A new synthesis of push-pull pyrroles, their oxidation to stable 3H-pyrroles and an unexpected anellation reaction

Article abstract of DOI:10.1002/ejoc.200900295

A. new synthesis of push-pull pyrroles of type 5 was developed starting from. bis(imidoyl chlorides) 1 and various iminodiacetic acid derivatives 3. The use of appropriate N-trifluoroacetyl residues as protecting/activating group proved to be the method, of choice for the straightforward, preparation of the 3,4-diarylamino-lH-pyrroles 5. When benzothiazole substructures are present in 2,5-position of heterocycles 5, a two-electron oxidation leads to 3H-pyrroles of type 6 in excellent yields. However, in the case of cyano or ester groups, a further oxidative process immediately led to the new 3H-pyrrolo[3,4-b] quinoxalines 7 via intramolecular ring anellation. 2009 Wiley-VCH Verlag GmbH & Co. KGaA,.

Full text of DOI:10.1002/ejoc.200900295

FULL PAPER
DOI: 10.1002/ejoc.200900295
A New Synthesis of Push-Pull Pyrroles, Their Oxidation to Stable
3H-Pyrroles and an Unexpected Anellation Reaction
Gunther Buehrdel,[a] Rainer Beckert,*[a] Petra Herzigova,[b] Eva Petrlikova,[b] Dirk Schuch,[a]
Eckhard Birckner,[c] and Helmar Goerls[d]
Keywords: Pyrrole / Cyclization / Acylation / Fused-ring systems / Fluorescence
A new synthesis of push-pull pyrroles of type 5 was devel-
electron oxidation leads to 3H-pyrroles of type 6 in excellent
oped starting from bis(imidoyl chlorides) 1 and various imino- yields. However, in the case of cyano or ester groups, a fur-
diacetic acid derivatives 3. The use of appropriate N-trifluo-
roacetyl residues as protecting/activating group proved to be
the method of choice for the straightforward preparation of
the 3,4-diarylamino-1H-pyrroles 5. When benzothiazole sub-
structures are present in 2,5-position of heterocycles 5, a two-
ther oxidative process immediately led to the new 3H-pyr-
rolo[3,4-b]quinoxalines 7 via intramolecular ring anellation.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
building blocks for heterocyclic as well as for carbocyclic
compounds.[4] In the course of a cycloacylation–prototrop-
ism sequence, a series of new thiophenes which possess
interesting spectral properties was synthesized.[4a] Our cur-
rent goal is to adapt these results in order to integrate these
di-electrophiles 1 into the synthesis of tetrasubstituted pyr-
roles (Figure 1).
Introduction
In the course of the last years derivatives of pyrrole have
become of major interest due to the fact that this five-mem-
bered heterocycle is present in a series of natural products
and in addition, pyrrolic compounds feature a wide variety
of interesting and useful optical and electronic properties.[1]
Especially highly substituted pyrroles have an important
function in natural dyes (porphyrins, bile pigments) and
were also isolated from maritime organisms. Such deriva-
tives often show a high biological activity and therefore
some synthetic strategies were developed for their total syn-
theses.[2] The blockbuster atorvastatin (Lipocor, Lipitor®) is
a representative example in which a high degree of substitu-
ents goes hand in hand with strong biological activity. Sub-
stituted pyrroles can be synthesised by several cyclization
reactions by using a widespread ensemble of building
blocks. One procedure to highly substituted pyrroles is sim-
ilar to the Hinsberg cyclisation: the ring-forming reaction
between CC and CNC building blocks to yield symmetrical
pyrrols.[3] During the last decade, it was clearly demon-
strated that compounds 1 are excellent (and selective) di-
electrophiles that can be employed in a wide range as CC
Figure 1. Synthetic entry to push-pull pyrroles.
[a] Institute of Organic and Macromolecular Chemistry, Friedrich-
Schiller-Universität,
Results and Discussion
Humboldtstr. 10, 07743 Jena, Germany
Fax: +49-3641-948212
E-mail: c6bera@uni-jena.de
The di-electrophiles 1 are easily accessible from simple
starting materials and an optimized protocol consisting of
a two-step one-pot reaction was used.[4b] The 4-octyloxy-
phenyl-substituted bis(imidoyl chloride) 1d was additionally
prepared in order to obtain derivatives with a better solubil-
ity in nonpolar solvents (Scheme 2).
[b] Faculty of Pharmacy, Charles University Hradec Kralove,
Heyrovskeho 1203, 50005 Hradec Kralove, Czech Republic
[c] Institute of Physical Chemistry, Friedrich-Schiller-Universität,
Lessingstr. 10, 07743 Jena, Germany
[d] Institute of Inorganic and Analytical Chemistry, Friedrich-
Schiller-Universität,
August-Bebel-Str. 2, 07743 Jena, Germany
3404
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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A New Synthesis of Push-Pull Pyrroles
The CNC building blocks diethyl iminodiacetate 2a and mild conditions and the pyrrole 4c was isolated as yellow
iminodiacetonitrile 2b which possess electron withdrawing crystalline solid in relatively low yield. The N-benzoyl group
groups, necessary for the Hinsberg-like cyclisation reaction, in 4a–c can be removed by heating in ethanol in the pres-
are commercially available (Scheme 1). In order to prevent ence of catalytic amounts of p-toluenesulfonic acid. The
undesired acylations at nitrogen atoms and simultaneously, corresponding 1H-pyrroles 5a–c were isolated as colourless
to activate the substrate, the NH in 2a,b must be trans- crystals after purification by flash chromatography and
formed. Firstly, we introduced the tosyl group for this recrystallisation.
reason, however, under the cyclisation conditions (THF/
KOtBu) only decomposition of the materials was observed.
The use of the benzoyl group (derivative 3a,b) was success-
ful and thus, upon cycloacylation, the corresponding pyr-
roles 4a–c were isolated (see discussion below). The tri-
fluoroacetate group proved to be an additional promising
protection/activation group. The corresponding N-pro-
tected compounds 3c,d were easily prepared by acylation
reactions of 2a,b with trifluoroacetic anhydride without any
base and were purified by distillation. Interestingly enough,
derivatives 3c,d were unknown as of yet (Scheme 1; for their
cyclisation see below). A further promising CNC building
block was obtained by condensation reaction of 2b with 2-
aminothiophenol. This smooth reaction yielded bis(benzo-
thiazolyl) derivative 2c (benzothiazole = Bth). The protec-
tion of 2c with trifluoroacetic anhydride allowed the synthe-
sis of trifluoroacetamide 3e in high yield as colourless crys-
tals.
Scheme 2.
Alternatively, employing the trifluoroacetamides 3c–e as
cyclization partners, the 1H-pyrroles 5 can be isolated di-
rectly after cyclisation reaction with 1. For example, 3c re-
acted with 1 under mild conditions forming a colourless
crystalline product in a satisfactory yield. However, elemen-
tal analysis and MS data confirmed not only the presence
of 1:1 cyclisation products but also an additional release of
the trifluoroacetate group. Due to the fact that higher yields
were obtained in this procedure, this protocol proved to be
the best choice for the synthesis of tetrasubstituted deriva-
tives of type 5 (Scheme 2). Evidence for the symmetric sub-
Scheme 1.
Diethyl N-benzoyliminodiacetate 3a reacted with di-elec- stitution pattern in these novel tetrasubstituted pyrroles 5
trophiles of type 1 under mild conditions (THF in the pres- (Scheme 2) was provided by single sets of resonances in the
ence of KOtBu at –78 °C) forming pale yellow crystalline 1H and 13C NMR spectra. Taking 5a as an example, the
products in moderate yields. Elemental analysis and MS following key signals were detected: the pyrrole NH proton
data confirmed the presence of 1:1 cyclisation products. at δ = 8.91 ppm and the NH protons of the tolylamino
Evidence for the symmetric substitution pattern in these group at δ = 6.51 ppm, the C=O of the COOEt group at δ
novel penta-substituted pyrroles 4a,b (Scheme 2) was pro- = 160.8 ppm in the 13C NMR spectrum. The pale yellow
vided by single sets of signals in the 1H and 13C NMR spec- solution of compound 5a (CHCl3: λmax: 351 nm, lg ε: 3.8)
1
tra. In the H NMR spectra, the NH protons of derivative displayed a yellow fluorescence with a large stokes shift (in
4a showed a chemical shift of δ = 6.92 ppm and the protons CHCl3: λEm = 550 nm). The cyclisation reaction between
from the 4-tolyl methyl group at δ = 2.20 ppm. In the 13C trifluoroacetamide 3d and 1 was accomplished under the
NMR spectrum, the signal for the benzoyl group was de- same conditions to the 3,4-bis(tolylamino)pyrrole-2,5-dicar-
tected at δ = 169.4 ppm and for the COOEt group of bonitrile (5c), however, in relatively low yield. While 5c
160.6 ppm. Solutions of compound 4a are dark yellow proved to be stable in the solid state, in solution fast oxi-
(CHCl3: λmax = 390 nm, lg ε = 3.9). N-benzoyliminodiace- dation reaction took place giving a new blue compound
tonitrile 3b reacted with di-electrophile 1b under similar (Scheme 3).
