Scope and applicability of an expedient synthesis leading to polysubstituted 3-(carboxyphenyl)pyrroles

Article abstract of DOI:10.1080/00397910701198898

A convenient three-step route toward a functionalized pyrrole building block for novel anti-inflammatory agents is reported. In contrast to previous strategies, the present approach focuses on inexpensive starting materials and application on a multigram

Full text of DOI:10.1080/00397910701198898

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Scope and Applicability of an Expedient
Synthesis Leading to Polysubstituted
3‐(Carboxyphenyl)pyrroles
Thomas Ullrich a , Michael Ghobrial a , Klaus Weigand a & Andreas L.
Marzinzik b
a Global Discovery Chemistry , Novartis Institutes for Biomedical Research ,
Vienna, Austria
b Global Discovery Chemistry , Novartis Institutes for Biomedical Research ,
Basel, Switzerland
Published online: 13 Oct 2010.
To cite this article: Thomas Ullrich , Michael Ghobrial , Klaus Weigand & Andreas L. Marzinzik (2007) Scope
and Applicability of an Expedient Synthesis Leading to Polysubstituted 3‐(Carboxyphenyl)pyrroles, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 37:7,
1109-1119, DOI: 10.1080/00397910701198898
To link to this article: http://dx.doi.org/10.1080/00397910701198898
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Synthetic Communicationsw, 37: 1109–1119, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701198898
Scope and Applicability of an Expedient
Synthesis Leading to Polysubstituted
3-(Carboxyphenyl)pyrroles
Thomas Ullrich, Michael Ghobrial, and Klaus Weigand
Global Discovery Chemistry, Novartis Institutes for Biomedical
Research, Vienna, Austria
Andreas L. Marzinzik
Global Discovery Chemistry, Novartis Institutes for Biomedical
Research, Basel, Switzerland
Abstract: A convenient three-step route toward a functionalized pyrrole building block
for novel anti-inflammatory agents is reported. In contrast to previous strategies, the
present approach focuses on inexpensive starting materials and application on a
multigram scale. A high degree of functional diversity is demonstrated in various
derivatives, and the scope and limitations of this route are discussed. Complementary
to the described tetrasubstituted pyrroles, a novel ring-closure protocol based on the
Feist–Benary condensation affords trisubstituted analogues.
Keywords: chalkones, Feist–Benary condensation, Paal–Knorr cyclization, pyrrole
synthesis, Stetter reaction
3-(p-Carboxyphenyl)pyrroles have been identified in a target-driven drug
discovery project to be suitable lipophilic anchors for the development of
novel anti-inflammatory agents. In particular, compound 1a (Fig. 1) served
as a structural template for a focused derivatization program.
Received in Poland July 6, 2006
Address correspondence to Thomas Ullrich, Global Discovery Chemistry, Novartis
Institutes for Biomedical Research, Brunner Strasse 59, A-1230 Wien, Vienna, Austria.
E-mail: thomas.ullrich@novartis.com
1109

1110
T. Ullrich et al.
Figure 1. Tetra-substituted 3-(carboxyphenyl)pyrroles.
We therefore sought a robust procedure to synthesize structural analogues
of 1a, keeping the benzoic acid moiety constant and varying the 1,2,5-subsitu-
tion pattern on the pyrrole core 1 (Fig. 1).
Most strategies for the synthesis of substituted pyrroles involve ring
formation, either from 1,4-dicarbonyl compounds and primary amines (Paal–
Knorr condensation)[1] or from condensation of a-aminocarbonyl derivatives
with activated a-methylene ketones.[2] Although a few reports describe interest-
ing routes to 2,3,5-triaryl-substituted pyrroles,[3a–c] Braun et al.[4a,b] reported
a powerful coupling–isomerization–Stetter–Paal–Knorr multicomponent
sequence, based on the Sonogashira coupling of (hetero)aryl-propynols with
electron-deficient (hetero)aryl halides in the first step (Scheme 1).
