An iodocyclization approach to substituted 3-iodothiophenes

Article abstract of DOI:10.1021/jo301001j

A novel approach to 3-iodothiophenes by direct iodocyclization of alkynylthiol derivatives is presented. A variety of 1-mercapto-3-yn-2-ols 5 (readily available from alkynylation of the corresponding alpha-mercapto ketones or alpha-mercapto esters) were smoothly converted into the corresponding 3-iodothiophene derivatives 6 in good yields by reaction with molecular iodine in the presence of NaHCO₃ at room temperature in MeCN as the solvent.

Full text of DOI:10.1021/jo301001j

Note
pubs.acs.org/joc
An Iodocyclization Approach to Substituted 3‑Iodothiophenes
Bartolo Gabriele,*,† Raffaella Mancuso,*,‡ Giuseppe Salerno,‡ and Richard C. Larock§
†Dipartimento di Scienze Farmaceutiche, Universita
̀
della Calabria, 87036 Arcavacata di Rende (CS), Italy
‡Dipartimento di Chimica, Universita
̀
della Calabria, 87036 Arcavacata di Rende (CS), Italy
§Department of Chemistry, Iowa State University, Ames, Iowa 50011, United States
S
* Supporting Information
ABSTRACT: A novel approach to 3-iodothiophenes by direct iodocyclization
of alkynylthiol derivatives is presented. A variety of 1-mercapto-3-yn-2-ols 5
(readily available from alkynylation of the corresponding alpha-mercapto
ketones or alpha-mercapto esters) were smoothly converted into the
corresponding 3-iodothiophene derivatives 6 in good yields by reaction with molecular iodine in the presence of NaHCO3 at
room temperature in MeCN as the solvent.
he iodocyclization of acetylenic substrates bearing a
suitably placed nucleophilic group is a powerful synthetic
Scheme 2. Formation of 3-Iodofurans (2), 3-Iodopyrroles (4),
and 3-Iodothiophenes (6) by the Iodocyclodehydration of 3-
Alkyne-1,2-diols (1), N-Tosyl-1-amino-3-alkyn-2-ols (3), and
1-Mercapto-3-alkyn-2-ols (5), Respectively
T
tool for the direct and regioselective synthesis of iodo-substituted
carbo- and heterocyclic derivatives (Scheme 1).1,2 The
Scheme 1. Iodocyclization of Acetylenic Substrates Bearing a
Suitably Placed Nucleophilic Group Leading to Iodo-
containing Carbo- and Heterocycles
Scheme 3. Synthesis of Starting Materials 5a−i and 5k−l by
Alkynylation of 3-Mercaptobutan-2-one, Ethyl 2-
mercaptopropanoate and Ethyl 2-mercaptoacetate
construction of such compounds from simple building blocks
under mild conditions, coupled with the presence of the iodo
substituent for further functionalization and diversification of the
product by a wide variety of cross-coupling reactions, makes such
processes particularly attractive in modern organic synthesis.
Although many important examples of the formation of
oxygen and nitrogen heterocycles by iodocyclization are known
(Scheme 1, Y = O or NR), the direct synthesis of iodothiophenes
starting from acyclic alkynylthiols has not yet been reported. In
particular, the formation of 3-iodofurans 2 and 3-iodopyrroles 4
by the iodocyclization of 3-alkyne-1,2-diols 13 and N-tosyl-1-
amino-3-alkyn-2-ols 3,4 respectively, has recently been published
(Scheme 2, Y = O or NTs). However, no analogous
iodocyclodehydration of 1-mercapto-3-alkyn-2-ols 5 has been
reported so far. We now wish to report such a process (Scheme 2,
Y = S), which allows a general and facile synthesis of 3-
iodothiophenes 65 under mild conditions starting from readily
available substrates.
Starting materials 5a−i, 5k, and 5l were prepared by addition
of the appropriate alkynyllithium or alkynylmagnesium bromide
to commercially available 3-mercaptobutan-2-one, ethyl 2-
mercaptopropanoate and ethyl 2-mercaptoacetate, according to
Scheme 3. In this way, differently substituted 1-mercapto-3-
alkyn-2-ols 5a−i and 1-mercapto-2,2-dialkynyl-2-ols 5k and 5l
could be easily obtained in fair to excellent yields (40−92%, see
the Experimental Section for details). 1-Mercapto-4-phenylbut-
3-yn-2-ol 5j was prepared as reported in the literature.6
Received: May 15, 2012
© XXXX American Chemical Society
A
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Note
a
Table 1. Synthesis of 3-Iodothiophenes 6 by Iodocyclodehydration of 1-Mercapto-3-alkyn-2-ols 5
a
Unless otherwise noted, all iodocyclization reactions were carried out at 25 °C in MeCN as the solvent (0.05 mmol of starting thiol 5 per mL of
b
MeCN) with a 5:I2:NaHCO3 molar ratio of 1:2:2 for 5 h. Conversion of thiol 5 was quantitative in all cases. Isolated yield based on starting thiol 5.
c
d
The reaction was carried out with a 5k:I2:NaHCO3 molar ratio of 1:3:3. The reaction was carried out with a 5l:I2:NaHCO3 molar ratio of 1:2:1.
