Synthesis of (E)-3-(1H-pyrrol-3-yl)prop-2-ene derivatives using organo-phosphorous reagents

Article abstract of DOI:10.1055/s-2006-926426

The synthesis of (E)-3-[1-(toluene-4-sulfonyl)-1H-pyrrol-3-yl]prop-2-ene derivatives from 1-(toluene-4-sulfonyl)-1H-pyrrole-3-carbaldehyde by the Horner-Wadsworth-Emmons (HWE) reaction, is described. However, the HWE reaction with diethyl methoxymethylpho

Full text of DOI:10.1055/s-2006-926426

1494
PAPER
Synthesis of (E)-3-(1H-Pyrrol-3-yl)prop-2-ene Derivatives Using Organo-
phosphorous Reagents
Synthesis of
(
E
)-3-
i
1
H
-
Py
k
r
rol-3-yl]pro
o
p-2-ene
D
eri
l
vativesaos Karousis,a Jürgen Liebscher,*b George Varvounis*a
a
Department of Chemistry, University of Ioannina, 45110 Ioannina, Greece
Fax +30(265)1098799; E-mail: gvarvoun@cc.uoi.gr
b
Institute für Chemie, Humboldt-Universität Berlin, Brook-Taylor-Strasse 2, 12489 Berlin, Germany
Fax +49(30)20937552; E-mail: liebscher@rz.hu-berlin.de
Received 12 September 2005; revised 21 October 2005
CHO
CHO
Abstract: The synthesis of (E)-3-[1-(toluene-4-sulfonyl)-1H-pyr-
rol-3-yl]prop-2-ene derivatives from 1-(toluene-4-sulfonyl)-1H-
pyrrole-3-carbaldehyde by the Horner–Wadsworth–Emmons
(HWE) reaction, is described. However, the HWE reaction with di-
ethyl methoxymethylphosphonate and diethyl (2-methoxy-
ethoxy)methylphosphonate gave a different product, namely,
diethyl {1-methoxy(or methoxyethoxy)-2-[1-(toluene-4-sulfonyl)-
1H-pyrrol-3-yl]vinyl}phosphonates, respectively. (E)-3-[1-(Tolu-
ene-4-sulfonyl)-1H-pyrrol-3-yl]prop-2-enes were easily hydroly-
sed to (E)-3-(1H-pyrrol-3-yl)prop-2-enes, two of which are natural
products.
i
ii
H3CO
OCH3
O
N
Ts
1
2
R
R
iii
N
N
H
Key words: pyrroles, phosphonates, Horner–Wadsworth–Emmons
reaction
Ts
4
5
a, R = CO2H; b, R = CONH2; c, R = CONMe2; d, R = CO2Et;
e, R = COMe; f, R = CN
3-(1H-Pyrrol-3-yl)prop-2-enes are considered an impor-
tant class of chemical compounds because of their appli-
cation in the synthesis of a variety of molecules of
biological interest. For example they have been used for
the synthesis of several members of the pyrrolobenzodiaz-
epine family of anticancer antibiotics, of certain ana-
logues of porphobilinogen that constitute the major
structural component of all naturally occurring porphy-
rins, and of analogues of various amino acids.1 Despite
these reports, 3-(1H-pyrrol-3-yl)prop-2-enes have not yet
been studied thoroughly.
Scheme 1 Reagents and conditions: (i) TsNH2, TsOH, toluene, re-
flux, 3 h; (ii) (a) 95% NaH, t-BuOK or LDA (Table 1), THF, –40 °C
(or –78 °C when LDA used); (b) phosphonate 3a–e or f, THF, –40 to
0 °C, then –40 °C; (c) aldehyde 2, THF, 0 – 5 °C; (d) aq sat. NH4Cl;
(iii) K2CO3, MeOH, r.t. 18 h.
5d using phosphonate ester 3d (Table 1) and 1H-pyrrole-
3-carbaldehyde. The ester 5d was hydrolyzed to the acid
5a and then used to synthesise N-[4-(4-benzhydrylpiper-
azin-1-yl)butyl]-3-(1H-pyrrol-3-yl)acrylamide.
Keller-Schierlein and co-workers2 described the isolation
of propenoic acid 5a and of propenamide 5b from Strep-
tomyces parvulus (Scheme 1). Larsen and Hjeds3 synthe-
sised 5a by performing initially a Doebner condensation
between methyl 3-formyl-1H-pyrrole-1-carboxylate and
malonic acid, followed by basic hydrolysis. The amide 5b
was synthesised by Keller-Schierlein and co-workers2 by
the action of ammonia on the acid chloride of compound
5a. The first application of organophosphorus chemistry
towards the synthesis of this type of compounds was
described by Magnus4 who synthesised methyl 4-[(E)-3-
(benzyloxy)-3-oxoprop-1-enyl]-1-(toluene-4-sulfonyl)-
1H-pyrrole-2-carboxylate by reacting the anion of phos-
phonate ester (EtO)2P(O)CH2CO2Bn with methyl 4-
formyl-1-(toluene-4-sulfonyl)-1H-pyrrole-2-carboxylate.