Scheme 1. Reported multicomponent synthesis of tetrasubstituted pyrroles.[4a]

Polysubstituted 3-(carboxyphenyl) pyrroles
1111
Unfortunately, only few adequately substituted propargyl alcohols are
commercially available, and their preparation requires additional synthetic
steps. For our purposes, we decided to replace the Sonogashira reaction
with a simple aldol-type condensation, which was also amenable to bulk inter-
mediate upscaling. Scheme 2 demonstrates that the synthesis of chalkones 3
and subsequent Stetter 1,4-addition of a carboxaldehyde effectively provide
1,4-diketones, which could undergo Paal–Knorr condensation. Importantly,
none of the three steps require protection of the carboxyl moiety, as a basic
environment ensures its deprotonated form.
In the first step, it was essential that the synthesis of chalkones 3 worked
well for all substrates, irrespective of the electronic nature of the correspond-
ing acetophenone. Thus, under basic aqueous conditions (2N NaOH/
EtOH)[5a,b] with subsequent acidic workup (to effect both liberation of the
carboxylate and elimination of the hydroxyl group to the saturated system),
electron-deficient aromatic ketones (e.g., 4-fluoroacetophenone, Table 1,
entry b) as well as electron-rich ones (e.g., 4-methoxyacetophenone, entry
c) gave chalkones in yields similar to unsubstituted acetophenone (entry a).
Because of the insoluble character of the benzoic acid moiety, all
Scheme 2. Three-step synthesis of 3-(carboxyphenyl)pyrroles: Reagents and typical
conditions: a) 2 N NaOH, EtOH, rt, 4 h; b) K2CO3, triethylamine, 3-benzyl-5-(2-hydro-
xyethyl)-4-methyl-thiazolium chloride, EtOH, reflux, 8 h; c) EtOH, reflux, 3h.

1112
T. Ullrich et al.
Table 1. Substitution pattern and yields for the three-step synthesis of pyrroles 1
Yield (%)
Entry
R1
R2
R3
Step 1 Step 2 Step 3 Total
a
b
c
d
e
Phenyl
4-Fluorophenyl
4-Methoxyphenyl
4-Cyanophenyl
4-tBuNHSO2-
phenyl
Methyl
Methyl
Methyl
Methyl
Methyl
2-Furyl 77
2-Furyl 75
2-Furyl 85
2-Furyl 77
2-Furyl 64
95
63
90
64
51
79
46
58
46
33
43
86
85a
85a
85a
f
4-(N-BOC)
aminophenyl
Methyl
Methyl
2-Furyl 56
79
58
26
g
h
i
Methyl
Methyl
2-Phenylethyl
2-Furyl 36
2-Furyl 32
2-Furyl 77
59
85a
95
95
32
7
26
53
53
4-Pyridyl
Phenyl
Phenyl
96
73b
73b
j
2-(Dimethylamino) 2-Furyl 77
ethyl
k
Phenyl
2-(1-Morpholin-yl) 2-Furyl 77
ethyl
95
70b
51
l
Phenyl
Phenyl
2-Phenylethyl Methyl 77
2-Methoxyethyl Methyl 77
50
50
30b
39b
12
15
m
aNot purified by chromatography. Yield estimated by TLC.
bCyclization by microwave irradiation (5 min, 1808C).
compounds could be isolated by filtration after acidic workup. The scope of
this reaction is not limited to substituted acetophenones but can also be
applied to heteroaryl ketones. However, 4-acetylpyridine (entry h) gave
poorer yields (32%), as the workup was more pH sensitive because of the
added basic functionality. Acetone (R1 ¼ Me, entry g) was prone to double
condensation under the chosen reaction conditions but sufficient amounts of
the corresponding unsaturated methyl ketone (36% yield) could be obtained.
