Regioselective palladium-catalyzed cross-coupling reactions in the synthesis of novel 2,3-disubstituted thiophene derivatives

Article abstract of DOI:10.1016/S0040-4020(01)00764-5

A reactivity optimization study of the palladium-catalyzed cross-coupling reactions of 2,3-dibromothiophene and organometallic reagents has been conducted. Regioselective coupling at the C2 position, accomplished most notably by Suzuki coupling, was combined with a Stille reaction at C3 using Fu's modification, to afford the 2,3-disubstituted thiophene derivatives.

Full text of DOI:10.1016/S0040-4020(01)00764-5

TETRAHEDRON
Pergamon
Tetrahedron 57 >2001) 7871±7881
Regioselective palladium-catalyzed cross-coupling reactions in the
synthesis of novel 2,3-disubstituted thiophene derivatives
p
Raquel Pereira, Beatriz Iglesias and Angel R. de Lera
Departamento de Qu Âõ mica Org a nica, Facultad de Ciencias, Universidade de Vigo, 36200 Vigo, Spain
Received 23 April 2001; revised 12 July 2001; accepted 25July 2001
AbstractÐA reactivity optimization study of the palladium-catalyzed cross-coupling reactions of 2,3-dibromothiophene and organometallic
reagents has been conducted. Regioselective coupling at the C2 position, accomplished most notably by Suzuki coupling, was combined with
a Stille reaction at C3 using Fu's modi®cation, to afford the 2,3-disubstituted thiophene derivatives. q 2001 Elsevier Science Ltd. All rights
reserved.
1
. Introduction
cesses would allow differentiation between the two reactive
positions >C2 and C3) and, consequently, selective intro-
duction of two differently functionalized alkenyl, aryl or
alkynyl chains.
The preparation of polyfunctionalized heterocyclic com-
pounds is of interest in research ®elds as diverse as natural
product synthesis, drug design, molecular recognition and
materials science. In this regard, thiophene-based com-
pounds are considered an important class of materials
which show intrinsic electronic properties such as lumi-
nescence, redox activity and electron-transport. Over the
past few years, the isolation of naturally occurring
thiophene derivatives has stimulated much interest as a
consequence of their wide range of photobiological activi-
The recent report describing regioselective coupling reac-
1
6
tions of 2,3-dibromofuran prompted us to disclose our
®ndings on the reactivity of 2,3-dibromothiophene 1 using
a variety of palladium-catalyzed cross-coupling reactions
with organometallic reagents.
1
,2
ties. This has led in turn to the biologically-guided
synthesis of novel thiophene-containing compounds.3±6
2. Results and discussion
2.1. Regioselective Pd 0)-catalyzed coupling at carbon
atom C2
Given the ready availability of halogenated thiophenes and
the current development of metal-catalyzed cross-coupling
chemistry, it is not unexpected that most of these synthetic
thiophene derivatives have been prepared by applying
transition metal-catalyzed carbon±carbon bond-forming
reactions. Representative examples of the use of the
17
The Sonogashira coupling, i.e. the reaction of organic
electrophiles with copper acetylides, generated in situ
from the corresponding terminal alkynes, has become the
method of choice for the preparation of internal alkynes,
aryl alkynes or enynes. The active Pd >0) species required
for the catalytic cycle is produced from the Pd >II) pre-
catalyst following an initial alkyne dimerization process.
The choice of reaction conditions >solvent, temperature¼)
depends on the reactivity of the starting halide, although a
tertiary amine is required for neutralizing the HX formed
along the cycle.
3
,7
7c,8
3,7e,9
Tamao±Kumada±Corriu,
Suzuki,
Negishi,
and Heck couplings have been
Sonogashira,
4
,5,10
3,4,11
12
Stille
reported in the literature. By contrast, there are only a few
reports on the use of dihalogenated thiophenes as electro-
philic components in metal-catalyzed cross-coupling
reactions.7c,8c,d,10a,b,13,14
In connection with a project directed at the preparation of
novel 2,3-disubstituted thiophene derivatives, we reasoned
that 2,3-dibromothiophene 1, easily prepared from 3-bromo-
2,3-Dibromothiophene 1 was reacted with a series of
alkynes under the conditions previously reported
1
5
thiophene, could become a valuable starting material.
