Novel synthesis of the pyrrolo[2,1-c][1,4]benzodiazocine ring system via a Dieckmann condensation

Article abstract of DOI:10.1016/j.tet.2008.07.029

A novel four-step synthesis to the pyrrolo[2,1-c][1,4]benzodiazocine ring system is described. 1H-Pyrrole-2-carbaldehyde was alkylated with ethyl or methyl bromoacetate and the resulting ethyl or methyl (2-formyl-1H-pyrrol-1-yl)acetates oxidised with potassium permanganate to the corresponding 1-[(2-ethoxy or methoxy)-2-oxoethyl]-1H-pyrrole-2-carboxylic acids. The latter was converted into their acid chlorides by reaction with thionyl chloride and without isolation transformed into the respective methyl 2-({[1-(2-ethoxy or methoxy-2-oxoethyl)-1H-pyrrol-2-yl]carbonyl}amino)benzoates by reaction with methyl anthranilate. Dieckmann condensation of methyl 2-({[1-(2-methoxy-2-oxoethyl)-1H-pyrrol-2-yl]carbonyl}amino)benzoate provided the pyrrolo[2,1-c][1,4]benzodiazocine.

Full text of DOI:10.1016/j.tet.2008.07.029

Tetrahedron 64 (2008) 10009–10013
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Novel synthesis of the pyrrolo[2,1-c][1,4]benzodiazocine ring system
via a Dieckmann condensation
*
Konstantina Koriatopoulou, Nikolaos Karousis, George Varvounis
Department of Chemistry, University of Ioannina, GR-451 10 Ioannina, Greece
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 May 2008
Received in revised form 25 June 2008
Accepted 10 July 2008
Available online 15 July 2008
A novel four-step synthesis to the pyrrolo[2,1-c][1,4]benzodiazocine ring system is described. 1H-Pyrrole-
2-carbaldehyde was alkylated with ethyl or methyl bromoacetate and the resulting ethyl or methyl
(2-formyl-1H-pyrrol-1-yl)acetates oxidised with potassium permanganate to the corresponding 1-[(2-
ethoxy or methoxy)-2-oxoethyl]-1H-pyrrole-2-carboxylic acids. The latter was converted into their acid
chlorides by reaction with thionyl chloride and without isolation transformed into the respective methyl
2-({[1-(2-ethoxy or methoxy-2-oxoethyl)-1H-pyrrol-2-yl]carbonyl}amino)benzoates by reaction with
methyl anthranilate. Dieckmann condensation of methyl 2-({[1-(2-methoxy-2-oxoethyl)-1H-pyrrol-2-
yl]carbonyl}amino)benzoate provided the pyrrolo[2,1-c][1,4]benzodiazocine.
Keywords:
Pyrroles
Oxidation
Dieckmann condensation
Pyrrolobenzodiazocine
Ó 2008 Published by Elsevier Ltd.
1. Introduction
character of these compounds. 3,8-Diazatricyclo[5.1.0.02,4]octanes
were prepared from cis-benzenetriimine by N,N0-disubstitution,
The addition of medium-sized rings containing two nitrogen
atoms as substituents in biologically active compounds is known
to increase the pharmaceutical potency of the compounds. One
example is the diazocine ring. The tethering of octahydro-1,4-diazo-
cines to guanidine has produced derivatives of superior anti-hy-
pertensive activity to that of guanidine.1 Several methods have been
employed for the synthesis of 1,4-diazocines. Sarges and Tretter2
nitrosation and N2O-elimination reactions. Their [
p
2sþ
s
2sþ
s2s]
cycloreversion to 1,4-dihydro-1,4-diazocines occurred at low
temperature.5 Reduction of N,N0-[(1E,2E)-1,2-diphenylethane-1,2-
diylidene]dianiline with sodium to the corresponding dianion
followed by substitution of 1,4-dichlorobutane gave directly
1,2,3,4-tetraphenyl-1,4,5,-6,7,8-hexahydro-1,4-diazocine. Three more
tetraaryl derivatives were synthesised in this manner.6
treated methyl
b
-bromomethyl-cinnamate with N,N0-dimethyl-
So far, three pyrrolobenzodiazocine ring systems are known.