Nishikawa5 followed a similar methodology to synthesise
Considering the advantages of the Horner–Wadsworth–
Emmons (HWE) reaction over the Wittig reaction6, we
chose phosphonates 3a–f (Table 1) as substrates and stud-
ied the reaction of their anions with carbaldehyde 2
(Scheme 1). A search in the literature revealed that 1H-
pyrrole-3-carbaldehydes have been synthesised by eight
routes, which are the acid-catalysed isomerisation of 1H-
pyrrole-2-carbaldehydes,7 Vilsmeier–Haack formylation
or Friedel–Crafts acylation at position 4 of 2-substituted
1H-pyrroles followed by removal of the deactivating sub-
stituent,8 Vilsmeier–Haack formylation of 1-(triisopro-
pylsilyl)-1H-pyrrole and then removal of the bulky
trialkylsilyl moiety,9 Friedel–Crafts acetylation of 1-(ar-
ylsufonyl)-1H-pyrrole followed by transformation of
acetyl to formyl,10 and reaction of commercially available
2,5-dimethoxytetrahydrofuran-3-carbaldehyde with pri-
mary amines.11a In the latter reaction Hamdan and
Wasley11b used benzenesulfonamide in boiling acetic acid
and obtained 1-benzenesulfonyl-1H-pyrrole-3-carbalde-
hyde in 53% yield. Heating the latter in methanol contain-
SYNTHESIS 2006, No. 9, pp 1494–1498
x
x
.
x
x
.2
0
0
6
Advanced online publication: 11.04.2006
DOI: 10.1055/s-2006-926426; Art ID: P14105SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of (E)-3-(1H-Pyrrol-3-yl)prop-2-ene Derivatives
1495
Table 1 Conversion of 1-Tosyl-1H-pyrrole-3-carbaldehyde 2 into Olefins 4a–f or 10a,b
Entry
Phosphonate
Base (equiv)
LDA (2)
Time (h)
Product
4a
Yield (%)a
1
2
3
4
5
6
7
8
(EtO)2P(O)CH2CO2H (3a)
(EtO)2P(O)CH2CONH2 (3b)
(EtO)2P(O)CH2CONMe2 (3c)
(EtO)2P(O)CH2CO2Et (3d)
(EtO)2P(O)CH2COMe (3e)
(EtO)2P(O)CH2CN (3f)
12
12
0.5
0.5
12
12
4
67
58
82
74
88
76
44
39
t-BuOK (2)
NaH (1.2)
NaH (1.2)
NaH (1.1)
NaH (1.1)
LDA (1.2)
LDA (1.2)
4b
4c
4d
4e
4f
(EtO)2P(O)CH2OMe (3g)
(EtO)2P(O)CH2O(CH2)2OMe (3h)
10a
10b
4
a Yields of isolated products.
ing potassium carbonate afforded 1H-pyrrole-3- b-hydroxyphosphonates, that were then treated with t-
carbaldehyde in excellent yield. We found it more conve- BuOK.
nient to heat 2,5-dimethoxytetrahydrofuran-3-carbalde-
hyde in toluene with 4-toluenesulfonamide and a catalytic
amount of 4-toluenesulfonic acid since the product, 2
(Scheme 1) was isolated in 72% yield.
Unexpected results were obtained when phosphonate 3g
or 3h was treated with LDA (1.2 equiv) in THF at –78 °C,
pyrrole-3-carbaldehyde 2 added, and then the reaction
mixture allowed to reach room temperature before being
Pyrrole 2 was preferred over 1H-pyrrole-3-carbaldehyde heated to reflux for four hours. The work-up involved the
for the HWE reaction because only a single step is re- addition of an aqueous solution of NaHCO3 that gave in-
quired for its preparation. Moreover, the tosyl group of stead of the corresponding enol ethers 8, the vinylphos-
pyrrole 2 confers stability to the pyrrole ring, neutralises phonates 10a,b (Scheme 2).
its acidic nature, and, activates the formyl group into un-
dergoing addition reactions under milder conditions.
Phosphonates 3c12 and e13 were easily prepared by the ylphosphonate with two equivalents of LDA and diethyl
Michaelis–Arbuzov reaction between triethylphosphite chlorophosphate to give an intermediate methylenebis-
and the corresponding alkyl halides in good yields, where-
Only one similar reaction has been reported in the litera-
ture, namely the treatment of diethyl a-benzyloxymeth-
as phosphonates 3a,b,d and f were commercially avail-
able (Table 1).