Regioselective palladium-catalyzed cross-coupling pro-
13
Pd>PPh ) Cl , Et N, CuI, Ph P, 608C], and the results
[
are listed in Table 1. TMS-acetylene 2a >entry 1) was
3 2 2 3 3
included in the survey in order to corroborate the results
reported by Brandsma et al. Alkynes 2f, 2g and 2h
Keywords: thiophenes; Sonogashira reactions; Stille reactions; Suzuki
reactions; heterocycles.
Corresponding author. Tel.: 134-986-812316; fax: 134-986-812382;
e-mail: qolera@uvigo.es
13
18
19
²
p
²
Alkyne 2h is commercially available.
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020>01)00764-5

7872
R. Pereira et al. / Tetrahedron 57 +2001) 7871±7881
Table 1. Sonogashira coupling reactions of 2,3-dibromothiophene 1 with terminal alkynes
a
b
Entry
Alkyne
Reaction conditions
T >8C)
t >h)
Yield >%)
1/3 Ratio
3
4
c
1
2
3
4
5
6
7
8
9
2a >nˆ0, RˆTMS)
2b >nˆ1, RˆOH)
2c >nˆ2, RˆOH)
2d >nˆ3, RˆOH)
2e >nˆ4, RˆOH)
2f >nˆ5 , RˆOH)
2g >nˆ6, RˆOH)
2h >nˆ7, RˆOH)
2i >nˆ4, RˆOTBDMS)
A
A
A
A
A
A
A
A
A
60
60
60
60
60
80
60
60
60
84
3
3
2
56
12
11
60
ND
±
d
32
42
32
1/1
2.3/1
1/2
1/4
3/1
2.3/1
1/2
1/1
4/1
d
d
d
3
2.55 25
6
3
3
3
3
2
20
20
42
42
56
55
43
40
e
f
f
10
2j >nˆ3, RˆCH
3
)
A
±
±
a
b
c
d
e
f
Conditions: A: 1 >1 mol equiv.), 2 >1.1 mol equiv.), Pd>PPh
3
)
2
Cl
2
>0.004 mol equiv.), CuI >0.008 mol equiv.), Ph
3
3
P >0.005mol equiv.), Et N.
1
Starting material/product ratio determined by integration of the H NMR spectra.
ND: Not determined due to its volatility.
Dimeric products 4b, 4c, 4d and 4e are commercially available.
2 3
iPr NH used instead of Et N.
1
An inseparable mixture of 2,3-dibromothiophene 1, product 3j and alkyne dimer 4j was obtained. Integration of its H NMR spectrum showed a 1/3j/4j ratio
of 4:1:2.
Scheme 1.
Scheme 2.
were prepared by isomerization of the corresponding
internal alkynes.18 Protection of commercially available
hex-5-yn-1-ol as tert-butyldimethylsilyl ether provided
tively), in the case of alkynes 2b, 2c, 2f, 2g and 2j >entries 2,
3, 6, 7 and 10) the coupling is very slow, proceeding with
low conversion rates, and leading to the isolation of the
alkyne dimer as the main product. Since alkyne dimers >in
amounts greater than those generated on forming the
2
0
known compound 2i. Since the quality of the copper
catalyst is a crucial factor for the success of these type of
organometallic processes, we rigorously puri®ed this salt
1
7
14-electron PdL complex) are the most common by-
2
2
1
following literature procedures. Addition of PPh3 is
required to avoid deposition of Pd >0) due to the high
temperatures needed to induce coupling of aryl and hetero-
aryl bromides, which are particularly unreactive if no
electron-withdrawing substituents are present on the ring.
products in the Sonogashira coupling reactions, there has
been much synthetic effort devoted to ®nding new experi-
mental procedures to avoid this undesired pathway.
2
2
Several of these modi®cations >changes in the base, catalyst,
solvent, amount of alkyne, use of cosolvents) have been
tried in our case with alkyne 2j without success. Alkynes
2h and 2i >entries 8 and 9) proved to be slightly more
reactive, although the mono-substituted product 3 was
isolated in a disappointing 42% yield, and dimerization
was an important competing process for alkyne consump-
tion >Scheme 1).
