Synthesis of formyl-thienylpyrroles: Versatile building blocks for NLO materials

Article abstract of DOI:10.1016/j.tet.2006.02.004

Several formyl-substituted 1-alkyl(aryl)-2-(2′-thienyl)pyrroles 3-7 were synthesized by functionalization of the pyrrole or thiophene ring of thienylpyrroles 2 using different methods: Vilsmeier formylation or metalation followed by reaction with DMF.

Full text of DOI:10.1016/j.tet.2006.02.004

Tetrahedron 62 (2006) 3493–3501
Synthesis of formyl-thienylpyrroles: versatile building blocks
for NLO materials
a
a
b
M. Manuela M. Raposo,a, Ana M. R. C. Sousa, A. Maurıcio C. Fonseca and G. Kirsch
*
´
a
´
Centro de Quımica, Universidade do Minho, Campus de Gualtar 4710-057 Braga, Portugal
´
b
´ ´
Laboratoire d’Ingenierie Moleculaire et Biochimie Pharmacologique, UFR SciFA, Universite de Metz,
ˆ
1, Boulevard Arago, Metz Technopole, 57078 Metz Cedex 3, France
Received 5 January 2006; revised 31 January 2006; accepted 2 February 2006
Available online 28 February 2006
Abstract—Several formyl-substituted 1-alkyl(aryl)-2-(20-thienyl)pyrroles 3–7 were synthesized by functionalization of the pyrrole or
thiophene ring of thienylpyrroles 2 using different methods: Vilsmeier formylation or metalation followed by reaction with DMF.
q 2006 Elsevier Ltd. All rights reserved.
1. Introduction
Vilsmeier formylation and metalation followed by
quenching with DMF constitute the most significant routes
for the preparation of formyl-substituted pyrroles and
thiophenes.4–5
Formylation is a key process in organic synthesis, with the
resulting aldehyde function being a ‘crossroads’ intermedi-
ate. Not surprisingly, a large number of methods have been
developed for this reaction. Reagents for electrophilic
formylation are mostly of the form Y–CH]XC. Thus the
reactions attributed to Vilsmeier (ClCH]NRC2 ), Rieche
(e.g., MeOCHCl2/MeO]CHClC), Gatterman (Zn[CN]2/
HCl/HC]NH22C), Gatterman–Koch (CO/HCl/Lewis
acid/HC]OC) and even Duff (CH2]NHC2 — followed
by dehydrogenation of initially formed RCH2NH2) all fit
this pattern.1
The formyl-derivatives obtained can further react to afford
more complex molecules, which have made of formyl-
thiophenes and formyl-pyrroles some of the most important
molecules to be used as building blocks in biological active
compounds, supramolecular chemistry and molecular
electronics.6–25
During the last years we have been concerned with the
studies of several organic and organometallic compounds
such as oligothiophenes, thienylpyrroles, thienylphthala-
zines, thienyl and bithienyl–Mo complexes bearing donor
and electron acceptor units motivated by their potential
applications in optical and electronic devices.25–34 Recently,
we have investigated donor–acceptor substituted thienyl-
pyrroles. Due to their solvatochromic, electrochemical and
non-linear optical properties, donor–acceptor thienylpyrrole
derivatives could be used for the manufacture of semi-
conductor materials or materials with strong non-linear
optical (NLO) properties.28–31 Conjugated 1-(alkyl)aryl-2-
(20-thienyl)pyrroles, as strong p-electron donor moieties
functionalized with the formyl-group on the thiophene or on
the pyrrole moiety, could be used as precursors in the
preparation of functional p-conjugated systems with several
applications (e.g., NLO).
Organolithiums are beyond any doubt the most useful
metalated heterocycles. Usually they are prepared by direct
deprotonation of acidic hydrogens using strong bases or,
particulary useful in the case of the less acidic sites in
aromatic rings, by halogen exchange between a halogenated
heterocycle and an organolithium compound or lithium
metal. Another frequent alternative is the so-called ortho-
lithiation or ‘directed ortho-metalation’ (DoM), which is the
metalation of an aromatic ring adjacent to a heteroatom-
containing functional group by providing the lithium base
with a point of coordination, thus increasing reactivity close
to the coordination site. The lithiated species generated
by all these methods are able to react with all kinds of
electrophiles.2–3
As part of our continuing interest in non-linear optical
material, in this paper, we describe the synthesis of formyl-
thienylpyrroles, 3–7 prepared from 1-propyl-2-(20-thienyl)-
pyrrole 2a and 1-aryl-2-(20-thienyl)pyrroles 2b–f.35
Keywords: Formyl-substituted thienylpyrroles; Reactivity studies;
Vilsmeier formylation; Metalation; UV–visible spectroscopy.
*
Corresponding author. Tel.: C351 253 604381; fax: C351 253 678983;
e-mail: mfox@quimica.uminho.pt
0040–4020/$ - see front matter q 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.02.004

3494
M. M. M. Raposo et al. / Tetrahedron 62 (2006) 3493–3501
2. Results and discussion
Accordingly, Vilsmeier formylation of thienylpyrroles 2a–c
proceeded selectively in the pyrrole ring to form the
corresponding formyl-substituted thienylpyrroles 3–4.
2.1. Synthesis
2.1.1. Synthesis of 1-n-propyl-2-(20-thienyl)pyrrole 2a. I0n
order to compare the reactivity of 1-alkyl- and 1-aryl-2-(2 -
thienyl)pyrroles through the Vilsmeier reaction and through
the metalation followed by quenching with DMF, 1-propyl-
2-(20-thienyl)pyrrole 2a was synthesized from N-propyl-4-
(20-thienyl)-4-oxobutanamide 1a using a combination of the
Friedel–Crafts and the Lawesson reactions.35,36 Direct
amidation of 4-oxo-(20-thienyl)butanoic acid36 with propyl-
amine was carried out through DCC–BtOH mediated
reaction. Amide 1a was obtained as a colourless solid in
good yield (80%).
In our studies of Vilsmeier–Haack formylation of 1-propyl-
2-(20-thienyl)pyrrole 2a, the 5-position of the pyrrole ring
was found to be much more reactive than the 3-position. The
Vilsmeier–Haack formylation of 2a, with DMF/POCl3 at
60 8C for 2 h produced a mixture of 5-formyl- 3a (63%), and
3-formyl- derivative 4a, in lower yield (5%) (Table 1,
entries 1–2). Under the same experimental conditions
1-aryl-2-(20-thienyl)pyrroles 2b–c behave quite differently
giving a mixture of the 5- and 3-formyl-derivatives in
similar yields. Formylation of 2b gave a mixture of 3b
(19%) and 4b (22%), (Table 1, entries 3–4) and formylation
of 2c gave a mixture of 3c (12%) and 4c (10%). In
comparison to alkylpyrrole 2a the formyl derivatives of
1-aryl-2-(20-thienyl)pyrroles 2b–c were obtained in lower
yields (Scheme 1).
Recently, we have demonstrated that the reaction of
secondary aryl-(20-thienyl)-4-oxobutanamides with
Lawesson’s reagent (LR) can yield thienylpyrroles and/or
bithiophenes in different ratios depending on the
substituent(s) of the precursor arylamines.35 In the case of
the secondary n-propyl amide 1a, treatment with an
equimolar amount of LR gave only the thienylpyrrole 2a
in 47% yield.
S
a
b
c
R1 = n-Propyl
R1 = Phenyl
R1 = 4-MeOPhenyl
N
R1
2 a-c
POCl3 / DMF / 60oC
2.1.2. Vilsmeier formylation. Electrophilic substitution
reactions of thienylpyrroles were found to be very selective.
According to earlier reports, the pyrrole nitrogen atom has a
greater ability to delocalize the positive charge of
s-complexes than the sulfur atom in thiophene; pyrrole is
therefore considerably more reactive towards electrophilic
substitution than thiophene. Even when both a-positions of
the pyrrole ring are occupied, electrophilic substitution will
preferentially occur in the b-position of the pyrrole
ring rather than the a-position of the thiophene ring.4,37–40
The reactivity of these systems has been demonstrated with
the use of electrophilic reactions producing derivatives
with the electrophile substituted primarily on the pyrrole
ring.28–31,39–46
OHC
S
S
CHO
N
N
+
R1
R1
4 a-c
3 a-c
Scheme 1. Synthesis of formyl-thienylpyrroles 3–4 from thienylpyrroles 2
by Vilsmeier formylation.
