Synthesis of tetrasubstituted thiophenes on solid-support using the Gewald reaction

Article abstract of DOI:10.1016/S0040-4039(01)01470-8

The Gewald reaction was performed on solid support. This reaction combines a ketone or aldehyde, an activated nitrile, and sulfur in the presence of a suitable amine base to make tri- and tetrasubstituted thiophenes. After optimizing conditions for maximum yield and purity, the scope of the reaction was investigated. Finally, this method is highlighted in the synthesis of two biologically relevant compounds.

Full text of DOI:10.1016/S0040-4039(01)01470-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 7181–7184
Synthesis of tetrasubstituted thiophenes on solid-support using
the Gewald reaction
Georgette M. Castanedo and Daniel P. Sutherlin*
Department of Bioorganic Chemistry, Genentech, Inc., One DNA Way, South San Francisco, CA 94080, USA
Received 10 July 2001; revised 3 August 2001; accepted 8 August 2001
Abstract—The Gewald reaction was performed on solid support. This reaction combines a ketone or aldehyde, an activated
nitrile, and sulfur in the presence of a suitable amine base to make tri- and tetrasubstituted thiophenes. After optimizing
conditions for maximum yield and purity, the scope of the reaction was investigated. Finally, this method is highlighted in the
synthesis of two biologically relevant compounds. © 2001 Elsevier Science Ltd. All rights reserved.
Tri- and tetrasubstituted thiophenes 2 prepared via the
Gewald reaction1 (Scheme 1) provide important scaf-
folds for medicinal applications. The core structure
formed in the multicomponent condensation between a
ketone or aldehyde 1, an activated nitrile, and sulfur is
found in inhibitors of the phosphatase PTP1B,2 sero-
tonin receptor subtype 5-HT1A,3 human leukocyte elas-
tase,4 and adenosine receptor A3.5 In addition, this
thiophene scaffold is prevalent in screening libraries
available from commercial sources and is therefore a
likely candidate for analog synthesis.6 Recently, the
utility of this scaffold as a starting point for further
parallel synthesis has been described.7
3-carboxy substituted 2-aminothiophenes that present
two additional functionalities for further elaboration.
This being our choice of nitrile, an ester linkage
through the acid labile phenoxybenzylalcohol resin
linker (Wang)8 was a logical choice for resin attach-
ment. In addition, it was found that ethyl esters of
some Gewald products proved difficult to hydrolyze via
traditional saponification, making an acid-mediated
cleavage using the Wang linker beneficial.
Acylation of Argogel® Wang resin 3 with cyanoacetic
acid under standard DIC/DMAP coupling conditions
gave the resin-bound cyanoacetic ester 4 (Scheme 2).
The generation of such a highly functionalized core
structure and its prevalence in medicinal chemistry
prompted us to investigate this reaction on solid sup-
port. Performing the Gewald reaction on solid support
would eliminate a necessary purification step and make
this reaction more amenable for high throughput
library synthesis. Reactions with activated nitriles such
as ethyl cyanoacetate (X=CO2Et, Scheme 1) result in
Scheme 1. Gewald synthesis of tetrasubstituted thiophenes.
* Corresponding author. Tel.: 1-650-225-3171; fax: 1-650-225-2061;
e-mail: sutherlin.dan@gene.com
Scheme 2. Solid-phase route to thiophenes.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01470-8

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Table 1. Products from solid-phase synthesis, yields and purities
The PEG based support was chosen due to its favorable
swelling properties in ethanol, the reaction solvent. The
Gewald reaction was performed in a 10 mL reaction
vessel on a Quest™ 210 synthesizer. The resin was
suspended in ethanol containing the ketone or alde-
hyde, morpholine, and solid sulfur (0.75 M in each
component) and heated at reflux for 18 h to form the
resin-bound thiophene 5. After cooling to room temper-
ature, the resin was washed extensively with alternating
methanol, DMF, and methylene chloride. Direct isola-
tion of the aminothiophene 5 was inefficient due to
decomposition of the product during TFA cleavage.
Acylation of the amine using acetyl chloride resulted in
products 6 stable to the cleavage conditions.