Stetter 1,4-addition[6] of furfural (R3 ¼ 2-furyl) to various chalkones 3
usually gave good yields of 1,4-diketones 4 in the presence of two different
bases after several hours of heating in ethanolic solution (1 equivalent of
K2CO3 was used to deprotonate the acid and 1 equivalent of triethylamine
was later added to promote the reaction). In some cases, crude products
were purified by flash chromatography; others were judged sufficiently pure
by thin-layer chromatography (TLC) to continue the synthesis without purifi-
cation (as indicated in Table 1). The catalyst responsible for an Umpolung of
furfural was carefully chosen; toxic cyanides were not considered an option, as
it was intended to scale up the synthesis for development purposes, and alkali
cyanides are inappropriate for the Umpolung of aliphatic aldehydes because of
their high basicity.[6] The more recently reported thiazolium catalysts worked

Polysubstituted 3-(carboxyphenyl) pyrroles
1113
nicely in our hands, and we opted for the commercially available 3-benzyl-
5-(2-hydroxyethyl)-4-methyl-thiazolium chloride[6] (CAS 4568-71-2). Employ-
ment of this catalyst was also applicable to aliphatic aldehydes, as exemplified
by acetaldehyde (entries l and m) where yields dropped notably to 50%,
presumably because of autocondensation.
Paal–Knorr cyclization of 1,4-diketones 4 was conveniently achieved by
treatment with excess primary amine and acetic acid at elevated tempera-
tures.[7] In the simple case of R2 ¼ Me, it was sufficient to react 4 in an
ethanolic solution of methylamine under reflux. In the case of bulkier and
functionalized amines, higher temperatures and/or extended reaction
periods were required to promote cyclization. Up to a scale of approx. 1 g,
this could be achieved by microwave irradiation[8] in a closed vessel,
whereas larger batches had to be carried out in pressurized autoclave
systems. For instance, the N-(2-methoxy)ethyl substituent was once intro-
duced in 46 h under reflux in EtOH and once by microwave irradiation in
an Emrys OptimizerTM (5 min, 1808C, entry m). In most cases, acidification
upon completion of the reaction afforded the crystalline products 1 in yields
of 50–95% (after purification), except for R1 or R3 ¼ methyl (entries l and
m) where yields were only 30–40%, hinting at lower activation of the corre-
sponding 1,4-diketones toward nucleophilic attack by the primary amine.
Importantly, the described route is tolerant of many functional groups that
were introduced with the ketone scaffold R1 [e.g., halogen, methoxy, cyano,
BOC-protected amine, and N-(t-butyl)sulfonamide]. Not surprisingly, unpro-
tected amines, free carboxylic acids, ketones or aldehydes were not compati-
ble with the synthesis. Table 1 summarizes selected scaffolds that have been
investigated in our series.
The synthesis of analogous, five-unsubstituted pyrroles (R1 ¼ H) was
accomplished by a different route (Scheme 3), as unsaturated aldehydes are
not suitable substrates for Stetter reactions. Thus, the dithioacetal of furfural
(5)[9] was benzylated to 6[10] and deprotected in good yields. Interestingly,
the only suitable reagent for dethioacetalization was found to be mercury
acetate,[11] whereas less hazardous reagents such as Clayfen,[12] CAN,[13] or
DMSO/HCl[14] proved to be inefficient. The obtained 2-oxoethylbenzoate 7
was then transformed into the desired N-methyl pyrrole 8 by applying a
modified Feist–Benary condensation[15] with 1,2-dibromoethylacetate[16]
and methylamine. This conversion represents, to the best of our knowledge,
the first such condensation performed on benzyl ketones rather than b-ketoe-
sters where the 1,3-dicarbonyl system activates the CH2 group. Thus, the
phenyl ring proved to be sufficient to promote cyclization. These findings
nicely complement previous reports of benzyl ketones cyclizing with chloroa-
cetamides to give pyrrolin-2-ones.[17] Finally, ester hydrolysis yielded car-
boxylic acid 9.