In order to interpret the results obtained we consider several
factors: (i) an appreciably larger nucleophilicity of the
pyrrole ring compared to that of thiophene; (ii) a decrease in
the electron density in the pyrrole ring due to the
competitive conjugation of the N-aryl group with the
unshared electron pair on nitrogen and also due to its
negative inductive effect; (iii) possible steric influence due
to the n-propyl group for attack at the a-position of the
pyrrole ring.44
To our knowledge, there is only one previous study
describing the formylation of thienylpyrroles and this
study was performed through the Vilsmeier–Haack reaction
on the simple 2-(20-thienyl)pyrrole and 2-(30-thienyl)-
pyrrole. Bouka et al. obtained exclusively derivatives
formylated on the a-position of the pyrrole ring.40
3-Substituted pyrroles are the most difficult to synthesize
since most electrophilic aromatic substitution reactions and
lithiation reactions of N-substituted pyrroles occur at the
2-position and so functionalization at the 3-position of
Therefore, we decided to study the reactivity of different
thienylpyrroles bearing N-alkyl or N-aryl groups on the
pyrrole ring through the Vilsmeier–Haack reaction and
metalation followed by reaction with DMF.
Table 1. Yields, 1H NMR, IR and UV–visible data of formyl-thienylpyrroles 3–4
Entry
Pyrrole
Formyl-pyrrole
Yield (%)
dH (ppm)a
IR yCHO (cmK1
)
lmax (nm) (3)b
1
2
3
4
5
6
2a
2a
2b
2b
2c
2c
3a
4a
3b
4b
3c
4c
63
5
19
22
12
10
9.54
9.54
9.39
9.82c
9.38
9.81c
1658
1662
1660
1661
1655
1661
321.5 (24,650)
293.5 (5440)
340.5 (20,100)
325.0 (7440)
343.0 (21,559)
—
a For the CHO proton of formyl-thienylpyrroles 3–4 (300 MHz, CDCl3).
b All the UV–visible spectra were run in ethanol.
c For the CHO proton of formyl-thienylpyrroles 3–4 (300 MHz, acetone-d6).

M. M. M. Raposo et al. / Tetrahedron 62 (2006) 3493–3501
3495
pyrrole is a challenging goal in synthetic research. Bulky
substituents on the nitrogen atom promote 3-substitution.
This observation led to new approaches to the synthesis of
3-substituted pyrroles, as these are normally found only as
by products in reactions leading predominantly to 2-substi-
tution.47–49 As 3-formyl N-arylpyrroles are key synthetic
intermediates to highly biologically active compounds the
preparation of new derivatives, even in fair yields, still
remains an attractive goal.10–11,44,46
were0detected. 0These signals were attributed, respectively, to
the 4 , 30 and 5 -H protons in the thiophene moiety.
2.1.3. Metalation followed by reaction with DMF. As
(50-formyl-20-thienyl)pyrroles could not be synthesized
solely by the Vilsmeier–Haack reaction, we tried to prepare
these compounds by lithiation followed by treatment
with DMF.
The electron-rich five member aromatic N-substituted
pyrrole, furan and thiophene are lithiated at C-2 by direct
deprotonation with a lithium-containing base. Several
authors have reported the a-lithiation of N-arylpyrroles
using different experimental conditions: n-BuLi-TMEDA
chelate, n-BuLi-tBuOK (LiCKOR) superbase, tert-BuLi-
secondary amides, Na/dry ether/0 8C/tert-BuLi, tert-
BuLi/K78 8C/THF, n-BuLi/THF/K78 8C, n-BuLi-
TMEDA/THF/K75 8C.49–54
The structures of formyl-substituted pyrrole derivatives 3–4
were unambiguously confirmed by their analytical and
spectral data. Inthe1HNMRspectrumof5-formyl-substituted
pyrrole derivatives 3a–c two signals at about 6.40–6.64 and
6.96–7.17 ppm were detected. Both signals appear as doublets
with coupling constants of 4.2–4.5 Hz indicating the presence
of two adjacent protons (3-H and 4-H) at the corresponding
pyrrole moiety. In the 1H NMR spectrum of 3-formyl-
substituted pyrrole derivatives 4a–c two signals at about
6.47–6.79 and 6.78–7.19 ppm were detected. Both signals
appear as doublets with coupling constants of 3.0–3.3 Hz.
These signals were attributed to the 5-H and 4-H in the pyrrole
moiety. Thepositionoftheformylgroupinpyrrole derivatives
4a–c was also confirmed through the analysis of 2D NOESY
spectra. Thus, the 2D NOESY spectra of compounds 4a–c
shows a cross peak of the pyrrole ring 4-H with the formyl
group and also a cross peak of the formyl group with the
thiophene ring 30-H. On the contrary, the 2D NOESY
spectrum of compound 4a shows a cross peak of the NCH2
protons of the n-propyl group with the 5-H proton of the
pyrrole ring but there is no cross peak of the pyrrole ring 5-H
with the formyl group. This is taken as evidence for the
attachment of the formyl group at ring position 3. In all the 1H
NMR spectra of formyl-substituted pyrrole derivatives 3a–c
and 4a–c three signals at about 6.90–7.20 (multiplet),
6.72–7.20 (double doublet) and 7.19–7.63 (double doublet)
Recently, novel methods for site-selective lithiation in a or
benzylic positions of 1-(methoxyphenyl), 1-(chlorophenyl),
1-(bromophenyl), 1-(trifluoromethylphenyl) and 1-(methyl-
phenyl)pyrroles have also been reported.55–59
To our knowledge, the formylation of thienylpyrroles
through lithiation followed by quenching with DMF has
not been previously reported, and success would open
the way to a new range of formyl-functionalized
thienylpyrroles.
The metalation of thienylpyrroles 2 was carried out with
n-BuLi in dry ether at 0 8C for 1 h. Subsequently, the
organolithium derivatives were converted to the corre-
sponding formyl compounds, by addition of DMF followed
by refluxing the mixture for 1 h (Scheme 2, Table 2).
In order to compare the reactivity of pyrroles 2 under
i) n-BuLi / 0oC / dry ether
ii) DMF / reflux
S
OHC
S
N
N
5 a
2 a
CH3
CH3
S
b
c
d
e
f
R2 = H
R2 = 4-OMe
R2 = 2,4-diOMe
R2 = 3,4,5-triOMe
R2 = 4-F
N
i) n-BuLi / 0oC / dry ether
ii) DMF / reflux
2 b-f
R2
S
S
S
OHC
OHC
+
+
N
N
N
OMe
CHO
R2
5 b-f
7 d
R2
6 c-d
CHO
OMe
Scheme 2. Synthesis of formyl-thienylpyrroles 5–7 from thienylpyrroles 2 by metalation followed by reaction with DMF.

3496
M. M. M. Raposo et al. / Tetrahedron 62 (2006) 3493–3501
Table 2. Yields, 1H NMR, IR and UV–visible data of formyl-thienylpyrroles 5–7
Entry
Pyrrole
lmax (nm) (3)a
Formyl-pyrrole
Yield (%)
dH (ppm)b
IR yCHO (cmK1
)
lmax (nm) (3)a
1
2
3
4
5
6
7
8
9
2a
2b
2c
2c
2d
2d
2d
2e
2f
291.0 (1800)
294.5 (9208)
290.0 (11,410)
—
286.5 (10,093)
—
—
5a
5b
5c
6c
5d
6d
7d
5e
5f
68
78
63
9.87
9.75
9.74
9.81,c 10.48c
9.73
9.75, 10.45
10.45
9.77
1659
1659
1659
1659, 1684
1652
1657, 1690
1693
1659
374.0 (9474)
374.0 (19,180)
379.0 (18,613)
374.0 (10,605)
384.5 (18,158)
377.0 (16,040)
—
5
48, 34d
18d
8, 14d
12
281.5 (8477)
289.5 (7939)
377.0 (11,860)
373.5 (15,191)
25
9.75
1659
a All the UV–visible spectra were run in ethanol.
b For the CHO proton of formyl-thienylpyrroles 5–7 (300 MHz, CDCl3).
c For the CHO proton of formyl-thienylpyrroles 5–7 (300 MHz, acetone-d6).
d Yields for compounds 5d–7d obtained for 2 h of lithiation followed by 2 h of reaction with DMF.
the experimental conditions described above, the reaction
time studied for all derivatives (for the metalation and for
the reaction with DMF) was 1 h. As a consequence of the
limited reaction time, in some cases, unreacted starting
materials remained in the reaction mixtures.
spectra of formyl-substituted thiophene derivatives 5a–f
three signals at about 6.20–6.42 (multiplet) 6.53–6.77
(double doublet), and 6.82–6.97 (multiplet) were detected.