G. M. Castanedo, D. P. Sutherlin / Tetrahedron Letters 42 (2001) 7181–7184
7183
1,3- and 1,4-cyclohexadione, which gave a complex
mixture of products.
A highly concentrated reaction solution was necessary
to obtain respectable yields of the thiophene product.
Time course experiments showed an 8 h reaction time
to be optimal with shorter times resulting in isolated
starting material, cyanoacetic acid, once the resin was
cleaved with TFA. Performing the reaction at a higher
temperature in refluxing butanol (from 78 to 118°C) or
the use of pyridine, a reported alternative solvent,9 at
room temperature provided no improvement in yield.
To demonstrate the utility of this reaction we per-
formed the synthesis of a known PTP1B (protein
tyrosine phosphatase 1B) inhibitor 11 and an adenosine
receptor A3 inhibitor 12 using this new route (Scheme
3). For the phosphatase inhibitor 11,2 Boc-4-piperidone
7 was used in the Gewald reaction to give thiophene 9.
Acylation with methyl oxalylchloride followed by TFA-
mediated cleavage and Boc deprotection gave the
methyl ester (100% crude yield and 97% purity). This
crude material was then treated with 3 equiv. of LiOH
in THF/H2O for 1 h to give 11. The diacid was
precipitated in a 10% acetic acid/water solution and
filtered to give 11 in 81% yield (based on resin loading).
To establish the scope of this reaction on solid support
a variety of ketones and aldehydes were investigated
(Table 1). Following the condensation all compounds
were acylated with acetyl chloride prior to cleavage
from the resin with TFA. Product homogeneity was
analyzed by LC–MS10 and structure confirmation was
obtained by NMR. Cyclic ketones performed best in
this reaction (entries 1–4), resulting in both high yields
(84–92%, measured as crude weights based on loading)
and purity (75–95%, estimated by HPLC11). These
results compare favorably to yields observed in the
literature for cyclopentanone (82%) and cyclohexanone
(59%) using ethyl cyanoacetate.1b One example of a
cyclic ketone (entry 5), resulted in a lower yield (27%)
and purity (63%), also in agreement with previous
results. Benzophenone (entry 6), gave no measurable
product. Successful condensation of aryl ketones have
been reported in a two-step process by isolating the
Knoevenagel–Cope condensation product between the
ketone and nitrile prior to thiolation and ring closure.1b
Aldehydes (entries 7 and 8), performed well giving
products of sufficient purities (80–100%) with lower
recoverable yields (ꢀ45%). This also seems to be the
case for b- and a-keto esters (entries 9 and 10), which
are reasonable substrates (64 and 87% purity) with
lower recovered yields (46 and 34%). Not shown are
Compound 12 is known to inhibit the adenosine recep-
tor A3 with an IC50 of 0.6 mM.3 The solid-phase
Gewald reaction was performed with 4-piperidone
ethylcarbamate 7 to give aminothiophene 10 which was
coupled with phenylacetic acid using DIC/DMAP.
Reaction was slow and required an additional treat-
ment with fresh reagents over 6 h to complete. Cleavage
from the resin with TFA gave the acid in 72% crude
yield and 78% purity. The acid was then alkylated with
ethyliodide in DMF using Cs2CO3. Silica gel chro-
matography was performed to give 12 in 20% overall
yield.
Highly functionalized, biologically active scaffolds are
ideal tools for medicinal chemists. By performing the
Gewald reaction on solid-support, appropriately pro-
tected and functionalized ketones or aldehydes like
those found in Table 1 could be starting points for
larger libraries. The 3-carboxylthiophene could be fur-
ther elaborated post cleavage, as shown in the synthesis
of thiophene 12, or with other solution-phase schemes,
such as amide-bond couplings. These and other alterna-
tives are being investigated.
Representative procedure
Synthesis of compound 11. Cyanoacetic acid (1.25 g 14.7
mmol) was activated with diisopropylcarbodiimide (3.9
ml, 25.0 mmol) and dimethylaminopyridine (45 mg,
0.37 mmol) in dichloromethane (130 ml) for 20 min,
added to Argo-Gel Wang Resin (10 g, 0.37 mmol/g
loading) and agitated with nitrogen for 3 h. The reac-
tion was drained and rinsed three times each with
MeOH, dichloromethane (DCM), DMF, and again
with DCM and dried under vacuum.
The resin (300 mg, 0.11 mmol) was distributed into a
Quest™ 210 10 ml reaction vessel. Boc-4-piperidone
(598 mg, 3.0 mmol), elemental sulfur (96 mg, 3.0
mmol), and morpholine (262 ml, 3.0 mmol) were added
to the reaction vessel in 4 ml of EtOH, and the mixture
was agitated and refluxed for 8 h. The vessel was then
drained and the resin washed as described above.
Methyl chlorooxoacetate (111 ml, 1.0 mmol) and diiso-
propylethylamine (175 ml, 1.0 mmol) were added to the
Scheme 3.