In summary, we have been able to devise an expedient three-step route
toward 3-(p-carboxyphenyl)pyrroles with a high degree of functional
diversity, as demonstrated by a variety of substituents in position 5. This

1114
T. Ullrich et al.
Scheme 3. Synthesis of 5-unsubstituted pyrroles. Reagents: a) n-BuLi, methyl 4-(bro-
momethyl)benzoate, TMEDA, THF, 2 788C, 25 h; b) Hg(OAc)2, H2O/acetonitrile, rt,
30 min; c) 1,2-dibromoethyl acetate, methylamine (THF solution), EtOH, rt, 48 h; d)
LiOH, THF/H2O/MeOH, 508C, 2 h.
route is suitable for large-scale production of the target molecules. To obtain
the five-unsubstituted analogues, we developed a novel synthetic approach
based on a modified Feist–Benary condensation of a benzyl ketone. The
scope of the latter reaction will be studied, and results shall be reported in
due course.
EXPERIMENTAL
Starting materials were purchased from Aldrich or Fluka. All reactions were
monitored by TLC using silica-gel F254 plates (Merck), detected by UV
light. Flash chromatography was carried out on silica gel 60 (40–63 mM,
Merck) or with prepacked BiotageTM cartridges with the indicated solvent
system. Melting points were measured on a Bu¨chi melting-point apparatus
1
B-545 and are uncorrected. HNMR spectra were recorded at 400 MHz on a
Bruker FT-NMR spectrometer as ppm downfield from tetramethylsilane
with multiplicity, number of protons, and coupling constants. The following
abbreviations are used to indicate spin multiplicities: s (singlet), bs (broad
signal), d (doublet), t (triplet), and m (multiplet). Mass spectra were
recorded on a Finnigan AQA spectrometer, applying electrospray ionization
(ESI).

Polysubstituted 3-(carboxyphenyl) pyrroles
1115
General Procedure for the Synthesis of Tetrasubstituted Pyrroles
1a–m
Aqueous NaOH 2N, (66 mmol) was added to a stirred slurry of the desired ketone
(33 mmol) and 4-carboxybenzaldehyde (2) (33 mmol) in EtOH (120 ml). The
obtained mixture was stirred at ambient temperature for 4 h, acidified with 1 N
HCl, and filtered. The filter cake was triturated with hot EtOH. After cooling,
the solid material was collected and dried to give chalkone 3. To a slurry of 3
(3.49 mmol) in anhydrous EtOH (20 mL), subsequently Na2CO3 (3.49 mmol),
freshly distilled carboxaldehyde (4.19 mmol), 3-benzyl-5-(2-hydroxyethyl)-4-
methyl-thiazolium chloride (0.690 mmol), and triethylamine (3.49 mmol) were
added under argon. The mixture was stirred at reflux temperature for 6 h. After
cooling, the mixture was partitioned between 1 N HCl and EtOAc. After exhaus-
tive extraction of the aqueous layer, the combined extracts were washed with
brine, dried (Na2SO4), and evaporated to give crude diketone 4. A solution of
this material (2.35 mmol) in EtOH (10 mL) was treated with primary amine
(11.8 mmol) and—in the case of amines other than methylamine—acetic acid
(7 mmol). The mixture was heated to reflux for 3 h or irradiated in an Emrys
OptimizerTM for 5 min at 180 8C. After cooling, the mixture was partitioned
between 1 N HCl and EtOAc. After exhaustive extraction of the aqueous layer,
the combined extracts were washed with brine, dried (Na2SO4), and evaporated.
The crude product was recrystallized from, or triturated with, EtOAc.
Data
4-(2-Furan-2-yl-1-methyl-5-phenyl-1H-pyrrol-3-yl)benzoic
acid
(1a):
1
mp ¼ 2128C. H NMR (400 MHz, CDCl3): d (ppm) ¼ 7.99 (d, 2H, 8.7 Hz),
7.56 (dd, 1H, J ¼ 1.9 Hz, 0.8 Hz), 7.43–7.39 (m, 4H9, 7.34–7.39 (m, 1H),
7.36 (d, 2H, J ¼ 8.7 Hz), 6.51 (s, 1H), 6.50 (dd, 1H, J ¼ 3.3 Hz, 1.9 Hz),
6.41 (dd, 1H, J ¼ 3.3 Hz, 0.8 Hz), 3.56 (s, 3H). MS (ESI): m/z ¼ 344 [MH þ ].
