3-Hydroxy-1H-pyrrole

Article abstract of DOI:10.1055/s-0029-1217422

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 s

Full text of DOI:10.1055/s-0029-1217422

PAPER
2535
3-Hydroxy-1H-pyrrole
yrrole wrence Hill,a S. Haider Imam,a Hamish McNab,*b William J. O’Neillb
3
-Hydroxy-1
H
-
p
a
a
Durham Organics Ltd., Units 12-14, Langley Moor Industrial Estate, Langley Moor, Durham, DH7 8JE, UK
b
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
Received 8 April 2009
iour of the corresponding N,N-disubstituted amino-
methylene 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,
Abstract: Flash vacuum pyrolysis (FVP) of tert-butyl {[(2,2-di-
methyl-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 di-
methyl sulfoxide solution, and predominantly as the keto tautomer and report the first studies of its chemical properties.
in water. 3-Hydroxy-1H-pyrrole reacts readily with mild electro-
philes, 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.
O
H
H
products
Y
N
X
Key words: gas-phase reactions, heterocycles, pyrroles, electro-
philic aromatic substitutions, tautomerism
4
O
Pyrroles with oxygen-containing functionalities are of in-
terest 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 report-
ed only once,2 generated by a multistep sequence culmi-
nating 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 commer-
cially available precursors. Spectroscopic details and rate
and equilibrium studies of ketonisation of 1E were report-
ed (Figure 1),2 but nothing is known of the chemical prop-
erties of this compound.
O
O
FVP
H
Y
O
O
Y
N
H
X
2
N
H
3
X
X = EWG
O
O
Y
H
Y
X
N
H
N
H
X
6
5
Scheme 1
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 es-
ter group (X = CO2R) in which the group R bears a b-hy-
drogen atom, should be capable of retro-ene elimination6
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
OH
O
N
H
N
H
keto form 1K
enol form 1E
Figure 1
In the previous paper,3 we have shown that the ‘normal’
1,3-H shift of N-unsubstituted methyleneketenes4 3 [gen-
erated by flash vacuum pyrolysis (FVP) of aminomethyl-
ene derivatives of Meldrum’s acid 2] leading to
imidoylketenes 4 can be circumvented when an electron-
withdrawing group (X) is present in the a-position of the
side chain.3 In such cases, a 1,4-H shift takes place, lead-
ing to azomethine ylides 5 which collapse to N-unsubsti-
O
O
H
H
OH
O
FVP
O
R
– CO2
– R2C=CH2
O
N
H
N
H
H
H
H O
N
H
R
1E
Scheme 2
tuted 1,2-dihydropyrrol-3-ones (3-hydroxypyrroles when In practice, the aminomethylene Meldrum’s acid deriva-
Y = H) 6 (Scheme 1). This is the normal thermal behav- tives 2a and 2b derived respectively from glycine ethyl
ester3 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,
SYNTHESIS 2009, No. 15, pp 2535–2538
x
x.
x
x
.
2
0
0
9
Advanced online publication: 23.06.2009
DOI: 10.1055/s-0029-1217422; Art ID: P05309SS
© Georg Thieme Verlag Stuttgart · New York

