Gas-phase synthesis of N-unsubstituted 3-hydroxypyrroles and 1H-pyrrol-3(2H)-ones

Article abstract of DOI:10.1055/s-0029-1217397

Flash vacuum pyrolysis (FVP) at 600°C of methylaminomethylene derivatives of Meldrum's acid bearing electron-withdrawing substituents on the methyl group, provides N-unsubstituted 3-hydroxypyrroles and/or 1H-pyrrol-3(2H)-ones in high yield. Georg Thieme V

Full text of DOI:10.1055/s-0029-1217397

PAPER
2531
Gas-Phase Synthesis of N-Unsubstituted 3-Hydroxypyrroles and
1H-Pyrrol-3(2H)-ones
S
ynthesis of 3-H
a
ydroxypyr
w
roles and
1
H
-Pyrr
r
H
)
e
-
ones nce Hill,a Gordon A. Hunter,b S. Haider Imam,a Hamish McNab,*b William J. O’Neillb
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
Formation of N-unsubstituted 3-hydroxypyrroles by the
Meldrum’s route has been unsuccessful, despite the ex-
ploration of various possible N-protecting groups.7,8 The
synthesis of such compounds still relies on multistep con-
densation sequences.1a,9
Abstract: Flash vacuum pyrolysis (FVP) at 600 °C of methylami-
nomethylene derivatives of Meldrum’s acid bearing electron-with-
drawing substituents on the methyl group, provides N-unsubstituted
3-hydroxypyrroles and/or 1H-pyrrol-3(2H)-ones in high yield.
Key words: gas-phase reactions, pericyclic reactions, heterocycles,
pyrroles, regioselectivity
We have also shown that in the cases where the group R1
(Scheme 1) also contains an a-hydrogen atom, the H-shift
step can be highly selective.2 Thus, for 1 (R1 = Me,
R2 = CH2Ph) hydrogen transfer from the benzyl group
(leading to 1-methyl-2-phenyl-3-hydroxypyrrole) takes
place exclusively.2 We have now discovered that an ester
substituent activates the hydrogen transfer even more than
a benzyl group; FVP of 1a (R1 = CH2Ph, R2 = CO2Et)
gives ethyl 1-benzyl-3-hydroxypyrrole-2-carboxylate
(4a) exclusively in 30% isolated yield (Scheme 2).
In previous papers1 we have shown that flash vacuum py-
rolysis (FVP) at 600 °C of N,N-disubstituted aminometh-
ylene derivatives of Meldrum’s acid 1 provides a
convenient synthetic route to sensitive 1-substituted,2 1,2-
disubstituted,2 1,2,2-trisubstituted2 and 1,2,5-tri-
substituted3 3-hydroxypyrroles 4 (enol) and/or 1H-pyrrol-
3(2H)-ones 4 (keto) (Scheme 1). The mechanism involves
creation of the methyleneketene intermediates 2, followed
by a sigmatropic 1,4-hydrogen transfer to provide azo-
methine ylides 3 which collapse to 4 by electrocyclisa-
tion.4,5 In the case of 1 (R1 = H), an alternative 1,3-
hydrogen atom shift at the methyleneketene stage pro-
vides an imidoylketene 5, which leads to alternative prod-
ucts (Scheme 1).6
OH
O
O
N
FVP
O
O
CO2Et
N
CO2Et
4a
1a
O
H
H
H
products
Scheme 2
N
R2
5
Taken together, these results suggest that an ester group
might be capable of activating the 1,4-hydrogen shift by
four orders of magnitude or more. Therefore, in the
R1 = H case, this mode of reaction might be able to com-
pete with the 1,3-H shift leading to the imidoylketenes.
This idea is supported by DFT calculations at B3LYP/6-
31G** level,10 which show that the 1,4-H shift (leading to
the pyrrolone) is preferred by approximately 50 kJ mol–1
over the 1,3-shift leading to the imidoylketene (Figure 1).