The reactions of 2,3-dibromothiophene 1 and alkynes 2 are
regioselective processes which yield, in agreement with
1
3
Brandsma's ®nding with TMS-acetylene 2a >entry 1),
the C2 modi®ed compound 3 as the only substitution
product. However, the corresponding diynes 4 were also
³
isolated in variable amounts. Whereas the reaction of 1
with pent-4-yn-1-ol 2d or hex-5-yn-1-ol 2e >entries 4 and
Given the low reactivity of 2,3-dibromothiophene, the
2
3
5) proceeds in a moderate yield >60 and 56%, respectively)
to give the monosubstituted products 3d and 3e, together
with the alkyne dimerization product >32 and 25%, respec-
recent report by Buchwald and Fu describing the room
temperature Sonogashira coupling of aryl bromides, using
the accelerating effect of a bulky trialkylphosphine, was
taken into consideration. In our hands, however, the modi®-
cation [Pd>PhCN) Cl /PtBu ] proved ineffective with
2
2
3
³
alkynes 2e and 2j, leading to very slow reactions at room
temperature >less than 50% conversion after 48 h). The
It must be mentioned that alkyne dimer 4a was also detected, although it
could not be isolated due to its high volatility.

R. Pereira et al. / Tetrahedron 57 +2001) 7871±7881
Table 2. Stille cross-coupling of 2,3-dibromothiophene 1 with organostannanes 5 and 6
7873
Entry
Stannane
Mol equiv.
[
Reaction
conditions
T >8C)
t >h)
Yield >%)
a
RsnBu
3
]
7
8
9
b
b
1
2
3
4
5
6
7
8
9
5
5
6
6
6
5
5
5
5
6
6
6
1.1
1.5A
1.1
1.1
1.5A
1.1
1.5B
1.5B
2.1
1.1
1.5B
1.5B
A
9
451 5. 51 2
9
40
60
1
252
67
±26 55
257
252
41
ND
4 571 0. 5
60
ND
6
b
A
A
17
ND
±
±
b
1.54 5N D
70
71
4
16
±
±
±
B
251
252
31
B
B
27 51
72
33
±
11
±
1
1
1
0
1
2
±
251
2 35 1
3 4. 5
±
a
Conditions: A: 1 >1 mol equiv.), Pd
2 3 3 2 3 3
>dba) >0.02 mol equiv.), AsPh >0.2 mol equiv.), NMP. B: 1 >1 mol equiv.), Pd >dba) >0.01 mol equiv.), PtBu
>0.05mol equiv.), CsF >2 mol equiv.), dioxane.
ND: Not determined.
b
alkyne dimer was again the main product on heating the
mixture to 608C.
We also explored Fu's modi®cation of the Stille reaction
that uses PtBu as palladium ligand and CsF to activate the
3
2
8
tin reagent. As expected, this modi®cation led to an
increase in the reactivity of 2,3-dibromothiophene, with
the coupling to stannanes proceeding at room temperature
in short reaction times >entries 6, 7, 8, 10 and 11). Unfortu-
nately, the greater reactivity translated into a reduced
discrimination of both C±Br bonds by the stannane, and a
signi®cant decrease in the regioselectivity was observed
>entries 7, 8, 11 and 12).
The coupling of 2,3-dibromothiophene 1 with different
2
4
organostannanes under the Stille reaction conditions was
also explored >Scheme 2). We ®rst selected the modi®ed
reaction conditions developed by Farina [Pd >dba) /
2
5
2
3
AsPh as palladium/ligand combination in NMP]. Table 2
3
shows the results obtained for the coupling of dibromide
1
2
and representative alkenyl >5) and heteroaryl >6)
6
27
organotin compounds. The coupling took place regio-
selectively at C2, although the disubstituted product 8 was
also obtained in low yields >entries 2 and 5). It must be
pointed out as well that minor amounts of the organo-
stannane dimer 9 >entries 1 and 2) were detected in the
coupling of dienyl stannane 5 under Farina's conditions.
The reactions of 2,3-dibromothiophene under the Suzuki
2
9
coupling conditions >Scheme 3) are summarized in
Table 3. The scope and limitations of this coupling were
3
0
analyzed using an aryl >10) and a vinyl boronic acid >11).
