The meldrum's acid route to prodigiosin analogues

Article abstract of DOI:10.1055/s-0029-1218735

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

Full text of DOI:10.1055/s-0029-1218735

PAPER
1707
The Meldrum’s Acid Route to Prodigiosin Analogues
P
rodigiosin Analog
o
ues rdon 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
Received 15 February 2010
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 with-
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-hydroxy-
thiophene by regioselective O-alkylation and formylation. Conden-
sation of these aldehydes with activated pyrroles in the presence of out purification. Conditions for highly regioselective O-
phosphoryl chloride provides analogues of prodigiosin, which dif-
alkylation of N-substituted 3-hydroxypyrroles have been
previously established8 and were applied successfully to 5
fer from the natural products in the nature of the heteroatoms.
Key words: gas-phase reactions, heterocycles, pyrroles, prodigi-
osins
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 pu-
rification. The regioselectivity of electrophilic substitu-
There has been much interest in the synthesis of the pro- tion reactions of 3-hydroxy- and 3-alkoxypyrroles has
digiosin family of antibiotics 1, originally isolated from also been established9 and was found to be applicable to
the microorganism Serratia marcescens, because of their Vilsmeier formylation conditions; the 2-carboxaldehydes
antibacterial, cytotoxic, and immunosuppressive activi- 8 and 9 were obtained as the only regioisomers, in 75%
ties (Figure 1).1 A number of classic total syntheses have yield.
been reported,2 but the problem of routine, scaleable for-
mation 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-hydroxypyrroles4 and 3-
hydroxythiophenes5 to create prodigiosin analogues in
which the pyrrole (ring A) was replaced by a thiophene
moiety and in which the alkoxypyrrole (ring B) was re-
placed by an N-substituted alkoxypyrrole or by an alkoxy-
thiophene 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 nat-
ural products.
O
O
O
O
OH
O
SMe
FVP
FVP
2
S
X
X
S
S
Me2NH
4E X = S
5E X = NMe
4K X = S
5K X = NMe
MeOTs
OMe
O
O
O
OMe
DMF
POCl3
O
CHO
X
X
S
NMe2
S
S
6 X = S
7 X = NMe
8 X = S
9 X = NMe
3
OMe
Rn
H
N
A
HN
B
C
Scheme 1
N
H
X–
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
Figure 1 General structure of prodigiosins
The Meldrum’s acid route to prodigiosin analogues in-
volves a four- or five-step synthesis starting from the The range of ‘ring C’ pyrroles within the natural products
known5 methylthio compound 2 (Scheme 1). The thiophe- structures is extensive, and many are of formidable com-
none 4K (3-hydroxythiophene 4E) was readily generated plexity.1 In order to establish the methodology, our initial
as a stable, crystalline solid, by flash vacuum pyrolysis reactions focused on commercially available kryptopyr-
(FVP) of 2 at 625 °C (76%).5 Alternatively, treatment of role (2,4-dimethyl-3-ethylpyrrole) 11 with only one va-
cant carbon ring position. N-Alkylation provided the
tetrasubstituted pyrrole 12 (Figure 2). 2-Undecylpyrrole
SYNTHESIS 2010, No. 10, pp 1707–1711
Advanced online publication: 09.04.2010
DOI: 10.1055/s-0029-1218735; Art ID: P02210SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
1
0
(13), present as ring C in undecylprodigiosin was synthe-
sized by a literature method.11

1708
G. A. Hunter et al.
PAPER
Et
Me
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 b-form of
prodigiosin free base,14 but very different hydrogen-bond-
ing regimes are observed when rings A and/or B have a
free NH.14
OMe
Et
Me
Me
CHO
Me
N
N
H
N
H
Me
12
10
11
OMe
N
NH2
(CH2)10Me
N
Condensation of 3-methoxypyrrole-2-carboxaldehyde
(10) with kryptopyrrole gave the prodigiosin analogue 25
lacking ring A, but with the B–C hydrogen-bonding re-
gime 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
N
H
H
S
13
17
18
Figure 2 Pyrroles 10–13, thiophene 17, and pyrazole 18
2-Methyl-3-pentylpyrrole (16), found in prodigiosin it-
self, was made in two steps, by photochemical ring con-
traction of 4-pentylpyridine N-oxide (14) in the presence
of copper(II) ions10 followed by Wolff–Kischner reduc-
tion of the formyl group of 15 (Scheme 2). Although this
route is reasonably concise,12 the ring contraction step oc-
curred in very low yield (20%) and was not amenable to
scale-up. The final Wolff–Kischner step was also less ef-
ficient than expected. 3-Methoxythiophene (17) and 3-
aminopyrazole (18) were also used as ring C analogues,
on account of their complementary hydrogen-bonding
properties.