Eur. J. Org. Chem. 2009, 3404–3412
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R. Beckert et al.
FULL PAPER
Figure 2. ORTEP plot (50% probability ellipsoids) of the solid-
state molecular structure of 5d, selected bond lengths in Å: S1–C5
1.751(4), S2–C12 1.751(4), N2–C5 1.310(6), N3–C12 1.314(5), N1–
C1 1.358(5), N1–C4 1.364(5), C1–C2 1.398(6), C2–C3 1.411(6),
C3–C4 1.388(6), N4–C2 1.406(6), N5–C3 1.408(5).
groups. The absorption and fluorescence characteristics of
compounds 5 have been investigated in dilute solutions at
room temperature. Absorption and fluorescence spectra of
selected compounds in toluene are presented in Figure 3.
Data of steady state absorption and fluorescence measure-
ments in toluene are summarized in Table 1. Position and
intensity of the long wavelength absorption are determined
by the substitution at the pyrrol ring in 2,5-position. The
bathochromic shift increases in the order Y = CN, COOEt,
benzothiazole. The long wavelength absorption edge of all
Scheme 3.
The cyclisation reaction between 3e and 1 also led to compounds 5 are characterized by a long tail which should
NH-pyrrols of type 5. In this manner, the bis(benzothiazo- be due to flexibility of the arylamino groups in 3- and 4-
lyl)-substituted derivatives 5d–h were isolated as yellow position. The long wavelength absorption band of the
crystals in moderate to good yields. Derivative 5g was syn- benzothiazolyl-substituted compounds shows two peaks of
thesised starting from 3e and bis(imidoyl chloride) 1d in nearly the same intensity separated by 20 nm and distinct
order to obtain derivative with a better solubility in nonpo- higher absorption coefficients. The fluorescence spectra are
lar solvents. The yellow solutions of compound 5d (CHCl3: broad and with one exception (5h) unstructured and have
λmax = 385 and 405 nm, lg ε = 4.4) display strong blue to Stokes shifts from 2500 to 7000 cm–1. The fluorescence
yellow fluorescence, whereby the emission wavelength de- quantum yields vary from 0.8 to 0.03. The decrease of the
pends on the nature of the solvent (for discussion of the quantum yields correlates with the increase of the Stokes
fluorescence properties of pyrroles 5 see below). Further shifts. For the 2,5-bis(benzothiazolyl)-3,4-bis(diarylamino)-
structural details were obtained from a single-crystal X-ray pyrroles 5 a strong effect of the donor strength of the sub-
analysis of 5d. The result of this structure determination stituent at the arylamino groups on the fluorescence quan-
showed that 5d is a monomer in the solid state (Figure 2). tum yield is observed. With increasing donor strength in
The bond lengths and angles were in the expected range the order 5h, 5e, 5d and 5f (see Table 1) the quantum yields
for a 1H-pyrrole. The bond lengths and the torsion angles decrease (5g showing the same spectroscopic characteristics
between the pyrrole and the benzothiazole rings suggest a as 5f).
conjugation between both heterocycles. The π-systems of
In order to investigate the excited state deactivation pro-
the two tolyl rings are nearly perpendicular with respect to cesses and to distinguish between radiative and nonradia-
the central pyrrole functionality. The lone pairs of N4 and tive deactivation the fluorescence kinetics of the com-
N5 are also oriented perpendicular to the pyrrole and inter- pounds are measured in toluene. The kinetics show mono-
act with the π-system of the tolyl group. The asymmetric exponential decay for all compounds with lifetimes from
unit of one molecule contains crystal chloroform leading to 1 ns to 3 ns. The values are given in Table 2 together with
a slight interaction between N2 and the proton of N1.
the calculated radiative and nonradiative rate constants.
All 1H-pyrrole solutions of type 5 display fluorescence The data shows that the decrease of the fluorescence quan-
whereby the emission maxima, Stokes shift and the inten- tum yields are as well due to the decrease of the radiative
sity (quantum yield) depend on the nature of the substitu- rate constant kf, as the increase of the nonradiative rate
ent in the 2-/5-position as well as on the 3,4-arylamino constants knr with increasing donor strength.
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A New Synthesis of Push-Pull Pyrroles
istic solvent dependence can be assumed for a charge-trans-
fer fluorophore where a charge separation in the excited
state occurred.
As mentioned above, the pyrroles 5 can easily be oxidised
under the formation of blue compounds. Whereas the 2,5-
dicyanopyrrole 5c was oxidised in solution by air within
two days, the other pyrroles are relatively stable in solution.
However after several days, the colour of the solutions
changed to a slightly green. In order to study this behaviour
we tested the electrochemical activity of derivatives 5. The
cyclovoltammetric measurements showed that the pyrroles
5 can be oxidized reversibly. Employing square-wave mea-
surements on derivative 5d, five peaks at 0.991, 1.221, 1.401,
1.616 and at 1.782 V can be ascribed to five different elec-
tron transfer steps. The quasi-reversibility of the three first
oxidation steps was confirmed by cyclovoltammetric mea-
Figure 3. Absorption and fluorescence spectra of selected pyrroles
5 in toluene.
Table 1. Absorption maxima λa and coefficients ε, fluorescence
maxima λf, Stokes shifts ∆νaf and fluorescence quantum yields Φf
in toluene.
surements ∆E1 = 0.067 V, ∆E2 = 0.094 V and ∆E3
=
0.119 V. Based on these observations, a suitable oxidation
reagent for the pyrroles 5 proved to be lead dioxide. Upon
treatment with PbO2 under mild conditions (dichlorometh-
ane, room temp.), the 3H-pyrroles of type 6 were isolated
in excellent yields. Elemental analysis and MS data con-
firmed the elimination of two hydrogen atoms. Evidence for
the unsymmetrical structure of the 3H-pyrroles 6a–c
(Scheme 3) was provided by double sets of signals in the 1H
and 13C NMR spectra. In contrast to 4 and 5 the methyl
groups of derivative 6a form two different spin systems in
their NMR spectra (1H NMR: δ = 2.67/2.45 ppm. 13C
NMR: 22.8/21.6 ppm). In solution, the 3H-pyrroles 6 dis-
[a]
λa
ε[b]
λf[a]
[nm]
∆νaf
Φf
[nm]
₍–1 cm–1]
[cm–1]
5a
5b
5c
5h
5e
5d
5f
340, 381 sh 6300
335, 381 sh 7100
515
505
438
6800
6400
6400
0.12
0.14
0.04
0.80
0.64
0.39
0.15
342
7900
381, 402
385, 404
384, 407
386, 407
37100
31600
22900
25100
446, 462 2450
462
478
498
3100
3650
4500
[a] Maxima of the long wavelength absorption spectra and of the
fluorescence spectra. Values printed in italics indicate the major
peak. sh: shoulder. [b] Absorption coefficients at the long wave-
length absorption maxima in CHCl3.
play a dark turquoise color (6a: UV/Vis in CHCl3: λmax
=
730 nm, lg ε = 3.7). This broad absorption band with a
maximum at about 730 nm originates from a azamerocyan-
ine chromophore. Encouraged by these results, the pyrroles
without benzothiazole substructures 5a–c were integrated
in the investigations with respect to their oxidative transfor-
mation.
Table 2. Excited state deactivation: fluorescence quantum yields
(Φf), lifetimes (τ) and rate constants of radiative (kf) and radiation-
less (knr) deactivation in toluene.
[a]
Φf
τ [ns]
kf[a] [ns–1]
knr [ns–1]
Under similar mild conditions, blue products were iso-
lated in very good yields. Somewhat surprisingly, the MS
data indicated in this case the loss of four hydrogen atoms.
Evidence for the structure of 3H-pyrrolo[3,4-b]quinoxalines
5a
5b
5c
5h
5e
5d
5f
0.12
0.14
0.04
0.80
0.64
0.39
0.15
2.72
3.24
0.89
2.10
2.39
2.46
2.65
0.044
0.043
0.045
0.38
0.27
0.16
0.32
0.27
1.08
0.10
0.15
0.25
0.32
1
7 was mainly provided by their H NMR spectra. In ad-
0.057
dition to the characteristic signals for one 4-tolyl substruc-
ture, two “doublets” δ = 8.51, 7.60 ppm and a “singlet” at
δ = 7.18 ppm for the aromatic protons were detected. As
key signal, a further singlet for an aromatic methyl group
[a] kf = Φf/τ, knr = (1 – Φf)/τ.