4-Mercapto-3-methyl-1-phenylpent-1-yn-3-ol (5a) was sub-
jected to iodocylization under conditions similar to those already
employed for similar substrates,3,4 involving the use of molecular
iodine as the iodinating agent in the presence of NaHCO3 as the
B
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Note
Scheme 4. Proposed Mechanism for the Iodocyclization of 1-Mercapto-3-yn-2-ols 5 to 3-Iodothiophenes 6
gel 60 (70−230 mesh). Evaporation refers to the removal of solvent
under reduced pressure.
base (molar ratio of 5a:I2:NaHCO3 = 1:1:1) in MeCN as the
solvent (substrate concentration = 0.05 mmol of 5a per mL of
MeCN) at 25 °C. After 5 h reaction time, substrate conversion
was complete, and analysis of the reaction mixture revealed the
formation of the desired 3-iodo-4,5-dimethyl-2-phenylthiophene
(6a), which could be isolated in 55% yield (Table S1, entry 1,
Supporting Information). After a brief optimization study (see
Table S1, Supporting Information), the yield of 6a could be
improved to 71% under conditions similar to those initially
employed, but using a 5a:I2:NaHCO3 molar ratio of 1:2:2 (Table
1, entry 1).
We next tested the reactivity of other 1,2-dialkyl-substituted 1-
mercapto-3-alkyn-2-ols 5b−i, bearing different substituents on
the triple bond (aryl, alkenyl, or alkyl, Table 1, entries 2−9). As
can be seen, good yields of the corresponding 3-iodothiophenes
6b−i have been obtained with all the substrates employed. The
reaction also worked nicely when R1 = R2 = H, as in the case of 1-
mercapto-4-phenylbut-3-yn-2-ol 5j, which was smoothly con-
verted into 3-iodo-2-phenythiophene in 82% yield (Table 1,
entry 10). This result shows that the Ingold-Thorpe and reactive
rotamer effects7 are not at work in our reaction. We also tested
the reactivity of 1-mercapto-2,2-dialkynyl-2-ols 5k and 5l
(bearing an additional alkynyl substituent at C-2). With these
substrates, better results in terms of product yield were observed
by using a molar ratio 5:I2:NaHCO3 of 1:3:3 (Table 1, entry 11)
or 1:2:1 (Table 1, entry 12) rather than 1:2:2 (Table 1, entries 1−
10). Interestingly, the triple bond at C-3 in the corresponding
products 6k and 6l was not affected (Table 1, entries 11 and 12).
Thus, this process allows an easy entry into multifunctionalized
thiophenes in one step starting from very simple substrates.
A plausible mechanism for the iodocyclization of 1-mercapto-
3-yn-2-ols 5 to 3-iodothiophenes 6 is shown in Scheme 4.
According to the previous literature,1−4 it involves the formation
of an iodonium cation I as the key intermediate, followed by 5-
endo-dig cyclization and dehydrative aromatization.
Preparation of 1-Mercapto-3-alkyn-2-ols 5a−i. To a cooled
(−78 °C), stirred solution of BuLi (1.6 M in hexane) (28 mL, 44.8
mmol) in anhydrous THF (16 mL), maintained under nitrogen, was
added dropwise a solution of the 1-alkyne (44.5 mmol) (phenyl-
acetylene, 4.55 g; p-methylphenylacetylene, 5.17 g; p-bromophenylace-
tylene, 8.05 g; 3-ethynylthiophene, 4.81 g; 1-ethynylcyclohex-1-ene,
4.72 g; 1-hexyne, 3.66 g; 4-phenyl-1-butyne, 5.79 g; 3-phenyl-1-propyne,
5.17 g; tert-butylacetylene, 3.66 g) 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, was added, at the same temperature under
nitrogen, a solution of 3-mercapto-2-butanone (1.77 g, 17.0 mmol) in
anhydrous THF (5 mL). The resulting mixture was stirred for an
additional 2 h at −78 °C and then allowed to warm up 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
products were purified by column chromatography using 95:5 hexane−
AcOEt as eluent.
Note: 1-(4-Bromophenyl)-4-mercapto-3-methylpent-1-yn-3-ol (5c)
could not be obtained in a pure state even after repeated purification by
column chromatography, so it was used crude for the next
iodocyclization step.
4-Mercapto-3-methyl-1-phenylpent-1-yn-3-ol (5a). Mixture of
diastereoisomers A+B, A:B ratio = 2.0, determined by 1H NMR.
Yield: 3.16 g, starting from 1.77 g of 3-mercapto-2-butanone (90%).