OMe
Me
OMe
HN
S
H
N
CH2Me
N
S
N
H
N
Me
–
26
25
PO2Cl2
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 hydroxy-
thiophene by FVP of an appropriate methylene Mel-
drum’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.
(CH2)4Me
(CH2)4Me
(CH2)4Me
CHO
hν
N
N
N
O–
14
H
H
15
16
Scheme 2
In most cases, the final step to give the prodigiosin ana-
logue was a phosphoryl chloride catalyzed condensation
of the aldehydes 8 and 9 with a 2-unsubstituted pyrrole
1H and 13C NMR spectra were recorded at 250 MHz and 63 MHz
under published conditions13 (Scheme 3) and provided the respectively unless otherwise stated. Chemical shifts are given in
ppm relative to TMS. Mass spectra were recorded under electron
impact conditions unless otherwise stated.
three-ring systems 19–24 (68–97%). The final products
were isolated and characterized as their dichlorophos-
phate 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 deriva-
tive 23, which decomposed within 72 hours of formation,
even when stored at –20 °C.
5-(l-Dimethylamino-l-thienylmethylene)-2,2-dimethyl-l,3-diox-
ane-4,6-dione (3)
Treatment of 25 with an excess of Me2NH in MeCN gave 3 (65%);
mp 205–207 °C (dec.).
1H NMR (CDCl3): d = 7.66 (d, 3J = 5.0 Hz, 1 H), 7.39 (d, 3J = 3.8
Hz, 1 H), 7.12 (dd, 3J = 3.8, 5.0 Hz, 1 H), 3.34 (s, 6 H), 1.67 (s, 6 H).
13C NMR (CDCl3): d = 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).
R2
OMe
OMe
Y
11–13,16,17
POCl3
R3
S
S
CHO
X
–
X
R4
PO2Cl2
19 X = S, Y = HN+, R2 = R4 = Me, R3 = Et
20 X = S, Y = MeN+, R2 = R4 = Me, R3 = Et
8 X = S
9 X = NMe
Anal. Calcd for C13H15NO4S: C, 55.5; H, 5.35; N, 5.0. Found: C,
55.6; H, 5.45; N, 4.95.
21 X = S, Y = HN+, R2 = (CH2)10Me, R3 = R4 = H
22 X = S, Y = HN+, R2 = Me, R3 = H, R4 = (CH2)4Me
23 X = S, Y = S+, R2 = R3 = H, R4 = OMe
1-Methyl-5-(2-thienyl)pyrrol-3(2H)-one (5)
24 X = NMe, Y = HN+, R2 = R4 = Me, R3 = Et
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,
Scheme 3
Synthesis 2010, No. 10, 1707–1711 © Thieme Stuttgart · New York

PAPER
Prodigiosin Analogues
1709
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.
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): d = 9.92 (s, 1 H), 7.36–7.30 (m, 2 H), 7.04 (dd,
1H NMR (CDCl3): d (tautomers 5E and 5K both present – data for
3J = 3.8 Hz, 5.0 Hz, 1 H), 6.88 (s, 1 H), 3.98 (s, 3 H).
3
4
5K quoted) = 7.54 (dd, J = 5.0 Hz, J = 1.2 Hz, 1 H), 7.38 (dd,
3J = 3.7 Hz, 4J = 1.2 Hz, 1 H), 7.12 (dd, 3J = 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): d = 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).
13C NMR (CDCl3): d = (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),
Anal. Calcd for C10H8O2S2: C, 53.6, H, 3.55. Found: C, 54.1; H, 3.6.
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.
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.
O-Alkylation of 3-Hydroxypyrrole 5 and 3-Hydroxythiophene
4; General Procedure
1H NMR (CDCl3): d = 9.54 (s, 1 H), 7.31 (dd, 3J = 5.0 Hz, 4J = 1.2
Hz, 1 H), 7.09 (dd, 3J = 3.6 Hz, 4J = 1.2 Hz, 1 H), 7.01 (dd, 3J = 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): d = 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).
The reported method for regioselective O-alkylation of 3-hydroxy-
pyrroles 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 solu-
tion 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 dimethylimida-
zolidinone (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.
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.
3-Methoxy-5-(2-thienyl)thiophene (6)
Compound 4 gave 6 (90%); bp 122–124 °C/0.2 Torr.