These signals were attributed, respectively, to the 4, 3 and
5-H protons in the pyrrole moiety.
Through this method thienylpyrroles 2a–b and 2e–f were
selectively lithiated at the a-position of the thiophene ring
giving formyl-derivatives 5a–b and 5e–f.
2.2. UV–visible study of formyl-substituted
thienylpyrroles
The electronic spectra of formyl-thienylpyrrole derivatives
were recorded in ethanol (Tables 1–2).
The methoxy group is known as a moderately strong ortho
directing substituent with electron withdrawal and electron
donor properties.3,55,60 At the same time, for compounds
2c–d the 4-methoxy and the 2,4-dimethoxy group(s) have an
a-directing effect in the aromatic ring. Consequently, the
formylation of the aromatic ring was also observed for
thienylpyrroles 2c–d (Table 2, entries 4, 6 and 7,
compounds 6c–d, 7d) due to the ortho directing effect of
the methoxy groups (Scheme 2) giving a mixture of several
formylated derivatives with 2-(50-formyl-20-thienyl)-
pyrroles 5c–d being the major products.
All the formyl-substituted thienylpyrroles 3–7 synthesized
exhibit intense absorptions in the UV–visible range. The
position of these absorptions is influenced by the structure of
the compounds, for example, by the substituent on the
nitrogen atom of the pyrrole ring and by the position of
substitution of the formyl group on the thiophene, pyrrole or
on the aromatic ring(s).
Communication between the electron donating and
accepting termini can be evaluated by comparing the
lmax values. Dramatic differences in energy occur upon
formyl-substitution of thienylpyrroles 2. For example,
thienylpyrrole 2d (lmaxZ286.5 nm) is shifted 98 nm
For compound 2d we studied also the effect of the reaction
time for the metalation step and for the reaction with DMF.
Metalation of thienylpyrrole 2d for 2 h followed by 2 h of
reflux with DMF gave a mixture of 4 compounds:
thienylpyrrol0e 2d (18%), 1-(200,400-dimethoxyphenyl)-2-
(50-formyl-2 -thienyl)pyrrole0 5d (34%), 1-(300-formyl-
200,400-dimethoxyph0e0 nyl)-2-(2 -thienyl)pyrrole 0 7d (14%)
and 1-(300-formyl-2 ,400-dimethoxyphenyl)-2-(5 -formyl-20-
thienyl)pyrrole 6d (18%) (Table 2, entries 5–7). The
experiment showed that, instead of improving the yield of
compound 5d we obtained the diformylated compound 6d
and a higher yield for the formyl-aryl derivative 7d as a
result of the increase of the reaction time.
upon formyl substitution (formyl- derivative 5d, lmax
Z
384.5 nm) (Table 2, entry 5). This effect has been
attributed to the stabilization of LUMO by the electron-
withdrawing groups.61 The influence of the substituent on
the nitrogen atom of the pyrrole ring is demonstrated by
comparison of the absorption maxima of compounds 5a
and 5d as the longest wavelength transition is shifted from
374.0 nm in 1-(n-propyl)-2-(50-formyl-200-0th0i0enyl)pyrrole
5a (Table 2,0entry 1) to 384.5 nm for 1-(2 ,4 -dimethoxy-
phenyl)-2-(5 -formyl-20-thienyl)pyrrole 5d (Table 2, entry
5). The influence of the position of the formyl group on the
pyrrole ring on lmax of absorption for formyl derivatives 3
Compounds 5e and 5f were obtained but in lower yields. It
should be recorded that we could not isolate any benzylic
formyl product from these reactions.
and 4 is noteworthy. The difference in lmax values (Dlmax
)
between compounds (3a–b and 4a–b) is in the range of
15–28 nm (Table 1, entries 1–4). As expected, the presence
of the formyl group on the 5-position of the pyrrole ring
(3a–3b), relative to the same acceptor group in the
3-position (4a–4b), results in a bathochromic shift in the
lmax of absorption for 3a–3b due to more extensive
electron delocalization.
1H NMR spectra of (50-formyl-20-thienyl)pyrrole
derivatives 5a–f showed two signals at about 6.61–7.12
and 7.49–7.71 ppm. Both signals appear as doublets with
coupling constants of 3.9–4.2 Hz indicating 0the presence
of two adjacent protons (30-H and 4 -H) at the
corresponding thiophene moiety. In all the 1H NMR

M. M. M. Raposo et al. / Tetrahedron 62 (2006) 3493–3501
3497
3. Conclusions
described in Refs. 35, 36, by reacting 4-oxo-(2-thienyl)-
butanoic acid (5.4 mmol) in CH2Cl2 with 1,3-dicyclo-
hexylcarbodiimide (7.1 mmol) and BtOH (7.1 mmol) and
adding propylamine (5.4 mmol) at rt.
Starting from the readily available thienylpyrroles 2,
commercial reagents and simple and convenient procedures
were used to synthesize new formyl-thienylpyrroles in fair
to good yields, via two methods: Vilsmeier formylation and
lithiation followed by reaction with DMF.
4.2.1. N-Propyl-4-(20-thienyl)-4-oxobutanamide 1a. Col-
ourless solid (80%). Mp: 96.2–97.6 8C (EtOH). IR (liquid
film) n 3311 (NH), 3029, 1661 (C]O), 1645 (C]O), 1552,
1523, 1420, 1397, 1248, 1179, 1063, 983, 954, 910, 851,
Vilsmeier–Haack formylation of 2 was made at the 3- and
5-positions on the pyrrole ring to give compounds 3–4.
These results are in accordance with the greater nucleophi-
licity of the pyrrole ring versus the thiophene ring as has
been shown earlier in the case of the tricyanovinylatio0n
reaction and azo coupling reaction of 1-alkyl(aryl)-2-(2 -
thienyl)pyrroles 2.28,29
1
717 cmK1. H NMR (CDCl3) d 0.92 (t, 3H, JZ7.2 Hz,
CH3), 1.52 (m, 2H, CH2CH3), 2.61 (t, 2H, JZ7.8 Hz,
CONHCH2), 5.78 (br s, 1H, NH), 7.13–7.15 (m, 1H, 40-H),
7.65 (dd, 1H, JZ5.1, 1.2 Hz, 50-H), 7.78 (dd, 1H, JZ3.7,
1.2 Hz, 30-H). 13C NMR (CDCl3) d 11.30, 22.76, 30.26,
34.62, 41.27, 128.16, 132.23, 133.73, 143.59, 171.71,
192.09. Anal. Calcd for C11H15NO2S: C, 58.63; H, 6.72;
N, 6.22; S, 14.23. Found: C, 58.63; H, 6.71; N, 6.23;
S, 13.98.
The lithiation of thienylpyrroles 2a–b and 2e–f, followed by
quenching with DMF, occurred selectively on the a-position
of the thiophene ring giving formyl derivatives 5a–b and
5e–f. For compounds 2c–d with methoxy group(s) on
the aryl ring was obtained a mixture of formyl-derivatives
5c–d, 6c–d and 7d with the formyl group on the thiophene
ring and/or on the0 aryl ring. The major compounds formed
were (50-formyl-2 - thienyl)pyrroles 5c–d.
(ii) Reaction of amide 1a with Lawesson’s reagent.
Thienylpyrrole 2a was obtained using the experimental
method described in Refs. 35, 36, by heating the amide 1a
(2.3 mmol) in toluene (12 ml) with the Lawesson reagent
(2.3 mmol) at reflux during 30 min.