Yellow oil. IR (film): ν = 3448 (s, br), 2567 (vw), 2230 (vw), 756 (s),
692 (s) cm−1; 1H NMR (300 MHz, CDCl3): δ = 7.47−7.40 [A (m, 2 H)
+ B (m, 2 H)], 7.37−7.28 [A (m, 3 H) + B (m, 3 H)], 3.37 [B (s, br, 1
H)], 3.29 [A (quintuplet, J = 6.7, 1 H)], 3.01−2.92 [B (m, 1 H)], 2.82 [A
(s, br, 1 H)], 1.96 [A (d, J = 6.7, 1 H)], 1.77 [B (d, J = 10.9, 1 H)], 1.65 [B
(s, 3 H)], 1.63 [A (s, 3 H)], 1.56 [B (d, J = 6.9, 3 H)], 1.43 [A (dd, J = 6.7,
0.8, 3 H)]; 13C NMR (75 MHz, CDCl3): δ = 131.74, 131.69, 128.5,
128.3, 122.32, 122.28, 91.4, 89.4, 85.0, 84.4, 72.0, 71.3, 48.5, 46.3, 26.8,
25.5, 22.0, 18.5; GC-MS: diastereomer A: m/z = 206 (0.5) [M+], 145
(100), 43 (72); diastereoisomer B: m/z = 206 (0.6) [M+], 145 (100), 43
(81); anal. calcd for C12H14OS (206.30): C, 69.86; H, 6.84; S, 15.64;
found C, 69.71; H, 6.85; S, 15.67
4-Mercapto-3-methyl-1-p-tolylpent-1-yn-3-ol (5b). Mixture of
diastereoisomers A+B, A:B ratio = 1.5, determined by 1H NMR.
Yield: 2.99 g, starting from 1.77 g of 3-mercapto-2-butanone (80%).
Yellow oil. IR (film): ν = 3434 (m, br), 2566 (vw), 2229 (w), 816 (s)
cm−1; 1H NMR (300 MHz, CDCl3): δ = 7.36−7.27 [A (m, 2 H), + B (m,
2 H)], 7.13−7.06 [A (m, 2 H) + B (m, 2 H)], 3.43 [B, (s, br, 1 H)], 3.27
[A (quintuplet, J = 6.6, 1 H)], 3.00−2.87 [A (m, 1 H) + B (m, 1 H)],
2.33 [A (s, 3 H) + B (s, 3 H)], 1.96 [A (d, J = 6.6, 1 H)], 1.78 [B (d, J =
10.3, 1 H)], 1.64 [B (s, 3 H)], 1.62 [A (s, 3 H)], 1.53 [B (d, J = 6.6, 3
H)], 1.42 [A (d, J = 6.6, 3 H)]; 13C NMR (75 MHz, CDCl3): δ = 138.6,
131.7, 131.6, 129.0, 119.2, 90.6, 88.7, 85.1, 84.5, 72.0, 71.3, 48.5, 46.3,
26.8, 25.6, 21.9, 21.5, 18.6; GC-MS: diastereomer A: m/z = 220 (M+,
<0.5%), 159 (100); diastereomer B: m/z = 220 (M+, <0.5%), 159 (100);
anal. calcd for C13H16OS (220.33): C, 70.87; H, 7.32; S, 14.55; found C,
70.95; H, 7.31; S, 14.64.
In conclusion, we have reported a novel, general and facile
method for the direct synthesis of 3-iodothiophenes by the
iodocyclodehydration of 1-mercapto-3-alkyn-2-ols. The reac-
tions are carried out under mild conditions (25 °C) in MeCN as
the solvent in the presence of an excess of I2 as the iodine source
and NaHCO3 as the base. The method can be successfully
applied to variously substituted substrates, including 1-mercapto-
2,2-dialkynyl-2-ols (bearing an additional alkynyl substituent at
C-2), which are converted into the corresponding thiophene
derivatives without affecting the alkynyl group at C-3.
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
4-Mercapto-3-methyl-1-thiophen-3-yl-pent-1-yn-3-ol (5d). Mix-
1
ture of diastereomers A+B, A:B ratio = 1.6, determined by H NMR.
Yield: 3.28 g, starting from 1.77 g of 3-mercapto-2-butanone (91%).
Yellow oil. IR (film): ν = 3419 (m, br), 2561 (vw), 2231 (w), 783 (s)
cm−1; 1H NMR (300 MHz, CDCl3): δ = 7.46−7.41 [A (m, 1 H) + B (m,
1 H)], 7.28−7.22 [A (m, 1 H) + B (m, 1 H)], 7.12−7.07 [A (m, 1 H) + B
C
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Note
(m, 1 H)], 3.48−3.38 [B (m, 1 H)], 3.26 [A (quintuplet, J = 6.7, 1 H)],
3.03−2.89 [A (m, 1 H), + B (m, 3 H)], 1.94 [A, (d, J = 6.7, 1 H)], 1.76 [B
(d, J = 10.3, 1 H)], 1.63 [B (s, 3 H)], 1.61 [A (s, 3 H)], 1.52 [B (d, J = 6.7,
3 H)], 1.41 [A (d, J = 6.7, 3 H)]; 13CNMR (75 MHz, CDCl3): δ = 129.8,
129.0, 125.4, 121.3, 91.0, 89.1, 80.1, 79.6, 72.0, 71.3, 48.2, 46.1, 26.8, 25.5
21.8, 18.6 ; GC-MS: diastereomer A: m/z = 212 (0.5) [M+], 151 (62),
43 (100); diastereomer B: m/z = 212 (1) [M+], 151 (70), 43 (100); anal.
calcd for C10H12OS2 (212.33): C, 56.57; H, 5.70; S, 30.20; found C,
56.65; H, 5.68; S, 30.18.