The classical Suzuki reaction conditions [Pd>PPh ) and
3
4
Scheme 3.
Table 3. Suzuki cross-coupling of 2,3-dibromothiophene 1 with boronic acids 10 and 11
Entry
Organoborane
Mol equiv.
Reaction
conditions
T >8C)
t >h)
Yield >%)
a
[
R±B>OH)
2
]
1
2
13
14
1
2
3
4
5
6
7
8
10
11
11
10
10
11
11
11
1.1
A
100
4
81
2
±
2.5A
2.5B
1.5C
1.5C
1.5D
2.5D
2.5D
± 6 455. 5
62 5
2156
100
100
± 5
4
21
40
40
4.5
4.5
8
8
±
±
7
7
±
8
b
b
d
c
55
55
90
46
44
12
ND
±
564
a
Conditions: A: 1 >1 mol equiv.), Pd>PPh
>
>
THF was used as solvent.
ND: Not determined.
Dioxane was used as solvent.
3
)
4
>0.08 mol equiv.), K
5mol equiv.), THF. C: 1 >1 mol equiv.), Pd>OAc) >0.01 mol equiv.), K
0.01 mol equiv.), KF >3 mol equiv.), 15 >0.02 mol equiv.).
2
CO
3
>4 mol equiv.), dioxane. B: 1 >1 mol equiv.), Pd>PPh
3 4
) >0.1 mol equiv.), 10% TlOH
2
PO >2 mol equiv.), 15 >0.02 mol equiv.), toluene. D: 1 >1 mol equiv.), Pd>OAc)
3 4
2
b
c
d

7874
R. Pereira et al. / Tetrahedron 57 +2001) 7871±7881
Scheme 4. >i) sec-BuLi, THF; >ii) MeOH.
Scheme 5.
K CO in re¯uxing dioxane] were adopted ®rst, the results
2
of which are shown in Table 3 >entries 1 and 2).
Considering that the three variants of the palladium-
catalyzed cross-coupling reactions share the ®rst oxidative
addition step, it is concluded that the oxidative addition of
Pd >0) at position 2 of 2,3-dibromothiophene 1 is favored
over that at C3, which eventually determines the regio-
selectivity of the reaction. The facile oxidative addition
into the carbon±bromine bond at position 2 must be a conse-
quence of the inherent higher electrophilicity of C2 over C3,
as well as the lower double bond character of C3±C4 vs
3
Phenylboronic acid 10 reacted smoothly with 2,3-dibromo-
thiophene under these conditions to yield the monosubsti-
3
1
tuted product 12a >81%) together with a small amount
§
2%) of the bis-substituted product 13a >entry 1). Vinyl-
>
boronic acid 11 led exclusively to the C2-substituted
product 12b, although in this case boronic acid dimerization
seems to be an important competing process >entry 2).
1
6
C2±C3, as it seems to be the case for 2,3-dibromofuran.
3
2
Application of Kishi's modi®cation >TlOH, THF, room
temperature) to the reaction of 11 and 1 gave similar results,
namely regioselective substitution at position 2 >51% yield
of 12b), together with the competing process of boronic acid
dimerization >entry 3). We also explored the improved
procedure recently reported by Buchwald for the room
temperature Suzuki coupling of aryl bromides, or the even
less-reactive aryl chlorides, with aryl boronic acids. This
modi®cation, the use of palladium acetate and o->di-tert-
butylphosphino)biphenyl >15) in different base/solvent
systems, proved inef®cient, requiring instead more drastic
conditions >toluene, 1008C, 8 h; entry 5), with low yields
2.2. Pd 0)-catalyzed cross-coupling at carbon atom C3
In order to prove the synthetic potential of 2,3-dibromo-
thiophene, further substitution at C3 position of the thio-
phene nucleus was required. Prompted by the previous
®nding that the modi®ed Stille reaction conditions
3
3
2
8
developed by Fu provided an enormous increase in the
reactivity of position C3, we treated 3-bromo-2-substituted
thiophenes 3e and 12a, in dioxane containing CsF, with
dienyl stannane 5 in the presence of catalytic quantities of
Pd >dba) and PtBu >Scheme 5). Disubstituted products 17
2
3
3
>
entries 4, 5, 6 and 7) and poor regioselectivity >entry 8).
and 19 were obtained in good yields >76 and 80%, respec-
tively), along with the hydrodebromination product at C3
position. This side reaction perhaps suggests an ineffective
transmetalation or reductive elimination in the overall cycle.