4.2.2. 1-Propyl-2-(20-thienyl)pyrrole 2a. Orange oil
(47%). UV (EtOH): lmax nm (3/MK1 cmK1) 291.0 (1803),
225.5 (2054). IR (liquid film) n 3102, 2964, 2932, 2874,
1508, 1470, 1430, 1383, 1345, 1299, 1234, 1201, 1108,
1070, 941, 896, 844, 783, 711, 613 cmK1. 1H NMR (CDCl3)
d 0.92 (t, 3H, JZ7.2 Hz, (CH2)2CH3), 1.65–1.68 (m, 2H,
CH2CH2CH3), 3.97 (t, 2H, JZ7.2 Hz, NCH2), 6.17–6.22
(m, 1H, 4-H), 6.31 (dd, 1H, JZ3.6, 1.8 Hz, 3-H), 6.76–6.88
(m, 1H, 5-H), 7.01 (dd, 1H, JZ3.6, 1.2 Hz, 30-H), 7.06–7.09
(m, 1H, 40-H), 7.29 (dd, 1H, JZ5.1, 1.2 Hz, 50-H). 13C
NMR (CDCl3) d 11.17, 24.74, 48.99, 107.71, 110.16,
122.68, 124.71, 125.29, 126.28, 127.16, 134.97. MS (EI)
m/z (%): 191 (MC, 100), 162 (50), 149 (34), 130 (7), 121
(13), 111 (40), 104 (15). HRMS: m/z (EI) for: C11H13NS;
calcd 191.0768; found: 191.0763.
The formyl-derivatives 3–7 studied exhibit an absorption
band in the UV–visible range influenced by the structure of
the compounds: the type of substituent on the nitrogen atom
of the pyrrole ring and also by the position of the formyl
group on the thiophene or on the pyrrole ring.
The conjugated formyl derivatives of 1-alkyl(aryl)-2-(20-
thienyl)pyrroles will be used in the future, as precursors in
the preparation of compounds with a stronger electronwith-
drawing group for potential applications in NLO.22,25
4. Experimental
4.1. General
1H NMR spectra were obtained on a Varian Unity Plus
Spectrometer at 300 MHz and 13C NMR spectra were
determinated on a Varian Unity Plus Spectrometer at
75.4 MHz using the solvent peak as internal reference.
The solvents are indicated in parenthesis before the
chemical shift values (d relative to TMS). Mps were
determined on a Gallenkamp apparatus and are uncorrected.
Infrared spectra were recorded on a Perkin Elmer 1600
FTIR spectrophotometer. UV–visible absorption spectra
were obtained using a Shimadzu UV/2501PC spectro-
photometer. EI mass spectra EI (70 eV) and HRMS were
run on a Unicam GC–MS 120. Elemental analysis was
carried out on a Leco CHNS-932. Column chromatography
was performed on Merck silica gel 60 (Art 9385). Light
petroleum refers to solvent boiling in the range 40–60 8C.
4.2.3. General procedure for the synthesis of formyl
derivatives 3–4 of 1-alkyl(aryl)-2-(20-thienyl)pyrroles
2a–c through Vilsmeier formylation. POCl3 (0.46 mmol)
was added to DMF (0.46 mmol) at 0 8C and the mixture was
stirred for 15 min at 0 8C. After this time pyrroles 2
(0.39 mmol) dissolved in DMF (1 ml) were added dropwise
with stirring. The reaction mixture was then heated 2 h at
60 8C. The solution was then poured slowly into 5 ml
saturated sodium acetate aqueous solution and stirred
30 min. The organic layer was diluted with ether, washed
with saturated NaHCO3 aqueous solution, and dried with
anhydrous MgSO4. Evaporation of the organic extract under
reduced pressure gave a mixture of 5-formyl- 3 and
3-formylpyrroles 4, which were purified by ‘flash’ chroma-
tography on silica with increasing amounts of ether in light
petroleum as eluent.
The synthesis of 1-aryl-2-(20-thienyl)pyrroles 2b–f has been
described elsewhere.35
Vilsmeier for0mylation of 2a gave a mixture of 5-formyl-
1-propyl-2-(2 -thienyl)pyrrole 3a and 3-formyl-1-propyl-2-
(20-thienyl)pyrrole 4a. The first component eluted was
5-formyl-1-propyl-2-(20-thienyl)pyrrole 3a as a green
oil (63%). UV (EtOH): lmax nm (3/MK1 cmK1), 321.5
4.2. Synthesis of 1-propyl-2-(20-thienyl)pyrrole 2a
(i) Synthesis of N-propyl-4-(20-thienyl)-4-oxobutanamide
1a. Amide 1a was obtained using the experimental method

3498
M. M. M. Raposo et al. / Tetrahedron 62 (2006) 3493–3501
(24,650). IR (liquid film): n 2964, 1658 (C]O), 1509, 1473,
1428, 1396, 1314, 1294, 1251, 1225, 1198, 1154, 1042, 847,
776, 702 cmK1. 1H NMR (CDCl3) d 0.90 (t, 3H, JZ7.5 Hz,
(CH2)2CH3), 1.70–1.82 (m, 2H, CH2CH2CH3), 4.41 (t, 2H,
JZ7.8 Hz, NCH2), 6.40 (d, 1H, JZ4.2 Hz, 3-H), 6.96 (d,
1H, JZ4.2 Hz, 4-0H), 7.12–7.16 (m, 1H, 40-H), 7.18 (dd, 1H,
JZ3.6, 1.2 Hz, 3 -H), 7.44 (dd, 1H, JZ5.1, 1.2 Hz, 50-H),
9.54 (s, 1H, CHO). 13C NMR (CDCl3) d 10.80, 24.68, 47.50,
111.89, 124.73 (two overlapped signals), 127.00, 127.42,
127.59, 132.17, 132.51, 136.36. MS (EI) m/z (%): 219 (MC,
100), 218 (21), 204 (16), 202 (74), 190 (28), 177 (80), 176
(77), 162 (18), 148 (16), 121 (30), 104 (7). HRMS: (EI) m/z
(%) for C12H13NOS; calcd 219.0718; found 219.0720. The
second component eluted was 3-formyl-1-propyl-2-(20-
thienyl)pyrrole 4a as a brown oil (5%). UV (EtOH): lmax
nm (3/MK1 cmK1), 293.5 (5440), 248.0 (10,388), 211.0
(8678). IR (liquid film): n 1662 (C]O), 1485, 1446, 1382,
1257, 849, 765, 706 cmK1. 1H NMR (CDCl3) d 0.87 (t, 3H,
JZ7.5 Hz, (CH2)2CH3), 1.65–1.82 (m, 2H, CH2CH2CH3),
3.87 (t, 2H, JZ7.2 Hz, NCH2), 6.47 (d, 1H, JZ3.3 Hz, 5-
H), 6.78 (d, 1H, JZ3.3 Hz, 4-H), 7.13–7.20 (m, 2H, 30and
40-H), 7.54 (dd, 1H, JZ5.1, 1.2 Hz, 50-H), 9.54 (s, 1H,
CHO). MS (EI) m/z (%): 219 (MC, 100), 218 (19), 190 (12),
174 (11), 162 (24), 149 (10), 130 (4), 121 (6), 104 (7), 89
(5). HRMS: (EI) m/z (%) for C12H13NOS; calcd 219.0718;
found 219.0708.
component eluted was 5-formyl-1-phenyl-2-(20-thienyl)pyr-
role 3c as a yellow solid (12%). Mp: 110.5–111.9 8C. UV
(EtOH): lmax nm (3/MK1 cmK1), 343.0 (21,559), 257.5
(8165), 226.5 (14,668). IR (liquid film): n 1655 (CHO),
1512, 1495, 1395, 1337, 1319, 1248, 1230, 1193, 1162,
1103, 1052, 832, 805, 779, 765, 709 cmK1 1H NMR
.
(CDCl3) d 3.89 (s, 3H, OCH3), 6.63 (d, 1H, JZ4.5 Hz, 3-H),
6.80 (dd, 1H, JZ3.8, 1.2 Hz, 30-H), 6.88–6.92 (m, 1H, 40-
H), 7.00 (d, 2H, JZ9.0 Hz, 2!Ar-H), 7.150 (d, 1H, JZ
4.5 Hz, 4-H), 7.19 (dd, 1H, JZ5.1, 1.2 Hz, 5 -H), 7.26 (d,
2H, JZ9.0 Hz, 2!Ar-H), 9.38 (s, 1H, CHO). 13C NMR
(CDCl3) d 55.49, 110.58, 114.45, 120.38, 126.41, 126.51,
127.16, 129.54, 129.88, 132.71, 134.76, 136.69, 160.17,
178.88. MS (EI) m/z (%): 283 (MC, 100), 254 (19), 240
(30), 175 (48), 147 (18), 121 (16), 108 (6). HRMS: (EI) m/z
(%) for C16H13NO2S; calcd 283.0667; found 283.0664.