Derivatives of 6,11-dihydropyrrolo[1,2-b][2,5]-benzodiazocine were
obtained by heating 1-{2-[(acyl-amino)methyl]benzyl}pyrroles
with phosphoryl chloride.7 (2-Nitrophenyl)acetyl chloride, gener-
ated in situfrom(2-nitrophenyl)acetic acidandthionylchloride, was
reacted with proline or 3-hydroxyproline to give (4-unsubstituted
or 4-hydroxy)-1-[(2-nitrophenyl)acetyl]proline that was selectively
reduced to the aniline analogue. The latter was cyclised with dicyclo-
hexylcarbodiimide to give (2-unsubstituted or 2-hydroxy)-1,2,3,6,-
11,12a-hexahydropyrrolo[2,1-c][1,4]benzodiazocine-5,12-dione.8
[(3-Acetyl or 3-propionyl)-2-methyl-5-(2-nitrophenyl)-1H-pyrrol-
1-yl]-acetic acid underwent catalytic hydrogenation and the
5-amino derivative was cyclised by thionyl chloride to give (2-acetyl
or 2-propionyl)-3-methyl-5,6-dihydropyrrolo[1,2-e][1,5]benzodi-
azocin-7(8H)-one.9
ethylenediamine to give 1,4-dimethyl-2-phenylpiperidine-2-acetic
acid methyl ester, which, after hydrolysis to the corresponding acid
and treatment with triethylamine and dicyclohexylcarbodiimide,
was transformed into 1,4-dimethyl-7-phenyl-1,2,3,4-tetrahydro-
1,4-diazocin-5(8H)-one. The 7-naphthyl derivative was prepared
analogously. 1,4-Dibenzyl-octahydro[1,4]diazocine was prepared
by condensing N,N0-dibenzylethane-1,2-diamine with 1,3-dibromo-
propane.3 The first aromatic 1,4-diazocine derivatives were
synthesised by Vogel and co-workers4 in 1979. 3,8-Dioxatri-
cyclo[5.1.0.02,4]octane was transformed into 3,8-bis(methylsul-
fonyl)-3,8-diazatri-cyclo[5.1.0.02,4]oct-5-ene, which was thermally
ringexpanded to 1,4-bis(methylsulfonyl)-1,4-dihydro-1,4-diazocine
and the methylsulfonyl groups removed with potassium in liquid
ammonia to give the 1,4-dihydro-1,4-diazocine. NMR spectroscopy
and X-ray crystallography used to prove the 10p electron aromatic
2. Results and discussion
We have previously described the synthesis of 4,5-dihy-
dropyrrolo[1,2-b][2,5]benzodiazocin-6(11H)-imine or 6(11H)-one
* Corresponding author. Tel.: þ30 26510 98 382; fax: þ30 26510 98 799.
E-mail address: gvarvoun@cc.uoi.gr (G. Varvounis).
0040-4020/$ – see front matter Ó 2008 Published by Elsevier Ltd.
doi:10.1016/j.tet.2008.07.029

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K. Koriatopoulou et al. / Tetrahedron 64 (2008) 10009–10013
(erroneously described as pyrrolo[2,1-c][1,4]-benzodiazocines) by
the cyclisation of 2-{[2-(aminomethyl)-1H-pyrrol-1-yl]-methyl}-
benzonitrile or ethyl 2-{[2-(aminomethyl)-1H-pyrrol-1-yl]meth-
yl}benzoate, respectively, with ethanolic sodium methoxide.10 We
now present a novel synthesis of the pyrrolo[2,1-c][1,4]-benzo-
diazocine ring system 1 shown in Scheme 1. The interest in this ring
system stems from its close structural relation to the pharmaco-
logically important 1,4-benzo-diazepine CNS agents.11
an acetone–water mixture has been used successfully by Rapoport
and co-workers14 to oxidise methyl 4-formyl-1-methyl-1H-pyr-
role-2-carboxylate to 5-(methoxycarbonyl)-1-methyl-1H-pyrrole-
3-carboxylic acid in 88% yield. More recently, similar oxidative
conditions were used to convert 2-(2-formyl-1H-pyrrol-1-yl)thio-
phene-3-carbonitrile into 1-(3-cyanothiophen-2-yl)-1H-pyrrole-
2-carboxylic acid,15 and 1-(2-chloropyridin-3-yl)-1H-pyrrole-2-carb-
aldehyde into 1-(2-chloropyridin-3-yl)-1H-pyrrole-2-carboxylic
acid.16 For our purpose this entailed the N-alkylation of 1H-pyrrole-
2-carbaldehyde 8 with ethyl bromoacetate in acetone containing
K2CO3 to give ester 7a, followed by oxidation of 7a with potassium
permanganate in a 1:1 v/v ratio of acetone and water at room
temperature, to afford the acid 3a (Scheme 3). Compounds 7a and
3a were obtained in 83 and 81% yields, respectively. Similarly,
alkylation of aldehyde 8 with methyl bromoacetate gave ester 7b in
86% yield and then oxidation of 7b gave acid 3b in 83% yield. In the
1H NMR spectrum of 3a in CDCl3 the chemical shifts at 6.31, 6.98
and 7.56 ppm corresponding to H-4, H-3 and H-5 are all further
downfield than the respective chemical shifts of 3b in DMSO-d6 at
6.15, 6.86 and 7.12 ppm corresponding to the same protons. Fur-
thermore, the hydroxyl proton of 3b appears as a broad singlet at
12.25 ppm, while the signal due to the hydroxyl proton of 3a is very
broad and cannot be detected.
