Synthesis of substituted thiophenes by palladium-catalyzed heterocyclodehydration of 1-mercapto-3-yn-2-ols in conventional and nonconventional solvents

Article abstract of DOI:10.1021/jo301943k

A variety of readily available 1-mercapto-3-yn-2-ols 5 were conveniently converted into the corresponding thiophenes 6 in good to high yields in MeOH as the solvent at 50-100 °C in the presence of catalytic amounts (1-2%) of PdI₂ in conjunction with KI (KI:PdI₂ molar ratio = 10). The catalyst could be made recyclable employing an ionic liquid, such as BmimBF₄, as the solvent under suitable conditions.

Full text of DOI:10.1021/jo301943k

Note
pubs.acs.org/joc
Synthesis of Substituted Thiophenes by Palladium-Catalyzed
Heterocyclodehydration of 1‑Mercapto-3-yn-2-ols in Conventional
and Nonconventional Solvents
Bartolo Gabriele,*,† Raffaella Mancuso,‡ Lucia Veltri,‡ Vito Maltese,‡ and Giuseppe Salerno‡
†Dipartimento di Scienze Farmaceutiche and ‡Dipartimento di Chimica, Universita
Italy
̀
della Calabria, 87036 Arcavacata di Rende (CS),
S
* Supporting Information
ABSTRACT: A variety of readily available 1-mercapto-3-yn-2-
ols 5 were conveniently converted into the corresponding
thiophenes 6 in good to high yields in MeOH as the solvent at
50−100 °C in the presence of catalytic amounts (1−2%) of
PdI2 in conjunction with KI (KI:PdI2 molar ratio = 10). The
catalyst could be made recyclable employing an ionic liquid,
such as BmimBF4, as the solvent under suitable conditions.
best reaction conditions in term of yield of 6a, which
etal-catalyzed heterocyclodehydration of unsaturated
Msubstrates bearing a suitably placed nucleophilic group corresponded to the use of PdI2 + 10KI as the catalyst, in
MeOH as the solvent at 50 °C, with a substrate concentration
of 0.5 mmol of 5a per mL of MeOH. Under these optimized
conditions, the reaction after 3 h led to the formation of 6a in
88% isolated yield (Table 1, entry 1). The reaction was then
applied to other differently substituted 1-mercapto-3-yn-2-ols
5b−i (Table 1, entries 2−9).
is a powerful methodology for the direct and atom-economical
synthesis of heterocycles starting from readily available starting
materials under essentially neutral conditions.1,2 In this field, we
have contributed several examples,2 including the synthesis of
quinolines from 1-(2-aminoaryl)-2-yn-1-ols2f−h and the syn-
thesis of benzothiophenes from 1-(2-mercaptophenyl)-2-yn-1-
ols.2c
The results reported in Table 1 illustrate that the R3
substituent could be an alkyl as well an aryl group and that
the heterocyclodehydration process was slower when the R3
group was an aromatic ring substituted with an electron-
releasing group at the para position (as in the case of 4-
mercapto-3-methyl-1-p-tolylpent-1-yn-3-ol 5c, entry 3) or a π-
excessive heteroaromatic substituent (as in the case of 4-
mercapto-3-methyl-1-(thiophen-3-yl)pent-1-yn-3-ol 5e, entry
5). On the other hand, a para-electron-withdrawing group on
R3 caused an augmentation of the reaction rate, as shown by the
results obtained with 4-mercapto-3-methyl-1-(4-nitrophenyl)-
pent-1-yn-3-ol 5d (entry 4). These results show that the
heterocyclodehydration process is quite sensitive to the
electrophilicity of the coordinated triple bond undergoing the
intramolecular nucleophilic attack by the mercapto group,
which leads to the formation of a vinylpalladium species as
intermediate I (Scheme 2; anionic iodide ligands are omitted
for clarity). The latter then undergoes protonolysis followed by
dehydration or vice versa to give the final product with
regeneration of PdI2 (Scheme 2). When R1 was hydrogen, as in
the case of 1-mercapto-4-phenylbut-3-yn-2-ol 5f, longer
reaction times were required, and the product yield was
A particularly attractive process, recently developed by
several research groups,1b−e,g,j−l including ours,2d consists in
the formation of substituted furans 2 and pyrroles 4 by
heterocyclodehydration of 3-yne-1,2-diols 1 and 1-amino-3-yn-
2-ol derivatives 3, respectively, as shown in Scheme 1. On the
other hand, the analogous process starting from 1-mercapto-3-
yn-2-ols 5 to obtain substituted thiophenes 6 has been reported
in the literature in only one example, concerning the Au/Ag-
catalyzed conversion of 1-mercapto-4-phenylbut-3-yn-2-ol to 2-
phenylthiophene.1c In this work, we report a general method
for the catalytic conversion of 1-mercapto-3-yn-2-ols 5 to
substituted thiophenes 6,3,4 based on the use of a very simple
catalytic system, consisting of PdI2 in conjunction with an
excess of KI, under neutral and mild reaction conditions.