Anal. Calcd for C16H13NO2S: C, 67.83; H, 4.69; N, 4.94; S,
11.33. Found: C, 67.58; H, 4.96; N, 4.91; 00S, 10.82. The
second component eluted was 3-formyl-1-(4 -methoxyphe-
nyl)-2-(20-thienyl)pyrrole 4c as pale yellow solid (10%).
Mp: 99.7–101.0 8C. IR (liquid film): n 1661 (CHO), 1512,
1449, 1300, 1242, 1028, 835, 763 cmK1. 1H NMR (acetone-
d6) d 3.86 (s, 3H, OCH3), 6.76 (d, 1H, JZ3.0 Hz, 5-H), 7.00
(d, 2H, JZ9.0 Hz, 2!Ar-H), 7.08 (dd, 1H, JZ3.0, 1.0 Hz,
4-H), 7.09–7.13 (m, 1H, 40-H), 7.16 (dd, 1H, JZ3.4, 1.2 Hz,
30-H), 7.25 (d, 2H, JZ9.0 Hz, 2!Ar-H), 7.61 (dd, 1H, JZ
5.1, 1.2 Hz, 50-H), 9.81 (s, 1H, CHO). 13C NMR (CDCl3) d
55.46, 107.85, 114.24, 125.43, 125.68, 127.03, 127.55,
128.40, 129.54, 129.90, 130.51, 131.47, 135.23, 186.71. MS
(EI) m/z (%): 283 (MC, 100), 254 (13), 240 (26), 210 (5),
175 (11), 121 (8). HRMS: (EI) m/z (%) for C16H13NO2S;
calcd 283.0667; found 283.0666. Anal. Calcd for
C16H13NO2S: C, 67.83; H, 4.59; N, 4.94; S, 11.33. Found:
C, 67.64; H, 4.98; N, 4.91; S, 11.03.
Vilsmeier formylation of 2b gave a mixture of 5-formyl-1-
phenyl-2-(20-thienyl)pyrrole 3b and 3-formyl-1-phenyl-2-
(20-thienyl)pyrrole 4b. The first component eluted was
5-formyl-1-phenyl-2-(20-thienyl)pyrrole 3b as a pale
yellow solid (19%). Mp: 72.6–73.9 8C. UV (EtOH): lmax
nm (3/MK1 cmK1), 340.5 (20,100), 253.0 (8630). IR
(liquid film): n 1660 (CHO), 1596, 1511, 1497, 1469,
1433, 1406, 1361, 1318, 1046, 847, 775, 695, 547 cmK1
.
1H NMR (CDCl3) d 6.64 (d, 1H, JZ4.2 Hz, 3-H), 6.72
(dd, 1H, JZ3.9, 1.2 Hz, 30-H), 6.86–6.90 (m, 1H, 40-H),
7.17 (d, 0 1H, JZ4.2 Hz, 4-H), 7.19 (dd, 1H, JZ5.1,
1.2 Hz, 5 -H), 7.33–7.39 (m, 2H, 2!Ar-H), 7.49–7.56 (m,
3H, 3!Ar-H), 9.39 (s, 1H, CHO). 13C NMR (CDCl3) d
109.72, 110.96, 120.51, 126.43, 126.62, 127.21, 128.87,
129.34, 129.46, 132.66, 136.45, 137.15, 178.76. MS (EI)
m/z (%): 253 (MC, 100), 225 (12), 175 (11), 147 (10), 121
(20), 77 (12). HRMS: (EI) m/z (%) for C15H11NOS; calcd
253.0561; found 253.0558. The second component eluted
was 3-formyl-1-phenyl-2-(20-thienyl)pyrrole 4b as a pale
yellow solid (22%). Mp: 106.9–107.8 8C. UV (EtOH):
lmax nm (3/MK1 cmK1) 325.0 (7440). IR (liquid film): n
1661 (CHO), 1596, 1496, 1473, 1449, 1413, 1241, 848,
4.2.4. General procedure for the synthesis of formyl-
derivatives of 1-alkyl(aryl)-2-(20-thienyl)pyrroles 2a–f,
via metalation with n-BuLi followed by reaction with
DMF. A 2.5 M solution of n-BuLi in hexanes (0.44 ml,
1.1 mmol) was dropped under Ar at 0 8C to a stirred solution
of thienylpyrroles 2 (1.0 mmol) in anhydrous ether. The
reaction mixture was then stirred 1 h at 0 8C and was
allowed to stand 15 min at rt. DMF (0.05 ml, 1.0 mmol)
dissolved in anhydrous ether (2 ml) was added dropwise at
rt. The mixture was heated at reflux for 1 h. The mixture was
poured into water (20 ml) and extracted with (3!50 ml) of
ethyl acetate. The combined organic extracts were washed
with H2O (100 ml), dried with MgSO4 and the solvent
was evaporated under reduced0 pressure to give the
crude 1-alkyl(aryl)-2-(50-formyl-2 -thienyl)pyrroles 5 or a
mixture of formyl-derivatives 5, 6 and 7, which were
purified by ‘flash’ chromatography on silica with increasing
amounts of ether in light petroleum as eluent.
1
762, 695 cmK1. H NMR (acetone-d6) d 6.79 (d, 1H, JZ
3.0 Hz, 5-H), 7.10–7.13 (m, 1H, 40-H), 7.15–7.19 (m, 2H,
4-H and 30-H), 7.30–7.36 (m, 2H, 2!Ar-H), 7.43–7.49
(m, 3H, 3!Ar-H), 7.63 (dd, 1H, JZ5.1, 1.2 Hz, 50-H),
9.82 (s, 1H, CHO). 13C NMR (CDCl3) d 108.14, 110.95,
125.44, 126.27, 127.09, 128.20, 128.48, 129.18, 130.61,
132.66, 134.92, 138.60, 186.76. MS (EI) m/z (%): 253
(MC, 100), 224 (19), 209 (14), 180 (5), 121 (11), 77 (22).
HRMS: (EI) m/z (%) for C15H11NOS; calcd 253.0561;
found 253.0576.
Metalation of thienylpyrrole 2a followed by a reaction wit0h
DMF gave a mixture of 2a and 1-propyl-2-(50-formyl-2 -
thienyl)pyrrole 5a. The first compound eluted was
thienylpyrrole 2a (19%). The second compound eluted
was 1-propyl-2-(50-formyl-20-thienyl)pyrrole 5a as an
orange oil (68%). UV (EtOH): lmax nm (3/MK1 cmK1
)
Vilsmeyer formylation of 2c gave a mixture of 5-formyl-1-
(400-methoxyphenyl)-2-(20-thienyl)pyrrole 3c and 3-formyl-
1-(400-methoxyphenyl)-2-(20-thienyl)pyrrole 4c. The first
374.0 (9474). IR (liquid film): n 1659 (C]O), 1554, 1513,
1475, 1436, 1381, 1283, 1229, 1061, 941, 808, 724, 668,
611, 506 cmK1. 1H NMR (CDCl3) d 0.93 (t, 3H, JZ7.5 Hz,

M. M. M. Raposo et al. / Tetrahedron 62 (2006) 3493–3501
3499
(CH2)2CH3), 1.77–1.90 (m, 2H, CH2CH2CH3), 4.08 (t, 2H,
JZ7.5 Hz, NCH2), 6.20–6.22 (m, 1H, 4-H), 6.53 (dd, 1H,
JZ3.9, 1.8 Hz, 3-H), 6.82–6.86 (m, 1H, 5-H), 7.12 (d, 1H,
JZ3.9 Hz, 30-H), 7.71 (d, 1H, JZ3.9 Hz, 40-H), 9.87 (s, 1H,
CHO). 13C NMR (CDCl3) d 11.06, 24.61, 49.64, 108.70,
112.38, 112.44, 125.56, 125.70, 137.22, 140.94, 145.32,
182.54. MS (EI) m/z (%): 219 (MC, 100), 218 (9), 191 (19),
177 (26), 176 (23), 162 (17), 148 (7), 104 (7), 78 (2).
HRMS: (EI) m/z (%) for C12H13NOS; calcd 219.0718;
found 219.0718.