O
H
N
O
O
N
H
N
N
Cl3C
Cl3C
CO2Et
HO
CO2Me
6
5
1
H
N
O
NH2
CO2Me
N
N
HO
O
R
CO2Me
R
R
4
3
2
O
ii
i
OHC
OHC
N
N
N
H
OHC
OHC
(a) R = CO2Et
(b) R = CO2Me
HO
N
N
CO2R
3 (81–83%)
CO2R
7 (83–86%)
(a) R = Et, (b) R = Me
H
8
8
7
Scheme 1.
Scheme 3. Reagents and conditions: (i) BrCH2CO2Et or BrCH2CO2Me, K2CO3, acetone;
(ii) KMnO4, Me2CO, H2O.
Initially we chose trichloroacetylpyrrole 6 as starting material.
This compound was synthesised in 80% yield according to Bailey
and Anderson12 by reacting 1H-pyrrole with trichloroacetyl chlo-
ride. A literature search revealed only one example of N-alkylation
of pyrrole 6 that is with chloroacetone and K2CO3 in acetone as
solvent gave 3-methylpyrrolo[2,1-c][1,4]oxazin-1-one. The N-alkyl
intermediate was not isolated.13 In the first attempted synthesis
(Scheme 2) of 1H-pyrrole-2-carboxylic acid 3a, pyrrole 6 was
alkylated with ethyl bromoacetate in acetone in the presence of
K2CO3 to give unreacted starting material 6, trichloro-acetylpyrrolyl
ester 5a and ethoxycarbonylmethyl ester 9, in 46, 36 and 15% yields,
respectively. The use of DMF, DMSO or THF instead of acetone
as solvent resulted in lower yields of ester 5a. The selective hy-
drolysis of ester 5a with 2 M K2CO3 in acetone at room temperature
furnished acid 3a in 83% yield.
According to our retrosynthetic plan the next step involved the
acquisition of amides 2a,b. The first attempt to couple anthranilic
acid 4 with acids 3a,b using N,N0-dicyclohexylcarbodiimide as
coupling agent, failed. This reagent has been used successfully by
Molteni17 to couple 1-substitutedpyrrole-2-carboxylic acids with
phenyl hydrazine.
We have recently described the in situ conversion of 1-(2-
nitrophenyl)-1H-pyrrole-2-carboxylic acid with thionyl chloride
to its acid chloride and then reaction with aryl amines to yield
the corresponding N-aryl-1-(2-nitrophenyl)-1H-pyrrole-2-carbox-
amides.18 Applying this method the acids 3a,b (Scheme 4) were
heated with thionyl chloride for 1 h in order to generate in situ the
acid chlorides 10a,b. Excess thionyl chloride was removed and then
reaction with methyl anthranilate 4 took place in a 1:1 pyridine–
toluene mixture, at room temperature for 48 h. The corresponding
amides 2a,b were isolated in 57 and 64% yields, respectively.
O
O
O
i
+
N
H
N
H
N
O
Cl3C
Cl3C
O
O
CO2Et
EtO2C
i
N
N
9 (15%)
6
5a (36%)
HO
Cl
CO2R
CO2R
ii
10
3
ii
O
N
H
N
HO
CO2Et
3a (83%)
N
O
CO2R
CO2Me
(a) R = Et (65%), (b) R = Me (73%)
Scheme 2. Reagents and conditions: (i) BrCH2CO2Et, K2CO3, acetone; (ii) (a)
2
2 M K2CO3, acetone, (b) 2 M HCl.
Scheme 4. Reagents and conditions: (i) SOCl2, reflux; (ii) methyl anthranilate,
pyridine.