2-Mercapto-3,6,6-trimethyl-hept-4-yn-3-ol (5i). Mixture of diaster-
eomers A+B, A:B ratio = 1.1, determined by H NMR. Yield: 2.91 g,
1
starting from 1.77 g of 3-mercapto-2-butanone (92%). Yellow oil. IR
(film): ν = 3436 (m, br), 2570 (vw), 2220 (w), 915 (m), cm−1; 1H NMR
(300 MHz, CDCl3): δ = 3.23 [B (s, br, 1 H)], 3.20−3.07 [A (m, 1 H)],
2.91−2.79 [B (m, 1 H)], 2.72 [A (s, br, 1 H)], 1.89 [A (d, J = 6.6, 1 H)],
1.68 [B (d, J = 10.6, 1 H)], 1.51 [B (s, 3 H), 1.50 [A (s, 3 H)], 1.46 [B (d,
J = 6.6, 3 H)], 1.36 [A (d, J = 6.6, 3 H)], 1.24 [B (s, 9 H)], 1.22 [A (s, 9
H)]; 13C NMR (75 MHz, CDCl3): δ = 93.8, 93.2, 80.9, 78.9, 73.6, 70.7,
48.6, 46.5, 30.9, 26.9, 25.7, 23.2, 22.0, 20.5, 18.5; GC-MS: diastereomer
A: m/z = 186 (absent) [M+], 125 (40), 43 (100); diastereomer B: m/z =
186 (absent) [M+], 125 (38), 43 (100); anal. calcd for C10H18OS
(186.32): C, 64.46; H, 9.74; S, 17.21; found C, 64.52; H, 9.72; S, 17.19.
Preparation of 1-Mercapto-2,2-dialkynyl-2-ols 5k and 5l. To a
suspension of Mg turnings (0.6 g, 24.7 mmol) in anhydrous THF (5
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 the
1-alkyne (39.8 mmol) (phenylacetylene, 4.06 g; 1-hexyne, 3.27 g) in
anhydrous THF (10 mL) at 0 °C with stirring. After additional stirring at
0 °C for 15 min, the mixture was allowed to warm up to room
temperature, and then was heated at 45 °C and stirred for 2 h. To the hot
solution of the 1-alkynylmagnesium bromide thus obtained, was added,
dropwise and under nitrogen, a solution of ethyl 2-mercaptopropanoate
(1.33 g, 9.94 mmol) or ethyl 2-mercaptoacetate (1.20 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 (50 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, products 5k and
5l were purified by column chromatography on silica gel using 95:5
hexane−AcOEt as the eluent.
1-Cyclohex-1-enyl-4-mercapto-3-methyl-pent-1-yn-3-ol (5e).
1
Mixture of diastereomers A+B, A:B ratio = 2.0, determined by H
NMR. Yield: 3.11 g, starting from 1.77 g of 3-mercapto-2-butanone
(87%). Yellow oil. IR (film): ν = 3434 (m, br), 2570 (vw), 2216 (m), 919
(s) cm−1; 1H NMR (300 MHz, CDCl3): δ = 6.16−6.06 [A (m, 1 H) + B
(m, 1 H)], 3.30 [B (s, br, 1 H)], 3.19 [A (quintuplet, J = 6.6, 1 H)],
2.95−2.83 [B (m, 1 H)], 2.82 [A (s, br, 1 H)], 2.15−2.03 [A (m, 4 H) +
B (m, 4 H)], 1.92 [A (d, J = 6.6, 1 H)], 1.73 [B (d, J = 10.3, 1 H)], 1.68−
1.53 [A (m, 4 H) + B (m, 4 H)], 1.61 [B (s, 3 H)], 1.59 [A (s, 3 H)], 1.48
[B (d, J = 7.3, 1 H)], 1.37 [A (d, J = 6.6, 1 H)]; 13C NMR (75 MHz,
CDCl3): δ = 135.5, 119.9, 88.6, 86.8, 86.6, 86.2, 71.9, 71.2, 48.5, 46.3,
29.2, 29.1, 26.8 25.63, 25.58, 22.2, 21.9, 21.4, 18.5; GC-MS:
diastereomer A: m/z = 210 (<0.5) [M+], 192 (23), 149 (100), 91
(21); diastereomer B: m/z = 210 (<0.5) [M+], 149 (100); anal. calcd for
C12H18OS (210.34): C, 68.52; H, 8.63; S, 15.25; found C, 68.63; H,
8.61; S, 15.23
2-Mercapto-3-methylnon-4-yn-3-ol (5f). Mixture of diastereomers
1
A+B, A:B ratio = 1.4, determined by H NMR. Yield: 2.69 g, starting
from 1.77 g of 3-mercapto-2-butanone (85%). Yellow oil. IR (film): ν =
1
3447 (m, br), 2567 (vw), 2240 (vw), 917 (m) cm−1; H NMR (300
MHz, CDCl3): δ = 3.22 [B (s, br, 1 H)], 3.14 [A (quintuplet, J = 6.9, 1
H)], 2.86 [B (dq, J = 10.5, 6.9, 1 H)], 2.75 [A (s, br, 1 H)], 2.26−2.16 [A
(m, 2 H), + B (m, 2 H)], 1.89 [A (d, J = 10.5, 1 H), 1.71 [B (d, J = 6.9, 1
H)], 1.53−1.38 [A (m, 4 H) + B (m, 4 H)], 1.52 [B (s, 3 H)], 1.51 [A (s,
3H)], 1.46 [B (d, J = 6.9, 1 H)], 1.36 [A (d, J = 10.5, 1 H)], 0.92 [B (t, J =
7.3, 3 H)], 0.91 [A (t, J = 7.3, 3 H)]; 13C NMR (75 MHz, CDCl3): δ =
85.6, 85.1, 82.6, 80.6, 71.6, 70.9, 48.4, 46.4, 30.8, 30.7, 27.0, 25.9, 22.0,
21.8, 18.6, 18.3, 13.6; GC-MS: diastereomer A: m/z = 186 (<0.5) [M+],
125 (95), 43 (100); diastereomer B: m/z = 186 (<0.5) [M+], 125 (98),
43 (100); anal. calcd for C10H18OS (186.32): C, 64.46; H, 9.74; S, 17.21;
found C, 64.53; H, 9.72; S, 17.20.