The regioselective introduction of the substituent at the C2
position of 2,3-dibromothiophene through Sonogashira,
Stille and Suzuki couplings was con®rmed by the analysis
of the debromination product, generated upon treatment of
compound 3i with sec-BuLi followed by a MeOH quench.
3. Summary and conclusion
1
H NMR analysis of thiophene chemical shifts and coupling
constants pattern for product 16 unequivocally showed that
2,3-Dibromothiophene 1 undergoes regioselective Pd >0)-
catalyzed cross-coupling reactions at C2 with a variety of
organometallic reagents. The observed regioselectivity is
most likely due to the electron de®ciency at this position,
which renders a facile oxidative addition of Pd >0) in the
C±Br bond. According to the experimental ®ndings, the
Suzuki coupling led to the highest regioselectivity. Stille
the new hydrogen atom had been incorporated at position 3
>
Scheme 4).
§
2,3-Diphenylthiophene is commercially available.

R. Pereira et al. / Tetrahedron 57 +2001) 7871±7881
7875
1
9
conditions are less convenient, since the disubstituted thio-
phene is obtained in greater proportion than using the
Suzuki reaction. Sonogashira coupling, in contrast, gave
inconsistent results, depending upon the alkyne structure.
Pd >0)-catalyzed coupling at the less-reactive C3±Br is by
far more challenging. It was nevertheless accomplished
through Fu's modi®cation of the Stille reaction. Ready
access to 2,3-disubstituted thiophenes is therefore possible
by means of a two-step strategy that makes use of consecu-
tive Pd >0)-catalyzed cross-coupling reactions with organo-
metallic compounds.
the residue >858C/0.5mm Hg; lit. 90±948C/4 mmHg) gave
0.48 g >96%) of oct-7-yn-1-ol >2g) as a colorless oil.
4.1.2. Non-8-yn-1-ol 2h). According to the general pro-
cedure for alkynol isomerization, the reaction of non-2-
yn-1-ol >0.30 g, 2.14 mmol) afforded, after distillation
>1008C/0.5mmHg), 0.26 g >8 5% ) of alkynol 2h as a color-
less oil.
4.1.3. tert-Butyldimethylsilyl hex-5-yn-1-yl ether 2i). To
a solution of hex-5-yn-1-ol >0.30 g, 3.06 mmol) in DMF
>7 mL) was added imidazol >0.50 g, 7.65 mmol), followed
by tert-butyldimethylsilyl chloride >0.60 g, 4.28 mmol).
After stirring at 258C for 1 h, the mixture was diluted with
H O and extracted with tert-butyl methyl ether >TBME)
4
. Experimental
2
>
3£10 mL). The combined organic layers were washed
4
.1. General
with H SO ) and evaporated.
4
Puri®cation of the residue by chromatography >SiO , 95:5
2
2
O >7£30 mL), dried >Na
2
Solvents were dried according to published methods and
were distilled before use. HPLC grade solvents were used
for HPLC puri®cations. All other reagents were commercial
compounds of the highest purity available. Analytical thin-
layer chromatography >TLC) was performed using Merck
silica gel >60 F-254) plates >0.25 mm) precoated with
a ¯uorescent indicator. Column chromatography was
performed using Merck silica gel 60 >particle size 0.040±
hexane/AcOEt) afforded 0.60 g >92%) of a colorless oil
identi®ed as alkyne 2i.