O
P(O)(OEt)2
H
OR1
H
Treatment of phosphonates 3c,d,e and f with a slight ex-
cess of NaH (1.1–1.2 equiv) lead to the corresponding
monocarbanions whereas treatment of 3a with LDA (2
equiv) or 3b with t-BuOK (2 equiv) lead to the corre-
sponding dicarbanions. Addition of a solution of aldehyde
2 to these anions and reaction at room temperature for 0.5
to 12 hours led to propenoates 4a–f in moderate to good
yields (Scheme 1, Table 1). Compound 4c which is
formed in excellent yield, is a potential key intermediate
for the synthesis of unsaturated analogues of porothramy-
cin.14 The reactions are stereoselective and only the E-iso-
mers of compounds 4a–f were obtained since in 1H NMR
spectra of these compounds the two vinylic protons ap-
pear as doublets with J values of 15–16 Hz.
It has been reported by Kluge and Clousdale15 that when
phosphonates 3 (R1 = alkyl or silyl) (Scheme 2) were
treated with LDA and then the resulting non-stabilised
carbanions reacted with aldehydes or ketones, the formed
intermediate, i.e. deprotonated b-hydroxyphosphonates 6,
could be converted into enol ethers 8, in either one step by
heating to reflux or in two steps by adding water to give
H
OR1
H
R2
R2
8
7
1. LDA
LiO
P(O)(OEt)2
2. R2CHO
(RO)2P(O)CH2OR1
H
OR1
H
R2
3
6
R1 = Me or (CH2)2OMe
R
2 = 1-tosyl-1H-pyrrol-3-yl
Li
H
OR1
OR1
P(O)(OEt)2
O
H
N
P(O)(OEt)2
H
N
Ts
Ts
10a R1 = Me
10b R1 = (CH2)2OMe
9
Scheme 2
Synthesis 2006, No. 9, 1494–1498 © Thieme Stuttgart · New York

1496
N. Karousis et al.
PAPER
(E)-3-[1-(Toluene-4-sulfonyl)-1H-pyrrol-3-yl]-2-propene De-
phosphonate lithium salt, which reacted with formalde-
hyde to afford diethyl a-benzyloxyvinylphosphonate.16
The mechanistic explanation we propose for the unusual
outcome of the reaction between alkoxymethylphospho-
nates 3g,h and aldehyde 2 is as follows. In the first step the
deprotonated phosphonate 3 adds to the carbonyl group to
give intermediate lithium alkoxide 6. In the normal HWE-
reaction the enol ether 8 is formed via a four-membered
transition state 7 and elimination of diethyl phosphate. In
the case of a-alkoxy-substituted phosphonates 3g,h the
primary adduct 6 can be expected to exist as conformation
9, where chelation of the Li-cation by the a-alkoxy group
is possible. This prevents the formation of a four-mem-
rivatives 4a–f and Diethyl {1-Alkoxy-2-[1-(toluene-4-sulfonyl)-
1H-pyrrol-3-yl]vinyl}phosphonates 10a,b; General Procedure
The appropriate base [95% NaH, t-BuOK or LDA (prepared from
diisopropylamine and 1.5 M n-BuLi in hexane), 14.4 to 30 mmol,
Table 1] was suspended in anhyd THF (10 mL) under argon, and
cooled to –40 °C (or –78 °C when LDA used). A solution of phos-
phonate 3 (12 mmol) in anhyd THF (15 mL) kept at the same tem-
perature, was added dropwise. The stirred mixture was allowed to
warm to 0 °C and then cooled again to –40 °C before adding drop-
wise a solution of 2 (10.9 mmol) in anhyd THF (15 mL). The mix-
ture was stirred for the allocated time (Table 1) while the
temperature was maintained at 0–5 °C and then poured into aq sat.
NH4Cl solution (50 mL) [or the mixture was allowed to reach r.t. be-
fore being refluxed for 4 h, and then poured into a sat. aq solution
bered intermediate 7 leading to enol ethers 8. Thus b- of NaHCO3 (50 mL) for 3g,h]. The organic layer was separated and
the aqueous layer extracted with CH2Cl2 (3 × 15 mL) [or extracted
with EtOAc (3 × 15 mL) for 3g,h]. The combined organic extracts
were washed with brine (25 mL) and dried (Na2SO4). The organic
solvents were evaporated under vacuo and the crude product puri-
fied either by recrystallisation or by column chromatography. Reac-
tion conditions are given in Table 1.
elimination of LiOH from 9 occurs similarly to an aldol
condensation resulting in a-alkoxy substituted vinylphos-
phonates 10a,b. The difference in the outcome of the re-
action of the alkoxymethylphosphonates 3 with 1-
(toluene-4-sulfonyl)-1H-pyrrole-3-carbaldehyde 2 (for-
mation of 10) on one hand and with aliphatic and aromatic
aldehydes or ketones in the other (formation of 8), is ob-
viously attributed to the effect of the toluene-4-sulfonyl
substituent of 2.