We began our investigation with 2-mercapto-3-methylnon-4-
yn-3-ol 5a, which was initially allowed to react in MeOH
(substrate concentration = 0.2 mmol of 5a per mL of MeOH)
at 80 °C in the presence of PdI2 (1 mol %) and KI (10 mol %).
After 2 h, analysis of the reaction mixture evidenced the
formation of the desired 5-butyl-2,3-dimethylthiophene 6a in
77% GLC yield. We then screened the reaction parameters, in
order to find the optimal conditions for the preparation of 6a.
The specific results are reported in the Supporting Information
(Table S1). From this brief optimization study, we found the
Received: September 7, 2012
Published: October 8, 2012
© 2012 American Chemical Society
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Note
Scheme 1. Formation of Substituted Furans (2), Pyrroles (4), and Thiophenes (6) by Heterocyclodehydration of 3-Yne-1,2-
diols (1), 1-Amino-3-yn-2-ol Derivatives (3), and 1-Mercapto-3-yn-2-ols (5), Respectively
Table 1. Synthesis of Substituted Thiophenes 6 by PdI2/KI-Catalyzed Heterocyclodehydration of 1-Mercapto-3-yn-2-ols 5 in
a
MeOH
a
All heterocyclodehydration reactions were carried out in MeOH as the solvent (0.5 mmol of starting thiol 5 per mL of MeOH) in the presence of
b
c
PdI2 and KI (KI:PdI2 molar ratio = 10). Conversion of thiol 5 was quantitative. Isolated yield based on starting thiol 5. Substrate conversion was
74%.
somewhat lower (Table 1, entry 6). This result clearly shows
that the reactive rotamer effect5,6 is at work under our
conditions.
We also tested the reactivity of 1-mercapto-2,2-dialkynyl-2-
ols 5g−i, bearing an additional alkynyl substituent at C-2. The
results, reported in Table 1, entries 7−9, show that these
substrates could be converted into the corresponding
thiophenes 6g−i in good yields without affecting the alkynyl
substituent. As expected in view of the reactive rotamer effect, a
substrate lacking an alkyl substituent at C-1, such as 7-
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Note
hexane) (28 mL, 44.8 mmol) in anhydrous THF (16 mL), maintained
under nitrogen, was added dropwise a solution of p-nitrophenylace-
tylene (6.55 g, 44.5 mmol) in anhydrous THF (6 mL). To the
resulting mixture was added, at the same temperature under nitrogen,
a solution of LiBr (1.56 g, 18 mmol) in anhydrous THF (6 mL). After
additional stirring for 0.5 h, a solution of 3-mercapto-2-butanone (1.77
g, 17.0 mmol) in anhydrous THF (5 mL) was added, at the same
temperature under nitrogen. The resulting mixture was stirred for
additional 2 h at −78 °C and then allowed to warm to room
temperature. Saturated NH4Cl (20 mL) and 1 N HCl (10 mL) were
added, and the mixture was extracted with Et2O (3 × 50 mL). The
collected organic phases were washed with brine (40 mL) and dried
over Na2SO4. After filtration and evaporation of the solvent, the crude
product was purified by column chromatography using 95:5 hexane/
AcOEt as eluent, to give pure 5d as a mixture of diastereoisomers A +
B, A:B ratio = 3.0, determined by 1H NMR. Yield: 4.06 g, starting from