4-[5-(4-Fluorophenyl)-2-furan-2-yl-1-methyl-1H-pyrrol-3-yl]benzoic acid
1
(1b): mp ¼ 2118C. H NMR (400 MHz, CDCl3): d (ppm) ¼ 7.98 (d, 2H,
J ¼ 8.6 Hz); 7.53 (dd, 1H, J ¼ 1.9 Hz, 0.8 Hz); 7.45 (dd, 2H, J ¼ 8.8 Hz,
5.3 Hz); 7.36 (d, 2H, J ¼ 6.8 Hz); 7.14 (t, 2H, J ¼ 8.6 Hz); 6.50 (dd, 1H,
J ¼ 3.3 Hz, 1.9 Hz); 6.47 (s, 1H); 6.40 (dd, 1H, J ¼ 3.3 Hz, 0.8 Hz), 3.51
(s, 3H). MS (ESI): m/z ¼ 362 [MH þ ].
4-[2-Furan-2-yl-5-(4-methoxyphenyl)-1-methyl-1H-pyrrol-3-yl] benzoic
1
acid (1c): mp ¼ 2398C. H NMR (400 MHz, DMSO-d6): d (ppm) ¼ 7.82
(dd, 1H, J ¼ 1.9 Hz, 0.8 Hz); 7.81 (d, 2H, J ¼ 7.9 Hz); 7.46 (d, 2H,
J ¼ 7.1 Hz); 7.28 (d, 2H, J ¼ 7.9 Hz); 7.03 (t, 2H, J ¼ 7.1 Hz); 6.64 (dd,
1H, J ¼ 3.3 Hz, 1.9 Hz); 6.61 (dd, 1H, J ¼ 3.3 Hz, 0.8 Hz); 6.52 (s, 1H);
3.79 (s, 3H); 3.44 (s, 3H). MS (ESI): m/z ¼ 374 [MH þ ].

1116
T. Ullrich et al.
4-[5-(4-Cyanophenyl)-2-furan-2-yl-1-methyl-1H-pyrrol-3-yl]benzoic acid
(1d): mp ¼ 225 8C. 1H NMR (400 MHz, DMSO-d6): d (ppm) ¼ 7.92
(d, 2H, J ¼ 8.4 Hz); 7.83 (dd, 1H, J ¼ 1.9 Hz, 0.8 Hz); 7.81 (d, 2H,
J ¼ 7.8 Hz); 7.77 (d, 2H, J ¼ 7.8 Hz); 7.28 (d, 2H, J ¼ 8.4 Hz); 6.82
(s, 1H); 6.68–6.64 (m, 2H); 3.53 (s, 3H). MS (ESI): m/z ¼ 369 [MH þ ].
4-[5-(4-tert-(Butylsulfamoyl)phenyl)-2-furan-2-yl-1-methyl-1H-pyrrol-3-
yl]benzoic acid (1e): mp ¼ 2298C. 1H NMR (400 MHz, DMSO-d6):
d (ppm) ¼ 7.89 (d, 2H, J ¼ 8.4 Hz); 7.82 (s, 1H); 7.81 (d, 2H, J ¼ 8.4 Hz);
7.74 (d, 2H, J ¼ 8.4 Hz); 7.57 (s, 1H); 7.29 (d, 2H, J ¼ 8.4 Hz); 6.76
(s, 1H); 6.67–6.64 (m, 2H); 3.53 (s, 3H); 1.12 (s, 9H). MS (ESI): m/
z ¼ 479 [MH þ ].