R1 = H
O
O
O
FVP
R2
OH
H
H
O
O
N
R2
1
N
2
R2
R1
N
R1
1 4 (enol)
R
O
O
The predictions have been borne out in practice
(Figure 2). The precursors 1b–e were first made in 89–
97% yield by treatment of methoxymethylene Meldrum’s
acid 6 with the hydrochloride salt of the appropriate ami-
no acid esters in acetonitrile containing triethylamine.
Yields of the nitrile 1f and the trifluoromethyl compound
1g were 89% and 95%, respectively.
H
H
H
R2
N
N
R2
1 4 (keto)
R
3
R1
Scheme 1
FVP of 1b at 600 °C gave the known ethyl 3-hydroxypyr-
role-2-carboxylate (4b) (85%) as a yellow solid (2 steps;
81% overall). The two known routes9 to this compound
SYNTHESIS 2009, No. 15, pp 2531–2534
x
x.
x
x
.
2
0
0
9
Advanced online publication: 23.06.2009
DOI: 10.1055/s-0029-1217397; Art ID: P05209SS
© Georg Thieme Verlag Stuttgart · New York

2532
L. Hill et al.
PAPER
components were formed, but the pyrrole 4g could be
identified as a 54:46 mixture of its hydroxypyrrole
4
5
[d = 5.84 ppm (3J and J = 3.0 Hz; JHF = 1.0 Hz); 6.61
(3J = 3.2 Hz and JHF = 0.7 Hz)] and pyrrolone (d = 5.30
5
and 8.09 ppm) tautomers in CDCl3. The hydroxypyrrole
was present exclusively in DMSO-d6 (d = 5.70 and 6.69
ppm). This product was characterized as its acetoxy deriv-
ative 7.
In conclusion, the work described here provides a conve-
nient two-step synthesis of 1-unsubstituted 3-hydroxypyr-
roles and pyrrol-3(2H)-ones bearing conjugative, or
strong inductively electron-withdrawing groups at the 2-
position. The application of this methodology to provide
a two-step route to 3-hydroxypyrrole itself is reported in
the following paper.11
Figure 1 Energy surface for pyrrolone formation and (in red)
imidoylketene formation (cf. Scheme 1, R2 = CO2Et)
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. 13C NMR signals refer to one CH unless oth-
erwise stated. Mass spectra were recorded under electron impact
conditions. 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 liq-
uid N2. Pyrolysis conditions are quoted as follows: substrate, quan-
tity (w), furnace temperature (Tf), inlet temperature (Ti), pressure
range (P), pyrolysis time (t) and product(s).
both require four steps (11 and 28% overall yields, respec-
tively). In order to confirm that the N-H does not migrate
during the pyrolysis, the N-D analogue 1b¢ was generated
in situ in the inlet tube. No deuterium incorporation at
C(4) or C(5) of 4b could be detected by 1H NMR spectros-
copy.
The other amino acid ester derivatives 1c–e gave the new
pyrrolones 4c–e in 65–99% yields. The nitrile 4f was
obtained in 74% yield, and exists exclusively as the
hydroxypyrrole tautomer in CDCl3.
Aminomethylene Derivatives of Meldrum’s Acid 1
Method A:7 Et3N (0.28 mL per mmol) was added to a solution of the
amine salt (1 equiv) in MeCN (15 mL per mmol). Methoxymethyl-
ene Meldrum’s acid 6 (1 equiv) was added and the solution stirred
for 2.5 h at r.t. The solvent was removed, the residue dissolved in
CH2Cl2 and washed with HCl (2 M, 100 mL). The organic layer was
dried (MgSO4) and the solvent removed to give the product.
O
O
N
OAc
O
O
O
O
D
O
O
CF3
N
H
Method B:2 To a solution of the amine (1 equiv) dissolved in the
minimum amount of MeCN, was added methoxymethylene Mel-
drum’s acid 6 (1 equiv). The mixture was allowed to stand for 15
min and the solvent removed to give the product.