Another interesting property is the solvent dependence at δ = 2.58 ppm clearly underlined that an ortho-ring-fusion
of the fluorescence by benzthiazolyl-substituted pyrroles. process took place. A single-crystal X-ray analysis of 7b
Whereby only a moderate solvatochromism is observed, an confirmed the molecular structure (Figure 4). Compound
enhanced red shift of the fluorescence spectra is observed 7b is a monomer in the solid state with the bond lengths
in solvents of increasing polarity which indicates a large and angles being in the expected range. Typically, an alter-
difference in the dipole moments of the ground (So) and nation of bond lengths in the 3H-pyrrole core was detected
excited electronic state S1. For example, the absorption confirming the presence of an azamerocyanine-like chromo-
maximum of 5e in cyclohexane lies at 399 nm, this maxi- phore. The C2–C3 bond (1.46 Å) lies in the range for single
mum is shifted in DMSO to 411 nm. 5e displays in cyclo- carbon–carbon bonds in a butadiene system (Figure 4). The
hexane an emission maximum at λ = 444 nm and a quan- π-system of the 4-tolyl ring is nearly perpendicular with re-
tum yield of 70%; in toluene: 462 nm, 64%; in CHCl3: spect to the central 3H-pyrrolo-quinoxaline functionality.
477 nm, 45%; in ethyl acetate: 483 nm, 36%; in acetonitrile: In the UV/Vis spectra, a broad absorption at about 600 nm
498 nm, 24%, and in DMSO: 526 nm, 13%. This character- is originating from the azamerocyanine chromophore
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R. Beckert et al.
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whereas another one at about 380 nm can be ascribed to an the formation of the aminyl radical B. Finally, radical B is
enamino-ester subchromophore. A series of other oxidation able to intramolecularly substitute the attached aromatic
reagents for the oxidation of 5a–c was tested successfully, ring to give C and finally 7. However, kinetic studies re-
however, lead tetraacetate in the presence of potassium car- vealed that cylization reactions of aminyl radical cations are
bonate proved to be another suitable system. It must be much faster than those of the corresponding neutral radi-
noted that all attempts to isolate compounds of type 6 cals.[6] The mechanism in which the key intermediates are
which possess ester or cyano groups failed. Even the use aminyl radicals/radical cations is supported by the following
of substoichiometric amounts of oxidation reagents led to experimental facts:
mixtures consisting of starting material 5 and tricyclic de-
a) Generally, anilines can easily be oxidised and the thus
rivatives 7. On the other hand, when 6a–c were oxidized formed amine radical cations tend to deprotonate quickly.
with lead tetraacetate in the presence of potassium carbon- Aryl-substituted aminyl radicals are relatively stable and
ate at 60 °C, only inseparable mixtures of yellow colored/ under suitable conditions they undergo aromatic substitu-
fluorescent compounds were obtained.
tion reactions. As an example tetraphenyl hydrazines disso-
ziates in two diphenyl aminyl radicals, when heated. Sub-
sequently, they react under intramolecular substitution to
give derivatives of N,NЈ-diphenylphenazine.[7]
b) Other authors also suggest that aminyl cations formed
via oxidation processes undergo a final intramolecular cy-
clization reaction with the attached aromatic ring.[8]
Figure 4. ORTEP plot (50% probability ellipsoids) of the solid state
molecular structure of 7b, selected bond lengths in Å: N1–C1
1.386(3), N1–C4 1.327(3), N2–C2 1.368(3), N3–C3 1.315(3), N2–
C5 1.399(3), N3–C10 1.380(3), C1–C2 1.400(3), C2–C3 1.460(3),
C3–C4 1.446(3).
The electrochemical activity of 3H-pyrrole 6a can be de-
tected employing square wave measurements which showed
two peaks at –0.552 V and 0.724 V. The ring-fused 3H-pyr-
roloquinoxaline 7a is also electrochemically active and a
peak at –0.630 V can be observed. The 3H-pyrroles of type
6 can be reduced chemically with sodium dithionite in a
water/THF mixture under the formation of the correspond-
ing 1H-pyrroles 5. Under the same conditions, the 3H-pyr-
roloquinoxalines 7 were reduced to yield the 1H-pyrrolo-
quinoxalines 8 (Scheme 3). The leuco compound 8a proved
to be stable enough towards air thus allowing its isolation
Scheme 4.
Conclusions
Push-pull pyrroles of type 4 and 5 were prepared by a
Hinsberg-like cyclisation reaction starting from bis(imidoyl
chlorides) 1 and various iminodiacetic acid derivatives 3.
The use of appropriate N-trifluoroacetyl residues as pro-
tecting/activating groups proved to be the method of choice
for the preparation of 1H-pyrroles 5. The pyrroles 5 exhibit
a strong solvatofluorescence with large Stockes shifts and
quantum yields up to 80%. The oxidation of the 3,4-di-
arylamino-1H-pyrroles 5 was studied. When benzothiazole
substructures are present in 2,5-position of heterocycles 5,
a two-electron oxidation leads to 3H-pyrroles of type 6 in
excellent yields. However, in the case of cyano or ester
groups, a further oxidative process immediately led to the
new 3H-pyrrolo[3,4-b]quinoxalines 7 via intramolecular
ring anellation.
1
and to obtain the H NMR spectroscopic data. The yellow
solutions of compounds 8 display a strong yellow fluores-
cence (8a: CHCl3: λmax = 440 nm, λEm = 550 nm; 8c:
CHCl3: λmax = 422 nm, λEm = 510 nm). In solution com-
pounds 8 were relatively fast reoxidised by air under the
formation of parent compounds 7.
We postulate the following mechanism (Scheme 4) for the
unexpected formation of the 3H-pyrroloquinoxalines of
type 7. First the “normal” oxidation takes place leading to
the intermediar formation of 6 which can also be regarded
as an azafulvene and which is isoelectronic to the well
known 4H-imidazoles.[4e,5] A following oxidation step then
formed the radical cation A derived from a secondary
amine. A relatively strong acidity was predicted for these
Experimental Section
General: The reagents described in the following section were pur-
compounds and consequently, deprotonation may result in chased from commercial sources and were used directly unless
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A New Synthesis of Push-Pull Pyrroles
otherwise stated in the text. All solvents were of reagent grade and
were dried according to common practice and were distilled prior
to use. Compounds 1a,b were synthesized according to the litera-
ture.[4b] Reactions were monitored by TLC, carried out on 0.2 mm
Merck silica gel plates (60 F254). The 1H and 13C NMR spectra
were recorded on Bruker AVANCE 250 and 400 spectrometers,
shifts are relative to the signals of the solvent. Melting points were
measured with a Galen III apparatus (Boëtius system) or with a
Kofler-type apparatus and are uncorrected. Electrochemical mea-
surements were carried out in CH2Cl2 with a Metrohm 663 VA
Stand using platinum electrodes (reterence electrode SCE) and tet-
rabutylammoniumhexafluorophosphate as conductive salt.
amine in 50 mL of pyridine was cooled down to 0 °C. Within
20 min 7.6 mL (9.2 g, 67 mmol) of benzoyl chloride was added. The
mixture was stirred for 4 h at room temp. To the formed slurry
100 mL of ice was added, the residue was filtered off, washed with
a diluted potassium carbonated solution and water. The crude
product was washed with 5 mL of ethanol and was recrystallized
from ethanol to yield 3b as colourless crystals. Yield 9.3 g (93%),
m.p. 132 °C (ethanol), 132 °C.[10] 1H NMR (250 MHz, CDCl3): δ
= 7.8–7.5 (m, 5 H, CH-Ph) 4.57 (s, 4 H, CH2) ppm. 13C NMR
(63 MHz, CDCl3): δ = 171.3 (C=O), 133.5, 131.6, 129.4, 127.4,
116.5 (CN), 37.6 (CH2) ppm. MS (EI): m/z (%) = 199 (100) [M+],
130 (50), 77 (90). C11H9N3O (199.21): calcd. C 66.32, H 4.55, N
21.09; found C 66.52, H 4.71, N 21.01.
Bis(imidoyl chlorides) 1. General Procedure: To a solution of
0.1 mol of the corresponding aniline in 50 mL of toluene 4.6 mL
(6.6 g, 0.052 mol) of oxalyl chloride, dissolved in 50 mL of toluene
was added within 10 min. A slurry of the corresponding oxanilide
occurred, the mixture was stirred for 20 min at room temp. To the
slurry 22.0 g (0.105 mol) of phosphorus pentachloride was added.
The mixture was heated under reflux until no further hydrogen
chloride is formed. The dark yellow reaction mixture was concen-
trated in vacuo to dryness and the crude product was recrystallized
from n-heptane.
Trifluoroacetamides 3c,d. General Procedure: The solution of
50 mmol of diethyl iminodiacetate (2a) or iminodiacetonitrile (2b)
in 50 mL of dry CH2Cl2 was cooled down to 0 °C. Within 20 min
7.7 mL (11.6 g, 55 mmol) of trifluoroacetic anhydride was added.
The mixture was stirred for 24 h at room temp., the solvent was
evaporated in vacuo and after vacuum distillation the product was
obtained as colourless oil, in the case of 3d it solidified upon stand-
ing to give a colourless crystalline solid.