2536
L. Hill et al.
PAPER
but many impurities were present. However, FVP of the acetylenedicarboxylate is reacted with 1-substituted 3-hy-
tert-butyl ester 2B at 600 °C gave a clean sample of 1E droxypyrroles.15
1
(55%) whose H NMR spectrum in DMSO-d6 is consis-
tent with the published data of the hydroxy tautomer
OAc
O
[Figure 2 (a)].2 HSQC extension to the carbon dimension
gives the data shown in Figure 2 (b); assignments are con-
H
N
Me
N
N
H
N
H
8
sistent with those of 1-substituted 3-hydroxypyrroles pre-
viously reported.9
9
AcCl
OH
OH
O
O
O
O
FVP
H
N
H
O
O
O
O
OH
N
H
1E
O
O
1E
7
N
H
X
OMe
(55% from 2b)
2a X = CO2Et
2b X = CO2t-Bu
N
H
DMAD
O
10
O
O
Scheme 3
FVP
CO2Me
CO2Me
N
H
3-Hydroxypyrrole 1E is reported to ‘resinify very rapid-
ly’2 and, in our hands, it cannot be purified by distillation
or chromatography. It is best generated immediately be-
fore 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 trifluoro-
acetic acid-d, rapid deuterium exchange takes place at the
2- and 4-positions.
O
O
12
N
H
11
Scheme 4
In conclusion, 3-hydroxypyrrole 1E can now be made re-
producibly 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 condi-
tions and reacts readily with soft electrophiles at the 2-po-
sition.
(a) δH
(b) δC
OH
OH
5.61
98.19
6.16
100.51
6.43
114.99
N
1H and 13C NMR spectra were recorded at 250 MHz and 63 MHz
respectively unless otherwise stated. Chemical shifts are given rel-
ative to TMS. Mass spectra were recorded under electron impact
conditions. UV/Vis gives e in dm3 mol–1 cm–1.
N
H
H
Figure 2 (a) 1H NMR chemical shifts (d) of 1E; (b) 13C NMR che-
mical shifts (d) of 1E.
Flash vacuum pyrolysis (FVP) reactions were carried out by distil-
In reactions of 3-hydroxypyrrole 1E, the yield is quoted lation of the substrate in vacuo through an electrically heated silica
furnace tube (35 × 2.5 cm). Products were trapped in a U-tube situ-
for the two steps from 2b. Thus, 3-hydroxypyrrole 1E is
ated at the exit point of the furnace and cooled with liquid N2. Py-
readily acylated with acetyl chloride in the presence of tri-
rolysis conditions are quoted as follows: substrate, quantity (w),
ethylamine to provide the O-acetoxy compound 8 (49%).
3-Hydroxypyrrole 1E reacts rapidly with soft electro-
furnace temperature (Tf), inlet temperature (Ti), pressure range (P),
pyrolysis time (t), and product(s).
philes at the 2-position (Scheme 4). For example, cou-
pling with diazonium salts provides the hydrazone 9
(56%)12 and reaction with methoxymethylene-substituted
Meldrum’s acid 7 gives 10 (61%). Compound 10 is trans-
formed 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 ad-
dition product 12 (41%) which adopts the tautomer shown
exclusively. The analogous tautomer is obtained when
dimethyl acetylenedicarboxylate is reacted with indox-
yl,14 but an alternative tautomer is formed when dimethyl
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 hy-
drochloride (0.419 g, 2.5 mmol) in MeCN (40 mL). Methoxymeth-
ylene-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): d = 9.61 (br m, 1 H), 8.07 (d, 3J = 14.6 Hz, 1 H),
4.09 (d, 3J = 5.8 Hz, 2 H), 1.70 (s, 6 H), 1.49 (s, 9 H).
13C NMR (CDCl3): d = 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).
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PAPER
3-Hydroxy-1H-pyrrole
2537
MS: m/z (%) = 285 (M+, 29), 229 (14), 184 (23), 172 (32), 126
(100).
13C NMR (90 MHz, CDCl3): d = 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).
Anal. Calcd for C13H19NO6: C, 54.75; H, 6.65; N, 4.9. Found: C,
54.95; H, 6.65; N, 4.95.
UV/Vis (MeOH): lmax (e) = 456 (11,100), 373.0 (7,750), 260.0 nm
(6,400).
3-Hydroxy-1H-pyrrole (1E)
MS: m/z (%) = 201 (M+, 100), 106 (26).
FVP of 2b (w 0.0988 g, Tf 600 °C, Ti 200 °C, P 2.6–2.8 × 10–2 Torr,
t 5 min) gave 3-hydroxypyrrole 1E2 (ca. 55%; NMR yield based on
a cyclohexane standard) as an orange-brown oil.
HRMS: m/z [M]+ calcd for C11H11N3O: 201.08966; found:
201.08964.
1H NMR (360 MHz, DMSO-d6): d (enol tautomer 1E) = 9.95 (br s,
1 H), 7.79 (br s, 1 H), 6.43 (td, 3J = 2.7 Hz, 4J = 1.7 Hz, 1 H), 6.16
(td, 3J = 2.7 Hz, 3J = 2.4 Hz, 1 H), 5.61 (td, 3J = 2.4 Hz, 4J = 1.7 Hz,
1 H); data consistent with literature values.2
5-(3-Hydroxy-1H-pyrrol-2-ylmethylene)-2,2-dimethyl-1,3-di-
oxane-4,6-dione (10)
FVP of 2b (w 0.108 g, Tf 600, Ti 200 °C, P 2.3–2.5 × 10–2 Torr,
t 23 min) gave an orange-brown oil, which was dissolved in a mix-
ture 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 extract-