1b'
OMe
7
6
CO2Et
1b R1 = H, R2 = CO2Et
1c R1 = Me, R2 = CO2Me
1d R1 = iBu, R2 = CO2Me
1e R1 = Ph, R2 = CO2Me
1f R1 = H, R2 = CN
O
O
Ethyl [(2,2-Dimethyl-4,6-dioxo-1,3-dioxan-5-ylidenemeth-
yl)benzylamino]acetate (1a)
Using general method B, N-benzylglycine ethyl ester (1.93 g, 10
mmol) gave 1a as a yellow solid (2.60 g, 75%); mp 88–89 °C (from
EtOH).
O
O
H
N
1g R1 = H, R2 = CF3
R1
R2
1H NMR (CDCl3): d (2 rotamers, 9:1; major rotamer) = 8.24 (s, 1
H), 7.27–7.14 (m, 5 H), 4.63 (s, 2 H), 4.47 (s, 2 H), 4.02 (q, 3J = 7.1
Hz, 2 H), 1.55 (s, 6 H), 1.09 (t, 3J = 7.1 Hz, 3 H).
4b R1 = H, R2 = CO2Et (hydroxypyrrole form)
4c R1 = Me, R2 = CO2Me
4d R1 = iBu, R2 = CO2Me
4e R1 = Ph, R2 = CO2Me
4f R1 = H, R2 = CN (hydroxypyrrole form)
4g R1 = H, R2 = CF3
O
R2
R1
13C NMR (CDCl3): d (major rotamer) = 166.80 (Cq), 165.29 (Cq),
160.49 (Cq), 159.59, 132.70 (Cq), 128.73 (2 CH), 127.90 (2 CH),
102.53 (Cq), 86.12 (Cq), 64.37 (CH2), 61.18 (CH2), 52.53 (CH2),
26.06 (2 CH3), 13.51 (CH3) (one CH overlapping).
N
H
Figure 2
MS: m/z (%) = 228 [(M – 119)+, 17], 271 (39), 216 (17), 91 (100).
All the previous examples have employed a conjugative
electron-withdrawing group to stabilize the site of high
electron density in the azomethine ylide 3. In order to ex-
plore if a strong inductive electron-withdrawing group
can fulfill this role, the trifluoromethyl compound 1g was
synthesized and pyrolysed at 600 °C. The 1H NMR spec-
trum of the pyrolysate showed that at least four significant
Anal. Calcd for C18H21NO6: C, 62.2; H, 6.05; N, 4.05. Found: C,
62.0; H, 6.1; N, 4.15.
Ethyl [(2,2-Dimethyl-4,6-dioxo-1,3-dioxan-5-ylidenemeth-
yl)amino]acetate (1b)
Using general method A, glycine ethyl ester hydrochloride (1.396
g, 10 mmol) gave 1b as a yellow solid (2.432 g, 95%); mp 125–
126 °C (from EtOH).
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Synthesis of 3-Hydroxypyrroles and 1H-Pyrrol-3(2H)-ones
2533
1H NMR (CDCl3): d = 9.65 (br s, 1 H), 8.09 (d, 3J = 14.5 Hz, 1 H),
4.25 (q, 3J = 7.2 Hz, 2 H), 4.19 (d, 3J = 6.1 Hz, 2 H), 1.69 (s, 6 H),
1.30 (t, 3J = 7.2 Hz, 3 H).
1H NMR (DMSO-d6): d = 9.89 (s, 1 H), 8.34 (s, 1 H), 4.62 (s, 2 H),
1.62 (s, 6 H).
13C NMR (DMSO-d6): d = 160.71, 117.03, 104.16, 85.77, 37.76
(CH2), 26.75 (2 CH3), two carbonyl signals not apparent due to re-
stricted rotation.
13C NMR (CDCl3): d = 167.35 (Cq), 165.23 (Cq), 163.63 (Cq),
160.21, 104.52 (Cq), 86.06 (Cq), 62.34 (CH2), 50.24 (CH2), 26.90 (2
CH3), 14.04 (CH3).
MS: m/z (%) = 211 (M+, 71), 210 (60), 153 (100), 109 (16), 108
(45).