Diethyl N-(Trifluoroacetyl)iminodiacetate (3c): Colourless oil, yield
12.2 g (86%), bp. 110–112 °C (0.2 mbar), 1H NMR (250 MHz,
CDCl3): δ = 4.25 (m, 8 H, CH2), 1.28 (m, 6 H, CH3) ppm. 13C
NMR (63 MHz, CDCl3): δ = 167.6 (COOEt), 167.5 (COOEt),
N,NЈ-Bis(4-methoxyphenyl)oxaldiimidoyl Chloride (1c): Yellow crys-
tals, yield 12.9 g (74%), m.p. 150 °C. 1H NMR (250 MHz, CDCl3):
3
3
δ = 7.29 (d, J = 8 Hz, 4 H,CH-Ar), 6.97 (d, J = 8 Hz, 4 H, CH-
Ar), 3.86 (s, 6 H, OCH3) ppm. 13C NMR (63 MHz, CDCl3): δ =
158.8, 138.1, 136.3 (Cl-C=N), 123.8, 114.1, 55.5 (OCH3) ppm.
2
1
157.6 (q, J = 40 Hz, COCF3), 115.4 (q, J = 290 Hz, CF3), 62.1
(OCH2), 61.8 (OCH2), 49.3 (q, 4J = 4 Hz, CH2), 49.1 (q, 4J = 1 Hz,
CH2), 13.9 (CH3) ppm. MS (EI): m/z (%) = 285 (20) [M+], 239 (45),
59 (100). C10H14F3NO5 (285.22): calcd. C 42.11, H 4.95, N 4.91;
found C 41.89, H 4.79, N 4.73.
N,NЈ-Bis(4-octyloxyphenyl)oxaldiimidoyl Chloride (1d): Yellow
crystals, yield 17.0 g (64%), m.p. 93 °C. 1H NMR (250 MHz,
3
3
CDCl3): δ = 7.29 (d, J = 8 Hz, 4 H, CH-Ar), 6.96 (d, J = 8 Hz,
4 H, CH-Ar), 4.00 (t, 3J = 6.5 Hz, 4 H,OCH2), 1.78 (m, 4 H, CH),
1.38 (m, 20 H, CH), 0.90 (m, 6 H, CH) ppm. 13C NMR (63 MHz,
CDCl3): δ = 158.5, 137.9, 135.9 (C=N), 123.8, 114.6, 68.3 (OCH2),
31.8, 29.3, 29.2, 26.0, 22.6, 14.0 ppm. MS (EI): m/z (%) = 536 (4),
534 (10), 532 (15) [M+], 301 (10), 268 (25), 266 (100) [M/2]+, 154
(30). C30H42Cl2N2O2 (533.59): calcd. C 67.53, H 7.93, N 5.29;
found C 67.38, H 7.79, N 5.18.
N-(Trifluoroacetyl)iminodiacetonitrile (3d): Colourless crystals,
yield 8.5 g (89%), bp. 104–105 °C (0.5 mbar), m.p. 54 °C. 1H NMR
(250 MHz, CDCl3): δ = 4.54 (s, 4 H, CH2CN) ppm. 13C NMR
2
1
(63 MHz, CDCl3): δ = 156.3 (q, J = 40 Hz, COCF3), 115.2 (q, J
= 290 Hz, CF3), 112.8 (CN), 112.5 (CN), 36.1 (q, 4J = 4 Hz, CH2),
35.0 (CH2) ppm. MS (EI): m/z (%) = 191 (10) [M+], 122 (100), 69
(40). C6H4F3N3O (191.11): calcd. C 37.71, H 2.11, N 21.99; found
C 37.21, H 1.93, N 21.86.
N,NЈ-Bis(3-trifluoromethylphenyl)oxaldiimidoyl Chloride (1e): Pale
yellow crystals, yield 16.6 g (82%), m.p. 84–86 °C. 1H NMR
(400 MHz, CDCl3): δ = 7.6–7.5 (m, 4 H, CH-Ar), 7.40 (s, 2 H, CH-
Ar), 7.3 (m, 2 H, CH-Ar) ppm. 13C NMR (100 MHz, CDCl3): δ =
146.0, 136.6 (C=N), 131.7 (q, J = 32 Hz, C-CF3), 129.7, 123.5 (q,
J = 272 Hz, CF3), 123.3 (q, J = 4 Hz), 117.5 (q, J = 4 Hz) ppm.
19F NMR (188 MHz, CDCl3): δ = –63.2 (s, 6 F, CF3) ppm.
Preparation of N,N-Bis(2-benzothiazolylmethyl)trifluoroacetamide
(3e): A solution consisting of 15.6 g (50 mmol) of bis(2-benzo-
thiazolylmethyl)amine (2c) and 14 mL (10.1 g, 0.1 mol) of triethyl-
amine in 100 mL of dry CH2Cl2 was cooled down to 0 °C. Within
20 min 7.7 mL (11.6 g, 55 mmol) of trifluoroacetic anhydride was
added. The mixture was stirred for 24 h at room temp. To the mix-
ture 100 mL of water was added and the water layer was extracted
to times with CH2Cl2. The combined organic layers were washed
with water three times, after drying over Na2SO4 the solvent was
evaporated in vacuo. The crude product was recrystallized from
CHCl3/n-heptane to yield 3e as colorless crystals. Yield 22.1 g
Bis(2-benzothiazolylmethyl)amine (2c): A modified procedure to
ref.[9] was used. In 20 mL of xylene 5.0 g (52 mmol) of iminodiace-
tonitrile, 13.8 g (110 mmol) of 2-aminothiophenol were heated in
the presence of 0.5 mL of quinoline to 150 °C until no further am-
monia gas is formed (ca. 1 h). Upon cooling down the product 2c
crystallised from the reaction mixture, the crude product was
washed with diethyl ether and after drying it was used without
any further purification. Recrystallisation from CHCl3/n-heptane
yielded 2c as colourless crystals. 14.7 g (91%), m.p. 134 °C (CHCl3/
n-heptane) 1H NMR (250 MHz, CDCl3): δ = 8.1–7.8 (m, 4 H, CH-
Ar), 7.5–7.3 (m, 4 H, CH-Ar), 4.41 (s, 4 H, CH2), 2.78 (s, 1 H,
NH) ppm. 13C NMR (63 MHz, CDCl3): δ = 171.4 (C=N), 153.3,
135.1, 126.0, 125.0, 122.9, 121.8, 50.9 (CH2) ppm. MS (EI): m/z
(%) = 311 (10) [M+], 268 (10), 163 (30), 149 (100), 108 (10), 45 (10).
C16H13N3S2 (311.43): calcd. C 61.71, H 4.21, N 13.45, S 20.59;
found C 61.74, H 4.23, N 13.39, S 20.85.
1
(92%), m.p. 103 °C. H NMR (250 MHz, CDCl3): δ = 8.2–7.8 (m,
4 H, CH-Ar), 7.5–7.4 (m, 4 H, CH-Ar), 5.23 + 5.21 (m, 4 H, CH2)
ppm. 13C NMR (63 MHz, CDCl3): δ = 164.3 (C=N), 164.0 (C=N),
157.3 (q, 2J = 40 Hz, COCF3), 152.9, 152.5, 135.5, 135.1, 126.5,
126.3, 125.8, 125.7, 123.5, 123.3, 121.8, 116.2 (q, 1J = 290 Hz, CF3),
4
49.3 (q, J = 4 Hz, CH2), 48.4 (CH2) ppm.
Synthesis of the Pyrroles 4 and 5 by Cycloacylation with 1: The
solution of 5 mmol of the corresponding N-protected compound
3a–e in 50 mL of dry THF was cooled down to 78 °C and 1.7 g
(15 mmol) of tBuOK was added. To the solution 5.1 mmol of the
corresponding bis(imidoyl chloride) 1 was added. The deep red re-
action mixture was stirred at 30 °C for 10–20 min. The mixture
was neutralized to pH 7 by addition of HCl/isopropyl alcohol. The
N-Benzoyliminodiacetonitrile (3b): The solution of 4.7 g (50 mmol)
of iminodiacetonitrile 2b and 14 mL (10.1 g, 0.1 mol) of triethyl-
Eur. J. Org. Chem. 2009, 3404–3412
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3409

R. Beckert et al.
FULL PAPER
mixture was concentrated in vacuo to dryness. The remaining solid
was dissolved in CHCl3 (by 4c, 5e, 5h CHCl3/methanol) and was
dried with Na2SO4. Upon removal of the solvent in vacuo, the resi-
due was purified by column chromatography on silica gel (CHCl3/
n-heptane, or CHCl3/methanol) and the crude product was purified
by recrystallization from CHCl3/n-heptane to yield 4a–c and 5a–h.
