De novo synthesis of thiophenes on a polymeric support

Article abstract of DOI:10.1016/j.tetlet.2007.03.111

The Hinsberg thiophene synthesis was expanded to support bound thioglycolic acid derived synthons, which reacted with arils to give thiophenes in high purity.

Full text of DOI:10.1016/j.tetlet.2007.03.111

Tetrahedron Letters 48 (2007) 3535–3538
De novo synthesis of thiophenes on a polymeric support
Antonio Traversone and Wolfgang K.-D. Brill*
Department of Chemistry, Nerviano Medical Sciences S.r.l., Viale Pasteur 10, 20014 Nerviano, Mi, Italy
Received 23 February 2007; revised 15 March 2007; accepted 19 March 2007
Available online 23 March 2007
Abstract—The Hinsberg thiophene synthesis was expanded to support bound thioglycolic acid derived synthons, which reacted with
arils to give thiophenes in high purity.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Thiophenes are of great importance both as pharmaco-
phoric entities1 and to material sciences2 due to their
unique electronic properties. We intended to utilize the
Hinsberg thiophene synthesis3 method to facilitate
access to highly substituted thiophenes via parallel
synthesis. The latter involves the reaction of a ‘dimethyl
sulfide motif’ flanked by two carbanion stabilizing
groups, such as thiodiglycolic diesters with 1,2-dicar-
bonyl-components. In solution phase, the mechanism
of the Hinsberg synthesis is often thought to proceed
via a multi-step process initiated by a Stobbe condensa-
tion,4 though in some cases, evidence for alternative
mechanisms have been reported.5
(1) using standard procedures.6 Compound 2b was syn-
thesized according to the procedure of Bhaskar Reddy
et al.,7 2c was obtained by aminolysis of thiodiglycolic
anhydride.8 Compound 3a was esterified using isopropyl
chloroformate-activation followed by an isopropanol
quench9 to give 4. Resin 3d was converted to the sup-
port-bound thioglycolic acid (5) by thiol exchange.10
The latter could then be derivatized with the appropriate
alkylating agents to give resins 3b,e (Scheme 1).11 The
support bound latent ‘di-carbanion’-analogs could then
be reacted with various 1,2-dicarbonyl components.12 In
this scope and limitation study we screened, solvents,
reaction temperature and bases (Table 1). Both NMP
and THF were equally useful as solvents. The complex-
ation of the enolate and the 1,2-diketo-component by
the counter ion of the base had dramatic impact on
the reaction. Thus, Schwesinger base P113 promoted
only little conversion and bound tightly to the solid
phase. In fact, it could not be washed off without
concomitant cleavage of the product. In turn, KOtBu
appeared to be the base of choice, as it promoted clean
formation of thiophenes with minimal premature cleav-
age of the product and without occurrence of massive
filter-clotting precipitations.
The complexity of the mechanism is likely the cause of
complex reaction mixtures and low product yields
observed in many applications of the Hinsberg method.
We thought that linking thiodiglycolic acid or suitable
carbanion analogs to bulky polymeric support may
facilitate the removal of many side products from the
reaction mixture. Thus, an ester linkage to a bulky chlo-
rotrityl support is likely to resist premature, solvolytic
cleavage of the product and may prevent possible lac-
tone formation, as suggested by the Stobbe condensa-
tion mediated mechanism.4
At low temperature, ester 4 reacted with 7a to substan-
tial amounts of monoester 8b suggesting that the
thiophene formation proceeds at least in part via two
consecutive Knoevenagel reactions. At higher tempera-
tures ester 8b was not obtained after prolonged reac-
tion times, probably due to hydrolysis caused by the
water liberated during the dehydration step (Scheme 2,
Table 1).
At first, a selection of suitable carbanion analogs was
synthesized on a polymeric support. Thus various acids,
such as 2a–d were bound to a chlorotrityl chloride resin
Keywords: Thiophenes; Hinsberg reaction; Knoevenagel; Chlorotrityl
resin; Arils; Intramolecular Wittig reaction.
*
Corresponding author. Tel.: +39 033 158 1437; fax: +39 033 158
1347; e-mail: wolfgang.brill@nervianoms.com
The conditions of entry 10 in Table 1 were then used to
obtain various thiophenes (Scheme 3, Table 2).14 The
‘Knoevenagel-route’ was evidenced by the formation
In partial requirement for the degree ‘CTF’ (pharmaceutical chemistry)
at the university of Genova.
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.03.111