MS: m/z (%) = 257 (M+, 49), 200 (55), 155 (61), 126 (100).
Anal. Calcd for C11H15NO6: C, 51.35; H, 5.85; N, 5.45. Found: C,
51.4; H, 5.85; N, 5.45.
Anal. Calcd for C9H10N2O4: C, 51.45; H, 4.75; N, 13.35. Found: C,
51.75; H, 4.6; N, 13.0.
Methyl 2-[(2,2-Dimethyl-4,6-dioxo-1,3-dioxan-5-ylidenemeth-
yl)amino]propionate (1c)
2,2-Dimethyl-5-[(2,2,2-trifluoroethylamino)methylene]-1,3-di-
oxane-4,6-dione (1g)
Using general method A, alanine methyl ester hydrochloride (0.349
g, 2.5 mmol) gave 1c as a yellow solid (0.623 g, 97%); mp 125–
126 °C (from EtOH).
Using general method B, 2,2,2-trifluoroethylamine (1.98 g, 20
mmol) gave 1g as an orange solid (4.82 g, 95%); mp 161–163 °C
(from EtOH).
1H NMR (CDCl3): d = 9.74 (br s, 1 H), 8.11 (d, 3J = 14.8 Hz, 1 H),
4.23 (quint, 3J = 7.3 Hz, 1 H), 3.78 (s, 3 H), 1.67 (s, 6 H), 1.59 (d,
3J = 7.3 Hz, 3 H).
1H NMR (CDCl3): d = 9.60 (br s, 1 H), 8.17 (d, 3J = 13.7 Hz, 1 H),
3.99 (quint, 3J = 8.3 Hz, 2 H), 1.73 (s, 6 H).
13C NMR (CDCl3): d = 165.16 (Cq), 163.11 (Cq), 160.92, 122.67
13C NMR (CDCl3): d = 170.46 (Cq), 165.15 (Cq), 163.67 (Cq),
158.29, 104.72 (Cq), 85.73 (Cq), 57.02, 53.06 (CH3), 26.88 (2 CH3),
18.74 (CH3).
(Cq, q, 1JHF = 281.4 Hz), 105.18 (Cq), 87.58 (Cq), 50.42 (q, 2JHF
=
33.7 Hz, CH2), 26.88 (2 CH3).
MS: m/z (%) = 253 (M+, 81), 196 (100), 167 (99), 151 (46), 123
(32).
MS: m/z (%) = 257 (M+, 30), 200 (30), 199 (13), 155 (18), 140
(100), 96 (55).
Anal. Calcd for C9H10F3NO4: C, 42.7; H, 3.95; N, 5.55. Found: C,
42.85; H, 3.85; N, 5.45.
Anal. Calcd for C11H15NO6·0.1H2O: C, 51.0; H, 5.8; N, 5.4. Found:
C, 50.95; H, 5.75; N, 5.4.
Ethyl 1-Benzyl-3-hydroxypyrrole-2-carboxylate (4a)
FVP of 1a (w 0.35 g, Tf 600 °C, Ti 200 °C, P 10–3 Torr, t 1 h) gave
4a as a yellow solid (0.074 g, 30%); (decomposed on attempted dis-
tillation).
Methyl 2-[(2,2-Dimethyl-4,6-dioxo-1,3-dioxan-5-ylidenemeth-
yl)amino]-4-methylpentanoate (1d)
Using general method A, leucine methyl ester hydrochloride (0.454
g, 2.5 mmol) gave 1d as a yellow solid (0.687 g, 92%); mp 106–
107 °C (from EtOH).
1H NMR (CDCl3): d = 7.35–7.19 (m, 3 H), 7.05–7.0 (m, 2 H), 6.66
(d, 3J = 3.0 Hz, 1 H), 5.82 (d, 3J = 3.0 Hz, 1 H), 5.29 (s, 2 H), 4.25
(q, 3J = 7.1 Hz, 2 H), 1.21 (t, 3J = 7.1 Hz, 3 H).