4.1.4. 3-Bromo-2- 2-trimethylsilylethyn-1-yl)thiophene
3a). General procedure for the Sonogashira reaction. To
a stirred solution of 2,3-dibromothiophene 1 >0.20 g,
0.83 mmol) in Et
of trimethylsilylacetylene 2a >0.08 g, 0.83 mmol) in Et
>1 mL), followed by Pd>PPh Cl >2.3 mg, 0.003 mmol)
and PPh >1.1 mg, 0.004 mmol), and the mixture was heated
N >1 mL) was added dropwise, a solution
3
N
3
0
.063 mm). Bulb-to-bulb distillations were carried out on
)
3
2
2
a Kugelrohr apparatus; boiling points refer to air bath
temperatures and are uncorrected. Melting points >mp)
were measured on a Gallenkamp apparatus and are uncor-
3
to 358C for 10 min. CuI >1.2 mg, 0.006 mmol) was then
added, and the reaction mixture was stirred at 608C for
3 h. After cooling down to 258C, the mixture was diluted
1
13
rected. Proton > H) and carbon > C) magnetic resonance
spectra >NMR) were recorded on a Bruker AMX-400
with AcOEt, poured into H
>3£5mL). The combined organic extracts were dried
>Na SO ) and evaporated. Puri®cation by chromatography
>SiO , hexane) afforded 0.12 g >56%) of 3-bromo-2->2-
trimethylsilylethyn-1-yl)thiophene >3a) as a colorless oil.
O and extracted with AcOEt
2
1
3
[
400 MHz >100 MHz for C)] Fourier transform spectro-
meter, and chemical shifts are expressed in parts per million
d) relative to tetramethylsilane >TMS, 0 ppm), dichloro-
2
4
>
2
1
13
methane >CH Cl , 5.32 ppm for H and 53.8 ppm for C),
2
2
1
acetone >CH COCH , 2.05ppm for H and 29.8 and
1
H NMR >400 MHz, CDCl ) d 0.25>s, 9H, Si>CH ) ),
3 3 3
3
3
1
06.5ppm for C) or chloroform >CHCl , 7.24 ppm for
3
2
6.91 >d, Jˆ5.4 Hz, 1H, H4), 7.14 >d, Jˆ5.4 Hz, 1H, H5);
) ), 95.5
3 3
3
1
13
H and 77.00 ppm for C) as internal reference.
13
13
C
C NMR >100 MHz, CDCl
3
) d 20.2 >q, 3£, Si>CH
multiplicities >s, singlet; d, doublet; t, triplet; q, quartet)
were assigned with the aid of the DEPT pulse sequence.
Infrared spectra >IR) were obtained on a MIDAC Prospect
Model FT-IR spectrophotometer. Absorptions are recorded
>s), 103.4 >s), 116.6 >s), 120.8 >s), 127.0 >d), 129.9 >d); IR
>KBr, ®lm) n 3108 >w, vC±H), 2961 >m, C±H), 2899 >w,
C±H), 2149 >s, CuC), 1500 >m), 1419 >m), 1347 >m), 1250
>s), 1175>m), 1146 >m), 1080 >m), 865>s), 760 >s), 711 >s),
2
1
1
81
1
in wavenumbers >cm ). Low-resolution mass spectra
were taken on an HP59970 instrument operating at 70 eV.
High-resolution mass spectra were taken on a VG Autospec
M instrument.
649 >m), 609 >m); MS m/z >%) 260 >M [ Br], 30), 258 >M
[ Br], 28), 246 >14), 245>100), 244 >13), 243 >94); HRMS
7
9
8
1
79
calcd for C
257.9534, found 259.9514 and 257.9536.