1.77 g of 3-mercapto-2-butanone (95%). Yellow oil. IR (film) ν 3393
(m, br), 2975 (m), 2930 (m), 2870 (w), 2566 (vw), 2197 (vw), 1592
(m), 1510 (m), 1342 (s), 1108 (m), 854 (m), 752 (w) cm−1; 1H NMR
(300 MHz, CDCl3) δ 8.28−8.21 [B (m, 2 H)], 8.17−8.09 [A (m, 2
H)], 7.65−7.59 [A (m, 2 H)], 7.55−7.49 [B (m, 2 H)], 4.11 [B (q, J =
7.2, 1 H)], 3.77 [A (q, J = 7.0, 1 H)], 1.47 [A (d, J = 7.0, 3 H)], 1.44
[A (s, 3 H) + B (s, 3 H)], 1.42 [B (distorted d, J = 7.2, 3 H)], 1.26 [B
(d, J = 7.2, 1 H)], 1.24 [A (d, J = 7.0, 1 H)]; 13C NMR (75 MHz,
CDCl3) δ 143.1, 140.4, 130.7, 129.2, 127.0, 126.6, 123.65, 123.59,
86.7, 84.2, 56.9, 55.2, 23.6, 18.6, 14.8, 12.3; GC−MS m/z 251 (absent)
[M+], 234 (14), 233 (100), 218 (56), 203 (11), 186 (14), 172 (36),
171 (36), 153 (12), 152 (11), 128 (9), 115 (13). Anal. Calcd for
C12H13NO3S (251.30): C, 57.35; H, 5.21; N, 5.57; S, 12.76. Found: C,
57.41; H, 5.20; S, 12.74.
Scheme 2. Proposed Mechanism for the PdI2/KI-Catalyzed
Heterocyclodehydration of 1-Mercapto-3-yn-2-ols 5 to
Substituted Thiophenes 6
(mercaptomethyl)trideca-5,8-diyn-7-ol 5h, was less reactive
than 1-mercapto-2,2-dialkynyl-2-ols 5g and 5i, bearing a
secondary thiol group.
In order to verify the possibility to recycle the catalytic
system, we also carried out the heterocyclodehydration reaction
of 5 in an ionic liquid (IL) as the solvent.7 We chose
mercaptoalkynol 5b as model substrate for testing the feasibility
of the process in an IL. The results obtained by employing
some ILs, with 1 mol % of catalyst at 80 °C for 24 h and with a
substrate concentration of 0.2 mmol of 5b per mL of IL, are
shown in the Supporting Information (Table S2). The best
result in terms of product yield (82%) was obtained with
BmimBF4, which was accordingly chosen as the reference IL
solvent for the next experiments, aimed at assessing the
recyclability of the catalyst-IL system. The results of these
experiments, reported in the Supporting Information (Table
S3), show that the catalyst-IL system could be recycled sixth
times with comparable yields in several examples.
Preparation of 1-Mercapto-2,2-dialkynyl-2-ols 5g−i. Sub-
strates 5h and 5i were prepared as we already reported.8 7-(1-
Mercaptoethyl)trideca-5,8-diyn-7-ol 5g was prepared as described
below.
In conclusion, we have reported a convenient and general
method for the heterocyclodehydration of readily available 1-
mercapto-3-yn-2-ols 5 to substituted thiophenes 6. The process
is catalyzed by a simple catalytic system, consisting of PdI2 in
conjunction with an excess of KI, under mild reaction
conditions (MeOH as the solvent at 50−80 °C) and can be
applied to a variety of substrates, including 1-mercapto-2,2-
dialkynyl-2-ols. The latter were converted into the correspond-
ing thiophene derivatives without affecting the additional
alkynyl substituent, which would allow further functionalization
at the thiophene ring. Moreover, the catalytic method has been
made recyclable using a suitable ionic liquid as the solvent, such
as BmimBF4.