3-(1-Mercapto-ethyl)-1,5-diphenyl-penta-1,4-diyn-3-ol (5k).
Yield: 1.31 g, starting from 1.33 g of ethyl 2-mercaptopropanoate
(45%). Yellow oil. IR (film): ν = 3436 (s, br), 2574 (vw), 2227 (m), 755
1
(s) cm−1; H NMR (300 MHz, CDCl3): δ = 7.67−7.01 (m, 10 H),
2-Mercapto-3-methyl-7-phenylhept-4-yn-3-ol (5g). Mixture of
1
diastereomers A+B, A:B ratio = 1.5, determined by H NMR. Yield:
3.46−3.34 (m, 1 H), 1.97 (d, J = 9.1, 1 H), 1.68 (d, J = 4.9, 3 H) (Note:
the OH signal was too broad to be detected); 13C NMR (75 MHz, CDCl3):
δ = 132.0, 131.9, 128.93, 128.90, 128.30, 128.26, 125.5, 121.8, 87.3, 86.3,
85.3, 84.8, 65.8, 47.7, 20.5; GC-MS: m/z = 292 (absent) [M+], 274
(100), 273 (28); anal. calcd for C19H16OS (292.40): C, 78.05; H, 5.52; S,
10.97; found C, 78.12; H, 5.50; S, 10.95.
1.59 g, starting from 1.77 g of 3-mercapto-2-butanone (40%). Yellow oil.
IR (film): ν = 3439 (m, br), 2559 (vw), 2237 (w), 698 (m) cm−1; 1H
NMR (300 MHz, CDCl3): δ = 7.32−7.03 [A (m, 5 H) + B (m, 5 H)],
3.09−2.92 [A (m, 1 H) + B (m, 1 H)], 2.83−2.70 [A (m, 2 H) + B (m, 2
H)], 2.54−2.42 [A (m, 2 H) + B (m, 2 H)], 1.75 [A (d, J = 6.7, 1 H)],
1.52 [B (d, J = 10.3, 1 H)], 1.45 [A (s, 3 H) + B (s, 3 H)], 1.31 [B (d, J =
6.7, 3 H)], 1.26 [A (d, J = 6.7, 3 H)] (Note: the OH signals were too broad
to be detected); 13C NMR (75 MHz, CDCl3): δ = 140.3, 128.4, 128.3,
126.3, 84.5, 84.1, 83.4, 81.7, 71.5, 70.9, 48.0, 46.0, 34.8, 26.8, 25.9, 21.4,
20.6, 20.5, 18.7; GC-MS: diastereomer A: m/z = 234 (1) [M+], 173
(74), 91 (100); diastereomer B: m/z = 234 (1) [M+], 173 (65), 125
(47), 91 (100); anal. calcd for C14H18OS (234.36): C, 71.75; H, 7.74; S,
13.68; found C, 71.82; H, 7.72; S, 13.67.
7-Mercaptomethyl-trideca-5,8-diyn-7-ol (5l). Yield: 1.21 g, starting
from 1.20 g of ethyl 2-mercaptoacetate (51%). Yellow oil. IR (film): ν =
3426 (m, br), 2567 (vw), 2231 (m), 729 (m) cm−1; 1H NMR (300 MHz,
CDCl3): δ = 3.08 (s, br, 1 H), 2.96 (d, J = 8.8, 2 H), 2.25 (t, J = 7.0, 4 H),
1.78 (t, J = 8.8, 1 H), 1.58−1.33 (m, 8 H), 0.91 (t, J = 7.3, 6 H); 13C
NMR (75 MHz, CDCl3): δ = 85.2, 79.4, 63.7, 39.5, 30.4, 22.0, 18.4,
13.6.; GC-MS: m/z = 238 (absent) [M+], 220 (24), 191 (100), 177 (54),
91 (34), 79 (30); anal. calcd for C14H22OS (238.39): C, 70.54; H, 9.30;
S, 13.45; found C, 70.63; H, 9.28; S, 13.43.