H11 BrSSi 259.9514 and C H11 BrSSi
9 9
4
.1.1. Oct-7-yn-1-ol 2g). General procedure for alkynol
4.1.5. 3- 3-Bromothien-2-yl)prop-2-yn-1-ol 3b). In
accordance to the general procedure described above, the
reaction of 2,3-dibromothiophene 1 >0.10 g, 0.41 mmol)
with prop-2-yn-1-ol 2b >0.03 g, 0.45mmol), in the presence
of Pd>PPh ) Cl >1.2 mg, 0.002 mmol), PPh >0.6 mg,
3 2 2 3
0.002 mmol), and CuI >0.6 mg, 0.003 mmol), for 3 h at
608C, provided, after puri®cation by chromatography
isomerization. Lithium wire >0.17 g, 24.50 mmol),
thoroughly washed ®rst with hexane and then with 95:5
hexane/EtOH mixture, was suspended on 1,2-diamino-
ethane >9.60 mL) and heated to 708C for 1 h. After cooling
down to 258C, potassium tert-butoxide >1.80 g, 15.80
mmol) was added in one portion and the mixture was stirred
at 258C for 1 h. Oct-3-yn-1-ol >0.50 g, 3.96 mmol) was then
added dropwise, and the ®nal reaction mixture was stirred at
>SiO
less solid >mp 56.68C, CH
bromothien-2-yl)prop-2-yn-1-ol >3b), and 8 mg >32%) of a
colorless solid >mp 110.88C, CH Cl ) identi®ed as hexa-2,4-
diyn-1,6-diol >4b). Data for 3b: H NMR >400 MHz,
, 99:1±95:5 CH Cl
/MeOH), 11 mg >12%) of a color-
2
2 2
Cl /hexane) identi®ed as 3->3-
2
2
2
58C for 3 h, after which time it was poured into ice. The
mixture was then extracted with CH Cl >3£10 mL) and the
2
2
2
2
1
combined organic extracts were washed with 10% HCl
3£30 mL). The resulting aqueous layer was extracted
with CH Cl >2£90 mL) and the combined organic phases
>
CD Cl
6.3 Hz, 2H, 2H1), 6.98 >d, Jˆ5.4 Hz, 1H, H4 ), 7.26 >d,
2
2
) d 1.88 >d, Jˆ6.2 Hz, 1H, OH), 4.51 >d, Jˆ
0
2
2
0
13
Jˆ5.4 Hz, 1H, H5 ); C NMR >100 MHz, CD
were ®nally dried >Na SO ) and evaporated. Distillation of
Cl
2
) d 51.5
2
2
4

7876
R. Pereira et al. / Tetrahedron 57 +2001) 7871±7881
>
1
>
t, C1), 76.7 >s), 95.4 >s), 116.1 >s), 120.0 >s), 127.5 >d),
30.0 >d); IR >KBr, ®lm) n 3600±3100 >br, O±H), 3108
m, vC±H), 2921 >m, C±H), 2859 >m, C±H), 2223 >m,
CuC), 1506 >m), 1429 >s), 1349 >s), 1206 >m), 1152 >m),
021 >s), 864 >s), 712 >s), 607 >m); MS m/z >%) 219
0.41 mmol) with hex-5-yn-1-ol 2e >0.04 g, 0.45mmol), in
the presence of Pd>PPh ) Cl >1.2 mg, 0.002 mmol), PPh
3
3
2
2
>0.6 mg, 0.002 mmol) and CuI >0.6 mg, 0.003 mmol), for
2.5h at 60 8C, afforded 0.06 g >56%) of alkynol 3e as a
yellow oil and 11 mg >25%) of a colorless solid >mp
50.98C, CH Cl ) identi®ed as dodeca-5,7-diyn-1,12-diol
1
1
81
1
81
1
>
[
>
[M11] [ Br], 8), 218 >M [ Br], 89), 217 >[M11]
79 79
2
2
1
1
Br], 33), 216 >M [ Br], 89), 215>20), 137 >100), 109
46), 108 >23), 65>22), 63 >20); HRMS calcd for
>4e). Data for 3e: H NMR >400 MHz, CDCl ) d 1.3±1.4
3
>m, 1H, OH), 1.6±1.8 >m, 4H, 2H212H3), 2.52 >t, Jˆ
8
5
1
79
5
C H BrOS 217.9224 and C H BrOS 215.9244, found
7
2
6.5Hz, 2H, 2H4), 3.71 >m, 2H, 2H1), 6.92 >d, Jˆ5.3 Hz,
7
0
0
CDCl ) d 19.6 >t), 24.7 >t), 31.7 >t), 62.3 >t, C1), 72.6 >s),
13
1H, H4 ), 7.11 >d, Jˆ5.3 Hz, 1H, H5 ); C NMR >100 MHz,
17.9217 and 215.9239.