Preparation of 7-(1-Mercaptoethyl)trideca-5,8-diyn-7-ol 5g. To a
suspension of Mg turnings (0.6 g, 24.7 mmol) in anhydrous THF (3
mL), maintained under nitrogen at reflux was added pure ethyl
bromide (0.8 mL) to start formation of the Grignard reagent. The
remaining bromide was added dropwise in THF solution (2.0 mL of
EtBr in 5 mL of THF; total amount of EtBr added, 4.09 g, 37.5 mmol).
The mixture was then allowed to reflux for an additional 20 min. After
cooling, the resulting solution of EtMgBr was transferred under
nitrogen to a dropping funnel and added dropwise under nitrogen to a
solution of 1-hexyne (3.27 g, 39.8 mmol) in anhydrous THF (6 mL) at
0 °C with stirring. After additional stirring at 0 °C for 15 min, the
mixture was allowed to warm to room temperature and then was
heated at 45 °C and stirred for 2 h. To the hot solution of the 1-
hexynylmagnesium bromide thus obtained was added, dropwise and
under nitrogen, a solution of ethyl 2-mercaptopropanoate (1.33 g, 9.94
mmol) in anhydrous THF (5 mL). The resulting mixture was allowed
to stir at 45 °C for 2 h. After cooling to room temperature, saturated
aqueous NH4Cl (50 mL) and Et2O (40 mL) were sequentially added,
the phases were separated, and the aqueous phase was extracted with
Et2O (3 × 50 mL). The collected organic layers were washed with
brine and dried over Na2SO4. After filtration and evaporation of the
solvent, product 5g was purified by column chromatography on silica
gel using 95:5 hexane/AcOEt as the eluent. Yield: 1.13 g, starting from
1.33 g of ethyl 2-mercaptopropanoate (45%). Yellow oil. IR (film) ν
3426 (m, br), 2957 (m), 2930 (m), 2231 (w), 1458 (m), 1251 (w),
1157 (w), 1041 (m) cm−1; 1H NMR (300 MHz, CDCl3) δ 3.21−3.08
(m, 1 H), 2.27 (t, J = 6.9, 2 H), 2.25 (t, J = 6.9, 2 H), 1.87 (d, J = 8.5, 1
H), 1.60−1.35 (m, 8 H), 1.51 (d, J = 6.9, 3 H), 0.92 (t, J = 7.3, 3 H),
0.91 (t, J = 7.3, 3 H); 13C NMR (75 MHz, CDCl3) δ 85.7, 85.2, 79.2,
78.1, 67.8, 47.8, 30.5, 30.4, 22.0, 20.4, 18.4, 13.6; GC−MS m/z 252
(absent) [M+], 236 (3), 192 (18), 191 (100), 190 (10), 161 (12), 148
(8), 147 (13), 135 (11), 128 (14), 115 (25), 107 (14), 103 (13), 93
(12), 92 (13), 91 (49), 80 (11), 77 (40). Anal. Calcd for C15H24OS
(252.42): C, 71.37; H, 9.58; S, 12.70. Found: C, 71.42; H, 9.57; S,
12.72.
EXPERIMENTAL SECTION
■
General Experimental Methods. Melting points are uncorrected.
1H NMR and 13C NMR spectra were recorded at 25 °C in CDCl3
solutions at 300 and 75 MHz, respectively, with Me4Si as an internal
standard. Chemical shifts (δ) and coupling constants (J) are given in
ppm and Hz, respectively. IR spectra were taken with an FT-IR
spectrometer. Mass spectra were obtained using a GC−MS apparatus
at 70 eV ionization voltage. All reactions were analyzed by TLC on
silica gel 60 F254 or on neutral alumina and by GLC using a gas
chromatograph and capillary columns with polymethylsilicone + 5%
phenylsilicone as the stationary phase. Column chromatography was
performed on silica gel 60 (70−230 mesh). Evaporation refers to the
removal of solvent under reduced pressure.