124.49, 125.07, 126.56, 127.02, 127.07, 132.36, 134.26,
137.01, 140.92, 144.81, 161.43, 182.53, 188.68. MS (EI)
m/z (%): 311 (MC, 100), 285 (5), 268 (30), 235 (6). HRMS:
(EI) m/z (%) for C17H13NO3S; calcd 311.0616; found
311.0625.
Metalation of thienylpyrrole 2d followed by a reaction
with DMF gave a mixture of thi0enylpyrrole 2d, 1-(200,400-
dimethoxyphenyl)-2-(50-formyl-2 -thienyl)pyrrole 5d and
1-(300-formyl-200,400-dimethoxyphenyl)-2-(20-thienyl)pyrrole
7d. The first compound eluted was pyrrole 2d as a green
solid (40%). The second component eluted was 1-(300-
formyl-200,400-dimethoxyphenyl)-2-(20-thienyl)pyrrole 7d as
a dark green oil (8%). IR (liquid film): n 3108, 1693 (C]O),
1659, 1581, 1492, 1442, 1397, 1334, 1288, 1232, 1186,
1164, 1121, 1096, 1013, 948, 842, 814, 716 cmK1. 1H NMR
(CDCl3) d 3.48 (s, 3H, OCH3), 3.96 (s, 3H, OCH3), 6.33–
6.38 (m, 1H, 4-H), 6.54 (dd, 1H, JZ4.2, 1.8 Hz, 3-H), 6.70
(dd,010 H, JZ3.6, 1.2 Hz, 30-H), 6.75 (d, 1H, JZ9.0 Hz, 600-H
or 5 -H), 6.80–6.83 (m, 1H, 5-H), 6.86–6.90 (m, 1H, 40-H),
7.08 (dd, 1H, JZ5.1, 1.2 Hz, 50-H), 7.42 (d, 1H, JZ9.0 Hz,
600-H or 500-H), 10.45 (s, 1H, CHO). 13C NMR (CDCl3) d
56.28, 61.44, 106.44, 109.59, 109.72, 119.05, 123.71,
123.88, 125.04, 125.72, 127.07, 128.54, 134.70, 135.92,
158.82, 161.18, 189.14. MS (EI) m/z (%): 313 (MC, 100),
298 (17), 284 (13), 270 (9), 255 (5), 121 (9). HRMS: (EI)
m/z (%) for C17H15NO3S; calcd 313.0772; found 313.0785.
The third compound0 eluted was 1-(200,400-dimethoxy-
phenyl)-2-(50-formyl-2 -thienyl)pyrrole 5d as a dark green
oil (48%). UV (EtOH): lmax nm (3/MK1 cmK1) 384.5
(18,158), 277.5 (6264), 233.0 (1312), 207.0 (30,609). IR
(liquid film): n 2962, 2838, 1652 (CHO), 1613, 1589, 1541,
1516, 1462, 1443, 1416, 1383, 1306, 1286, 1260, 1232,
1210, 1161, 1135, 1092, 1062, 1046, 1030, 928, 911, 803,
728 cmK1. 1H NMR (CDCl3) d 3.66 (s, 3H, OCH3), 3.89 (s,
3H, OCH3), 6.34–6.38 (m, 1H, 4-H), 6.52–6.58 (m, 2H,
300-H and 500-H), 6.74 (dd, 1H, JZ3.9, 1.8 Hz, 3-H), 6.80–
6.84 (m, 2H, 30-H and 5-H), 7.17 (d, 1H, JZ9.3 Hz, 600-H),
7.51 (d, 1H, JZ4.2 Hz, 40-H), 9.73 (s, 1H, CHO). 13C NMR
(CDCl3) d 55.54, 55.69, 99.72, 104.41, 109.56, 111.33,
121.03, 123.11, 127.34, 128.00, 129.78, 137.08, 140.00,
145.78, 156.40, 161.39, 182.51. MS (EI) m/z (%): 313 (MC,
100), 270 (8), 255 (8). HRMS: (EI) m/z (%) for
C17H15NO3S; calcd 313.0773; found 313.0770. Anal.
Calcd for C17H15NO3S: C, 65.16; H, 4.79; N, 4.47; S,
10.24. Found: C, 65.14; H, 5.07; N, 4.58; S, 10.04.
Metalation of thienylpyrrole 2b followed by a reaction wit0h
DMF gave a mixture of 2b and 1-phenyl-2-(50-formyl-2 -
thienyl)pyrrole 5b. The first compound eluted was
thienylpyrrole 02b (9%). The second compound eluted was
1-phenyl-2-(5 -formyl-20-thienyl)pyrrole 5b as a dark
orange oil (78%). UV (EtOH): lmax nm (3/MK1 cmK1
)
374.0 (19,180), 260.0 (7000). IR (liquid film): n 1659
(CHO), 1597, 1498, 1461, 1438, 1230, 1062, 916, 802, 724,
1
696, 667 cmK1. H NMR (CDCl3) d 6.36–6.38 (m, 1H,
4-H), 6.61 (d, 1H, JZ4.2 Hz, 30-H), 6.71 (dd, 1H, JZ3.6,
1.5 Hz, 3-H), 6.94–6.97 (m, 1H, 5-H), 7.28–7.33 (m, 2H,
2!Ar-H), 7.42–7.47 (m, 3H, 3!Ar-H), 7.49 (d, 1H, JZ
4.2 Hz, 40-H), 9.75 (s, 1H, CHO). 13C NMR (CDCl3) d
109.99, 113.05, 124.42, 126.88, 126.94, 128.42, 129.40
(two overlapped signals), 136.88, 139.38, 140.73, 145.25,
182.49. Anal. Calcd for C15H11NOS: C, 71.13; H, 4.35; N,
5.53; S, 12.67. Found: C, 70.98; H, 4.54; N, 5.58; S, 12.69.
Metalation of thienylpyrrole 2c followed by a reaction wit0h
DMF gave a mixture of 1-(400-methoxyphenyl)-2-(5 -
formyl-20-thienyl)pyrrole 5c and 1-(300-formyl-400-methox-
yphenyl)-2-(50-formyl-200-0 thienyl)pyrrole 6c. Th0e first com-
pound eluted was 1-(4 -methoxyphenyl)-2-(5 -formyl-20-
thienyl)pyrrole 5c as a green solid (63%). Mp: 96.6–97.4 8C.
UV (EtOH): lmax nm (3/MK1 cmK1) 379.0 (18,613), 270.0
inf. (6000), 230.5 (16,603), 203.5 (24,294). IR (liquid film):
n 1659 (CHO), 1609, 1539, 1515, 1462, 1444, 1412, 1299,
1250, 1231, 1182, 1169, 1158, 1106, 1061, 917, 836, 797,
755, 724, 666, 619 cmK1. 1H NMR (CDCl3) d 3.87 (s, 3H,
OCH3), d 6.32–6.36 (m, 1H, 4-H), 6.67 (d, 1H, JZ4.2 Hz,
30-H), 6.70 (dd, 1H, JZ3.6, 1.8 Hz, 3-H), 6.88–6.91 (m, 1H,
5-H), 6.95 (d, 2H, JZ9.0 Hz, 2!Ar-H), 7.22 (d, 2H, JZ
9.0 Hz, 2!Ar-H), 7.49 (d, 1H, JZ4.2 Hz, 40-H), 9.74 (s,
1H, CHO). 13C NMR (CDCl3) d 55.45, 109.63, 112.33,
114.41, 124.02, 127.13, 127.19, 128.21, 132.04, 136.98,
140.43, 145.32, 159.52, 182.46. MS (EI) m/z (%): 283 (MC,
100), 268 (54), 240 (6), 121 (8), 103 (5). HRMS: (EI) m/z
(%) for C16H13NO2S; calcd 283.0667; found 283.0665.