4-[5-(4-tert-(Butoxycarbonylamino)phenyl)-2-furan-2-yl-1-methyl-1H-
1
pyrrol-3-yl]-benzoic acid (1f): mp ¼ 1958C. H NMR (400 MHz, CDCl3):
d (ppm) ¼ 7.99 (d, 2H, J ¼ 8.5 Hz); 7.56 (dd, 1H, J ¼ 1.9 Hz, 0.8 Hz); 7.46
(d, 2H, J ¼ 8.5 Hz); 7.41 (d, 2H, J ¼ 8.5 Hz); 7.35 (d, 2H, J ¼ 8.5 Hz); 6.63
(s, 1H); 6.50 (dd, 1H, J ¼ 3.3 Hz, 1.9 Hz); 6.47 (s, 1H); 6.40 (dd, 1H,
J ¼ 3.3 Hz, 0.8 Hz); 3.53 (s, 3H); 1.55 (s, 9H). MS (ESI): m/z ¼ 459 [MH þ ].
4-(2-Furan-2-yl-1,5-dimethyl-1H-pyrrol-3-yl)benzoic
acid
(1 g):
1
mp ¼ 2238C. H NMR (400 MHz, DMSO-d6): d (ppm) ¼ 7.76 (dd, 1H,
J ¼ 1.9 Hz, 0.8 Hz); 7.74 (d, 2H, J ¼ 8.5 Hz); 7.17 (d, 2H, J ¼ 8.5 Hz);
6.61 (dd, 1H, J ¼ 3.3 Hz, 1.9 Hz); 6.52 (dd, 1H, J ¼ 3.3 Hz, 0.8 Hz);
6.22 (s, 1H); 3.35 (s, 3H); 2.26 (s, 3H). MS (ESI): m/z ¼ 282 [MH þ ].
4-(2-Furan-2-yl-1-methyl-5-pyridin-4-yl-1H-pyrrol-3-yl)benzoic
acid
1
(1 h): mp ¼ 2288C. H NMR (400 MHz, DMSO-d6): d (ppm) ¼ 8.62 (dd,
2H, J ¼ 6.2 Hz, 1.6 Hz); 7.83 (dd, 1H, J ¼ 1.9 Hz, 0.8 Hz); 7.81 (d, 2H,
J ¼ 8.5 Hz); 7.57 (d, 2H, J ¼ 6.2 Hz); 7.28 (dd, 2H, J ¼ 8.5 Hz); 6.88
(s, 1H); 6.69–6.65 (m, 2H); 3.57 (s, 3H). MS (ESI): m/z ¼ 345 [MH þ ].
4-(2-Furan-2-yl-1-phenethyl-5-phenyl-1H-pyrrol-3-yl)benzoic acid (1i):
mp ¼ 2108C. 1H NMR (400 MHz, CDCl3): d (ppm) ¼ 7.99 (d, 2H,
J ¼ 8.6 Hz), 7.61 (dd, 1H, J ¼1.9 Hz, 0.7 Hz), 7.37–7.46 (m, 4H), 7.36
(d, 2H, J ¼ 8.6 Hz), 7.13–7.17 (m, 3H), 6.77 (m, 2H), 6.53 (dd, 1H,
J ¼ 3.3 Hz, 1.9 Hz), 6.48 (s, 1H), 6.34 (dd, 1H, J ¼ 3.3 Hz, 0.7 Hz), 4.13
(t, 2H, J ¼ 8 Hz), 2.68 (t, 2H, J ¼ 8 Hz). MS (ESI): m/z ¼ 434 [MH þ ].
4-[1-(2-(Dimethylamino)ethyl)-2-furan-2-yl-5-phenyl-1H-pyrrol-3-yl]
1
benzoic acid (1j): mp ¼ 1898C. H NMR (400 MHz, CDCl3): d (ppm) ¼
7.90 (d, 2H, J ¼ 8.3 Hz), 7.54 (m, 1H), 7.41–7.49 (m, 4H), 7.37 (m, 1H),
7.29 (d, 2H, J ¼ 8.3 Hz), 6.48 (s, 1H), 6.45 (dd, 1H, J ¼ 3.2 Hz, 1.8 Hz),
6.42 (d, 1H, J ¼ 3.2 Hz), 4.19 (t, 2H, J ¼ 7.9 Hz), 2.46 (t, 2H, J ¼ 7.9 Hz),
2.12 (s, 6H). MS (ESI): m/z ¼ 401 [MH þ ].