(E)-3-[1-(Toluene-4-sulfonyl)-1H-pyrrol-3-yl]prop-2-enoic
Acid (4a)
Obtained as yellow microcrystals (EtOAc–hexane, 1:4); yield: 2.14
g (67%); mp 184–185 °C.
In conclusion, we have presented a short, efficient synthe-
sis of 1-(toluene-4-sulfonyl)-1H-pyrrole-3-carbaldehyde
and an efficient method for the preparation of (E)-3-[1-
(toluene-4-sulfonyl)-1H-pyrrol-3-yl]prop-2-ene deriva-
tives, by reacting 1-(toluene-4-sulfonyl)-1H-pyrrole-3-
carbaldehyde with appropriate phophonates. The reaction
of 1-(toluene-4-sulfonyl)-1H-pyrrole-3-carbaldehyde with
diethyl methoxymethylphosphonate or diethyl methoxy-
ethoxymethylphophonate did not give the expected enol
ethers but the corresponding vinylphosphonic acid diethyl
esters by a type of aldol condensation, for which a mech-
anistic interpretation is proposed.
IR (Nujol): 1690, 1340, 1150 cm–1.
1H NMR (250 MHz, CDCl3): d = 2.37 (s, 3 H, CH3), 6.23 (d,
J = 15.9 Hz, 1 H, H-a), 6.77 (t, J = 2.8 Hz, 1 H, H-4), 7.37 (dd,
J = 3.3, 1.5 Hz, 1 H, H-5), 7.42 (d, J = 15.9 Hz, 1 H, H-b), 7.45 (d,
J = 8.3 Hz, 2 H, H-3¢, H-5¢), 7.78 (br s, 1 H, H-2) 7.86 (d, J = 8.3
Hz, 2 H, H-2¢, H-6¢), 12.21 (s, 1 H, OH).
13C NMR (63 MHz, CDCl3): d = 21.1, 111.8, 118.4, 122.7, 123.2,
124.9, 126.9 (d), 130.4 (d), 134.8, 136.2, 145.8, 167.7.
MS (EI, 70 eV): m/z (%) = 292 (19), 291 (100, [M+]), 155 (5), 139
(6), 136 (8), 119 (17).
HRMS-EI: m/z calcd for C14H13NO4S [M+]: 291.0565; found:
291.0561.
(E)-3-[1-(Toluene-4-sulfonyl)-1H-pyrrol-3-yl]prop-2-enamide
(4b)
Obtained as colourless solid after column chromatography (EtOAc–
hexane, 1:2 to 1:0) and recrystallisation (EtOAc–hexane, 1:2);
yield: 1.83 g (58%); mp 195–196 °C.
Melting points were taken on a Büchi 510 apparatus and are uncor-
rected. IR spectra were recorded on a Perkin-Elmer 257 spectrome-
ter, as Nujol mulls and liquids between NaCl discs. NMR spectra
were measured at 300 MHz on Bruker AC 300 spectrometer, at 250
MHz on a Bruker AM 250 spectrometer or at 400 MHz on a Bruker
AMX 400 spectrometer using tetramethylsilane as internal stan-
dard. Mass spectra were obtained using a JEOL JMS-AX 505W or
a Bruker Apex III high resolution instruments Analytical TLC was
carried out on Fluka silica gel 60 F254. Preparative flash chromatog-
raphy was carried out for all separations using Merck 9385 silica
gel. Solvents and reagents were used as received from commercial
suppliers, except for CH2Cl2, MeOH, THF, EtOAc and hexane,
which were purified and dried according to standard procedures.
IR (Nujol): 3320, 3120, 1670, 1340, 1150 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.41 (s, 3 H, CH3), 5.71 (br s, 2 H,
NH2), 6.16 (d, J = 15.5 Hz, 1 H, H-a), 6.45 (dd, J = 3.3, 1.5 Hz, 1
H, H-4), 7.13 (t, J = 2.8 Hz 1 H, H-5), 7.29–7.31 (m, 3 H, H-3, H-
3¢, H-5¢), 7.45 (d, J = 15.5 Hz, 1 H, H-b), 7.75 (d, J = 8.3 Hz, 2 H,
H-2¢, H-6¢).
13C NMR (75 MHz, CDCl3): d = 20.9, 111.7, 117.9, 123.1, 123.9,
125.4, 126.8 (d), 130.2 (d), 134.4, 136.7, 146.1, 168.1.