1H NMR (500 MHz, CDCl3): d = 9.64 (br m, 1 H), 8.08 (d, 3J = 14.5
Hz, 1 H), 4.13 (td, 3J = 9.0, 5.5 Hz, 1 H), 3.80 (s, 3 H), 1.79 (m, 2
H), 1.71 (s, 6 H), 1.66 (m, 1 H), 0.97 (d, 3J = 7.0 Hz, 3 H), 0.96 (d,
3J = 7.0 Hz, 3 H).
13C NMR (CDCl3): d = 162.52 (Cq), 155.85 (Cq), 138.21 (Cq),
128.30 (2 CH), 127.86, 127.28, 126.24 (2 CH), 105.78 (Cq), 96.59,
59.81 (CH2), 52.84 (CH2), 14.18 (CH3).
13C NMR (90 MHz, CDCl3): d = 170.34 (Cq), 165.20 (Cq), 163.63
(Cq), 158.67, 104.76 (Cq), 85.70 (Cq), 60.70 (CH3), 52.89, 41.53
(CH2), 26.90 (CH3), 26.82 (CH3), 24.34, 22.50 (CH3), 21.41 (CH3).
MS: m/z (%) = 245 (M+, 24), 200 (10), 199 (19), 91 (100).
HRMS: m/z calcd for C14H15NO3 (M+): 245.1052; found: 245.1046.
MS: m/z (%) = 299 (M+, 16), 240 (15), 182 (100), 138 (18), 96 (15).
Ethyl 3-Hydroxypyrrole-2-carboxylate (4b)
Anal. Calcd for C14H21NO6: C, 56.2; H, 7.0; N, 4.75. Found: C,
56.4; H, 7.0; N, 4.75.
FVP of 1b (w 1.09 g, Tf 600 °C, Ti 200 °C, P 3.6–3.8 × 10–2 Torr, t
5 min) gave a brown oil (0.718 g), which was purified by Kugelrohr
distillation to give 4b as a yellow solid (0.558 g, 85%); mp 37–
38 °C, bp 72 °C (0.5 mmHg) [lit.9a 110 °C (0.05 Torr)]
Methyl [(2,2-Dimethyl-4,6-dioxo-1,3-dioxan-5-ylidenemeth-
yl)amino]phenylacetate (1e)
Using general method A, phenylglycine methyl ester hydrochloride
(2.060 g, 10 mmol) gave 1e as a yellow solid (2.828 g, 89%); mp
178–181 °C (from EtOH).
1H NMR (360 MHz, CDCl3): d = 8.30 (br s, 1 H), 7.74 (br s, 1 H),
6.71 (br s, 1 H), 5.87 (t, 3J = 2.9 Hz, 1 H), 4.35 (q, 3J = 7.1 Hz, 2 H),
1.37 (t, 3J = 7.1 Hz, 3 H).
MS: m/z (%) = 155 (53), 109 (100), 81 (41).
1H NMR (CDCl3): d = 10.32 (dd, 3J = 14.5, 6.6 Hz, 1 H), 8.08 (d, 3J
= 14.5 Hz, 1 H), 7.45–7.32 (m, 5 H), 5.21 (d, 3J = 6.6 Hz, 1 H), 3.80
(s, 3 H) 1.45 (s, 3 H), 1.43 (s, 3 H).
Deuteriation Experiment
Compound 1b (0.124 g) was heated in methanol-d4 (ca. 1 mL) and
the solvent removed under high vacuum. Pyrolysis of the resulting
solid (Tf 600 °C, Ti 200 °C, P 2.8 – 3.2 × 10–2 Torr, t 8 min) gave a
brown oil. The product 4b was dissolved in CDCl3. By H NMR
spectroscopy, no deuterium incorporation at C(4) or C(5) of 4b
could be detected.
13C NMR (CDCl3): d = 168.75 (Cq), 164.93 (Cq), 163.46 (Cq),
158.05, 134.21 (Cq), 129.50, 129.41 (2 CH), 127.14 (2 CH), 104.68
(Cq), 86.29 (Cq), 64.52, 53.26 (CH3), 26.77 (2 CH3).