(250 MHz, CDCl3): δ = 8.96 (s, 2 H, NH pyrrole), 7.1–7.0 (m, 4
H, CH-Ph), 6.8–6.6 (m, 8 H, CH-Ph, NH), 4.35 (q, J = 7.1 Hz, 4
3
H, OCH2), 1.33 (t, 3J = 7.1 Hz, 6 H, CH3) ppm. 13C NMR
(63 MHz, CDCl3): δ = 160.8 (C=O), 142.8, 128.3, 126.8, 120.1,
116.9, 114.1, 60.9, 14.3 ppm. MS (EI): m/z (%) = 393 (90) [M+],
347 (25), 301 (100), 77 (60). C22H23N3O4 (393.45): calcd. C 67.16,
H 5.89, N 10.68; found C 67.10, H 5.85, N 10.53. UV/Vis (CHCl3):
λmax (lg ε) = 335 (3.9), 381 (3.7) nm.
Diethyl
1-Benzoyl-3,4-bis(4-tolylamino)pyrrole-2,5-dicarboxylate
1
(4a): Colourless crystals, yield 1.4 g (53%), m.p. 172 °C. H NMR
(250 MHz, CDCl3): δ = 7.8–7.5 (m, 5 H, CH-Ph), 6.92 (s, 2 H,
NH), 6.84 (d, J = 8 Hz, 4 H, CH-Tol), 6.59 (d, J = 8 Hz, 4 H,
3,4-Bis(4-tolylamino)pyrrole-2,5-dicarbonitrile (5c): Colourless crys-
3
3
1
tals, yield 0.6 g (36%), m.p. 187 °C. H NMR (250 MHz, CDCl3):
3
CH-Tol), 4.06 (q, J = 7.1 Hz, 4 H, OCH2), 2.20 (s, 6 H, CH-Tol),
3
δ = 8.87 (s, 1 H, NH pyrrole), 7.05 (d, J = 8 Hz, 4 H, CH-Tol),
0.97 (t, 3J = 7.1 Hz, 6 H, CH3) ppm. 13C NMR (63 MHz, CDCl3):
δ = 169.4 (COPh), 160.6 (COOEt), 139.3, 134.7, 133.8, 130.1,
129.8, 129.0, 128.7, 119.8, 118.2, 116.1, 61.1, 20.6, 13.5 ppm. IR
(ATR): ν¯max = 3372 (NH), 2983 (CH), 2927 (CH), 1743, 1711,
1685, 1512, 1407, 1380, 1336, 1273, 1237, 1219, 1176, 1109, 1020,
807 cm–1. MS (EI): m/z (%) = 525 (10) [M]+, 329 (90), 105 (100),
77 (50) [C6H5]+. C31H31N3O5 (525.61): calcd. C 70.84, H 5.94, N
7.99; found C 70.68, H 6.06, N 8.16. UV/Vis (CHCl3): λmax (lg ε)
= 391 (3.9) nm.
3
6.71 (d, J = 8 Hz, 4 H, CH-Tol) 5.20 (s, 2 H, NH), 2.28 (s, 6 H,
CH-Tol) ppm. 13C NMR (63 MHz, CDCl3): δ = 139.5, 131.5,
130.6, 129.9, 117.0, 111.7, 97.7, 20.6 ppm. IR (ATR): ν¯max = 3330
(NH), 2924 (CH), 2873 (CH), 2209 (CN), 1679, 1612, 1535, 1509,
1187, 1104, 812 cm–1. MS (EI): m/z (%) = 327 (100) [M+], 312 (20),
91 (20). C20H17N5 (327.39): calcd. C 73.37, H 5.23, N 21.39; found
C 73.03, H 5.01, N 21.11. UV/Vis (CHCl3): λmax (lg ε) = 342 (3.8)
nm.
2,5-Bis(2-benzothiazolyl)-3,4-bis(4-tolylamino)pyrrole (5d): Yellow
crystals, yield 1.8 g (65%), m.p. 255–256 °C. H NMR (250 MHz,
Diethyl
1-Benzoyl-3,4-bis(phenylamino)pyrrole-2,5-dicarboxylate
1
(4b): Colourless crystals, yield 1.0 g (40%), m.p. 137–139 °C. 1H
3
CDCl3): δ = 12.04 (s, 1 H, NH pyrrole), 8.1–7.9 (m, 4 H, CH-Ar),
NMR (250 MHz, CDCl3): δ = 7.7–6.9 (m, 15 H, CH), 4.11 (q, J
3
= 7.1 Hz, 4 H, OCH2) 0.88 (t, J = 7.1 Hz, 6 H, CH3) ppm. 13C
3
7.5–7.3 (m, 4 H, CH-Ar), 7.28 (s, 2 H, NH), 6.81 (d, J = 8 Hz, 4
3
H, CH-Tol), 6.56 (d, J = 8 Hz, 4 H, CH-Tol), 2.10 (s, 6 H, CH3)
NMR (63 MHz, CDCl3): δ = 169.1 (COPh), 160.2 (COOEt), 142.3,
139.9, 129.5, 128.8, 126.4, 125.2, 124.9, 122.7, 121.4, 114.4, 61.6,
14.0 ppm. MS (EI): m/z (%) = 497 (60) [M+], 301 (100), 105 (80).
C29H27N3O5 (497.56): calcd. C 70.01, H 5.47, N 8.45; found C
69.65, H 5.22, N 8.04.
ppm. 13C NMR (63 MHz, CDCl3): δ = 156.8, 152.6, 144.1, 134.9,
129.7, 126.9, 126.5, 125.1, 124.3, 122.5, 122.3, 114.3, 79.6,
20.6 ppm. IR (ATR): ν¯max = 3397 (NH), 3371 (NH), 2999, 2916,
1613, 1538, 1511, 1491, 1311, 1241, 1214, 756 cm–1. MS (EI): m/z
(%) = 543 (70) [M+], 264 (80), 219 (100), 91 (40), 65 (40).
C32H25N5S2 (543.72): calcd. C 70.69, H 4.63, N 12.88, S 11.79;
found C 70.41, H 4.32, N 12.63, S 11.97. UV/Vis (CHCl3): λmax (lg
ε) = 385 (4.4), 405 (4.4) nm. Em: cyclohexane λmax = 452, toluene
1-Benzoyl-3,4-bis(4-tolylamino)pyrrole-2,5-dicarbonitrile (4c): Yel-
low crystals, yield 440 mg (27%), m.p. 153–155 °C. 1H NMR
(250 MHz, [D6]DMSO): δ = 8.19 (s, 2 H, NH), 7.8–7.6 (m, 5 H,
CH-Ph), 7.36 (d, 3J = 8 Hz, 4 H, CH-Tol), 6.89 (d, 3J = 8 Hz, 4
H, CH-Tol), 2.20 (s, 6 H, CH3) ppm. 13C NMR (63 MHz, [D6]-
DMSO): δ = 165.0 (C=O), 139.2, 137.0, 132.5, 130.5, 130.3, 129.2,
128.9, 117.9, 114.9, 111.3, 96.9, 20.7 ppm. MS (EI): m/z (%) = 431
(70) [M+], 327 (40), 155 (40), 105 (100), 91 (80) [C7H7+], 77 (100).
C27H11N5O (431.50): calcd. C 75.16, H 4.31, N 16.23; found C
74.88, H 4.01, N 15.91.
1
λmax = 475, CHCl3 λmax = 485, DMSO λmax = 550 nm. CV: ERED
= –0.684 V, EOX1 = 0.991 V, EOX2 = 1.221 V, EOX3 = 1.401 V, EOX
4
5
= 1.616 V, EOX = 1.782 V.
2,5-Bis(2-benzothiazolyl)-3,4-bis(phenylamino)pyrrole (5e): Yellow
1
crystals, yield 1.5 g (59%), m.p. 215–219 °C. H NMR (250 MHz,
CDCl3): δ = 10.38 (s, 1 H, NH pyrrole), 8.1–7.8 (m, 4 H, CH-Ar),
7.5–7.1 (m, 8 H, CH-Ar), 6.8–6.6 (m, 6 H, CH-Ar) 5.21 (s, 2 H,
NH) ppm. 13C NMR (63 MHz, CDCl3): δ = 156.0, 152.5, 145.3,
134.9, 129.3, 126.4, 125.7, 124.7, 124.3, 122.3, 121.6, 119.7,
114.7 ppm. IR (ATR): ν¯max = 3441 (NH), 3334 (NH), 3054, 2979,
1673, 1597, 1538, 1494, 1472, 1396, 1313, 1296, 1244, 1206, 1173,
1130, 752, 735 cm–1. MS (EI): m/z (%) = 515 (100) [M+], 218 (20),
77 (20). C30H21N5S2 (515.66): calcd. C 69.88, H 4.10, N 13.58, S
12.44; found C 69.74, H 4.01, N 13.38, S 12.24. UV/Vis (CHCl3):
λmax (lg ε) = 308 (4.2), 385 (4.5), 404 (4.5) nm. Em: cyclohexane
λmax = 444, toluene λmax = 462, CHCl3 λmax = 477, acetonitrile
λmax = 498, DMSO λmax = 526 nm.