Preparation of 1-Mercapto-3-alkyn-2-ols 5a−f. Substrates 5a,
5b, 5c, and 5e were prepared as we previously reported.8 1-Mercapto-
4-phenylbut-3-yn-2-ol 5f was prepared as described in the literature.1c
4-Mercapto-3-methyl-1-(4-nitrophenyl)pent-1-yn-3-ol 5d was pre-
pared as described below.
Preparation of 4-Mercapto-3-methyl-1-(4-nitrophenyl)pent-1-yn-
3-ol (5d). To a cooled (−78 °C), stirred solution of BuLi (1.6 M in
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General Procedure for the PdI2-Catalyzed Heterocyclodehy-
dration of 1-Mercapto-2,2-dialkynyl-2-ols 5 to Thiophenes 6.
To a solution of 5 (1.0 mmol) (5a, 186 mg; 5b, 206 mg; 5c, 220 mg;
5d, 251 mg; 5e, 212 mg; 5f, 178 mg; 5g, 252 mg; 5h, 292 mg, 5i, 238
mg) in anhydrous MeOH (2 mL) was added PdI2 (3.6 mg, 1.0 × 10−2
mmol, or 7.2 mg, 1.0 × 10−2 mmol, see Table 1) and KI (16.6 mg, 1.0
× 10−1 mmol, or 33.2 mg, 2.0 × 10−1 mmol) in this order under
nitrogen in a Schlenk flask. The mixture was allowed to stir at the
required temperature for the required time (see Table 1). After
cooling, solvent was evaporated, and products were purified by transfer
distillation (6a) or column chromatography on silica gel using as
eluent 9:1 hexane/acetone (6b), 98:2 hexane/AcOEt (6c, 6g), 95:5
hexane/AcOEt (6d, 6f), pure hexane (6e, 6i), or 98:2 hexane/acetone
(6h).