1-(Toluene-4-sulfonyl)-1H-pyrrole-3-carbaldehyde (2)
MS (EI, 70 eV): m/z (%) = 290 (48, [M+]), 234 (12), 155 (14), 135
2,5-Dimethoxytetrahydrofuran-3-carbaldehyde (9.61 g, 60 mmol)
was added dropwise to a stirred solution of 4-toluenesulfonamide
(10.27 g, 60 mmol) and 4-toluenesulfonic acid (1.14 g, 6 mmol) in
anhyd toluene (100 mL). The resulting mixture was refluxed for 3
h. After cooling, the mixture was diluted with EtOAc (125 mL) and
washed with aq 10% NaHCO3 (3 × 25 mL), brine (25 mL) and then
dried (Na2SO4). Evaporation of the solvent in vacuo followed by re-
crystallisation of the residual solid from Et2O–hexane (1:3) gave the
product (10.8 g, 72%); mp 62–62.5 °C (Lit.17 mp 61–62 °C).
(100), 108 (15), 91 (75), 65 (18).
HRMS-EI: m/z calcd for C14H14N2O3S [M+]: 290.0725; found:
290.0725.
(E)-N,N-Dimethyl-3-[1-(toluene-4-sulfonyl)-1H-pyrrol-3-
yl]prop-2-enamide (4c)
Obtained as colourless solid after column chromatography (EtOAc–
hexane, 1:4 to 9:1) and recrystallisation (EtOAc–hexane, 3:7);
yield: 2.43 g (82%); mp 139–140 °C.
Synthesis 2006, No. 9, 1494–1498 © Thieme Stuttgart · New York

PAPER
Synthesis of (E)-3-(1H-Pyrrol-3-yl)prop-2-ene Derivatives
1497
IR (Nujol): 1670, 1340, 1150 cm–1.
MS (EI, 70 eV): m/z (%) = 272 (45, [M+]), 221 (30), 155 (67), 125
(13), 111 (22), 91 (100), 71 (28), 55 (26).
HRMS-EI: m/z calcd for C14H12N2O2S [M+]: 272.0619; found:
272.0612.
1H NMR (300 MHz, CDCl3): d = 2.33 (s, 3 H, tosyl CH3), 2.95 (s,
3 H, amide CH3), 3.03 (s, 3 H, amide CH3), 6.40 (dd, J = 3.3, 1.5
Hz, 1 H, H-4), 6.51 (d, J = 15.3 Hz, 1 H, H-a), 7.05 (dd, J = 3.3, 2.6
Hz, 1 H, H-5), 7.19–7.24 (m, 3 H, H-2, H-3¢, H-5¢), 7.38 (d, J = 15.3
Hz, 1 H, H-b), 7.68 (d, J = 8.4 Hz, 2 H, H-2¢, H-6¢).
13C NMR (75 MHz, CDCl3): d = 21.6, 35.8, 37.3, 111.2, 116.8,
121.5, 122.1, 125.7, 126.9 (d), 130.1 (d), 134.0, 135.6, 145.4, 166.6.
MS (EI, 70 eV): m/z (%) = 318 (48, [M+]), 274 (72), 229 (11), 180
(21), 163 (100), 91 (32).
HRMS-EI: m/z calcd for C16H18N2O3S [M+]: 318.1038; found:
318.1042.
Diethyl {1-Methoxy-2-[1-(toluene-4-sulfonyl)-1H-pyrrol-3-
yl]vinyl}phosphonate (10a)
Obtained as yellow microcrystals after column chromatography
(EtOAc–hexane, 1:1 to 1.0) and recrystallisation (EtOAc–hexane,
1:1); yield: 1.98 g (44%); mp 100–102 °C.
IR (Nujol): 1640, 1340, 1150 cm–1.
1H NMR (250 MHz, CDCl3): d = 1.15–1.91 (m, 6 H, 2 × OCH2CH3),
2.37 (s, 3 H, tosyl CH3), 3.81 (s, 3 H, OCH3), 4.05–4.20 (m, 4 H,
2 × OCH2Me), 6.53 (s, 1 H, H-4), 6.58 (d, J = 10.3 Hz, 1 H, H-a),
7.10 (s, 1 H, H-5), 7.29 (d, J = 8.1 Hz, 2 H, H-3¢, H-5¢), 7.46 (s, 1
H, H-2), 7.75 (d, J = 8.1 Hz, 2 H, H-2¢, H-6¢).
13C NMR (63 MHz, CDCl3): d = 16.2 (d), 20.8, 58.9, 62.3 (d),
109.9, 114.6, 120.1, 120.8, 121.4, 126.9 (d), 130.0 (d), 135.2, 142.9,
145.2.