General Procedure for the Iodocyclization of 1-Mercapto-3-
alkyn-2-ols 5a−j and 1-Mercapto-2,2-dialkynyl-2-ols 5k and 5l
to Iodothiophenes 6a−l. To a solution of 5 (0.3 mmol) (5a, 62 mg;
5b, 66 mg; 5c, 86 mg; 5d, 64 mg; 5e, 63 mg; 5f, 56 mg; 5g, 70 mg; 5h, 66
mg, 5i, 56 mg; 5j, 53 mg; 5k, 88 mg; 5l, 72 mg) in MeCN (6 mL) were
added NaHCO3 (25 mg or 50 or 75 mg, 0.3 or 0.6 or 0.9 mmol, see
Table 1) and I2 (152 or 228 mg, 0.6 or 0.9 mmol, see Table 1) in this
order under nitrogen. The mixture was allowed to stir at 25 °C for 5 h.
Saturated aqueous Na2S2O3 was then added, and the mixture was
allowed to stir for 10 min. The phases were separated, and the aqueous
phase was extracted with Et2O (3 × 10 mL). The collected organic layers
were dried over Na2SO4. After filtration and evaporation of the solvent,
products 6a−l were purified by column chromatography on silica gel
using 99:1 hexane−AcOEt as the eluent.
2-Mercapto-3-methyl-6-phenyl-hex-4-yn-3-ol (5h). Mixture of
1
diastereomers A+B, A:B ratio = 2.0, determined by H NMR. Yield:
1.91 g, starting from 1.77 g of 3-mercapto-2-butanone (51%). Yellow oil.
1
IR (film): ν = 3432 (s, br), 2567 (vw), 2243 (w), 697 (m) cm−1; H
NMR (300 MHz, CDCl3): δ = 7.34−7.18 [A (m, 5 H) + B (m, 5 H)],
3.63 [B (s, 2 H)], 3.62 [B (s, 2 H)], 3.16 [A (quintuplet, J = 6.7, 1 H)],
2.94−2.79 [B (m, 1 H)], 1.86 [A (d, J = 6.7, 1 H)], 1.70 [B (d, J = 10.3, 1
H)], 1.56 [B (s, 3 H)], 1.54 [A (s, 3 H)], 1.46 [B (d, J = 6.7, 3 H)], 1.37
[A (d, J = 6.7, 3 H)] (Note: the OH signals were too broad to be detected);
13C NMR (75 MHz, CDCl3): δ = 136.5, 136.4, 128.51, 127.84, 127.77,
126.6, 84.8, 83.1, 83.0, 82.5, 71.7, 71.0, 48.2, 46.2, 27.0, 25.8, 24.9, 21.7,
18.7; GC-MS: diastereomer A: m/z = 220 (1) [M+], 159 (100), 115
(57); diastereomer B: m/z = 220 (2) [M+], 202 (26), 187 (34), 159
(100), 116 (29), 115 (69); anal. calcd for C13H16OS (220.33): C, 70.87;
H, 7.32; S, 14.55; found C, 70.93; H, 7.31; S, 14.54.
D
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The Journal of Organic Chemistry
Note
3-Iodo-4,5-dimethyl-2-phenylthiophene (6a). Yield: 67 mg, start-
ing from 62 mg of 5a (71%) (Table 1, entry 1). Yellow oil. IR (film): ν =
1598 (m), 1501 (m), 1441 (m), 1167 (m), 1012 (m), 749 (s), 695 (s)
cm−1; 1H NMR (300 MHz, CDCl3): δ = 7.56−7.47 (m, 2 H), 7.43−7.28
(m, 3 H), 2.42 (s, 3 H), 2.21 (s, 3 H); 13C NMR (75 MHz, CDCl3): δ =
137.6, 136.1, 132.4, 131.4, 129.5, 128.2, 127.9, 86.0, 17.3, 14.2; GC-MS:
m/z = 314 (100) [M+], 187 (36); anal. calcd for C12H11IS (314.19): C,
45.87; H, 3.53; S, 10.21; found C, 45.95; H, 3.51; S, 10.23.
3-Iodo-4,5-dimethyl-2-p-tolylthiophene (6b). Yield: 82 mg, starting
from 66 mg of 5b (83%) (Table 1, entry 2). Yellow solid, mp = 54−55
°C. IR (KBr): ν = 1519 (m), 1436 (m), 1164 (m), 1025 (m), 947 (m),
814 (s), 796 (s), 767 (s) cm−1; 1H NMR (300 MHz, CDCl3): δ = 7.47−
7.39 (m, 2 H), 7.24−7.16 (m, 2 H), 2.43 (s, 3 H), 2.37 (s, 3 H), 2.21 (s, 3
H); 13C NMR (75 MHz, CDCl3): δ = 137.8, 137.7, 135.9, 132.3, 131.3,
129.4, 129.0, 85.8, 21.3, 17.3, 14.2; GC-MS: m/z = 328 (100) [M+], 201
(26), 115 (24); anal. calcd for C13H13IS (328.21): C, 47.57; H, 3.99; S,
9.77; found C, 47.65; H, 4.01; S, 9.75
2-tert-Butyl-3-iodo-4,5-dimethylthiophene (6i). Yield: 57 mg,
starting from 56 mg of 5i (65%) (Table 1, entry 9). Yellow solid, mp
= 114−115 °C. IR (KBr): ν = 1463 (m), 1363 (m), 1214 (m), 1168 (m),
760 (s) cm−1; 1H NMR (300 MHz, CDCl3): δ = 2.36 (s, 3 H), 2.14 (s, 3
H), 1.50 (s, 9 H); 13C NMR (75 MHz, CDCl3): δ = 146.0, 136.5, 127.6,
81.4, 35.1, 30.1, 17.5, 14.0; GC-MS: m/z = 294 (36) [M+], 279 (100),
152 (22); anal. calcd for C10H15IS (294.20): C, 40.83; H, 5.14; S, 10.90;
found C, 40.86; H, 5.15; S, 10.88.