Since the acid 3a was obtained from pyrrole 6 in only 30% overall
yield, an alternative route was sought. Potassium permanganate in
In the key cyclisation step, compound 2b was converted into
pyrrolobenzodiazocine 1 by a Dieckmann condensation requiring

K. Koriatopoulou et al. / Tetrahedron 64 (2008) 10009–10013
10011
K2CO3 in DMSO at relatively high dilution. The first attempt in-
volved dropwise addition of a solution of 2b in DMSO to a sus-
pension of K2CO3 in DMSO at room temperature. TLC examination
of the reaction after 24 h revealed a very faint spot corresponding to
starting material and a new polar spot. No change occurred after
stirring for a further 64 h. When the reaction was repeated by
heating the suspension of K2CO3 in DMSO to 60 ꢀC while adding the
solution of 2b in DMSO dropwise and then stirring at that tem-
perature for 48 h, two new spots together with a very faint starting
material spot were detected by TLC. It is reasonable to assume that
the deprotonated transoid 2b overcomes the rotational barrier at
60 ꢀC and transforms to the deprotonated cisoid 11 so that cycli-
sation can take place to give pyrrolobenzodiazocine 12. The two
new spots detected by TLC are very likely to correspond to a tau-
tomeric mixture of pyrrolobenzodiazocines 12 and 1. In order to
isolate tautomer 1 the reaction mixture was cooled to 5 ꢀC and then
acidified with 2 M HCl to pH¼3–4. Stirring for 1 h at 5 ꢀC led to the
isolation of pyrrolobenzodiazocine 1 in 63% yield (Scheme 5).
acetate, hexane and methanol that were purified and dried
according to recommended procedures.19
4.1.1. Alkylation of 2,2,2-trichloro-1-(1H-pyrrol-2-yl)ethanone with
ethyl bromoacetate
To a stirred mixture of 2,2,2-trichloro-1-(1H-pyrrol-2-yl)etha-
none 6 (1.00 g, 5 mmol) and K2CO3 (1.38 g, 10.00 mmol) in dry
acetone (15 mL) under argon, a solution of ethyl bromoacetate (1.17 g,
7 mmol) in acetone (15 mL) was added dropwise over a period of
30 min. Stirring was continued at room temperature for 24 h, the
solvent was removed under reduced pressure, water (50 mL) was
added and then extracted with ethyl acetate (3ꢁ15 mL). The com-
bined organic extracts were washed with brine (15 mL), dried
(Na2SO4) and the solvent was evaporated under reduced pressure
to give an oily residue. The residue was subjected to flash column
chromatography on silica gel with [25% CH2Cl2/hexane] to give in
the first fraction starting material 6, in the second fraction ethyl
[2-(trichloroacetyl)-1H-pyrrol-1-yl]acetate 5a and in the third
fraction 2-ethoxy-2-oxoethyl 1H-pyrrole-2-carboxylate 9.
H
N
O
H
N
4.1.1.1. Ethyl [2-(trichloroacetyl)-1H-pyrrol-1-yl]acetate 5a. Yield
(0.51 g, 36%), as colourless microcrystals (ethyl acetate/hexane);
mp 71 ꢀC. [Found: C, 40.19; H, 3.35; N, 4.58. C10H10Cl3NO3 requires:
N
i
N
O
CO2Me
CO2Me
C, 40.23; H, 3.38; N, 4.69%.] nmax (Nujol) 1662, 1740 cmꢂ1
; dH
OMe
CO2Me
O
2b
(250 MHz, CDCl3) 1.78 (3H, t, J¼7.2 Hz, CH3), 4.26 (2H, q, J¼7.2 Hz,
CH2), 5.01 (2H, s, CH2), 6.31 (1H, dd, J¼4.0, 2.9 Hz, H-4), 6.99 (1H,
dd, J¼4.0, 1.7 Hz, H-3), 7.57 (1H, dd, J¼2.9, 1.7 Hz, H-5); dC (63 MHz,
CDCl3) 14.01, 51.77, 61.64, 95.23, 109.55, 121.76, 124.42, 133.56,
167.77, 179.18; m/z (EI) 297 (Mþ, 19), 234 (14), 180 (88), 152 (61), 142
(15), 124 (100), 94 (16%).