MS (EI, 70 eV): m/z (%) = 413 (100, [M+]), 306 (10), 278 (19), 258
(21), 248 (34), 202 (57), 155 (31), 138 (19), 106 (21), 91 (61), 65
(32).
HRMS-EI: m/z calcd for C18H24NO6PS [M+]: 413.0990; found:
413.0983.
Ethyl (E)-3-[1-(Toluene-4-sulfonyl)-1H-pyrrol-3-yl]prop-2-
enoate (4d)
Obtained as colourless solid after column chromatography (EtOAc–
hexane, 1:4 to 9:1) and recrystallisation (EtOAc–hexane, 1:4);
yield: 2.57 g (74%); mp 108–109 °C.
IR (Nujol): 1720, 1340, 1150 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.30 (t, J = 7.1 Hz, 3 H, ester CH3),
2.41 (s, 3 H, tosyl CH3), 4.24 (q, J = 7.1 Hz, 2 H, ester CH2), 6.13
(d, J = 15.8 Hz, 1 H, H-a), 6.48 (dd, J = 3.3, 1.5 Hz, 1 H, H-4), 7.15
(dd, J = 3.3, 2.6 Hz, 1 H, H-5), 7.31–7.33 (m, 3 H, H-2, H-3¢, H-5¢),
7.48 (d, J = 15.8 Hz, 1 H, H-b), 7.77 (d, J = 8.2 Hz, 2 H, H-2¢, H-6¢).
13C NMR (100 MHz, CDCl3): d = 14.3, 21.1, 59.9, 111.8, 118.4,
Diethyl {1-Methoxyethoxy-2-[1-(toluene-4-sulfonyl)-1H-pyrrol-
3-yl]vinyl}phosphonate (10b)
Obtained as an oil after column chromatography (EtOAc–hexane,
1:4 to 1.2); yield: 1.94 g (39%).
IR (Nujol): 1635, 1340, 1150 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.34 (t, J = 1.2 Hz, 6 H,
2 × CH2CH3), 2.39 (s, 1 H, tosyl CH3), 3.45 (s, 1 H, OCH3), 3.66 (t,
J = 4.2 Hz, 2 H, CH2OMe), 4.09–4.17 (m, 6 H, 3 × OCH2), 6.56 (s,
1 H, H-4), 6.60 (s, 1 H, CH=), 7.09 (dd, J = 3.2, 2.4 Hz, 1 H, H-5),
7.28 (d, J = 8.5 Hz, 2 H, H-3¢, H-5¢), 7.77 (d, J = 8.5 Hz, 2 H, H-2¢,
H-6¢), 7.80 (s, 1 H, H-2).
13C NMR (100.6 MHz, CDCl3): d = 16.8 (d), 22.1, 59.4, 62.8 (d),
70.8, 72.1, 115.3, 121.1, 121.7, 122.0, 122.3, 122.9, 127.5 (d), 130.5
(d), 136.3, 145.6.
122.7, 123.2, 124.9, 126.9 (d), 130.4 (d), 134.8, 136.2, 145.8, 168.6.
MS (EI, 70 eV): m/z (%) = 319 (100, [M+]), 274 (49), 247 (21), 155
(63), 135 (26), 119 (23), 118 (20), 91 (87).
HRMS-EI: m/z calcd for C16H17NO4S [M+]: 319.0876; found:
319.0868.
(E)-4-[1-(Toluene-4-sulfonyl)-1H-pyrrol-3-yl]but-3-en-2-one
(4e)
Obtained as colourless microcrystals (EtOAc–hexane, 3:7); yield:
3.05 g (88%); mp 93–94 °C.
IR (Nujol): 1680, 1660, 1340, 1150 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.29 (s, 3 H, CH3), 2.41 (s, 3 H,
CH3), 6.41 (d, J = 16.1 Hz, 1 H, H-a), 6.48 (d, J = 2.6 Hz, 1 H, H-
4), 7.15 (s, 1 H, H-5), 7.31 (d, J = 8.1 Hz, 2 H, H-3¢, H-5¢), 7.33 (d,
J = 16.1 Hz, 1 H, H-b), 7.36 (s, 1 H, H-2), 7.76 (d, J = 8.2 Hz, 2 H,
H-2¢, H-6¢).
13C NMR (100 MHz, CDCl3): d = 14.3, 21.1, 111.8, 118.4, 122.7,
123.2, 124.9, 126.9 (d), 130.4 (d), 134.8, 136.2, 145.8, 168.6.
MS (EI, 70 eV): m/z (%) = 457 (61, [M+]), 412 (3), 370 (4), 261
(100), 244 (5), 214 (3), 164 (3), 106 (6).
HRMS-EI: m/z calcd for C20H28NO7PS [M+]: 457.1324; found:
457.1318.