1
MS: m/z (%) = 319 (M+, 31), 260 (72), 202 (100), 158 (100).
Anal. Calcd for C16H17NO6: C, 60.55; H, 5.35; N, 4.40. Found: C,
60.25; H, 5.05; N, 4.35.
Methyl 2-Methyl-3-oxo-2,3-dihydro-1H-pyrrole-2-carboxylate
(4c)
FVP of 1c (w 0.306 g, Tf 600 °C, Ti 200 °C, P 2.3–2.4 × 10–2 Torr,
t 7 min) gave an orange oil, which solidified on concentration from
an acetone solution to give 4c as an orange solid (0.182 g, 99%); mp
79–81 °C.
[(2,2-Dimethyl-4,6-dioxo-1,3-dioxan-5-ylidenemethyl)ami-
no]acetonitrile (1f)
Using general method A, aminoacetonitrile hydrogen sulfate (1.54
g, 10 mmol) gave 1f as a yellow solid (1.86 g, 89%); mp 182–
184 °C (from EtOH).
Synthesis 2009, No. 15, 2531–2534 © Thieme Stuttgart · New York

2534
L. Hill et al.
PAPER
1H NMR (CDCl3): d = 8.10 (s, 1 H), 6.65 (br s, 1 H), 5.09 (d, 3J =
3.5 Hz, 1 H), 3.71 (s, 3 H), 1.57 (s, 3 H).
1H NMR (360 MHz, CDCl3): d = 8.69 (br s, 1 H), 6.72 (td, 3J = 3.3
Hz, 4J = 0.7 Hz, 1 H), 6.16 (td, 3J = 3.2 Hz, 4J = 0.7 Hz, 1 H), 2.28
(s, 3 H).
13C NMR (CDCl3): d = 198.19 (Cq), 168.28 (Cq), 165.48, 97.63,
69.32 (Cq), 53.16 (CH3), 20.99 (CH3).
13C NMR (90 MHz, CDCl3): d = 164.84 (Cq), 136.47 (Cq), 120.51
1
(Cq, q, JHF = 264.8 Hz), 118.35, 103.81, 20.45 (CH3), one Cq not
apparent.
MS: m/z (%) = 155 (M+, 100), 96 (87), 112 (23).
HRMS: m/z calcd for C7H9NO3 (M+): 155.05769; found:
155.05791.
MS: m/z (%) = 193 (M+, 30), 151 (100), 131 (63).
HRMS: m/z calcd for C7H6F3NO2 (M+): 193.03451; found:
193.03477.
Methyl 2-Isobutyl-3-oxo-2,3-dihydro-1H-pyrrole-2-carboxy-
late (4d)
FVP of 1d (w 0.450 g, Tf 600 °C, Ti 170 °C, P 2.6–4.2 × 10–2 Torr,
t 24 min) gave 4d as an orange solid (0.240 g, 81%); mp 91–92 °C.
Acknowledgment
1H NMR (500 MHz, CDCl3): d = 8.10 (t, 3J = 3.5 Hz, 1 H), 6.11 (br
s, 1 H), 5.16 (d, 3J = 3.5 Hz, 1 H), 3.76 (s, 3 H), 2.16 (q, 3J = 9.0 Hz,
1 H), 1.73 (m, 2 H), 0.91 (d, 3J = 7.0 Hz, 3 H), 0.90 (d, 3J = 7.0 Hz,
3 H).
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.) and The University of Edinburgh for the award of the
Colin and Ethel Gordon Scholarship (to G.A.H.). We are also
grateful to Dr. A. R. Turner for access to the EaStCHEM Research
Computing Facility.
13C NMR (90 MHz, CDCl3): d = 196.86 (Cq), 168.02 (Cq), 165.50,
99.02, 73.29 (Cq), 53.11, 43.99 (CH2), 25.39, 23.47 (CH3), 23.03
(CH3).