Deprotection of Pyrroles 4: A solution of 2 mmol of the corre-
sponding pyrrole 4a–c and 100 mg (0.5 mmol) of p-toluenesulfonic
acid in 10 mL of ethanol were heated under reflux until no starting
material could be detected (TLC, approx. 2 h). The solvent was
removed in vacuo, the residue was dissolved in CHCl3, the solution
was washed with sodium hydrogen carbonate solution, with water
and was then dried with Na2SO4. Upon removal of the solvent in
vacuo, the residue was purified by column chromatography on sil-
ica gel (CHCl3/n-heptane) to yield 5a (yield 0.4 g, 46%), 5b (0.3 g,
42%), 5c (0.2 g, 30%).
Diethyl 3,4-Bis(4-tolylamino)pyrrole-2,5-dicarboxylate (5a): Colour-
1
less crystals, yield 1.3 g (63%), m.p. 130 °C. H NMR (250 MHz,
2,5-Bis(2-benzothiazolyl)-3,4-bis(4-methoxyphenylamino)pyrrole-
(5f): Yellow crystals, yield 2.9 g (71 %), m.p. 219 °C. 1H NMR
(250 MHz, CDCl3): δ = 10.19 (s, 1 H, NH pyrrole), 8.0–7.8 (m, 4
H, CH-Ar), 7.4–7.3 (m, 4 H, CH-Ar), 6.72 (d, 3J = 8 Hz, 4 H, CH-
CDCl3): δ = 8.91 (s, 1 H, NH pyrrole), 6.84 (d, 3J = 8 Hz, 4 H,
CH-Tol), 6.60 (d, 3J = 8 Hz, 4 H, CH-Tol), 6.41 (s, 2 H, NH), 4.33
3
3
(q, J = 7.1 Hz, 4 H, OCH2), 2.19 (s, 6 H, Tol-CH), 1.32 (t, J =
7.1 Hz, 6 H, CH3) ppm. 13C NMR (63 MHz, CDCl3): δ = 160.8
(C=O), 140.8, 129.4, 128.9, 127.5, 117.0, 114.1, 60.8, 20.5,
14.3 ppm. MS (EI): m/z (%) = 421 (80) [M+], 375 (20), 330 (30),
329 (100). C24H27N3O4 (421.50): calcd. C 68.39, H 6.46, N 9.97;
found C 68.28, H 6.42, N 9.68. UV/Vis (CHCl3): λmax (lg ε) = 34
3
Ar), 6.61 (d, J = 8 Hz, 4 H, CH-Ar) 5.17 (s, 2 H, NH), 3.74 (s, 6
H, OCH3) ppm. 13C NMR (63 MHz, CDCl3): δ = 156.3, 153.8,
152.5, 138.7, 134.7, 126.5, 126.4, 124.7, 123.5, 122.2, 121.6, 116.7,
114.7, 55.6 ppm. IR (ATR): ν¯max = 3435 (NH), 3373 (NH), 3316,
3058, 2953, 2833, 1596, 1507, 1461, 1398, 1239, 1134, 886 cm–1.
MS (EI): m/z (%) = 575 (100) [M]+, 560 (10), 452 (10), 436 (20), 272
(30), 218 (40), 122 (30), 108 (20). C32H25N5O2S2 (575.72): calcd. C
66.76, H 4.38, N 12.16, S 11.14; found C 66.55, H 4.14, N 12.01,
1
2
(3.8), 381 (3.7) nm. CV: EOX = 1.045 V, EOX = 1.421 V.
Diethyl 3,4-Bis(phenylamino)pyrrole-2,5-dicarboxylate (5b): Colour-
less crystals, yield 1.1 g (57%), m.p. 99.5–100 °C. 1H NMR
3410
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 3404–3412

A New Synthesis of Push-Pull Pyrroles
S 10.87. UV/Vis (CHCl3): λmax (lg ε) = 316 (4.3), 386 (4.4), 407 λmax (lg ε) = 342 (4.8), 369 (4.7), 731 (3.7) nm. CV: ERED = 0.552
1
2
(4.4) nm. Em: cyclohexane λmax = 470, CHCl3 λmax = 525.
V, ERED = –0.724 V.
2,5-Bis(2-benzothiazolyl)-4-(phenylamino)-3-(phenylimino)-3H-pyr-
role (6b): Blue crystals, yield 812 mg (79%), m.p. 305–307 °C. 1H
NMR (250 MHz, CDCl3): δ = 8.63 (d, 3J = 8 Hz, 1 H, CH-Ar),
8.28 (d, J = 8 Hz, 1 H, CH-Ar), 7.95 (d, J = 8 Hz, 1 H, CH-Ar),
7.79–7.26 (m, 15 H, CH-Ar) ppm. 13C NMR (63 MHz, CDCl3): δ
= 163.4, 162.6, 154.8, 154.5, 149.6, 138.9, 137.1, 135.9, 135.2, 135.1,
133.8, 133.3, 130.5, 130.4, 129.5, 128.5, 125.9, 125.1, 123.9, 123.7,
2,5-Bis(2-benzothiazolyl)-3,4-bis(4-octoxyphenylamino)pyrrole 5g:
Yellow crystals, yield 1.6 g (42 %), m.p. 83–86 °C. 1H NMR
(250 MHz, CDCl3): δ = 10.16 (s, 1 H, NH pyrrole), 8.0–7.8 (m, 4
H, CH-Ar), 7.4–7.3 (m, 4 H, CH-Ar), 6.73 (d, 3J = 8 Hz, 4 H, CH-
3
3
3
Ar), 6.59 (d, J = 8 Hz, 4 H, CH-Ar), 5.14 (s, 2 H, NH), 3.86 (t,
3J = 6.5 Hz, 4 H, OCH2), 1.80 (m, 4 H CH), 1.4–1.2 (m, 20 H CH),
0.92 (m, 6 H CH) ppm. 13C NMR (63 MHz, CDCl3): δ = 156.3,
153.3, 152.6, 138.6, 134.7, 126.6, 126.4, 124.6, 123.5, 122.2, 121.6,
116.7, 115.4, 68.6, 31.8, 29.44, 29.41, 29.2, 26.1, 22.6, 14.1 ppm.
MS (EI): m/z (%) = 772 (40) [M]+, 658 (10), 546 (10), 452 (20), 345
(10), 226 (10), 221 (20), 109 (100). C46H53N5O2S2 (772.10): calcd.
C 71.56, H 6.92, N 9.07, S 8.31; found C 71.02, H 7.13, N 8.63, S
7.57.
122.3, 121.4, 121.0, 118.9, 117.9, 117.0 ppm. IR (ATR): ν¯max
=
3335 (NH), 3054 (CH), 2960 (CH), 2923 (CH), 1534, 1497, 1434,
1398, 1146, 1115, 1070, 1012, 921, 747, 715 cm–1. MS (EI): m/z (%)
= 513 (30) [M+], 511 (100), 436 (10), 255 (40), 146 (30), 102 (10).
C30H19N5S2 (513.65): calcd. C 70.15, H 3.37, N 13.03, S 12.48;
found C 69.77, H 3.10, N 12.79, S 12.15. UV/Vis (CHCl3): λmax (lg
ε) = 334 (4.7), 366 (4.6), 746 (3.5) nm.
2,5-Bis(2-benzothiazolyl)-3,4-bis(3-trifluoromethylphenylamino)pyr-
role 5h: Yellow crystals, yield 1.2 g (38%), m.p. 243 °C. H NMR
2,5-Bis(2-benzothiazolyl)-4-(4-methoxyphenylamino)-3-(4-methoxy-
1
phenylimino)-3H-pyrrole (6c): Blue crystals, yield 993 mg (87%),
(250 MHz, CDCl3): δ = 10.36 (s, 1 H, N H pyrrole), 8.01 (m, 2 H,
CH-Ar), 7.79 (m, 2 H, CHAr), 7.51 (m, 2 H, CH-Ar), 7.35 (m, 2
H, CH-Ar), 7.18 (m, 2 H, CH-Ar), 7.02 (m, 2 H, CH-Ar), 6.81 (m,
2 H, CH-Ar), 6.75 (m, 2 H, CH-Ar), 5.52 (s, 2 H, NH) ppm. 13C
NMR (63 MHz, CDCl3): δ = 155.7, 152.3, 144.9, 134.5, 131.6 (q,
2J = 32 Hz, CCF3), 129.6, 126.7, 125.1, 124.1, 124.0 (1J = 272 Hz,
1
3
m.p. 307–308 °C. H NMR (250 MHz, CDCl3): δ = 8.36 (d, J =
8 Hz, 1 H, CH-Ar), 8.23 (d, 3J = 8 Hz, 1 H, CH-Ar), 7.83–7.16 (m,
14 H, CH-Ar), 6.69 (s, 1 H, NH), 3.96 (s, 3 H, OCH3), 3.74 (s, 3
H, OCH3) ppm. 13C NMR (63 MHz, CDCl3): δ = 164.4, 163.5,
162.9, 161.3, 154.1, 146.2, 135.2, 134.6, 134.4, 134.1, 133.2, 131.7,
129.4, 125.9, 125.1, 124.8, 123.6, 123.2, 122.0, 121.3, 121.0, 119.3,
119.0, 118.2, 114.8, 97.1, 56.0, 55.7 ppm. MS (EI): m/z (%) = 573
(100) [M+ ], 571 (70), 466 (40) [M – C7 H7 O]+ , 287 (50).