Polysubstituted 3-(carboxyphenyl) pyrroles
1117
4-[2-Furan-2-yl-1-(2-morpholin-4-yl-ethyl)-5-phenyl-1H-pyrrol-3-yl]ben
1
zoic acid (1 k): mp ¼ 2198C. H NMR (500 MHz, CDCl3): d (ppm) ¼ 7.78
(d, 2H, J ¼ 8.4 Hz), 7.45 (m, 1H), 7.29–7.37 (m, 4H), 7.18–7.27 (m, 1H),
7.16 (d, 2H, J ¼ 8.4 Hz), 6.38 (dd, 1H, J ¼ 3.2 Hz, 1.9 Hz), 6.33 (s, 1H),
6.29 (d, 1H, J ¼ 3.2 Hz), 3.95 (t, 2H, J ¼ 7.3 Hz), 3.39 (m, 4H), 2.20
(t, 2H, J ¼ 7.3 Hz), 2.20 (m, 4H). MS (ESI): m/z ¼ 443 [MH þ ].
4-(2-Methyl-1-phenethyl-5-phenyl-1H-pyrrol-3-yl)benzoic acid (1l):
1
mp ¼ 1798C. H NMR (400 MHz, CDCl3): d (ppm) ¼ 8.12 (d, 2H, J ¼
8.4 Hz), 7.51 (d, 2H, J ¼ 8.4 Hz), 7.35–7.45 (m, 5H), 7.20–7.24 (m, 3H),
6.93 (m, 2H), 6.27 (s, 1H), 4.16 (t, 2H, J ¼ 7.7 Hz), 2.81 (t, 2H,
J ¼ 7.7 Hz), 2.36 (s, 3H). MS (ESI): m/z ¼ 382 [MH þ ].
4-[1-(2-Methoxyethyl)-2-methyl-5-phenyl-1H-pyrrol-3-yl]benzoic
acid
1
(1 m): mp ¼ 1548C. H NMR (400 MHz, CDCl3): d (ppm) ¼ 8.11 (d, 2H,
J ¼ 8.4 Hz), 7.53 (d, 2H, J ¼ 8.4 Hz), 7.40–7.46 (m, 4H), 7.32–7.36
(m, 1H), 6.36 (s, 1H), 4.15 (t, 2H, J ¼ 6.4 Hz), 3.48 (t, 2H, J ¼ 6.4 Hz),
3.24 (s, 3H), 2.50 (s, 3H). MS (ESI): m/z ¼ 336 [MH þ ].
Methyl 4-(2-Furan-2-yl-[1,3]dithian-2-ylmethyl)benzoate (6)
To a solution of 2-[1,3]dithian-2-yl-furan (5)[9] (18.2 g, 97.7 mmol) in
anhydrous THF (400 mL) at 2788C, TMEDA (113 g, 972 mmol) and
n-BuLi (1.6M in hexane, 61 mL, 97.7 mmol) were added subsequently via
dropping funnel. The mixture was stirred at that temperature for 60 min. A
solution of methyl 4-(bromomethyl)-benzoate (22.4 g, 97.7 mmol) in
anhydrous THF (100 mL) was added slowly, and the mixture was allowed
to reach ambient temperature. Stirring was continued for 20 h. The mixture
was carefully quenched with aq. NH4Cl, stirred for another 30 min, and
extracted with EtOAc. The combined extracts were washed with 1 N HCl,
aq. NaHCO3, and brine; dried (Na2SO4); and evaporated. The crude product
was purified by flash chromatography (SiO2, cyclohexane/EtOAc 10:1) to
1
give 6, mp ¼ 848C. H NMR (400 MHz, DMSO-d6): d (ppm) ¼ 7.72 (td,
2H, J ¼ 8.3 Hz, 1.8 Hz); 7.68 (dd, 1H, J ¼ 1.8 Hz, 0.8 Hz); 6.91 (d, 2H,
J ¼ 8.3 Hz); 6.38 (dd, 1H, J ¼ 3.3 Hz, 1.8 Hz); 6.27 (dd, 1H, J ¼ 3.3 Hz,
0.8 Hz); 3.79 (s, 3H); 3.42 (s, 2H); 2.87–2.77 (m, 2H); 2.75–2.64 (m, 2H);
2.00–1.91 (m, 1H); 1.82–1.68 (m, 1H). MS (ESI): m/z ¼ 334 (M þ H).