1H NMR (CDCl3): d = 7.20 (dd, 3J = 5.0 Hz, 4J = 1.2 Hz, 1 H), 7.16
(dd, 3J = 3.6 Hz, 4J = 1.2 Hz, 1 H), 7.00 (dd, 3J = 5.0, 3.6 Hz, 1 H),
6.86 (d, 4J = 1.6 Hz, 1 H), 6.14 (d, 4J = 1.6 Hz, 1 H), 3.81 (s, 3 H).
13C NMR (CDCl3): d = 158.14 (Cq), 137.38 (Cq), 135.95 (Cq),
127.61, 124.45, 123.45, 115.70, 95.63, 57.07.
1H NMR (CDCl3): d = 6.32 (s, 1 H), 3.47 (s, 3 H), 2.42 (q, 3J = 7.3
Hz, 2 H), 2.14 (s, 3 H), 2.05 (d, 4J = 0.7 Hz, 3 H), 1.10 (t, 3J = 7.3
Hz, 3 H), consistent with reported data.17
13C NMR (CDCl3): d = 127.13 (Cq), 124.34 (Cq), 120.66 (Cq),
117.48, 33.05, 17.67, 15.72, 9.80, 9.26.
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.
2-Methyl-3-pentylpyrrole (16)
4-Pentylpyridine-N-oxide (14): To a solution of 4-pentylpyridine18
(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 dis-
solved in CHCl3 (90 mL). The solution was added to a K2CO3 paste
(100 g K2CO3 in 100 mL H2O) with stirring, the mixture was fil-
tered, 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.
3
4
1H NMR (CDCl3): d = 7.24 (dd, J = 4.9 Hz, J = 1.2 Hz, 1 H),
7.09–7.02 (m, 2 H), 6.32 (d, 4J = 1.1 Hz, 1 H), 6.12 (d, 4J = 1.1 Hz,
1 H), 3.76 (s, 3 H), 3.62 (s, 3 H).
13C NMR (CDCl3): d = 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.
1H NMR (CDCl3): d = 7.98–7.86 (m, 2 H), 6.94–6.81 (m, 2 H), 2.37
(t, 3J = 7.7 Hz, 2 H), 1.44–1.32 (m, 2 H), 1.18–0.99 (m, 4 H), 0.65
(t, 3J = 6.6 Hz, 3 H).
13C NMR (CDCl3): d = 148.92 (Cq), 138.11, 125.46, 33.70, 30.53,
29.24, 21.77, 13.35.
Synthesis 2010, No. 10, 1707–1711 © Thieme Stuttgart · New York

1710
G. A. Hunter et al.
PAPER
MS: m/z (%) = 165 (M+, 30), 109 (24), 108 (100), 93 (46), 92 (24),
91 (17), 65 (17).
129.25, 124.87, 115.67 (Cq), 109.88, 59.92, 17.17, 13.89, 13.78,
10.06.
HRMS: m/z calcd for C10H15NO (M+): 165.1154; found: 165.1158.
MS (FAB): m/z = 330 (M+).
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 so-
lution 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 contin-
uously extracted with CH2Cl2 overnight. The organic layer was sep-
arated 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): d = 9.81 (br s, 1 H), 9.61 (s, 1 H), 7.03 (t, 3J = 2.5
Hz, 1 H), 6.15 (t, 3J = 2.5 Hz, 1 H), 2.75 (t, 3J = 7.6 Hz, 2 H), 1.61
(m, 2 H), 1.47–1.28 (m, 4 H), 0.90 (t, 3J = 6.8 Hz, 3 H).
13C NMR (CDCl3): d = 177.44, 138.31 (Cq), 129.05 (Cq), 126.00,
111.40, 31.35, 31.26, 25.13, 22.32, 13.86.
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]-2H-pyrrolium Dichlorophosphate (20)
Compound 8 and 3-ethyl-1,2,4-trimethylpyrrole (12; 15 min) gave
20 (93%).
1H NMR (CDCl3): d = 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, 3J = 7.7 Hz, 3 H).
13C NMR (CDCl3): d = 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.
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.
5-Undecyl-2-[3-methoxy-5-(2-thienyl)thienyl-2-methylene]-2H-
pyrrolium Dichlorophosphate (21)
Compound 8 and 2-undecylpyrrole (13;11 15 min) gave 21 (97%).
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 Torr (Lit.2a bp
95–99 °C/4 Torr).
1H NMR (CDCl3): d = 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, 3J = 7.7 Hz, 2 H), 1.75 (m, 2 H), 1.38–1.16 (m, 16
H), 0.86 (t, 3J = 6.6 Hz, 3 H).