11
H
N
O
H
O
N
4.1.1.2. 2-Ethoxy-2-oxoethyl-1H-pyrrole-2-carboxylate 9. Yield (0.14 g,
N
N
15%), as a pale yellow oil; nmax (Nujol) 1554, 1665, 3355 cmꢂ1
; dH
O
CO2Me
HO
CO2Me
(250 MHz, DMSO-d6) 1.20 (3H, t, J¼7.1 Hz, CH3), 4.14 (2H, q, J¼7.1 Hz,
CH2), 4.79 (2H, s, CH2), 6.20 (1H, dd, J¼4.0, 2.9 Hz, H-4), 6.87 (1H,
dd, J¼4.0, 2.2 Hz, H-3), 7.14 (1H, dd, J¼2.9, 2.2 Hz, H-5), 12.01 (1H, br
s, NH); dC (63 MHz, DMSO-d6) 14.19, 60.47, 60.94, 109.99, 116.12,
121.07, 125.00, 159.84, 168.24; m/z (ESI) 197.8 [MþH]þ, 219.8
[MþNa]þ; HRMS (ESI): [MþH]þ, found 198.0759. C9H12NO4 requires
198.0766.
1 (63%)
12
Scheme 5. Reagents and conditions: (i) (a) DMSO, K2CO3, 24 h, (b) 60 ꢀC, 48 h, (c) 5 ꢀC,
2 M HCl, 1 h.
3. Conclusion
4.1.1.3. 1-(2-Ethoxy-2-oxoethyl)-1H-pyrrole-2-carboxylic acid 3a. To
a solution of ethyl [2-(trichloroacetyl)-1H-pyrrol-1-yl]acetate 5a
(0.50 g, 1.67 mmol) in acetone (10 mL) was added aqueous 2 M
K2CO3 (25 mL) and the mixture was stirred for 4 h at room tem-
perature. Acetone was removed under reduced pressure, the solu-
tion was acidified with aqueous 2 M HCl to pH 3 and then extracted
with ethyl acetate (3ꢁ15 mL). The combined organic extracts were
washed with brine (15 mL), dried (Na2SO4) and the solvent was
evaporated under reduced pressure to afford a residue that was
purified by flash chromatography (33% ethyl acetate/hexane) to
give compound 3a (0.27 g, 83%), as colourless microcrystals
In summary, we have developed a new and efficient four-step
synthetic route to the pyrrolo[2,1-c][1,4]benzodiazocine ring
system from commercially available 1H-pyrrole-2-carbaldehyde
and methyl anthranilate. The steps leading to the product involve
alkylation, carboxylic acid to acid chloride transformation,
amide formation via acyl substitution and finally Dieckmann
condensation.
4. Experimental
4.1. General methods
(propan-2-ol). Mp 156–157 ꢀC; nmax (Nujol) 1713, 3012 cmꢂ1
; dH
(250 MHz, CDCl3) 1.27 (3H, t, J¼7.2 Hz, CH3), 4.23 (2H, q, J¼7.2 Hz,
CH2), 5.01 (2H, s, CH2), 6.31 (1H, dd, J¼4.5, 2.5 Hz, H-4), 6.98 (1H,
dd, J¼4.5, 1.5 Hz, H-3), 7.56 (1H, dd, J¼2.5, 1.5 Hz, H-5); dC (63 MHz,
CDCl3) 14.01, 51.77, 61.64, 109.55, 121.76, 124.42, 133.56, 161.84,
167.77; m/z (ESI) 220 [MþNa]þ; HRMS (ESI): [MþNa]þ found
220.0580. C9H11NNaO4 requires 220.0585.
Melting points were taken on a Bu¨chi 510 apparatus and are
uncorrected. Infrared spectra were recorded on a Perkin–Elmer 257
spectrometer, as Nujol mulls between sodium chloride discs. Ele-
mental analyses were performed on a Carlo Erba 1106 elemental
analyser. Nuclear magnetic resonance spectra were measured on
Bru¨ker Avance 250 or 400 spectrometers, using tetramethylsilane
as internal standard. Mass spectra were obtained by use of JEOL
JMS-AX 505W (low and high resolution) and Bruker Apex III (high
resolution) instruments. Analytical TLC was carried out on Fluka
silica gel 60 F254. Preparative flash chromatography was carried out
using Merck 9385 silica gel. Solvents and reagents were used as
received from the manufacturers except for dichloromethane, ethyl
4.1.2. Preparation of ethyl or methyl (2-formyl-1H-pyrrol-1-yl)-
acetates 7a,b: general procedure A
To a stirred mixture of 1H-pyrrole-2-carbaldehyde 8 (1.00 g,
10.51 mmol) and K2CO3 (2.90 g, 21.02 mmol) in dry acetone
(15 mL) under argon, a solution of ethyl or methyl bromoacetate
(12 mmol) in dry acetone (15 mL) was added dropwise over

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K. Koriatopoulou et al. / Tetrahedron 64 (2008) 10009–10013
a period of 30 min. The reaction mixture was left to stir at room
temperature for 18 h and then the solvent was evaporated under
reduced pressure. Water (50 mL) was added to the residue and
then extracted with ethyl acetate (3ꢁ15 mL). The combined or-
ganic extracts were washed with brine (15 mL), dried (Na2SO4)
and the solvent was evaporated under reduced pressure. The oily
residue was purified by dry flash chromatography [33% ethyl ac-
etate/hexane] to afford ethyl or methyl (2-formyl-1H-pyrrol-1-
yl)acetate 7a or 7b.