3536
A. Traversone, W. K.-D. Brill / Tetrahedron Letters 48 (2007) 3535–3538
O
O
a
S
R1
S
R1
Cl
HO
O
+
1
2a-d
3a-d
R1:
O
O
O
O
O
O
b
S
S
S
S
O
O
3a (50%)a
3b (70%)a
2a:
2b:
HO
OH
Ph
quantb
O
O
4
PS
:
HO
HO
Cl
3c (89%)a
3d (69%)a
N
O
2c:
2d:
O
O
c
SH
S
S
O
OH
HO
quantc
5
O
O
Br
R1
S
R1
d
SH
O
+
O
5
6a, b
3b, e
3b (68%)a
3e
R1:
O
6a:
6b:
Br
Br
Ph
P+(Ph)
O
O
TFA
P+(Ph)3
S
3 Br-
F3C
O
HO
60%a
6
Scheme 1. Reagents and conditions: (a) acid (3 equiv), DIPEA (3 equiv), DMAP (0.03 equiv), DMF, 12 h, rt, 50–70%; (b) isopropyl chloroformate,
DIPEA, iPrOH; (c) DMF/propane-1,3-dithiol 4:1 (v/v) (20 equiv thiol) 16 h, rt, quant; (d) halide (2 equiv), N-methylmorpholine (9 equiv), DMF,
18 h, rt, quant.; (a)Isolated yields from 1, (b)Isolated yields from 3a, (c)Isolated yields from 3d after TFA-cleavage.11
Table 1.
Entry
Base
Temperature (ꢁC)
Time (h)
Thiophenesa (%)
Yieldb (%)
8a
8b
1
2
3
4
5
8
9
10
LiHMDS
LiHMDS
NaHMDS
NaHMDS
NaOMe
KOtBu
rt
60
rt
60
60
rt
60
60
16
4
16
4
16
16
4
22
63
46
53
49
63
29
95
48
—
25
—
—
26
25
—
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
>95
KOtBu
KOtBu
16
a Determined by the integration based on area percent of the HPLC/MS-trace of the crude reaction at 220 nm.
b Isolated yield.
O
O
O
O
O
O
O
S
a
S
O
O
b
R1'
Ph
S
HO
S
HO
O
OH
+
+
PS
O
PS
O
O
Ph
Ph
Cl
Cl
Ph
Ph
Ph
Ph
8a: R1': -CO2H
R1: -CO2iPr
4
Ph
8b: R=R1': -CO2iPr
7a
Scheme 2. Reagents and conditions: (a) conditions of Table 1:10 equiv of base, 5 equiv of 7a; (b) 10% TFA, CH2Cl2.
O
O
O
R1'
R2
a
S
S
R1
O
O
R1'
b
S
HO
PS
O
PS
O
+
R2
R2
R2
Cl
Cl
R2
R2
7a-h
R1:
R1':
8a, 8c-h: -CO2H
4: -CO2iPr
3e: -[PPh3]+
3b: -COPh (failed to give thiophene)
3c :-CONEt2
8i-o:
8p:
-H
-CONEt2
Scheme 3. Reagents and conditions: (a) KOtBu, see Ref. 14; (b) 10% TFA, CH2Cl2 see Ref. 10.

A. Traversone, W. K.-D. Brill / Tetrahedron Letters 48 (2007) 3535–3538
3537
Table 2. The reaction in the box proceed via a Wittig olefination step16
of 8p from 3c (Table 2, entry 18). Thus, the initial attack
of 7a–g upon the less hindered ester enolate next to R1
(Schemes 2 and 3) formed an a-hydroxy carbonyl com-
pound. The latter could not attack the carbonyl group
of the hindered trityl-support ester completing a Stobbe
reaction.4 In turn, the a-hydroxy carbonyl compound
could either eliminate the starting material or perform
a second Knoevenagel reaction leading, after dehydra-
tion, to a thiophene. The latter path could only be likely,
if the a-hydroxy carbonyl intermediate was more basic
than the adjacent thioglycolic ester enolate. Conse-
quently, 1,2-diketo-building blocks bearing CH-acidic
protons methyl pyruvate and 2-ketoaldehydes did not
generate thiophenes. Glyoxal acetals were not suffi-
ciently soluble to interact well with the synthesis sup-
port. 1,2-Diketones bearing hetrocyclic substituents
(Table 2, entries 7 and 8) were probably consumed by
the basic reaction medium prior to the reaction with