13C NMR (CDCl3): d = 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:
1H NMR (CDCl3): d = 7.82 (br s, 1 H), 6.60 (m, 1 H), 6.04 (m, 1 H),
2.41 (t, 3J = 7.6 Hz, 2 H), 2.20 (s, 3 H), 1.63–1.50 (m, 2 H), 1.48–
3
428.2095.
1.30 (m, 4 H), 0.93 (t, J = 7.0 Hz, 3 H); data compatible with
reported19 spectrum.
4-Pentyl-5-methyl-2-[3-methoxy-5-(2-thienyl)thienyl-2-methyl-
ene]-2H-pyrrolium Dichlorophosphate (22)
Compound 8 and 2-methyl-3-pentylpyrrole (16; 30 min) gave 22
(77%).
1H NMR (CDCl3): d = 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, 3J = 7.7
Hz, 2 H), 1.60–1.48 (m, 3 H), 1.44–1.29 (m, 3 H), 0.91 (t, 3J = 6.4
Hz, 3 H).
13C NMR (CDCl3): d = 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.
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) con-
taining 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 be-
came red. If a solid formed, it was collected by filtration and washed
with n-pentane. If the product did not precipitate, the solvent was re-
moved under reduced pressure to give the product as a thick, in-
tensely colored oil. Compounds of this class may be sternutatory.
MS (FAB): m/z = 358 (M+).
HRMS (FAB): m/z calcd for C20H24NOS2 (M+): 358.1299; found:
358.1330.
3,5-Dimethyl-4-ethyl-2-[3-methoxy-5-(2-thienyl)thienyl-
2-methylene]-2H-pyrrolium Dichlorophosphate (19)
Compound 8 and kryptopyrrole 11 (1 min) gave 19 (72%); mp
180 °C (dec.) (EtOH).
1H NMR (CDCl3): d = 7.87 (d, 3J = 3.3 Hz, 1 H), 7.63 (s, 1 H), 7.43
(d, 3J = 4.4 Hz, 1 H), 7.07 (dd, 3J = 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, 3J = 7.5 Hz, 2 H), 2.25 (s, 3
H), 1.06 (t, 3J = 7.5 Hz, 3 H).
3-Methoxy-2-[3-methoxy-5-(2-thienyl)thienyl-2-methylene]-
2H-thiophenium Dichlorophosphate (23)
Compound 8 and 3-methoxythiophene (17; 15 min) gave 23 (84%).
1H NMR (acetone-d6): d = 7.79 (s, 1 H), 7.36 (dd. 3J = 5.1 Hz, 4J =
1.1 Hz, 1 H), 7.18 (m, 2 H), 7.09 (s, 1 H), 7.04 (dd, 3J = 5.1 Hz, 3.6
Hz, 1 H), 6.92 (d, 3J = 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:
13C NMR (CDCl3): d = 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,
321.0068.
Synthesis 2010, No. 10, 1707–1711 © Thieme Stuttgart · New York

PAPER
Prodigiosin Analogues
1711
3,5-Dimethyl-4-ethyl-2-[3-methoxy-l-methyl- 5-(2-thienyl)pyr-
rolyl-2-methylene]-2H-pyrrolium Dichlorophosphate (24)
Compound 9 and kryptopyrrole 11 (1 min) gave 24 (68%); mp
133.5 °C (dec.) (EtOH).
1H NMR (CDCl3): d = 11.26 (br s, 1 H), 7.57 (d, 3J = 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, 3J = 7.6 Hz,
2 H), 2.32 (s, 3 H), 1.04 (t, 3J = 7.6 Hz, 3 H).
13C NMR (CDCl3): d = 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: 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 Stu-
dentship (to K.W.) and Lonza Ltd. for a generous gift of Meldrum’s
acid.
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.
References
(1) Review: Fürstner, A. Angew. Chem. Int. Ed. 2003, 42, 2582.
(2) For example: (a) Rapoport, H.; Holden, K. G. J. Am. Chem.
Soc. 1962, 84, 635. (b) Boger, D. L.; Patel, M. J. Org. Chem.
1988, 53, 1405. (c) Wassermann, H. H.; Petersen, A. K.;
Xia, M.; Wang, J. Tetrahedron Lett. 1999, 40, 7587.
(3) (a) D’Allessio, R.; Rossi, A. Synlett 1996, 513.
(b) D’Allessio, R.; Bargiotti, A.; Carlini, O.; Calotta, F.;
Ferrari, M.; Gnocchi, P.; Isetta, A.; Monelli, N.; Rossi, A.;
Rossi, M.; Tibolla, M.; Vanotti, E. J. Med. Chem. 2000, 43,
2557.