MS (EI, 70 eV): m/z (%) = 289 (65, [M+]), 274 (41), 155 (42), 134
(51), 114 (28), 100 (28), 95 (24), 91 (100), 57 (26), 51 (35).
HRMS-EI: m/z calcd for C15H15NO3S [M+]: 289.0773; found:
289.0772.
Detosylation of (E)-3-(1H-Pyrrol-3-yl)prop-2-ene Derivatives
5a–d,f; General Procedure
A solution of 5 (10 mmol) and K2CO3 (50 mmol) in anhyd MeOH
(30 mL) was stirred under argon at r.t. for 18 h. The mixture was
poured into ice-water (150 mL) and the pH adjusted to 6–7 with 1
N HCl. The mixture was extracted with EtOAc (3 × 25 mL), washed
with brine (50 mL) and dried (Na2SO4). The solvent was removed
under vacuo and the crude product was purified by recrystallisation.
(E)-3-[1-(Toluene-4-sulfonyl)-1H-pyrrol-3-yl]prop-2-enenitrile
(4f)
Obtained as colourless solid after column chromatography (EtOAc–
hexane, 1:4 to 9:1) and recrystallisation (EtOAc–hexane, 1:2);
yield: 2.40 g (76%); mp 120–122 °C.
(E)-3-(1H-Pyrrol-3-yl)prop-2-enoic Acid (5a)
Yield: 1.22 g (89%); mp 179–180 °C (Lit.2 mp 180–182 °C).
IR (Nujol): 2250, 1340, 1150 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.42 (s, 3 H, CH3), 5.54 (d,
J = 16.4 Hz, 1 H, H-a), 6.41 (s, 1 H, H-4), 7.15 (s, 1 H, H-2), 7.18
(d, J = 16.4 Hz, 1 H, H-b), 7.33 (m, 3 H, H-5, H-3¢, H-5¢), 7.77 (d,
J = 8.1 Hz, 2 H, H-2¢, H-6¢).
13C NMR (100.6 MHz, CDCl3): d = 21.6, 95.1, 110.0, 122.0 122.1,
122.6, 124.2, 127.1 (d), 130.3 (d), 135.2, 142.2, 145.8.
(E)-3-(1H-Pyrrol-3-yl)prop-2-enamide (5b)
Yield: 1.27 g (93%); mp 143–144 °C (Lit.2 mp 141–142 °C).
(E)-N,N-Dimethyl-3-(1H-pyrrol-3-yl)prop-2-enamide (5c)
Obtained as pale-yellow microcrystals (EtOAc–hexane, 1:1); yield:
1.44 g (88%); mp 171–173 °C.
IR (Nujol): 3400, 1670 cm–1.
Synthesis 2006, No. 9, 1494–1498 © Thieme Stuttgart · New York

1498
N. Karousis et al.
PAPER
1H NMR (300 MHz, CDCl3): d = 2.97 (s, 3 H, CH3), 3.06 (s, 3 H,
CH3), 6.36 (s, 1 H, H-4), 6.47 (d, J = 15.1 Hz, 1 H, H-a), 6.69 (s, 1
H, H-5), 6.89 (s, 1 H, H-2), 7.55 (d, J = 15.1 Hz,1 H, H-b), 9.19 (br
s, 1 H, NH).
13C NMR (75 MHz, CDCl3): d = 35.91, 37.38, 105.80, 112.10,
119.91, 121.08, 121.41, 136.96, 168.02.
(11072/16-10-97) and partly by a PENED grant (15815/29-12-95),
from the General Secretariat of Research and Technology, Athens.
We are particularly grateful to A. Cakebread and R. Tye, King’s
College London, for mass spectra obtained on machines funded by
the University of London, and Schering AG, Berlin, Germany for
technical support.
MS (EI, 70 eV): m/z (%) = 164 (28, [M+]), 121 (28), 120 (100), 92
(50), 65 (25), 39 (13).
HRMS-EI: m/z calcd for C9H12N2O [M+]: 164.0950; found:
References
(1) Gribble, G. W. In Comprehensive Heterocyclic Chemistry
II, Vol. 2; Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V.,
Eds.; Pergamon: Oxford, 1996, 207.
(2) Keller-Schierlein, W.; Muller, A.; Hagmann, L.; Schneider,
U.; Zahner, H. Helv. Chim. Acta 1985, 68, 559.
(3) Labouta, I. M.; Jacobsen, P.; Thorbek, P.; Krogsgaard-
Larsen, P.; Hjeds, H. Acta Chem. Scand. B 1982, 36, 669.
(4) Carter, P.; Fitzjohn, S.; Halazy, S.; Magnus, P. J. Am. Chem.
Soc. 1987, 109, 2711.
164.0946.
Ethyl (E)-3-(1H-Pyrrol-3-yl)prop-2-enacetate (5d)
Obtained as colourless oil after column chromatography (EtOAc–
hexane, 1:4 to 1:1); yield: 1.58 g (95%).