3-Iodo-4,5-dimethyl-2-phenylthiophene (6j). Yield: 70 mg, starting
from 53 mg of 5j (82%) (Table 1, entry 10). Yellow oil. IR (film): ν =
1597 (w), 1482 (m), 1443 (m), 1137 (w) cm−1; 1H NMR (300 MHz,
CDCl3): δ = 7.63−7.56 (m, 2 H), 7.46−7.36 (m, 3 H), 7.27 (distorted d,
J = 5.3, 1 H), 7.13 (distorted d, J = 5.3, 1 H); 13C NMR (75 MHz,
CDCl3): δ = 142.4, 136.6, 134.3, 129.5, 128.42, 128.37, 126.7, 78.1; GC-
MS: m/z = 286 (76) [M+], 159 (17), 115 (100); anal. calcd for C10H7IS
(286.13): C, 41.98; H, 2.47; S, 11.21; found C, 42.04; H, 2.46; S, 11.23.
3-Iodo-5-methyl-2-phenyl-4-phenylethynylthiophene (6k). Yield:
106 mg, starting from 88 mg of 5k (88%) (Table 1, entry 11). Yellow
solid, mp = 80−81 °C. IR (KBr): ν = 2213 (vw), 1442 (m), 1215 (m),
2-(4-Bromophenyl)-3-iodo-4,5-dimethylthiophene (6c). Yield: 77
mg, starting from 86 mg of crude 5c (65%) (Table 1, entry 3). White
solid, mp = 104−105 °C. IR (KBr): ν = 1500 (m), 1384 (m), 1072 (s),
1
1169 (m), 1070 (m), 755 (s), 690 (s) cm−1; H NMR (300 MHz,
1
CDCl3): δ = 7.66−7.50 (m, 4 H), 7.45−7.25 (m, 6 H), 2.65 (s, 3 H); 13
C
1009 (s), 826 (s), 782 (s) cm−1; H NMR (300 MHz, CDCl3): δ =
NMR (75 MHz, CDCl3): δ = 143.0, 138.8, 136.4, 134.3, 131.5, 129.5,
129.4, 128.42, 128.39, 128.34, 127.0, 123.2, 94.4, 85.2, 84.2, 15.4; GC-
MS: m/z = 400 (100) [M+], 271 (20), 239 (17), 213 (17); anal. calcd for
C19H13IS (400.28): C, 57.01; H, 3.27; S, 8.01; found C, 57.12; H, 3.26; S,
8.09.
7.56−7.47 (m, 2 H), 7.45−7.36 (m, 2 H), 2.44 (s, 3 H), 2.21 (s, 3 H);
13C NMR (75 MHz, CDCl3): δ = 136.4, 136.2, 134.1, 132.8, 131.5,
131.1, 122.2, 86.4, 17.3, 14.2; GC-MS: m/z = 394 (100) [(M+2)+], 392
(98) [M+], 185 (23); anal. calcd for C12H10BrIS (393.08): C, 36.67; H,
2.56; Br, 20.33; S, 8.16; found C, 36.75; H, 2.54; Br, 20.31; S, 8.14.
3-(3-Iodo-4,5-dimethylthiopheny-2-yl)thiophene (6d). Yield: 62
mg, starting from 64 mg of 5d (65%) (Table 1, entry 4). Yellow oil. IR
(film): ν = 1529 (m), 1438 (s), 1398 (m), 1158 (m), 848 (m), 775 (m),
746 (m) cm−1; 1H NMR (300 MHz, CDCl3): δ = 7.63−7.56 (m, 1 H),
7.39−7.31 (m, 2 H), 2.42 (s, 3 H), 2.20 (s, 3 H); 13C NMR (75 MHz,
CDCl3): δ = 136.2, 135.1, 132.7, 131.6, 128.2, 125.3, 123.2, 85.6, 17.2,
14.1; GC-MS: m/z = 320 (100) [M+], 160 (12); anal. calcd for C10H9IS2
(320.21): C, 37.51; H, 2.83; S, 20.03; found C, 37.60; H, 2.81; S, 20.01.