MS: m/z (%) = 197 (M+, 11), 154 (53), 141 (100), 126 (22), 109
(32), 94 (69).
References
(1) Reviews: (a) McNab, H.; Monahan, L. C. Pyrroles, Vol. 2;
Jones, R. A., Ed.; Wiley: New York, 1992, 525. (b) Gaber,
A. M.; McNab, H. Synthesis 2001, 2059.
HRMS: m/z calcd for C10H15NO3 (M+): 197.10464; found:
197.10460.
(2) McNab, H.; Monahan, L. C. J. Chem. Soc., Perkin Trans. 1
1988, 863.
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Methyl 3-Oxo-2-phenyl-2,3-dihydro-1H-pyrrole-2-carboxylate
(4e)
FVP of 1e (w 1.050 g, Tf 600 °C, Ti 220 °C, P 4.2–5.5 × 10–2 Torr,
t 10 min) gave 4e as a brown solid (0.463 g, 65%); mp 177–179 °C
(from toluene).
1H NMR (DMSO-d6): d = 9.41 (br s, 1 H), 8.56 (br s, 1 H), 7.57–
7.35 (m, 5 H), 4.88 (s, 1 H), 3.67 (s, 3 H).
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Robb, M. A.; Cheeseman, J. R.; Montgomery, J. A. Jr.;
Vreven, T.; Kudin, K. N.; Burant, J. C.; Millam, J. M.;
Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi,
M.; Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.;
Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.;
Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.;
Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.;
Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.;
Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.;
Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.;
Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V.
G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.;
Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman,
J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.;
Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.;
Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith,
T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.;
Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.;
Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian03;
Gaussian Inc.: Wallingford CT, 2004.
13C NMR (DMSO-d6): d = 194.41 (Cq), 167.04, 166.91 (Cq), 135.13
(Cq), 127.92 (2 CH), 127.85, 126.31 (2 CH), 94.09, 73.24 (Cq),
52.88 (CH3).
MS: m/z (%) = 217 (M+, 17), 185 (20), 130 (22), 105 (47), 84 (100).
HRMS: m/z calcd for C12H11NO3 (M+): 217.07334; found:
217.07334.
2-Hydroxy-3-cyanopyrrole (4f)
FVP of 1f (w 0.208 g, Tf 600 °C, Ti 200 °C, P 2.3–2.9 × 10–2 Torr, t
10 min) gave 4f as an off-white solid (0.0877 g, 74%); mp 92–
94 °C.
1H NMR (CDCl3): d = 11.23 (br s, 1 H), 9.72 (br s, 1 H), 6.78 (d,
3J = 2.5 Hz, 1 H), 5.65 (m, 1 H).
13C NMR (CDCl3): d = 154.07 (Cq), 123.07, 114.78 (Cq), 97.85,
85.11 (Cq).
MS: m/z (%) = 108 (M+, 100), 84 (31), 53 (47).
HRMS: m/z calcd for C5H4N2O (M+): 108.03181; found:
108.03181.
3-Acetoxy-2-trifluoromethylpyrrole (7)
Pyrolysis of 1g (w 1.0126 g, Tf 600 °C, Ti 200 °C, P 3.0–3.2 × 10–2
Torr, t 22 min) gave an orange oil which contained 4g as a mixture
of tautomers (see discussion). The oil was dissolved in CH2Cl2 (20
mL), Et3N (0.7 mL) and AcCl (0.5 mL) were added and the mixture
stirred for 2.5 h at r.t. The solution was washed with HCl (2 M; 2 ×
40 mL) and NaHCO3 (sat.; 40 mL). The organic layer was dried
(MgSO4) and the solution concentrated to give an orange oil. Kugel-
rohr distillation gave 7 as a pale yellow oil (0.2208 g, 28%); bp 64–
66 °C (2 Torr).
(11) Hill, L.; Imam, S. H.; McNab, H.; O’Neill, W. J. Synthesis
2009, 2535.
Synthesis 2009, No. 15, 2531–2534 © Thieme Stuttgart · New York