chloride (10 mL). The mixture was gently heated to reflux under
argon for 1 h and then the excess thionyl chloride removed
in vacuo. Dry toluene (10 mL) was added to the oily residue and
evaporated in vacuo. The residue was dissolved in dry toluene
(10 mL) and a solution of methyl anthranilate (0.75 g, 5.0 mmol)
in dry pyridine (10 mL) was added dropwise under argon. The
reaction mixture was stirred at room temperature for 48 h. The
solvents were evaporated under reduced pressure, a 10% w/v
solution of NaHCO3 (50 mL) was added and extracted with
dichloromethane (3ꢁ20 mL). The combined organic extracts were
dried (Na2SO4) and the solvents removed under reduced pressure
to afford a residue that was purified by flash chromatography (15%
ethyl acetate/hexane) to give methyl 2-({[1-(2-ethoxy or methoxy-
2-oxoethyl)-1H-pyrrol-2-yl]carbonyl}amino)benzoate 2a or 2b.
4.1.2.1. Ethyl (2-formyl-1H-pyrrol-1-yl)acetate 7a. Yield (1.6 g, 83%),
as a colourless oil; nmax (Nujol) 1656, 1755 cmꢂ1
; dH (250 MHz,
CDCl3) 1.30 (3H, t, J¼7.1 Hz, CH3), 4.27 (2H, q, J¼7.0 Hz, CH2), 5.09
(2H, s, CH2), 6.33 (1H, dd, J¼4.0, 2.5 Hz, H-4), 6.95 (1H, dd, J¼2.5,
1.5 Hz, H-5), 7.57 (1H, dd, J¼2.9, 1.5 Hz, H-3), 9.57 (1H, s, CHO); dC
(63 MHz, CDCl3) 14.10, 50.23, 61.63, 110.19, 124.59, 131.67, 132.02,
168.33, 179.74; m/z (ESI) 182.1 [MþH]þ; HRMS (ESI): [MþH]þ,
found 182.0813. C9H12NO3 requires 182.0817.
4.1.4.1. Methyl 2-({[1-(2-ethoxy-2-oxoethyl)-1H-pyrrol-2-yl]carbo-
nyl}amino)benzoate 2a. Yield (1.04 g, 65%), as colourless micro-
crystals (propan-2-ol); mp 165–166 ꢀC; nmax (Nujol) 3303, 1743,
1666, 1541 cmꢂ1
;
dH (250 MHz, CDCl3) 1.28 (3H, t, J¼7.2 Hz, CH3),
4.1.2.2. Methyl (2-formyl-1H-pyrrol-1-yl)acetate 7b. Yield (1.64 g,
3.95 (3H, s, CH3), 4.24 (2H, q, J¼7.2 Hz, CH2), 5.13 (2H, s, CH2), 6.25
(1H, dd, J¼3.9, 2.6 Hz, H-4), 6.82 (1H, dd, J¼3.9, 1.8 Hz, H-3), 7.02–
7.08 (2H, m, H-5, H-50), 7.52 (1H, ddd, J¼8.9, 7.6, 0.9 Hz, H-40), 8.04
(1H, dd, J¼8.0, 1.4 Hz, H-30), 8.73 (1H, dd, J¼8.6 Hz, H-60), 11.76 (1H,
br, NH); dC (63 MHz, CDCl3) 14.29, 50.95, 52.53, 61.56, 108.74,
114.09, 114.83, 120.21, 122.03, 126.01, 129.20, 131.02, 134.70, 142.19,
160.10, 169.05, 169.15; m/z (ESI) 331.0 [MþH]þ, 353.0 [MþNa]þ;
HRMS (ESI): [MþNa]þ, found 353.1119. C17H18N2NaO5 requires
353.1113.