CDCl3) δ 144.4, 134.4, 128.9, 128.0, 127.4, 125.9, 124.8, 123.1; GC−
MS m/z 160 (100) [M+], 128 (15), 115 (42), 102 (7), 89 (10), 77
(6), 63 (8). Anal. Calcd for C10H8S (160.24): C, 74.96; H, 5.03; S,
20.01. Found: C, 74.98; H, 5.01; S, 20.01.
5-Butyl-3-hex-1-ynyl-2-methylthiophene (6g). Yield: 200 mg,
starting from 252 mg of 5g (85%) (Table 1, entry 7). Yellow oil. IR
(film) ν 2964 (s), 2931 (s), 2859 (m), 2360 (vw), 1465 (m), 1378
(w), 832 (m) cm−1; 1H NMR (300 MHz, CDCl3) δ 6.56 (s, 1 H), 2.66
(t, J = 7.5, 2 H), 2.42 (s, 3 H), 2.39 (t, J = 6.9, 2 H), 1.65−1.28 (m, 8
H), 0.94 (t, J = 7.3, 3 H), 0.91 (t, J = 7.3, 3 H); 13C NMR (75 MHz,
CDCl3) δ 141.4, 139.6, 126.3, 119.7, 91.7, 75.5, 33.6, 31.1, 29.6, 22.1,
22.0, 19.2, 14.2, 13.8, 13.7; GC−MS m/z 234 (19) [M+], 205 (4), 191
(100), 177 (8), 161 (16), 147 (42), 128 (14), 115 (31), 103 (9), 91
(16), 77 (12). Anal. Calcd for C15H22S (234.40): C, 76.86; H, 9.46; S,
13.68. Found: C, 76.88; H, 9.45; S, 13.67.
2-Butyl-4-hex-1-ynylthiophene (6h). Yield: 115 mg, starting from
238 mg of 5h (52%) (Table 1, entry 9). Yellow oil. IR (film) ν 2923
(s), 2853 (m), 2205 (vw), 1442 (m), 1384 (m), 752 (s), 686 (m)
cm−1; 1H NMR (300 MHz, CDCl3) δ 7.10 (d, J = 1.2, 1 H), 6.74−6.72
(m, 1 H), 2.74 (td, J = 7.5, 0.9, 2 H), 2.36 (t, J = 7.0, 2 H), 1.68−1.29
(m, 8 H), 0.93 (t, J = 7.3, 3 H), 0.91 (t, J = 7.3, 3 H); 13C NMR (75
MHz, CDCl3) δ 145.3, 126.8, 125.2, 122.3, 89.0, 76.1, 33.6, 30.9, 29.6,
22.1, 22.0, 19.1, 13.8, 13.7; GC−MS m/z 220 (45) [M+], 205 (12),
191 (5), 177 (100), 163 (16), 147 (10), 135 (29), 115 (11), 91 (13),
77 (9). Anal. Calcd for C14H20S (220.37): C, 76.30; H, 9.15; S, 14.55.
Found: C, 76.32; H, 9.14; S, 14.54.
5-Butyl-2,3-dimethylthiophene (6a).9 Yield: 148 mg, starting from
186 mg of 5a (88%) (Table 1, entry 1). Yellow oil. IR (film) ν 2961
1
(s), 2839 (w), 1464 (s), 1147 (w), 828 (m) cm−1; H NMR (300
MHz, CDCl3) δ 6.44, (s, 1 H, H-4), 2.69 (t, J = 7.7, 2 H), 2.27 (s, 3
H), 2.06 (s, 3 H), 1.66−1.53 (m, 2 H), 1.45−1.30 (m, 2 H), 0.92 (t, J
= 7.3, 3 H); 13C NMR (75 MHz, CDCl3) δ 140.9, 132.3, 129.8, 126.9,
33.9, 29.6, 22.2, 13.9, 13.5, 12.9; GC−MS m/z 168 (26) [M+], 125
(100), 111 (4), 91 (13), 77 (4). Anal. Calcd for C10H16S (168.30): C,
71.36; H, 9.58; S, 19.05. Found: C, 71.40; H, 9.56; S, 19.04.
2,3-Dimethyl-5-phenylthiophene (6b).10 Yield: 168 mg, starting
from 206 mg of 5b (89%) (Table 1, entry 2). Yellow amorphous solid,
mp = 46−47 °C, lit.10 46−47 °C. IR (KBr) ν 2915 (m), 2855 (w),
1
1598 (w), 1502 (m), 1444 (m), 1172 (w), 755 (s), 699 (s) cm−1; H
2-Methyl-5-phenyl-3-phenylethynylthiophene (6i). Yield: 233 mg,
starting from 292 mg of 5i (85%) (Table 1, entry 8). Yellow solid, mp
= 124−125 °C. IR (KBr) ν 2957 (s), 2931 (s), 2872 (m), 2234 (vw),
NMR (300 MHz, CDCl3) δ 7.55−7.47 (m, 2 H), 7.35−7.26 (m, 2 H),
7.24−7.16 (m, 1 H), 6.99 (s, 1 H), 2.33 (s, 3 H), 2.12 (s, 3 H); 13C
NMR (75 MHz, CDCl3) δ 139.1, 134.7, 134.0, 131.4, 128.7, 126.8,
126.0, 125.3, 13.6, 13.1; GC−MS m/z 188 (100) [M+], 187 (54), 173
(69), 153 (9), 128 (15), 115 (10), 102 (7), 77 (18). Anal. Calcd for
C12H12S (188.29): C, 76.55; H, 6.42; S, 17.03. Found: C, 76.60; H,
6.41; S, 16.99.
2,3-Dimethyl-5-p-tolylthiophene (6c). Yield: 152 mg, starting from
220 mg of 5c (75%) (Table 1, entry 3). Yellow amorphous solid, mp =
46−47 °C. IR (KBr) ν 2918 (m), 1516 (m), 1447 (w), 811 (s), 757
(m) cm−1; 1H NMR (300 MHz, CDCl3) δ 7.44−7.37 (m, 2 H), 7.16−
7.08 (m, 2 H), 6.94 (s, 1 H), 2.33 (s, 3 H), 2.32 (s, 3 H), 2.12 (s, 3 H);
13C NMR (75 MHz, CDCl3) δ 139.3, 136.6, 133.9, 132.0, 131.3, 129.4,
125.5, 125.3, 21.1, 13.6, 13.1; GC−MS m/z 202 (100) [M+], 201 (54),
171 (5), 153 (5), 141 (4), 128 (6), 115 (6), 101 (5). Anal. Calcd for
C13H14S (202.32): C, 77.18; H, 6.97; S, 15.8. Found: C, 77.26; H,
6.95; S, 15.79.