IR (Neat): 3150, 1720, 1340 cm–1.
1H NMR (250 MHz, CDCl3): d = 1.34 (t, J = 7.1 Hz, 3 H, ester CH3),
4.22 (q, J = 7.1 Hz, 2 H, ester CH2), 6.12 (d, J = 15.8 Hz, 1 H, H-a),
6.46 (dd, J = 3.8, 2.5 Hz, 1 H, H-4), 6.78 (d, J = 2.5 Hz, H-2) 7.02
(dd, J = 3.8, 2.5 Hz, 1 H, H-5), 7.66 (d, J = 15.8 Hz, 1 H, H-b), 8.75
(br s, 1 H, NH).
13C NMR (62.9 MHz, CDCl3): d = 14.4, 60.1, 106.5, 113.3, 120.1,
120.7, 121.6, 139.1, 168.3.
MS (EI, 70 eV): m/z (%) = 165 (87, [M+]), 120 (100), 92 (27), 65
(12), 43 (9).
(5) Nishikawa, Y.; Shindo, T.; Ishii, K.; Nakamura, H.; Kon, T.;
Uno, H. Chem. Pharm. Bull. 1989, 37, 684.
(6) Gosney, I.; Rowley, A. G. In Organophosphorus Reagents
in Organic Synthesis; Cadogan, J. I. G., Ed.; Academic
Press: London, 1979, 17–153.
(7) Carson, J. R.; Davis, N. M. J. Org. Chem. 1981, 46, 839.
(8) (a) Anderson, H. J.; Clase, A.; Loader, C. E. Synth. Commun.
1987, 17, 401. (b) Demopoulos, V. Org. Prep. Proced. Int.
1986, 18, 278.
(9) Bray, B. L.; Mathies, P. H.; Naef, R.; Solas, D. R.; Tidwell,
T. T.; Artis, D. R.; Muchowski, J. M. J. Org. Chem. 1990,
55, 6317.
(10) (a) Kakushima, M.; Hamel, P.; Frennete, R.; Rokach, J. J.
Org. Chem. 1983, 48, 3214. (b) Xiao, D.; Ketcha, D. M.
Org. Prep. Proced. Int. 1995, 27, 503.
(11) (a) Plieninger, H.; El Berins, R.; Hirsch, R. Synthesis 1973,
422. (b) Hamdan, A.; Wasley, J. W. F. Synth. Commun.
1983, 13, 741.
(12) Landor, P. D.; Landor, S. R.; Odyek, O. J. Chem. Soc.,
Perkin Trans. 1 1977, 93.
(13) Dawson, N. D.; Burger, A. J. Am. Chem. Soc. 1952, 74,
5312.
(14) Tsunkawa, M.; Kamei, H.; Konishi, M.; Miyaki, T.; Oki, T.;
Kawagushi, H. J. Antibiot. 1988, 41, 1366.
HRMS-ESI: m/z calcd for C9H11NO2 + Na [M +Na]+: 188.0687;
found: 188.0686.
(E)-3-(1H-Pyrrol-3-yl)prop-2-enenitrile (5f)
Obtained as a light-brown solid; yield: 1.11 g (94%); mp 106–108
°C.
IR (Nujol): 3380, 2250 cm–1.
1H NMR (300 MHz, CDCl3): d = 5.49 (d, J = 16.3 Hz, 1 H, H-a),
6.41 (dd, J = 4.0, 2.6 Hz, 1 H, H-4), 6.82 (d, J = 2.5 Hz, 1 H, H-5),
7.02 (dd, J = 4.0, 2.6 Hz, 1 H, H-2), 7.34 (d, J = 16.3 Hz, 1 H, H-b),
8.77 (br s, 1 H, NH).
13C NMR (75 MHz, CDCl3): d = 90.0, 105.6, 119.6, 120.3, 120.4,
121.4, 144.7.
MS (EI, 70 eV): m/z (%) = 118 (100, [M+]), 91 (19), 67 (19), 50 (4).
HRMS-EI: m/z calcd for C7H6N2 [M+]: 118.0531; found: 118.0529.
(15) Kluge, A. F.; Clousdale, I. S. J. Org. Chem. 1979, 44, 4847.
(16) Ruiz, M.; Fernandez, M. C.; Diaz, A.; Quintela, J. M.; Ojea,
V. J. Org. Chem. 2003, 68, 7634.
(17) Demopoulos, V. J. Heterocycl. Chem. 1988, 25, 635.
Acknowledgment
This work supported by a grant within the framework of Joint Re-
search and Technology Projects between Greece and Germany
Synthesis 2006, No. 9, 1494–1498 © Thieme Stuttgart · New York