86%), as a colourless oil; nmax (Nujol) 1658, 1751 cmꢂ1
; dH (250 MHz,
CDCl3) 3.75 (3H, s, CH3), 5.06 (2H, s, CH2), 6.29 (1H, dd, J¼4.2,
2.7 Hz, H-4), 6.92 (1H, dd, J¼2.7, 1.5 Hz, H-5), 6.98 (1H, dd, J¼4.2,
1.5 Hz, H-3), 9.52 (1H, s, CHO); dC (63 MHz, CDCl3) 49.97, 52.36,
110.14, 124.52, 131.57, 131.97, 168.70, 179.66; m/z (ESI) 189.8
[MþNa]þ; HRMS (ESI): [MþNa]þ, found 190.0484. C8H9NNaO3
requires 190.0480.
4.1.3. Preparation of 1-[(2-ethoxy or methoxy)-2-oxo-ethyl]-1H-
pyrrole-2-carboxylic acids 3a,b: general procedure B
4.1.4.2. Methyl 2-({[1-(2-methoxy-2-oxoethyl)-1H-pyrrol-2-yl]carb-
onyl}amino)benzoate 2b. Yield (1.09 g, 73%), as colourless micro-
crystals (propan-2-ol); mp 149–150 ꢀC; nmax (Nujol) 3307, 1760,
To a solution of ethyl or methyl (2-formyl-1H-pyrrol-1-yl)-
acetates 7a or 7b (8.30 mmol) in acetone (100 mL) was added
dropwise over 2 h a solution of KMnO4 (2.70 g,17 mmol) in acetone–
water (200 mL, 1:1). After 4 h of stirring at room temperature,
acetone was removed under reduced pressure and the remaining
aqueous solution was acidified with 1.5 M HCl to pH 3 followed by
the addition of aqueous 10% NaHSO3 (10 mL). The mixture was
extracted with ethyl acetate (3ꢁ30 mL) and the combined organic
extracts were washed with water (30 mL) and then carefully with
5% w/v NaHCO3 (3ꢁ30 mL). The combined bicarbonate extracts
were carefully acidified with aqueous 1.5 M HCl to pH 3, extracted
with ethyl acetate (3ꢁ30 mL), the combined organic extracts
washed with brine (30 mL), dried (Na2SO4), filtered and the solvent
was evaporated under reduced pressure leaving 1-[(2-ethoxy or
methoxy)-2-oxoethyl]-1H-pyrrole-2-carboxylic acid 3a or 3b.
1692, 1667 cmꢂ1
; dH (250 MHz, CDCl3) 3.77 (3H, s, CH3), 3.95 (3H, s,
CH3), 5.14 (2H, s, CH2), 6.26 (1H, dd, J¼4.1, 2.7 Hz, H-4), 6.82 (1H,
dd, J¼2.5, 1.8 Hz, H-3), 7.01–7.08 (2H, m, H-5, H-50), 7.52 (1H, ddd,
J¼8.8, 1.7 Hz, H-40), 8.03 (1H, dd, J¼8.0, 1.7 Hz, H-30), 8.72 (1H, dd,
J¼8.6 Hz, H-60), 11.76 (1H, br, NH); dC (63 MHz, CDCl3) 50.64, 52.36,
52.39, 108.66, 113.99, 114.73, 120.21, 121.92, 125.84, 129.06, 130.86,
134.53, 141.99, 159.93, 169.02, 169.46; m/z (ESI) 339.0 [MþNa]þ;
HRMS (ESI): [MþNa]þ, found 339.0962. C16H16N2NaO5 requires
339.0957.