Anal. Calcd for C16H13NO2S: C, 67.83; H, 4.59; N, 4.94; S,
11.33. Found: C, 67.78; H, 4.82; N0,0 5.02; S, 11.25. The
second compound eluted was 1-(3 -formyl-400-methoxy-
phenyl)-2-(50-formyl-20-thienyl)pyrrole 6c as a orange oil
(5%). UV (EtOH): lmax nm (3/MK1 cmK1) 374.0 (10,605),
270.0 inf. (5000). IR (liquid film): n 1684 (C]O), 1659
(C]O), 1611, 1499, 1462, 1394, 1273, 1234, 1122, 1019,
869, 817, 755, 726, 666 cmK1. 1H NMR (acetone-d6) d 4.11
(s, 3H, OCH3), 6.37–6.40 (m, 1H, 4-H), 6.80 (dd, 1H, JZ
3.8, 1.2 Hz, 3-H), 6.91 (d, 1H, JZ3.9 H0z0 , 30-H), 7.09–7.11
(m, 1H, 5-H), 7.4010 (d, 2H, JZ8.7 Hz, 5 -H), 7.65 (dd, 1H,
JZ8.7, 2.4 Hz, 6 -H), 7.69 (d, 1H, JZ2.4 Hz, 200-H), 7.75
(d, 1H, JZ3.9 Hz, 40-H), 9.81 (s, 1H, CHO), 10.48 (s, 1H,
CHO). 13C NMR (CDCl3) d 56.06, 110.18, 112.56, 112.92,
Metalation of thienylpyrrole 2d during 2 h followed by 2 h
of reflux with DMF gave a mixture of 4 compounds:
thienylpyrrol0e 2d (18%), 1-(200,400-dimethoxyphenyl)-2-
(50-formyl-2 -thienyl)pyrrole0 5d (34%), 1-(300-formyl-
200,400-dimethoxyph0e0 nyl)-2-(2 -thienyl)pyrrole 0 7d (14%)
and 1-(300-formyl-2 ,400-dimethoxyphenyl)-2-(5 -formyl-20-
thienyl)pyrrole 6d as a dark orange oil (18%). UV (EtOH):
lmax nm (3/MK1 cmK1) 377.0 (16,040), 260.5 (14,720). IR
(liquid film): n 1690 (C]O), 1657 (C]O), 1492, 1461,
1288, 1231, 1094, 1019, 812, 608 cmK1. 1H NMR (CDCl3)
d 3.48 (s, 3H, OCH3), 4.00 (s, 3H, OCH3), 6.39–6.42 (m,
1H, 4-H), 6.77 (dd, 1H, JZ3.6, 1.5 Hz, 3-H), 6.82 (d, 1H,
JZ9.0 Hz, 500-H), 6.85–6.90 (m, 2H, 30-H and 5-H), 7.46 (d,
1H, JZ9.0 Hz, 600-H), 7.54 (d, 1H, JZ4.2 Hz, 40-H), 9.75
(s, 1H, CHO), 10.45 (s, 1H, CHO). 13C NMR (CDCl3) d
56.35, 61.79, 106.96, 110.46, 112.23, 119.37, 123.62,

3500
M. M. M. Raposo et al. / Tetrahedron 62 (2006) 3493–3501
´
3. Chinchilla, R.; Najera, C.; Yus, M. Chem. Rev. 2004, 104,
2667.
125.26, 127.47, 127.87, 135.43, 137.30, 140.62, 144.74,
158.44, 161.99, 182.49, 188.79. MS (EI) m/z (%): 341 (MC,
100), 326 (7), 312 (13), 298 (7), 83 (9). HRMS: (EI) m/z (%)
for C18H15NO4S; calcd 341.0722; found 341.0710.
4. Jackson, A. H. In Pyrroles; Jones, R. A., Ed.; The Chemistry of
Heterocyclic Compounds; Wiley: New York, 1990; Vol. 48,
p 295; Part 1, and references cited therein.
5. Bird, C. W., Ed.; Comprehensive Heterocyclic Chemistry II;
Pergamon: Oxford, 1996; Vol. 2, p 1.
1-(300,400,500-Trimethoxyphenyl)-2-(50-formyl-20-thienyl)-
pyrrole 5e. Metalation of thienylpyrrole 2e followed by a
reaction with DMF gave a mixture of 0thienylpyrrole 2e and
1-(300,400,500-trimethoxyphenyl)-2-(5 -formyl-20-thienyl)-
pyrrole 5e. The first component eluted was thienylpyrrole
2e as a pale green sol0i0d (40%). The second component
eluted was 1-(300,400,5 -trimethoxyphenyl)-2-(50-formyl-
20-thienyl)pyrrole 5e as a yellow solid (12%). Mp: 113.5–
114.7 8C. UV (EtOH): lmax nm (3/MK1 cmK1) 377.0
(11,860), 265.0 inf. (6820). IR (liquid film): n 2935, 1659
(CHO), 1596, 1507, 1463, 1417, 1262, 1230, 1127, 1066,
1033, 1004, 840, 808, 727, 668 cmK1. 1H NMR (CDCl3) d
3.79 (s, 6H, 2!OCH3), 3.92 (s, 3H, OCH3), 6.34–6.37 (m,
1H, 4-H), 6.52 (br s, 2H, 200and 600-H), 6.66 (d, 1H, JZ
4.2 Hz, 30-H), 6.71 (dd, 1H, JZ3.8, 1.5 Hz, 3-H), 6.89–6.93
(m, 1H, 5-H), 7.52 (d, 1H, JZ3.9 Hz, 40-H), 9.77 (s, 1H,
CHO). 13C NMR (CDCl3) d 55.45, 109.63, 112.33, 114.41,
124.02, 127.13, 127.19, 128.21, 132.04, 136.98, 140.43,
145.32, 159.52, 182.46. MS (EI) m/z (%): 343 (MC, 100),
328 (50), 300 (6). HRMS: (EI) m/z (%) for C18H17NO4S;
calcd 343.0878; found 343.0896.
´
6. Castin˜eiras, A.; Carballo, R.; Perez, T. Polyhedron 2001, 20,
441.
7. Alonso, R.; Bermejo, E.; Castin˜eiras, A.; Carballo, R.; Perez, T.
J. Mol. Struct. 2002, 606, 155.
´
´
´
`
8. Rodrıguez-Argu¨elles, M.; Lopez-Silva, E. C.; Sanmartın, J.;
Pelagatti, P.; Zani, F. J. Inorg. Biochem. 2005, 99, 2231.
9. Won, D.-H.; Lee, C.-H. Tetrahedron Lett. 2003, 44, 6695.
10. Beecher, J. E.; Tirrell, D. A. Tetrahedron Lett. 1998, 39, 3927.
11. Haldar, P.; Guin, J.; Ray, J. K. Tetrahedron Lett. 2005, 46, 1071.
12. Pichon-Santander, C.; Scott, A. I. Tetrahedron Lett. 2000, 41,
2825.
´
13. Rodrıguez, J. G.; Lafuente, A.; Rubio, L. Tetrahedron Lett.
2004, 45, 5685.
14. Toba, M.; Takeoka, Y.; Rikukawa, M.; Sanui, K. Synth. Met.
2005, 152, 197.
15. Fan, Q.-L.; Zhang, G.-W.; Lu, X.-M.; Chen, Y.; Huang, Y.-Q.;
Zhou, Y.; Chan, H. S. O.; Lai, Y.-H.; Xu, G.-Q.; Huang, W.
Polymer 2005, 46, 11165.
16. Purkarthofer, T.; Gruber, K.; Fechter, M. H.; Griengl, H.
Tetrahedron 2005, 61, 7661.
1-(400-Fluorophenyl)-2-(50-formyl-20-thienyl)pyrrole 5f.
Metalation of thienylpyrrole 2f followed by a reaction
with DMF gave a0mixture of thienylpyrrole 2f and 1-(400-
fluorophenyl)-2-(5 -formyl-20-thienyl)pyrrole 5f. The first
component eluted was thienylpyrrole 2f as a pale yellow
solid (15%). The second component eluted was the 1-(400-
fluorophenyl)-2-(50-formyl-20-thienyl)pyrrole 5f as a
brown solid (25%). Mp: 112–114 8C. UV (EtOH): lmax
nm (3/MK1 cmK1) 373.5 (15,191), 257.6 (6386), 226.0
(8830), 204.0 (17,041). IR (liquid film): n 1659 (CHO),
1511, 1462, 1439, 1412, 1349, 1221, 1189, 1154, 1094,
1061, 1039, 916, 842 cmK.1 1H NMR (CDCl3) d 6.30–6.40
(m, 1H, 4-H), 6.63 (d, 1H, JZ4.2 Hz, 30-H), 6.65–6.75 (m,
1H, 3-H), 6.85–6.90 (m, 1H, 5-H), 7.13 (tap, 2H, JZ8.4 Hz,
300 and 500-H), 7.25–7.35 (m, 2H, 200 and 600-H), 7.49 (d, 1H,
JZ4.2 Hz, 40-H), 9.75 (s, 1H, CHO). MS (EI) m/z (%): 271
(MC, 100), 243 (3), 242 (8), 209 (5), 198 (6), 185 (5), 150
(9), 133 (6), 121 (6), 95 (5), 75 (4). HRMS: (EI) m/z (%) for
C15H10FNOS; calcd 271.0467; found 271.0465.