2-Cyclohex-1-enyl-3-iodo-4,5-dimethylthiophene (6e). Yield: 68
mg, starting from 63 mg of 5e (71%) (Table 1, entry 5). Yellow solid, mp
= 25−26 °C. IR (KBr): ν = 1435 (s), 758 (s) cm−1; 1H NMR (300 MHz,
CDCl3): δ = 6.02−5.95 (m, 1 H), 2.38−2.31 (m, 2 H), 2.36 (s, 3 H),
2.21−2.12 (m, 2 H), 2.14 (s, 3 H), 1.80−1.59 (m, 4 H); 13C NMR (75
MHz, CDCl3): δ = 140.4, 135.1, 132.3, 130.2, 130.1, 84.2, 30.0, 25.5,
22.9, 21.8, 17.0, 14.1; GC-MS: m/z = 318 (100) [M+], 163 (64), 148
(25), 79 (47); anal. calcd for C12H15IS (318.22): C, 45.29; H, 4.75; S,
10.08; found C, 45.33; H, 4.76; S, 10.12.
2-Butyl-4-hex-1-ynyl-3-iodo-thiophene (6l). Yield: 88 mg, starting
from 72 mg of 5l (85%) (Table 1, entry 12). White solid, mp = 32−34
1
°C. IR (KBr): ν = 2228 (vw), 1465 (s), 1332 (m), 741 (s) cm−1; H
NMR (300 MHz, CDCl3): δ = 7.26 (s, 1 H), 2.77 (t, J = 7.9, 2 H), 2.44
(t, J = 6.7, 2 H), 1.71−1.33 (m, 8 H), 0.95 (t, J = 7.3, 3 H), 0.94 (t, J = 7.3,
3 H); 13C NMR (75 MHz, CDCl3): δ = 143.8, 128.5, 124.8, 92.6, 86.6,
76.7, 32.6, 30.7, 22.1, 22.0, 19.1, 13.8, 13.6; GC-MS: m/z = 346 (44)
[M+], 303 (100), 177 (40), 147 (20), 134 (20); anal. calcd for C14H19IS
(346.27): C, 48.56; H, 5.53; S, 9.26; found C, 48.61; H, 5.52; S, 9.25.
ASSOCIATED CONTENT
■
S
* Supporting Information
Table S1 and copies of 1H and 13C NMR spectra for all products.
This material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*b.gabriele@unical.it; raffaella.mancuso@unical.it
■
2-Butyl-3-iodo-4,5-dimethylthiophene (6f). Yield: 59 mg, starting
from 56 mg of 5f (67%) (Table 1, entry 6). Yellow solid, mp = 115−117
1
°C. IR (KBr): ν = 1456 (s), 1375 (m) cm−1; H NMR (300 MHz,
Notes
CDCl3): δ = 2.73 (t, J = 7.7, 2 H), 2.37 (s, 3 H), 2.12 (s, 3 H), 1.68−1.52
(m, 2 H), 1.50−1.33 (m, 2 H), 0.94 (t, J = 7.3, 3 H); 13C NMR (75 MHz,
CDCl3): δ = 139.0, 134.4, 129.5, 86.8, 32.9, 32.3, 22.2, 16.8, 14.1, 13.9;
GC-MS: m/z = 294 (32) [M+], 251 (100), 125 (33); anal. calcd for
C10H15IS (294.20): C, 40.83; H, 5.14; S, 10.90; found C, 40.81; H, 5.15;
S, 10.89.
3-Iodo-4,5-dimethyl-2-phenethylthiophene (6g). Yield: 72 mg,
starting from 70 mg of 5g (70%) (Table 1, entry 7). Yellow oil. IR (film):
ν = 1603 (m), 1495 (m), 1453 (s), 1164 (m), 749 (s), 698 (s) cm−1; 1H
NMR (300 MHz, CDCl3): δ = 7.35−6.95 (m, 5 H, Ph), 3.07−2.82 (m, 4
H, CH2CH2Ph), 2.36 (s, 3 H, Me), 2.13 (s, 3 H, Me); 13C NMR (75
MHz, CDCl3): δ = 140.9, 137.6, 131.0, 130.0, 128.5, 128.4, 126.2, 87.2,
36.9, 34.6, 16.7, 14.1; GC-MS: m/z = 342 (19) [M+], 251 (100); anal.
calcd for C14H15IS (342.24): C, 49.13; H, 4.42; S, 9.37; found C, 49.20;
H, 4.41; S, 9.35.
2-Benzyl-3-iodo-4,5-dimethylthiophene (6h). Yield: 67 mg, starting
from 66 mg of 5h (68%). (Table 1, entry 8). Yellow oil. IR (film): ν =
1494 (m), 1452 (s), 1432 (m), 1073 (m), 1029 (m), 763 (m), 697 (s),
cm−1; 1H NMR (300 MHz, CDCl3): δ = 7.35−7.05 (m, 5 H), 4.00 (s, 2
H), 2.26 (s, 3 H), 2.06 (s, 3 H); 13C NMR (75 MHz, CDCl3): δ = 139.2,
137.5, 134.5, 130.7, 128.5, 128.3, 126.4, 87.6, 38.4, 16.6, 13.9; GC-MS:
m/z = 328 (100) [M+], 201 (58), 186 (26); anal. calcd for C13H13IS
(328.21): C, 47.57; H, 3.99; S, 9.77; found C, 47.62; H, 3.98; S, 9.80.
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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