ed 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.).
13C NMR (90 MHz, DMSO-d6): d (enol tautomer 1E) = 143.72 (q),
114.99, 100.51, 98.19.
1H NMR (500 MHz, H2O + D2O): d (keto tautomer 1K) = 8.27 (m,
1 H), 5.20 (d, 3J = 2.9 Hz, 1 H) 3.94 (d, 4J = 1.4 Hz, 2 H).
13C NMR (125 MHz, H2O + D2O): d (keto tautomer 1K) = 204.21
(q), 170.83, 99.23, 55.55 (CH2).
1H NMR (360 MHz, DMSO-d6): d = 11.64 (br s, 2 H), 8.10 (s, 1 H),
7.63 (t, 3J = 2.7 Hz, 1 H), 5.90 (t, 3J = 2.7 Hz, 1 H), 1.71 (s, 6 H).
Protonation of 3-Hydroxypyrrole 1E
A freshly prepared sample of 3-hydroxypyrrole 1E was dissolved in
TFA and the NMR spectra recorded.
13C NMR (90 MHz, DMSO-d6): d = 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).
1H NMR (500 MHz, TFA): d = 8.92 (s, 1 H), 6.34 (d, 3J = 2.0 Hz, 1
H), 5.03 (d, 3J = 2.0 Hz, 2 H); signals at d = 6.34 and 5.03 were not
observed when 1 was dissolved in TFA-d.
MS: m/z (%) = 237 (M+, 40), 179 (72), 135 (38), 107 (100).
13C NMR (125 MHz, TFA): d = 189.23 (q), 173.17, 100.17, 54.83
(CH2).
HRMS: m/z [M]+ calcd for C11H11NO5: 237.06317; found:
237.06274.
3-Acetoxy-1H-pyrrole (8)
Pyrano[3,2-b]pyrrol-5(1H)-one (11)
The product 1E from FVP of 2b (w 0.208 g, Tf 600 °C, Ti 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 ex-
tracted 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).
FVP of 10 (w 0.115 g, Tf 600 °C, Ti 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): d = 7.58 (d, 3J = 9.5 Hz, 1 H), 7.05 (t,
3J = 2.9 Hz, 1 H), 6.23 (t, 3J = 2.9 Hz, 1 H), 6.05 (d, 3J = 9.5 Hz, 1 H).
13C NMR (90 MHz, CDCl3): d = 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).
1H NMR (360 MHz, CDCl3): d = 8.03 (br s, 1 H), 6.82 (m, 1 H),
6.63 (td, 3J = 3.0 Hz, 3J = 2.3 Hz, 1 H), 6.09 (ddd, 3J = 3.0 Hz, 4J =
1.6 Hz, 1 H), 2.24 (s, 3 H).
HRMS: m/z [M]+ calcd for C7H5NO2: 135.03148; found:
135.03123.
13C NMR (90 MHz, CDCl3): d = 168.90 (q), 137.40 (q), 115.68,
107.01, 101.14, 20.90 (CH3).
Dimethyl 2-[(E)-3-Oxo-1,3-dihydro-2H-pyrrol-2-ylidene]succi-
nate (12)
FVP of 2b (w 0.0995 g, Tf = 600 °C, Ti 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 chromatog-
raphy (hexane–EtOAc, 3:2) gave 12 (0.0324 g, 41%) as a red solid;
mp 107–109 °C.
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-dihydropyrrol-3-one (9)
The pyrolysate 1E from FVP of 2b (w 0.094 g, Tf 600 °C, Ti 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 com-
bined 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): d = 9.03 (br s, 1 H), 7.80 (dd, 3J = 3.9
Hz, 3J = 3.4 Hz, 1 H), 5.33 (dd, 3J = 3.9 Hz, 4J = 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): d = 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).
1H NMR (360 MHz, CDCl3): d = 7.66 (t, 3J = 3.6 Hz, 1 H), 7.26–
7.12 (m, 4 H), 5.53 (d, 3J = 3.6 Hz, 1 H), 2.32 (s, 3 H).
HRMS: m/z [M]+ calcd for C10H11NO5: 225.06317; found:
225.06258.
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2538
L. Hill et al.
PAPER
(7) Review: McNab, H.; Monahan, L. C. In Pyrroles, Vol. 2;
Acknowledgment
Jones, R. A., Ed.; Wiley: New York, 1992, 525.
(8) McNab, H.; Withell, K. ARKIVOC 2000, (v), 806.
(9) (a) McNab, H.; Monahan, L. C. J. Chem. Soc., Perkin Trans.
2 1991, 1999. (b) McNab, H.; Monahan, L. C. J. Chem. Soc.,
Perkin Trans. 2 1988, 1459.
We are grateful to Durham Organics and the Engineering and Phy-
sical Sciences Research Council (EPSRC) UK, for a CASE award
(to W.J.O’N.).
(10) Blake, A. J.; McNab, H.; Monahan, L. C. J. Chem. Soc.,
Perkin Trans. 2 1988, 1455.
References
(11) Cf.:Blake, A. J.; McNab, H.; Monahan, L. C. J. Chem. Soc.,
Perkin Trans. 2 1988, 1463.
(12) Cf.: Blake, A. J.; McNab, H.; Monahan, L. C. J. Chem. Soc.,
Perkin Trans. 1 1991, 701.
(13) Cf.: Derbyshire, P. A.; Hunter, G. A.; McNab, H.; Monahan,
L. C. J. Chem. Soc., Perkin Trans. 1 1993, 2017.
(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.
(1) For example: Zotti, G.; Zecchin, S.; Schiavon, G.;
Groenendaal, L. B. Chem. Mater. 2000, 12, 2996.
(2) (a) Capon, B.; Kwok, F. C. Tetrahedron Lett. 1986, 27,
3275. (b) Capon, B.; Kwok, F. C. J. Am. Chem. Soc. 1989,
111, 5346.
(3) Hill, L.; Hunter, G. A.; Imam, S. H.; McNab, H.;
O’Neill, W. J. Synthesis 2009, 2531.
(4) Review: Gaber, A. M.; McNab, H. Synthesis 2001, 2059.
(5) McNab, H.; Monahan, L. C. J. Chem. Soc., Perkin Trans. 1
1988, 863.
(15) Hunter, G. A. Ph. D. Thesis; The University of Edinburgh:
Scotland, 1990.
(6) De Puy, C. H.; King, R. W. Chem. Rev. 1960, 60, 431.
Synthesis 2009, No. 15, 2535–2538 © Thieme Stuttgart · New York