1
1466 (m), 835 (m), 738 (m), 629 (w) cm−1; H NMR (300 MHz,
CDCl3) δ 7.57−7.49 (m, 4 H), 7.39−7.23 (m, 7 H), 2.59 (s, 3 H); 13
C
NMR (75 MHz, CDCl3) δ 143.0, 140.3, 133.9, 131.4, 128.9, 128.4,
128.1, 127.5, 125.5, 125.1, 123.4, 120.7, 91.6, 84.1, 14.6; GC−MS m/z
274 (86) [M+], 258 (19), 239 (40), 215 (19), 197 (46), 187 (22), 171
(28), 163 (22), 152 (50), 139 (27), 121 (31), 102 (26), 89 (39), 77
(100). Anal. Calcd for C19H14S (274.38): C, 83.17; H, 5.14; S, 11.69.
Found: C, 83.15; H, 5.15; S, 11.70.
11
Preparation of Ionic Liquids. Ionic liquids BmimNTf2 and
BmimOTf12 were prepared according to literature procedures. All
other ionic liquids were prepared as we previously described.2f
General Procedure for the Recyclable PdI2-Catalyzed
Heterocyclodehydration of 1-Mercapto-2,2-dialkynyl-2-ols 5
to Thiophenes 6 in BmimBF4. To a solution of 5 (0.4 mmol) (5b,
83 mg; 5e, 85 mg; 5g, 101 mg; 5h, 95 mg) in BmimBF4 (2 mL) were
added PdI2 (1.5 mg, 4.2 × 10−2 mmol) and KI (6.9 mg, 4.2 × 10−1
mmol) in this order under nitrogen in a Schlenk flask. The mixture
was allowed to stir at 80 °C for 24 h. After cooling, the product was
extracted with Et2O (6 × 4 mL), and the residue (still containing the
catalyst dissolved in the ionic liquid) was used as such for the next
recycle (see below). The collected ethereal phases were concentrated,
and products were purified as detailed in the general procedure in
MeOH (see above). The isolated yields obtained in each experiment
are reported in Table S3 (Supporting Information).
2,3-Dimethyl-5-(4-nitrophenyl)thiophene (6d). Yield: 182 mg,
starting from 251 mg of 5d (78%) (Table 1, entry 4). Yellow
amorphous solid, mp = 78−79 °C. IR (KBr) ν 1594 (m), 1514 (m),
1
1446 (s), 1102 (w), 851 (m), 736 (m) cm−1; H NMR (300 MHz,
CDCl3) δ 8.29−8.21 (m, 2 H), 7.55−7.47 (m, 2 H), 7.07 (s, 1 H),
2.42 (s, 3 H), 2.13 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 144.5,
141.5, 135.1, 131.1, 129.3, 123.6, 120.4 (2C), 13.7, 13.0; GC−MS m/z
232 (100) [M+], 218 (56), 203 (11), 186 (16), 172 (37), 171 (37),
153 (12), 128 (10), 115 (14). Anal. Calcd for C12H11NO2S (233.29):
C, 61.78; H, 4.75; N, 6.00; S, 15.8. Found: C, 61.82; H, 4.73; N,6.02;
S, 15.79.
Recycling Procedure. To the residue obtained as described above,
still containing the catalyst dissolved in the ionic liquid, was added a
solution of 5 (0.4 mmol) in Et2O (4 mL). Et2O was removed under
vacuum, and then the same procedure described above was followed.