C32H23N5O2S2 (573.70): calcd. C 67.00, H 4.04, N 12.21, S 11.18;
found C 66.68, H 3.76, N 11.88, S 11.07. UV/Vis (CHCl3): λmax (lg
ε) = 350 (4.8), 372 (4.7), 706 (3.7) nm.
3
3
CF3), 123.8, 122.4, 121.6, 117.8, 116.4 (q, J = 4 Hz), 111.5 (q, J
= 4 Hz) ppm. IR (ATR): ν¯max = 3419 (NH), 3388 (NH), 3324,
3065, 1616, 1597, 1469, 1334, 1117, 754 cm–1. MS (EI): m/z (%) =
651 (10) [M+], 219 (25), 161 (30), 111 (45), 97 (70), 83 (100), 69
(80), 57 (90). C32H19F6N5S2 (651.66): calcd. C 58.98, H 2.94, N
10.75, S 9.84; found C 58.86, H 2.96, N 10.81, S 9.78. UV/Vis
(CHCl3): λmax (lg ε) = 381 (4.5), 402 (4.6) nm. Em: cyclohexane
Diethyl 6-Methyl-4-(4-tolylamino)-3H-pyrrolo[3,4-b]quinoxaline-
1,3-dicarboxylate (7a): Blue crystals, yield 628 mg (75%), m.p.
λmax = 455, toluene λmax = 459, CHCl3 λmax = 466, DMSO λmax
=
1
3
229 °C. H NMR (250 MHz, CDCl3): δ = 8.51 (d, J = 8 Hz, 1 H,
488 nm.
3
4
3
CH-Ar), 7.60 (dd, J = 8, J = 2 Hz, 1 H, CH-Ar), 7.49 (d, J =
3
8 Hz, 2 H, CH-Tol), 7.34 (d, J = 8 Hz, 2 H, CH-Tol), 7.18 (m, 1
General Procedure for the Oxidation of Pyrroles of Type 5: To the
solution of 2 mmol of the corresponding pyrrole 5 in 50 mL of
CH2Cl2, 1.4 g (10 mmol) of potassium carbonate and 6.0 g
(25 mmol) of lead dioxide was added (alternatively, 2.5–3.5 g = 5.6–
8.1 mmol of lead tetraacetate can be used for oxidation). The reac-
tion mixture was stirred for 2 h at room temp. When starting mate-
rial can be detected after this period by TLC, additional 1.2 g
(5 mmol) of lead dioxide was added and stirring was continued for
2 h. The reaction mixture was filtered and the residue was washed
with CH2Cl2, the combined deeply blue organic solutions were
washed three times with water and were dried with Na2SO4. Upon
removal of the solvent in vacuo, the residue was purified by column
chromatography on silica gel (CHCl3/methanol) and the crude
product was purified by recrystallization from CHCl3/n-heptane to
yield 6a–c and 7a–c as deeply blue crystals.
H, CH-Ar), 4.57 (q, 3J = 7.1 Hz, 2 H, OCH2), 4.04 (q, 3J = 7.1 Hz,
2 H, OCH2), 2.58 (s, 3 H, CH-Ar), 2.53 (s, 3 H, CH-Ar), 1.51 (t,
3
3J = 7.1 Hz, 3 H, CH3), 1.21 (t, J = 7.1 Hz, 3 H, CH3) ppm. 13C
NMR (63 MHz, CDCl3): δ = 162.53, 162.47, 147.9, 146.1, 140.8,
137.0, 136.1, 132.8, 130.4, 129.63, 129.59 129.2, 127.0, 122.1, 116.1,
115.4, 60.9, 60.6, 22.8, 21.5, 14.5, 14.3 ppm. MS (EI): m/z (%) =
417 (50) [M+], 299 (95), 273 (100), 271 (90), 91 (100). MS (micro-
ESI) m/z (%) = 456 (10) [M + K+], 440 (100) [M + Na+]. HRMS:
calcd. for C24H23N3NaO4: 440.159; found 440.156. UV/Vis
1
(CHCl3): λmax (lg ε) = 292 (4.7), 378 (4.2), 594 (3.6) nm. CV: ERED
= 0.630 V.
Diethyl 4-(Phenylamino)-3H-pyrrolo[3,4-b]quinoxaline-1,3-dicarb-
oxylate (7b): Blue crystals, yield 560 mg (72%), m.p. 227 °C. 1H
NMR (250 MHz, CDCl3): δ = 8.65 (m, 1 H, CH-Ar), 7.8–7.7 (m,
3
5 H, CH-Ar), 7.5–7.4 (m, 3 H, CH-Ar), 4.58 (q, J = 7.1 Hz, 2 H,
2,5-Bis(2-benzothiazolyl)-4-(4-tolylamino)-3-(4-tolylimino)-3H-pyr-
role (6a): Blue crystals, yield 910 mg (84%), m.p. 290 °C (decomp).
1H NMR (250 MHz, CDCl3): δ = 8.33 (d, 3J = 8 Hz, 1 H, CH-
Ar), 8.14 (d, 3J = 8 Hz, 1 H, CH-Ar), 7.92 (d, 3J = 8 Hz, 1 H, CH-
Ar), 7.74 (d, 3J = 8 Hz, 1 H, CH-Ar), 7.57–7.19 (m, 12 H, CH-
Ar), 2.67 (s, 3 H, CH-Tol), 2.45 (s, 3 H, CH-Tol) ppm. 13C NMR
(63 MHz, CDCl3): δ = 163.5, 162.6, 154.6, 148.0, 145.8, 140.4,
136.3, 136.0, 135.3, 135.0, 132.6, 130.6, 130.0, 128.3, 128.1, 125.7,
125.0, 124.7, 123.6, 123.5, 122.0, 121.3, 121.0, 118.8, 118.5, 116.2,
22.8, 21.6 ppm. IR (ATR): ν¯max = 3052 (CH), 2918 (CH), 1532,
1511, 1433, 1412, 1163, 1119, 1073, 1008, 922, 746, 725 cm–1. MS
(EI): m/z (%) = 541 (80) [M+], 450 (100) [M – C7H7]+, 270 (60),
135 (60). C32H23N5S2 (541.70): calcd. C 70.95, H 4.28, N 12.93, S
3
3
OCH2), 4.04 (q, J = 7.1 Hz, 2 H, OCH2), 1.51 (t, J = 7.1 Hz, 3
H, CH3), 1.21 (t, 3J = 7.1 Hz, 3 H, CH3) ppm. 13C NMR (63 MHz,
CDCl3): δ = 162.36, 162.32, 148.9, 138.6, 137.9, 134.0, 133.2, 130.7,
130.2, 129.9, 129.2, 127.3, 126.9, 121.9, 117.2, 115.3, 61.1, 60.6,
14.5, 14.3 ppm. MS (EI): m/z (%) = 389 (75) [M+], 270 (100), 245
(95), 244 (90). MS (micro-ESI) m/z (%) = 428 (10) [M + K+], 412
(100) [M + Na+]. HRMS: calcd. for C22H19N3NaO4: 412.127;
found 412.128. UV/Vis (CHCl3): λmax (lg ε) = 288 (4.6), 357 (4.0),
600 (3.5) nm.
6-Methyl-4-(4-tolylamino)-3H-pyrrolo[3,4-b]quinoxaline-1,3-dicar-
bonitrile (7c): Blue crystals, yield 440 mg (68%), m.p. 291–293 °C.
1H NMR (250 MHz, CDCl3): δ = 8.46 (d, 3J = 8 Hz, 1 H, CH-
3
4
3
11.84; found C 70.55, H 3.99, N 12.46, S 11.23. UV/Vis (CHCl3): Ar), 7.74 (dd, J = 8, 1 H, J = 2 Hz, CH-Ar), 7.62 (d, J = 8 Hz,
Eur. J. Org. Chem. 2009, 3404–3412
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3411

R. Beckert et al.
FULL PAPER
2 H, CH-Tol), 7.42 (d, J = 8 Hz, 2 H, CH-Tol), 7.29 (s, 1 H, CH-
Crystal Data for 7b: C22H19N3O4, Mr = 389.40 gmol–1, purple
3
Ar), 2.62 (s, 6 H, CH-Ar) ppm. 13C NMR (63 MHz, CDCl3): δ = prism, size 0.05ϫ0.05ϫ0.05 mm3, monoclinic, space group P21/n,
148.6, 143.1, 140.1, 137.8, 132.5, 132.4, 131.4, 130.9, 129.7, 127.0,
126.8, 115.7, 114.8, 114.1, 113.7, 97.5, 23.1, 21.6 ppm. IR (ATR):
a = 12.0835(12), b = 10.9753(10), c = 14.0578(11) Å, β =
100.090(6)°, V = 1835.5(3) Å3, T = 90 °C, Z = 4, ρcalcd.