4.1.5. Methyl 6-hydroxy-12-oxo-11,12-dihydropyrrolo-[2,1-c][1,4]-
benzodiazocine-5-carboxylate 1
To
a stirred suspension of potassium carbonate (0.32 g,
2.37 mmol) in dry DMSO (80 mL) at 60 ꢀC and under an atmo-
sphere of argon, was added dropwise a solution of ester 2b
(0.25 g, 0.00079 mmol) in dry DMSO (80 mL). The reaction mix-
ture was stirred at 60 ꢀC for 48 h and then cooled to 5 ꢀC before
the pH was adjusted to 3–4 by addition of aqueous 2 M hydro-
chloric acid. Stirring was continued for 1 h at 5 ꢀC, water (800 mL)
was added and then extracted ethyl acetate (3ꢁ150 mL). The
combined organic extracts were washed with brine (100 mL),
dried (Na2SO4), filtered and the solvent was evaporated under
reduced pressure to give a residue. Crystallisation form ethyl ac-
etate/hexane gave compound 1 (0.14 g, 63%) as colourless micro-
crystals; mp 225–226 ꢀC; nmax (Nujol) 3120, 2950, 1720,
4.1.3.1. 1-(2-Ethoxy-2-oxoethyl)-1H-pyrrole-2-carboxylic acid 3a. Yield
(1.32 g, 81%), as colourless microcrystals (propan-2-ol); mp 156–
157 ꢀC; identical in all respects to the corresponding compound
described in Section 4.1.1.3.
4.1.3.2. 1-(2-Methoxy-2-oxoethyl)-1H-pyrrole-2-carboxylic
3b. Yield (1.26 g, 83%), as colourless microcrystals (diisopropyl
ether); mp 137–138 ꢀC; nmax (Nujol) 3012, 1713 cmꢂ1
dH (250 MHz,
acid
;
DMSO-d6) 3.69 (3H, s, CH3), 5.13 (2H, s, CH2), 6.15 (1H, dd, J¼3.7,
2.5 Hz, H-4), 6.86 (1H, dd, J¼3.7, 1.9 Hz, H-3), 7.12 (1H, dd, J¼2.5,
1.9 Hz, H-5), 12.25 (1H, br s, OH); dC (63 MHz, DMSO-d6) 50.81,
52.77, 108.63, 118.30, 123.38, 130.98, 162.82, 170.28; m/z (ESI) 205.9
[MþNa]þ; HRMS (ESI): [MþNa]þ, found 206.0424. C8H9NNaO4
requires 206.0429.
1681 cmꢂ1
; dH (250 MHz, CDCl3) 3.97 (3H, s, CH3), 6.33 (1H, dd,
J¼3.7, 2.7 Hz, H-2), 6.97–7.05 (2H, m, H-1, H-3), 7.11 (1H, ddd,
J¼8.2, 7.2, 1.0 Hz, H-8), 7.57 (1H, ddd, J¼8.1, 7.2, 1.0 Hz, H-9), 8.07
(1H, dd, J¼8.1, 1.0 Hz, H-10), 8.81 (1H, dd, J¼8.2, 1.0 Hz, H-7), 9.43
(1H, br s, OH), 11.83 (1H, br s, 1H, NH); dC (63 MHz, CDCl3) 52.6,
77.39, 110.63, 110.83, 114.83, 120.24, 122.25, 122.53, 131.12, 134.89,
140.23, 142.12, 159.54, 169.13, 210.31; m/z (ESI) 284.9 [MþH]þ,
306.9 [MþNa]þ; HRMS (ESI): [MþNa]þ, found 307.0691.
4.1.4. Preparation of methyl 2-({[1-(2-ethoxy or methoxy-2-
oxoethyl)-1H-pyrrol-2-yl]carbonyl}amino)benzoates 2a,b:
general procedure C
1-[(2-Ethoxy or methoxy)-2-oxoethyl]-1H-pyrrole-2-carboxylic
acid 3a or 3b (5.0 mmol) is dissolved in freshly distilled thionyl
C15H12N2NaO4 requires 307.0695.

K. Koriatopoulou et al. / Tetrahedron 64 (2008) 10009–10013
3. Majchrzak, M.; Kotelko, A.; Guryn, R. Acta Pol. Pharm. 1975, 32, 145.
10013
Acknowledgements
4. Altenbach, H.; Josef, S. H.; Wilhelm, M.; Voss, B.; Lex, J.; Vogel, E. Angew. Chem.
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This research was co-funded by the European Union in the
framework of the program ‘Pythagoras I’ of the ‘Operational
Program for Education and Initial Vocational Training’ of the
3rd Community Support Framework of the Hellenic Ministry of
Education, funded by 25% from national sources and by 75% from
the European Social Fund (ESF). We appreciate the use of NMR and
mass spectrometry facilities funded by the Horizontal Laboratory
and Unit Centres of the University of Ioannina and thank Dr. A.
Badeka for measuring low resolution mass spectra. We are grateful
to A. Cakebread and R. Tye for providing low and high resolution
mass spectra on instruments supported by the University of London
Intercollegiate Research Services Scheme.
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