(4) (a) McNab, H.; Monahan, L. C. J. Chem. Soc., Perkin Trans.
1 1988, 863. (b) Review: McNab, H.; Monahan, L. C. In
Pyrroles, Vol. 2; Jones, R. A., Ed.; Wiley: New York, 1992,
525. (c) Review: Gaber, A. M.; McNab, H. Synthesis 2001,
2059.
3,5-Dimethyl-4-ethyl-2-(3-methoxypyrrolyl-2-methylene)-2H-
pyrrolium Dichlorophosphate (25)
2-Formyl-3-methoxypyrrole (10;10 0.037 g, 0.3 mmol) and krypto-
pyrrole 11 (0.3 mmol) (60 min) gave 25 (86%).
1H NMR (CDCl3): d = 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, 3J = 7.4 Hz, 2
H), 2.24 (s, 3 H), 1.05 (t, 3J = 7.4 Hz, 3 H).
13C NMR (CDCl3): d = 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.
(5) McNab, H.; Hunter, G. A. J. Chem. Soc., Perkin Trans. 1
1995, 1209.
(6) Blake, A. J.; Hunter, G. A.; McNab, H. J. Chem. Soc., Chem.
Commun. 1990, 734.
3,5-Dimethyl-4-ethyl-2-(3-methoxypyrrolyl-2-methylene)-2H-
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 corre-
sponding base 25¢ (0.055 g, 80%); bp 220 °C/1.0 Torr.
1H NMR (CDCl3): d = 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, 3J = 7.6 Hz,
2 H), 2.22 (s, 3 H), 1.03 (t, 3J = 7.6 Hz, 3 H).
13C NMR (CDCl3): d = 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).
(7) Fürstner, A.; Grabowski, E. J. ChemBioChem 2001, 2, 706.
(8) Hunter, G. A.; McNab, H.; Monahan, L. C.; Blake, A. J.
J. Chem. Soc., Perkin Trans. 1 1991, 3245.
(9) Derbyshire, P. A.; Hunter, G. A.; McNab, H.; Monahan, L.
C. J. Chem. Soc., Perkin Trans. 1 1993, 2017.
(10) (a) Bellamy, F.; Martz, P.; Streith, J. Heterocycles 1975, 3,
395. (b) Bellamy, F.; Streith, J.; Fritz, H. Nouv. J. Chim.
1979, 3, 115. (c) Bellamy, F.; Streith, J. J. Chem. Res.,
Synop. 1979, 18; J. Chem. Res., Miniprint 1979, 101.
(11) Wasserman, H. H.; Rodgers, G. C.; Keith, D. D.
Tetrahedron 1976, 32, 1851.
(12) For example: Castro, A. J.; Deck, J. F.; Hugo, M. T.; Lowe,
E. J.; Marsh, J. P. Jr.; Pfeiffer, R. J. J. Org. Chem. 1963, 28,
857.
(13) van Koeveringe, J. A.; Lugtenburg, J. Recl. Trav. Chim.
HRMS: m/z calcd for C14H18N2O (M+): 230.1419; found: 230.1428.
Pays-Bas 1977, 96, 55.
(14) Jenkins, S.; Incarvito, C. D.; Parr, J.; Wasserman, H. H.
CrystEngComm 2009, 11, 242.
(15) Hill, L.; Hunter, G. A.; Imam, S. H.; McNab, H.; O’Neill, W.
J. Synthesis 2009, 2531.
(16) Heaney, H.; Ley, S. V. J. Chem. Soc., Perkin Trans. 1 1973,
499.
(17) Barrero, A. F.; Sanchez, J. F.; Oltra, J. E.; Teva, D.
J. Heterocycl. Chem. 1991, 28, 939.
(18) (a) Vaughn, T. H.; Vogt, R. R.; Nieuwland, J. A. J. Am.
Chem. Soc. 1934, 56, 2120. (b) Boekelheide, V.; Linn, W. J.
J. Am. Chem. Soc. 1954, 76, 1286.
3-{N-[3-methoxy-5-(2-thienyl)thienyl-2-methylene]}amino-
pyrazole (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 re-
duced pressure, and the crude product 26 was recrystallized (0.109
g, 63%); mp 130–131 °C (hexane–EtOAc).
1H NMR (DMSO-d6): d = 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-d6): d = 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.
(19) Williamson, N. R.; Simonsen, H. T.; Ahmed, R. A. A.;
Goldet, G.; Slater, H.; Woodley, L.; Leeper, F. J.; Salmond,
G. P. C. Mol. Microbiol. 2005, 56, 971.
Synthesis 2010, No. 10, 1707–1711 © Thieme Stuttgart · New York