=
ν¯max = 2922 (CH), 2852 (CH), 2215 (CN), 1557, 1509, 1391, 1358, 1.409 gcm–3, µ (Mo-Kα) = 0.99 cm–1, F(000) = 816, 11529 reflec-
1152, 1108, 1025, 825, 754 cm–1. MS (EI): m/z (%) = 323 (100)
[M+], 308 (10), 91 (10). MS (micro-ESI) m/z (%) = 363 (10) [M +
K+], 346 (100) [M + Na+], 324 (40) [M + H+]. HRMS: calcd. for
C20H14N5: 324.126; found 324.125. UV/Vis (CHCl3): λmax (lg ε) =
282 (4.5), 378 (4.1), 500 (3.4) nm.
tions in h(–14/15), k(–14/13), l(–18/18), measured in the range
2.05°ՅΘՅ27.44°, completeness Θmax = 99.5%, 4158 independent
reflections, Rint = 0.0843, 2319 reflections with Fo Ͼ 4σ(Fo), 264
parameters, 0 restraints, R1,obsd. = 0.0589, wR2
= 0.1332, R1,all
obsd.
= 0.1262, wR2,all = 0.1637, GOOF = 1.021, largest difference peak
and hole: 0.484/–0.297 eÅ–3.
Reduction of 3H-Pyrroles 6 and 3H-Pyrrolo[3,4-b]quinoxalines 7: To
the solution of 1 mmol of the corresponding 3H-pyrrole 6 or 7 in
20 mL of THF, 1.1 g (12 mmol) of sodium dithionite dissolved in
20 mL of water was added. The reaction mixture was stirred for
one hour at room temp. and then the yellow organic layer was
separated. The aqueous layer was extracted with CHCl3 and the
combined organic layers were dried with Na2SO4. Upon removal
of the solvent in vacuo, the residue was purified by column
chromatography on silica gel (CHCl3/n-heptane) to yield 5 and 8a–
c. The compounds of type 8 quickly reoxidize in the presence of
air.
Acknowledgments
We are grateful to Friedrich-Schiller-Universität, Jena for financial
support of the work of G. B. by a stipend.
[1] B. Jolicoeur, E. E. Chapman, A. Thompson, W. D. Lubell, Tet-
rahedron 2006, 62, 11531–11563.
[2] H. Fan, J. Peng, M. T. Hamann, J.-F. Hu, Chem. Rev. 2008,
108, 264–287.
Diethyl
6-Methyl-4-(4-tolylamino)-1H-pyrrolo[3,4-b]quinoxaline-
[3] a) G. Rravindran, S. Muthusubramanian, S. Selvaraj, S. Per-
umal, Arkivoc 2007, 12, 23–27 (07-2368DP); b) A. Gossauer,
in: Methoden der Organischen Chemie, Houben-Weyl, vol. E 6a,
663–664, Thieme, Stuttgart, 1994.
1,3-dicarboxylate (8a): 1H NMR (250 MHz, CDCl3): δ = 7.8–7.7
(m, 4 H, CH-Ar), 7.6–7.5 (m, 3 H, CH-Ar), 6.9 (s, 1 H, CH-Ar),
4.36 (q, 3J = 7.1 Hz, 2 H, OCH2), 3.89 (q, 3J = 7.1 Hz, 2 H, OCH2),
[4] a) G. Buehrdel, R. Beckert, E. Birckner, U.-W. Grummt, B.
Beyer, S. Kluge, J. Weston, H. Goerls, Eur. J. Org. Chem. 2007,
5404–5409; b) G. Buehrdel, R. Beckert, E. Petrlikova, P. Her-
zigova, V. Klimsova, J. Fleischhauer, H. Goerls, Synthesis 2008,
19, 3071–3080; c) G. Buehrdel, R. Beckert, B. Friedrich, H.
Goerls, J. Heterocycl. Chem. 2008, 45, 845–851; d) G. Buehrdel,
R. Beckert, D. Raabe, H. Görls, J. Sulfur Chem. 2006, 5, 401–
407; e) J. Atzrodt, J. Brandenburg, C. Käpplinger, R. Beckert,
W. G ünther, H. Görls, J. Fabian, J. Prakt. Chem./Chem.-Ztg.
1997, 339, 729–734; f) J. Wuckelt, M. Döring, P. Langer, H.
Görls, R. Beckert, Tetrahedron Lett. 1998, 39, 5269–5272; g)
D. Pufky, R. Beckert, M. Döring, O. Walther, Heterocycles
2002, 57, 1257–1264; h) D. Lindauer, R. Beckert, H. Görls, P.
Fehling, M. Döring, J. Prakt. Chem./Chem.-Ztg. 1995, 337,
143–152.
3
2.58 (s, 3 H, CH-Ar), 2.53 (s, 3 H, CH-Ar), 1.39 (t, J = 7.1 Hz, 3
H, CH3), 1.04 (t, J = 7.1 Hz, 3 H, CH3) ppm.
3
Crystal Structure Determination for 5d and 7b: The intensity data
for the compound was collected on a Nonius KappaCCD dif-
fractometer, using graphite-monochromated Mo-Kα radiation.
Data were corrected for Lorentz and polarization effects, but not
for absorption effects.[11] The structure was solved by direct meth-
ods (SHELXS)[12] and refined by full-matrix least-squares tech-
niques against Fo (SHELXL-97).[13] All hydrogen atoms were in-
2
cluded at calculated positions with fixed thermal parameters. For
the amine groups of 5d the hydrogen atoms were located by differ-
ence Fourier synthesis and refined isotropically. All other hydrogen
atoms were included at calculated positions with fixed thermal pa-
rameters. All non hydrogen atoms were refined anisotropically.[13]
XP (SIEMENS Analytical X-ray Instruments, Inc.) was used for
structure representations.
[5] J. Fabian, H. Görls, R. Beckert, J. Atzrodt, J. Prakt. Chem./
Chem.-Ztg. 1997, 339, 735–774.
[6] A. G. Fallis, I. M. Brinza, Tetrahedron 1997, 53, 17543–17594.
[7] P. Berkenkotter, R. F. Nelson, J. Electrochem. Soc. 1973, 120,
346–348.
CCDC-719950 (for 5d) and CCDC-719951 (for 7b) contains the
supplementary crystallographic data for this paper. These data can
be obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[8] M. Kobayashi, K. Uneyama, J. Org. Chem. 1996, 61, 3902–
3905.
[9] V. O. Rodionov, S. I. Presolski, S. Gardinier, Y.-H. Lim, M. G.
Finn, J. Am. Chem. Soc. 2007, 129, 12696–12704.
[10] J. R. Bailey, D. F. Snyder, J. Am. Chem. Soc. 1915, 37, 935–942.
[11] COLLECT, Data Collection Software, Nonius B. V., The Ne-
therlands, 1998; Z. Otwinowski, W. Minor, Processing of X-ray
Diffraction Data Collected in Oscillation Mode, in: Methods in
Enzymology, vol. 276, Macromolecular Crystallography, part A
(Ed.: C. W. Carter, R. M. Sweet), pp. 307–326, Academic Press,
New York, 1997.
Crystal Data for 5d: C32H25N5S2, CHCl3, Mr = 663.06 gmol–1, yel-
low prism, size 0.04ϫ0.04ϫ0.04 mm3, monoclinic, space group
P21/n, a = 16.4899(9), b = 10.7066(5), c = 17.3076(9) Å, β =
93.071(3)°, V = 3051.3(3) Å3, T = –90 °C, Z = 4, ρcalcd.
=
1.443 gcm–3, µ (Mo-Kα) = 4.71 cm–1, F(000) = 1368, 19174 reflec-
tions in h(–17/21), k(–13/13), l(–21/22), measured in the range
1.75°ՅΘՅ27.42°, completeness Θmax = 98.8%, 6867 independent
reflections, Rint = 0.0659, 4299 reflections with Fo Ͼ 4σ(Fo), 400
[12] G. M. Sheldrick, Acta Crystallogr., Sect. A 1990, 46, 467.
[13] G. M. Sheldrick, SHELXL-97 (rel. 97-2), University of
Göttingen, Germany, 1997.
parameters, 0 restraints, R1,obsd. = 0.0795, wR2
= 0.1884, R1,all
obsd.
= 0.1344, wR2,all = 0.2210, GOOF = 1.033, largest difference peak
Received: March 19, 2009
Published Online: May 15, 2009
and hole: 2.235/–1.325 eÅ–3.
3412
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 3404–3412