Methyl 4-(2-Furan-2-yl-2-oxoethyl)benzoate (7)
To a solution of 6 (6.00 g, 17.9 mmol) in 80% aq. acetonitrile (60 mL),
Hg(OAc)2 (14.3 g, 7.26 mmol) was added. After stirring at ambient tempera-
ture for 30 min, the mixture was filtered through celite and rinsed with Et2O.

1118
T. Ullrich et al.
The filtrate was washed with brine, dried (Na2SO4), and evaporated. The crude
product was passed through a plug of silica gel (toluene/EtOAc 20:1) to give
2.92 g (66%) of 7 as a yellow oil of sufficient purity for the following step. 1H
NMR (400 MHz, DMSO-d6): d (ppm) ¼ 8.02 (d, 1H, J ¼ 1.7 Hz); 7.90
(d, 2H, J ¼ 8.3 Hz); 7.62 (d, 1H, J ¼ 3.3 Hz); 7.42 (d, 2H, J ¼ 8.3 Hz);
6.74 (dd, 1H, J ¼ 3.3 Hz, 1.7 Hz); 4.28 (s, 2H); 3.82 (s, 3H). MS (ESI): m/
z ¼ 245 (M þ H).
4-(2-Furan-2-yl-1-methyl-1H-pyrrol-3-yl)benzoic Acid (9)
To a solution of 7 (3.24 g, 13.2 mmol) in anhydrous THF (20 mL), methyl-
amine (33% in EtOH, 16.5 mL, 132 mmol) was added. The resulting
solution was stirred for 30 min at ambient temperature under argon. 1,2-
Dibromoethyl acetate[16] (3.26 g, 13.2 mmol) in anhydrous THF (5 mL) was
added. After 24 h, another 16.5 mL of methylamine solution was added, and
the mixture was stirred until no more starting material was detected by TLC
(SiO2, cyclohexane/EtOAc 1:1, Rf (product) ¼ 0.65). The mixture was then
partitioned between 1 N HCl and EtOAc. After exhaustive extraction of the
aqueous layer, the combined extracts were washed with brine, dried
(Na2SO4), and evaporated. The crude product was purified by flash chromato-
graphy (SiO2, cyclohexane/EtOAc 3:1) to give 2.54 g (68%) of methyl ester
8. LiOH (8.5 mg, 0.355 mmol) was added to a solution of 8 (20 mg,
0.071 mmol) in THF/MeOH/H2O (3:1:1, 1 mL). After stirring at 608C for
2 h, the mixture was acidified with 1 N HCl and extracted with EtOAc. The
combined extracts were dried (Na2SO4) and evaporated to give 19 mg
1
(quant.) of 9, mp ¼ 1878C. H NMR (400 MHz, DMSO-d6): d (ppm) ¼
12.8 (bs, 1H); 7.86–7.67 (m, 3H); 7.20 (d, 2H, J ¼ 8.2 Hz); 6.98 (d, 1H,
J ¼ 2.4 Hz); 6.60 (s, 1H); 6.56 (d, 2H, J ¼ 2.9 Hz); 6.42 (d, 1H, J ¼
2.4 Hz); 3.53 (s, 3H). MS (ESI): m/z ¼ 268 (M þ H).
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