17. Takekuma, S.-I.; Takahashi, K.; Sakaguchi, A.; Shibata, I.;
Sasaki, M.; Minematsu, T.; Takekuma, H. Tetrahedron 2005,
61, 10349.
18. Hareau, G. P.-J.; Neya, S.; Funasaki, N.; Taniguchi, I.
Tetrahedron Lett. 2002, 43, 3109.
19. Simionescu, C. I.; Grigoras, M.; Cianca, I.; Olaru, N. Eur.
Polym. J. 1998, 34, 891.
20. Mignani, G.; Leising, F.; Meyrueix, R.; Samson, M.
Tetrahedron Lett. 1990, 31, 4743.
21. Effenberger, F.; Wurthner, F.; Steybe, F. J. Org. Chem. 1995,
60, 2082.
22. Eckert, K.; Schroder, A.; Hartmann, H. Eur. J. Org. Chem.
2000, 1327 and references cited therein.
`
23. Turbiez, M. P.; Frere, P.; Roncali, J. Tetrahedron 2005, 61, 3045.
24. Mason, C. R.; Skabara, P. J.; Cupertino, D.; Schofield, J.;
Meghdadi, F.; Ebner, B.; Sariciftci, N. S. J. Mater. Chem.
2005, 15, 1446.
25. Raposo, M. M. M.; Kirsch, G. Tetrahedron 2003, 59, 4891.
26. Raposo, M. M. M.; Fonseca, A. M. C.; Kirsch, G. Tetrahedron
2004, 60, 4071.
27. Batista, R. M. F.; Costa, S. P. G.; Raposo, M. M. M.
Tetrahedron Lett. 2004, 45, 2825.
Acknowledgements
28. Raposo, M. M. M.; Sousa, A. M. R. C.; Fonseca, A. M. C.;
Kirsch, G. Tetrahedron 2005, 61, 8249.
Thanks are due to Foundation for Science and Technology
´
(Portugal) for financial support through Centro de Quımica
(UM) and through POCTI, FEDER (Ref. POCTI/QUI/
37816/2001).
29. Raposo, M. M. M.; Sousa, A. M. R. C.; Kirsch, G.; Ferreira, F.;
Belsey, M.; de Matos Gomes, E.; Fonseca, A. M. C.
Tetrahedron 2005, 61, 11991.
30. Raposo, M. M. M.; Fonseca, A. M. C.; Sousa, A. M. R. C.;
Kirsch, G. Mater. Sci. Forum 2006, 514–516, 98.
31. Raposo, M. M. M.; Fonseca, A. M. C.; Sousa, A. M. R. C.;
Kirsch, G. Mater. Sci. Forum 2006, 514–516, 103.
32. Raposo, M. M. M.; Sampaio, A. M. B. A.; Kirsch, G.
J. Heterocycl. Chem. 2005, 42, 1245.
References and notes
1. March, J. Advanced Organic Chemistry, 4th ed.; Wiley-
Interscience: New York, 1992; p 542 and references cited
therein.
33. Costa, F.; Silva, C. J. R.; Raposo, M. M. M.; Fonseca, A. M.;
Neves, I. C.; Carvalho, A. P.; Pires, J. Microporous
Mesoporous Mater. 2004, 72, 111.
2. Schlosser, M. Angew. Chem., Int. Ed. 2005, 44, 376 and
references cited therein.

M. M. M. Raposo et al. / Tetrahedron 62 (2006) 3493–3501
3501
34. Fonseca, A. M. C.; Raposo, M. M. M.; Sousa, A. M. R. C.;
Kirsch, G.; Beley, M. Eur. J. Inorg. Chem. 2005, 21, 4361.
35. Raposo, M. M. M.; Sampaio, A. M. B. A.; Kirsch, G. Synthesis
2005, 2, 199.
48. Muchowski, J. M.; Naef, R. Helv. Chim. Acta 1984, 67, 1168
and references cited therein.
49. Kozikowski, A. P.; Cheng, X.-M. J. Org. Chem. 1984, 49,
3239.
36. Raposo, M. M. M.; Kirsch, G. Heterocycles 2001, 55, 1487.
37. Belen’kii, L. I. Khim. Geterotsikl. Soedin. 1980, 12, 1587.
38. Belen’kii, L. I. Heterocycles 1994, 37, 2029.
39. Boukou-Poba, J.-P.; Farnier, M.; Guilard, R. Tetrahedron Lett.
1979, 20, 1717.
50. Stefan, K.-P.; Schuhmann, W.; Parlar, H.; Korte, F. Chem. Ber.
1989, 122, 169.
51. Lomas, J. S.; Vaissermann, J. J. Chem. Soc., Perkin Trans. 2
1998, 1777.
52. Robertson, J.; Kuhnert, N.; Zhao, Y. Heterocycles 2000, 53,
2415.
40. Boukou-Poba, J.-P.; Farnier, M.; Guilard, R. Can. J. Chem.
1981, 59, 2962.
53. Selvi, S.; Pu, S.-C.; Cheng, Y.-M.; Fang, J.-M.; Chou, P.-T.
J. Org. Chem. 2004, 69, 6674.
41. Trofimov, B. A.; Korostova, S. E.; Mikhaleva, A. I.;
Nesterenko, R. N.; Sigalov, M. V.; Voronov, V. K.;
Polovnikova, R. I. Zh. Org. Khim. 1982, 18, 894.
42. Korostova, S. E.; Nesterenko, R. N.; Mikhaleva, A. I.;
Shevchenko, S. G.; Kalabin, G. A.; Polovnikova, R. I. Khim.
Geterotsikl. Soedin. 1990, 273.
54. Martineau, D.; Gros, P.; Fort, Y. J. Org. Chem. 2004, 69, 7914.
55. Faigl, F.; Fogassy, K.; Thurner, A.; Toke, L. Tetrahedron
1997, 53, 4883.
´ ´
56. Faigl, F.; Fogassy, K.; Szanto, Z.; Lopata, A.; Toke, L.
Tetrahedron 1998, 54, 4367.
´
´
57. Faigl, F.; Fogassy, K.; Szucs, E.; Kovacs, K.; Keseru, Gy.-M.;
43. Korostova, S. E.; Nesterenko, R. N.; Mikhaleva, A. I.;
Shevchenko, S. G.; Kalabin, G. A.; Polovnikova, R. I. Khim.
Geterotsikl. Soedin. 1991, 337.
¨
Harmat, V.; Bocskei, Zs.; Toke, L. Tetrahedron 1999, 55,
7881.
´
´
44. Korostova, S. E.; Mikhaleva, A. I.; Trofimov, B. A. Russ.
Chem. Rev. (Engl. Transl.) 1999, 68, 459.
58. Fogassy, K.; Kovacs, K.; Keseru, G. M.; Toke, L.; Faigl, F.
J. Chem. Soc., Perkin Trans. 1 2001, 1039.
59. Faigl, F.; Thurner, A.; Vass, B.; Toke, L. J. Chem. Res. (S)
2003, 132.
45. Trofimov, B. A.; Sobenina, L. N.; Demenev, A. P.; Mikhaleva,
A. I.; Ushakov, I. A.; Tarasova, O. A.; Smirnov, V. I.;
Petrushenko, K. B.; Vokin, A. I.; Murzina, N. M.; Myachina,
G. F. ARKIVOC 2001, ix, 37.
60. Snieckus, V. Chem. Rev. 1990, 90, 879 and references cited
therein.
46. Niziursky-Mann, R. E.; Cava, M. P. Heterocycles 1992, 34,
2003.
47. Majchrzak, M. W.; Simchen, G. Tetrahedron 1986, 42, 1299.
61. Casado, J.; Pappenfus, T. M.; Miller, L. L.; Mann, K. R.; Orti, E.;
Viruela, P. M.; Pou-Amerigo, R.; Hernandez, V.; Navarrete,
J. T. L. J. Am. Chem. Soc. 2003, 125, 2524.