3538
A. Traversone, W. K.-D. Brill / Tetrahedron Letters 48 (2007) 3535–3538
the support.15 Intriguingly, resin 3b also did not react
with 7a (Table 2, entry 17), while resin 3c bearing a
much less acidic enolate, reacted with 7a to afford 8p
(Table 2, entry 18).
5. Paranjpe, P. P.; Bagavant, G. Indian J. Chem. 1973, 11,
313–314.
6. Scicinski, J. J.; Congreve, M. S.; Jamieson, C.; Ley, S. V.;
Newman, E. S.; Vinader, V. M.; Carr, R. A. E. J. Comb.
Chem. 2001, 3, 387–396.
7. Bhaskar Reddy, D.; Muralidhar Reddy, M.; Ramana
Reddy, P. V. Indian J. Chem. 1993, 32 B, 1018–1023.
8. {[2-(Diethylamino)-2-oxoethyl]thio}acetic acid (2c): To
thiodiglycolic anhydride (3.96 g, 30 mmol) dissolved in
THF (15 mL) was added slowly under ice-cooling diethyl-
amine (6.18 mL, 4.39 g, 60 mmol). The reaction mixture
was stirred at rt for 2 h and then diluted with CH2Cl2
(150 mL). The reaction mixture was extracted with aq HCl
(2 M). The aq phase (pH ꢀ 1) was back-extracted with
CH2Cl2 (150 mL). The combined organic phases were
evaporated to dryness to afford 2c an oil which crystallizes
upon initiation with a glass rod (5.34 g, 86%).
However, our procedure was expandable to support-
bound carbanions stabilized by additional EWGs other
than esters or amides (Table 2). In the case of the sup-
port-bound phosphonium salt 3e a Wittig olefination
is likely to initiate the thiophene formation.16 Intrigu-
ingly, the presence of the nucleophile DMAP, which
may have allowed the equilibration of a proposed ole-
finic intermediate did not influence the outcome of the
reactions (Table 2, entries 9–15).
We have reported the first Hinsberg-based synthesis of
thiophenes on solid phase. Thiophene-2-carboxylic acids
and thiophene-2,5-dicarboxylic acids bearing aromatic
residues at C3 and C4 were obtained in high yields
and exceptional purity. The steric bulk of the resin linker
promoted the thiophene formations to proceed via two
consecutive Knoevenagel reactions and not via a Stobbe
mechanism. The reason why support-bound [(2-oxo-2-
phenylethyl)thio]acetic acid did not react is not clear.
1H NMR (400 MHz, DMSO) d 12.63 (1H, br s), 3.51 (2H,
s), 3.36 (2H, s), 3.27 (4H, q, J = 7.1 Hz), 1.13 (3H, t,
J = 7.1 Hz), 1.02 (3H, t, J = 7.1 Hz); 12.63 (1H, br s), 3.51
(2H, s), 3.36 (2H, s), 3.27 (4H, q, J = 7.1 Hz), 1.13 (3H, t,
J = 7.1 Hz), 1.02 (3H, t, J = 7.1 Hz); HRMS m/z Calcd
for C8H15NO3S: 206.0846 (M+H)+ Found: 206.0856.
9. Ferguson, J.; Marzabadi, C. Tetrahedron Lett. 2003, 44,
3573–3577.
10. Ranganathan, S.; Jayaraman, N. J. Chem., Soc., Chem.
Commun. 1991, 14, 934–936.
11. For instance TFA-cleavage of {[(Carboxymethyl)thio]-
methyl}(triphenyl)phosphonium
trifluoroacetate
(6):
Acknowledgments
Resin 3e (90 mg) was subjected to three consecutive
treatments with 10% TFA in CH2Cl2 for 5 min each.
The product solutions were combined and evaporated in
We wish to thank N. Colombo for the NMR spectro-
scopy, F. Riccardi Sirtori for the HRMS spectroscopy,
V. Desperati and F. Ciprandi for the preparative HPLC
purification. We thank Dr. E. Felder, Dr. Barbara
Salom, Professor C. Gennari, and Professor A. Ranise
for useful comments and the interest in this work.
1
vacuo. Yield: 36.4 mg (60% from 1); H NMR (400 MHz,
DMSO) d 12.85 (1H, br s), 7.77–7.96 (15H, m), 4.98 (2H,
d, JH–P = 10.6 Hz), 3.26 (2H, d, J = 1.1 Hz); HRMS m/z
Calcd for C21H20O2PS: 367.0916 (M)+ Found: 367.0915.
12. The reactions on solid phase were performed in a Bohdan
Miniblockꢂ using 5 mL PP-fritt reactors equipped with a
heating block and an orbital shaker. (Mettler-Toledo
Bohdan, 562 Bunker Court, Vernon Hills, IL 60610 USA).
13. Schwesinger, R. Chimia 1985, 39, 269–272.
Supplementary data
14. General procedure for synthesizing thiophenes: To each
reactor charged with 100 mg (0.06 mmol) of resins 3b, 3c,
3e or 4 suspended in dry THF (1 mL) were added diketone
(0.7 mmol) and 1 M KOtBu solution in THF (1.4 mL).
The suspensions were shaken at 60 ꢁC for 15 h. Then, the
reagents were filtered off and the resins were washed twice
with the following sequence of solvents: MeOH (2·), THF
(2·), H2Cl2 (2·). The products were cleaved off with
TFA,11 dried down in vacuo, and subjected to analytical
HPLC for purity determination. (gradient: 10–90%
MeCN–aq 0.1% TFA, 10 min) Products of inferior purity
were subjected to preparative mass triggerd HPLC using
the same gradient (Table 2).
Supplementary data consisting of the HPLC-traces of
crude thiophenes, NMR and HRMS data of compounds
8a,c–p is available. Supplementary data associated with
this article can be found, in the online version, at
doi:10.1016/j.tetlet.2007.03.111.
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