 h. The mixture was diluted with H₂O and extracted with EtOAc (3 × 20 mL). The combined organics were washed with 2 M HCl, brine (2 × 20 mL) and dried (MgSO₄) and the solvent was removed to give 10 (0.0547 g, 61%) as a brown solid; mp 199-201 ˚C (dec.).

^¹H NMR (360 MHz, DMSO-d ₆): δ = 11.64 (br s, 2 H), 8.10 (s, 1 H), 7.63 (t, ^³ J = 2.7 Hz, 1 H), 5.90 (t, ^³ J = 2.7 Hz, 1 H), 1.71 (s, 6 H).

^¹³C NMR (90 MHz, DMSO-d ₆): δ = 164.30 (q), 164.01 (q), 162.17 (q), 137.26, 133.89, 117.60 (q), 103.15 (q), 98.32, 92.74 (q), 26.57 (2 CH₃).

MS: m/z (%) = 237 (M⁺, 40), 179 (72), 135 (38), 107 (100).

HRMS: m/z [M]⁺ calcd for C₁₁H₁₁NO₅: 237.06317; found: 237.06274.

Pyrano[3,2- b ]pyrrol-5(1 H )-one (11)

FVP of 10 (w 0.115 g, T _f 600 ˚C, T _i 220 ˚C, P 2.4-2.6 × 10^-² Torr, t 24 min) gave 11 (0.0507 g, 77%) as an orange-brown solid; mp 155-157 ˚C.

^¹H NMR (360 MHz, CDCl₃): δ = 7.58 (d, ^³ J = 9.5 Hz, 1 H), 7.05 (t, ^³ J = 2.9 Hz, 1 H), 6.23 (t, ^³ J = 2.9 Hz, 1 H), 6.05 (d, ^³ J = 9.5 Hz, 1 H).

^¹³C NMR (90 MHz, CDCl₃): δ = 163.25 (q), 147.84 (q), 132.62, 123.27 (q), 115.16, 107.13, 97.65.

MS: m/z (%) = 135 (M⁺, 100), 107 (36).

HRMS: m/z [M]⁺ calcd for C₇H₅NO₂: 135.03148; found: 135.03123.

Dimethyl 2-[( E )-3-Oxo-1,3-dihydro-2 H -pyrrol-2-ylidene]succinate (12)

FVP of 2b (w 0.0995 g, T _f = 600 ˚C, T _i 200 ˚C, P 2.4-2.6 × 10^-² Torr, t 17 min) gave an orange-brown oil that was dissolved in DMF (2.5 mL). DMAD (0.05 mL) was added and the soln stirred at r.t. for 1 h. The mixture was diluted with H₂O and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with NaHCO₃ (2 × 20 mL) and brine (20 mL) and dried (MgSO₄); the solvent was removed to give a brown solid. Purification by column chromatography (hexane-EtOAc, 3:2) gave 12 (0.0324 g, 41%) as a red solid; mp 107-109 ˚C.

^¹H NMR (360 MHz, CDCl₃): δ = 9.03 (br s, 1 H), 7.80 (dd, ^³ J = 3.9 Hz, ^³ J = 3.4 Hz, 1 H), 5.33 (dd, ^³ J = 3.9 Hz, ⁴ J = 1.9 Hz, 1 H), 4.10 (s, 2 H), 3.82 (s, 3 H), 3.71 (s, 3 H).

^¹³C NMR (90 MHz, CDCl₃): δ = 190.03 (q), 171.23 (q), 168.64 (q), 154.82, 138.41 (q), 108.91 (q), 101.88, 52.51 (CH₃), 51.93 (CH₃), 29.38 (CH₂).

MS: m/z (%) = 225 (M⁺, 46), 193 (100), 165 (39), 134 (22) and 106 (21).

HRMS: m/z [M]⁺ calcd for C₁₀H₁₁NO₅: 225.06317; found: 225.06258.

Acknowledgment

We are grateful to Durham Organics and the Engineering and Physical Sciences Research Council (EPSRC) UK, for a CASE award (to W.J.O’N.).

References

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• 12 Cf.: Blake AJ. McNab H. Monahan LC. J. Chem. Soc., Perkin Trans. 1  1991,  701 
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• 13 Cf.: Derbyshire PA. Hunter GA. McNab H. Monahan LC. J. Chem. Soc., Perkin Trans. 1  1993,  2017 
  Crossref
• 14 Kawasaki T. Tang C.-Y. Nakanishi H. Hirai S. Ohshita T. Tanizawa M. Himori M. Satoh H. Sakamoto M. Miura K. Nakano F. J. Chem. Soc., Perkin Trans. 1  1999,  327 
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References

• 1 For example: Zotti G. Zecchin S. Schiavon G. Groenendaal LB. Chem. Mater.  2000,  12:  2996 
  CrossrefSearch in Google Scholar
• 2a Capon B. Kwok FC. Tetrahedron Lett.  1986,  27:  3275 
  Search in Google Scholar
• 2b Capon B. Kwok FC. J. Am. Chem. Soc.  1989,  111:  5346 
  Search in Google Scholar
• 3 Hill L. Imam SH. McNab H. O’Neill WJ. Synthesis  2009,  2531 
• 4 Review: Gaber AM. McNab H. Synthesis  2001,  2059 
  Thieme Connect
• 5 McNab H. Monahan LC. J. Chem. Soc., Perkin Trans. 1  1988,  863 
  Crossref
• 6 De Puy CH. King RW. Chem. Rev.  1960,  60:  431 
  CrossrefSearch in Google Scholar
• 7 Review: McNab H. Monahan LC. In Pyrroles   Vol. 2:  Jones RA. Wiley; New York: 1992.  p.525 
  Search in Google Scholar
• 8 McNab H. Withell K. ARKIVOC  2000,  (v):  806 
  Search in Google Scholar
• 9a McNab H. Monahan LC. J. Chem. Soc., Perkin Trans. 2  1991,  1999 
• 9b McNab H. Monahan LC. J. Chem. Soc., Perkin Trans. 2  1988,  1459 
• 10 Blake AJ. McNab H. Monahan LC. J. Chem. Soc., Perkin Trans. 2  1988,  1455 
  Crossref
• 11 Cf.: Blake AJ. McNab H. Monahan LC. J. Chem. Soc., Perkin Trans. 2  1988,  1463 
  Crossref
• 12 Cf.: Blake AJ. McNab H. Monahan LC. J. Chem. Soc., Perkin Trans. 1  1991,  701 
  Crossref
• 13 Cf.: Derbyshire PA. Hunter GA. McNab H. Monahan LC. J. Chem. Soc., Perkin Trans. 1  1993,  2017 
  Crossref
• 14 Kawasaki T. Tang C.-Y. Nakanishi H. Hirai S. Ohshita T. Tanizawa M. Himori M. Satoh H. Sakamoto M. Miura K. Nakano F. J. Chem. Soc., Perkin Trans. 1  1999,  327 
  Crossref
• 15 Hunter GA. Ph. D. Thesis   The University of Edinburgh; Scotland: 1990.