2,3-Dimethyl-5-(thiophen-3-yl)thiophene (6e). Yield: 151 mg,
starting from 212 mg of 5e (78%) (Table 1, entry 5). Yellow
amorphous solid, mp = 52−53 °C. IR (KBr) ν 1638 (m), 1384 (m),
1
1080 (w), 823 (m), 771 (s) cm−1; H NMR (300 MHz, CDCl3) δ
ASSOCIATED CONTENT
7.28−7.19 (m, 3 H), 6.85 (s, 1 H), 2.30 (s, 3 H), 2.10 (s, 3 H); 13C
NMR (75 MHz, CDCl3) δ 135.9, 134.1, 133.6, 131.4, 126.03, 125.96,
125.8, 118.4, 13.6, 13.0; GC−MS m/z 194 (100) [M+], 193 (58), 179
(67), 161 (15), 134 (10), 115 (9), 97 (10). Anal. Calcd for C10H10S2
(194.32): C, 61.81; H, 5.19; S, 33.00. Found: C, 61.80; H, 5.18; S,
33.02.
■
S
* Supporting Information
1
Tables S1−S3 and copies of H and 13C NMR spectra for all
products. This material is available free of charge via the
Internet at http://pubs.acs.org.
2-Phenylthiophene (6f).1c Yield: 80 mg, starting from 178 mg of 5f
(50%) (Table 1, entry 6). Yellow solid, mp = 34−35 °C, lit.1c 33−34
°C. IR (KBr) ν 2924 (m), 1600 (m), 1446 (m), 1072 (m), 755 (s),
AUTHOR INFORMATION
■
1
693 (s) cm−1; H NMR (300 MHz, CDCl3) δ 7.63−7.54 (m, 2 H),
Corresponding Author
7.39−7.20 (m, 5 H), 7.07−7.01 (m, 1 H); 13C NMR (75 MHz,
*E-mail: b.gabriele@unical.it.
9908
dx.doi.org/10.1021/jo301943k | J. Org. Chem. 2012, 77, 9905−9909

The Journal of Organic Chemistry
Note
(7) The use of ILs in organic synthesis has recently attracted great
attention, due to the very important characteristics of these
nonconventional solvents: they are stable, nonflammable, nonvolatile,
and recyclable and in some cases may even promote organic reactions.
For recent reviews, see: (a) Patel, D. D. Chem. Rec. 2012, 12, 329−
355. (b) Wong, W.-L.; Wong, K.-Y. Can. J. Chem. 2012, 90, 1−16.
(c) Payagala, T.; Armstrong, D. W. Chirality 2012, 24, 17−53.
(d) Dupont, J. Acc. Chem. Res. 2011, 44, 1223−1231. (e) Hallett, J. P.;
Welton, T. Chem. Rev. 2011, 111, 3508−3576. (f) Hubbard, C. D.;
Illner, P.; van Eldik, R. Chem. Soc. Rev. 2011, 40, 272−290. (g) Zhang,
Q.; Zhang, S.; Deng, Y. Green Chem. 2011, 13, 2619−2637.
(8) Gabriele, B.; Mancuso, R.; Salerno, G.; Larock, R. C. J. Org. Chem.
2012, 77, 7640−7645.
(9) Eichinger, K.; Mayr, P.; Nussbaumer, P. Synthesis 1989, 210−211.
(10) Gabriele, B.; Salerno, G.; Fazio, A. Org. Lett. 2000, 2, 351−352.
(11) Huddleston, J. G.; Visser, A. E.; Reichert, W. M.; Willauer, H.
D.; Broker, G. A.; Rogers, R. D. Green Chem. 2001, 156−164.
(12) Crosthwaite, J. M.; Aki, S. N. V. K.; Maginn, E. J.; Brennecke, J.
F. J. Phys. Chem. B 2004, 108, 5113−5119.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support from the Ministero dell’Istruzione, dell’Uni-
versita
■
̀
e della Ricerca (MIUR, Rome, Italy) is gratefully
acknowledged (Progetto di Ricerca d’Interesse Nazionale PRIN
2008A7P7YJ). Thanks are due to the European Commission,
FSE (Fondo Sociale Europeo) and Calabria Region for a
fellowship grant to R.M.
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