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G. M. Castanedo, D. P. Sutherlin / Tetrahedron Letters 42 (2001) 7181–7184
reaction vessel in 4 ml of DCM to acylate the free
amine. The reaction was agitated for 1 h, drained, and
rinsed as described above.
S. B.; Peters, G. H.; Norris, K.; Olsen, O. H.; Jeppesen,
C. B.; Lundt, B. F.; Ripka, W.; Moller, K. B.; Moller, N.
P. H. J. Biol. Chem. 2000, 275, 10300–10307.
3. Webb, T. R.; Melman, N.; Lvovskiy; Ji, X.; Jacobson, K.
A. Bioorg. Med. Chem. Lett. 2000, 10, 31–34.
4. Modica, M.; Santiagati, M.; Russo, F.; Parotti, L.; Gioia,
L. D.; Selvaggini, C.; Salmona, M.; Mennini, T. J. Med.
Chem. 1997, 40, 574–585.
5. Gutschow, M.; Kuerschner, L.; Neumann, U.; Peitsch,
M.; Loser, R.; Koglin, N.; Eger, K. J. Med. Chem. 1999,
42, 5437–5447.
6. Tetrasubstituted 2-aminothiophenes and libraries con-
taining them are available from, among others, Chem-
bridge (see Ref. 3), Maybridge, Aldrich, N. D. Zelinski
Institute, Bionet Research Ltd., and ChemDiv, Inc.
7. McKibben, B. P.; Cartwright, C. H.; Castelhano, A. L.
Tetrahedron Lett. 1999, 40, 5471–5474.
Products were cleaved from the resin for 1 h in a
mixture of 92.5% TFA, 5% dichloromethane, and 2.5%
water to afford the methyl ester following filtration and
evaporation. Lithium hydroxide monohydrate (13 mg,
0.30 mmol) was added to the ester in 4 mL of 50/50
THF/H2O. The reaction was agitated for 1 h and
evaporated. The product was redissolved in 0.5 mL of
H2O and precipitated by addition of 0.05 mL of AcOH
and filtered to give 22 mg of 11 (81% overall yield).
Acknowledgements
The authors wish to thank James Marsters for helpful
discussions.
8. Wang, S.-S. J. Am. Chem. Soc. 1973, 95, 1328.
9. Sowell, Sr., J. W.; Player, M. R. J. Heterocyclic Chem.
1995, 32, 1537–1540.
10. LC–MS was performed using a 50×4.6 mm column
packed with 5 micron C-18 starting at 0% CH3CN/H2O
and ramping to 90% CH3CN/H2O over 5 min with a 2
ml/min flow rate.
11. HPLC was performed using a 100×4.6 mm column
packed with 5 micron C-18 starting at 5% CH3CN/H2O
and ramping to 100% CH3CN/H2O over 15 min with a
1.2 ml/min flow rate.
References
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1966, 99, 94–100; (b) Sabnis, R. W.; Rangnekar, D. W.;
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2. Iversen, L. F.; Anderson, H. S.; Branner, S.; Mortensen,