3
4
.1.6. 4- 3-Bromothien-2-yl)but-3-yn-1-ol 3c). Following
98.3 >s), 115.0 >s), 121.4 >s), 125.8 >d), 129.7 >d); IR >KBr,
®lm) n 3600±3100 >br, O±H), 3107 >m, vC±H), 2939 >s,
C±H), 2866 >m, C±H), 2226 >m, CuC), 1429 >m), 1347
the general procedure for the Sonogashira reaction,
treatment of 2,3-dibromothiophene 1 >0.10 g, 0.41 mmol)
with but-3-yn-1-ol 2c >0.03 g, 0.45mmol), in the presence
of Pd>PPh ) Cl >1.2 mg, 0.002 mmol), PPh3 >0.6 mg,
0
6
1
81
>m), 1060 >s), 863 >s), 709 >s); MS m/z >%) 260 >M [ Br],
1
79
34), 258 >M [ Br], 33), 242 >25), 240 >25), 216 >24), 214
>28), 212 >30), 203 >34), 201 >72), 199 >74), 179 >45), 177
>39), 175>39), 1 51 >30), 148 >26), 147 >24), 135>100), 123
3
2
2
.002 mmol) and CuI >0.6 mg, 0.003 mmol), for 2 h at
08C, afforded 11 mg >11%) of compound 3c as a yellow
8
1
oil and 13 mg >42%) of a colorless solid >mp 49.38C,
CH Cl ) identi®ed as octa-3,5-diyn-1,8-diol >4c). Data for
>25), 122 >99), 120 >49); HRMS calcd for C H BrOS
10 11
7
9
259.9693 and C H BrOS 257.9714, found 259. 9697
2
2
10 11
1
c: H NMR >400 MHz, CDCl ) d 1.97 >br s, 1H, OH), 2.73
3
and 257.9720.
3
>
>
t, Jˆ6.2 Hz, 2H, 2H2), 3.82 >t, Jˆ6.2 Hz, 2H, 2H1), 6.91
0 0
C
13
d, Jˆ5.4 Hz, 1H, H4 ), 7.12 >d, Jˆ5.4 Hz, 1H, H5 );
4.1.9. 7- 3-Bromothien-2-yl)hept-6-yn-1-ol 3f). Follow-
ing the general procedure described above, the reaction of
2,3-dibromothiophene 1 >0.10 g, 0.41 mmol) with hept-6-
yn-1-ol 2f >0.05g, 0.45mmol), in the presence of
Pd>PPh ) Cl >1.2 mg, 0.002 mmol), PPh3 >0.6 mg,
NMR >100 MHz, CDCl ) d 24.2 >t, C2), 60.8 >t, C1), 74.2
3
>
>
s), 94.9 >s), 115.7 >s), 120.9 >s), 126.3 >d), 129.8 >d); IR
KBr, ®lm) n 3600±3100 >br, O±H), 3107 >m, vC±H),
2
942 >m, C±H), 2886 >m, C±H), 2229 >w, CuC), 1506
m), 1428 >m), 1348 >m), 1044 >s), 864 >s), 710 >s), 607
3
2
2
>
0.002 mmol) and CuI >0.6 mg, 0.003 mmol), for 3 h at
808C, afforded 0.02 g >20%) of alkynol 3f as a yellow oil
and 0.03 g >56%) of a colorless solid >mp 64.38C, CH Cl )
1
m); MS m/z >%) 233 >[M11] [ Br], 8), 232 >M [ Br],
81
1 81
>
1 79
9), 230 >M [ Br], 78), 202 >36), 201 >100), 200 >36), 199
7
>
2
2
2
2
8
7
1
98), 121 >46), 120 >26); HRMS calcd for C H BrOS
identi®ed as tetradeca-6,8-diyn-1,14-diol >4f). Data for 3f:
H NMR >400 MHz, CDCl ) d 1.5±1.7 >m, 6H, 2H21
8
7
31.9380 and C H7 BrOS 229.9401, found 231.9385and
9
1
8
3
29.9406.
2H312H4), 2.47 >t, Jˆ6.9 Hz, 2H, 2H5), 3.66 >t, Jˆ
0
6
.3 Hz, 2H, 2H1), 6.90 >d, Jˆ5.4 Hz, 1H, H4 ), 7.09 >d,
0
>t), 25.0 >t), 28.1 >t), 32.2 >t), 62.8 >t, C1), 72.5 >s), 98.5 >s),
13
4
.1.7. 5- 3-Bromothien-2-yl)pent-4-yn-1-ol 3d). Accord-
Jˆ5.4 Hz, 1H, H5 ); C NMR >100 MHz, CDCl ) d 19.8
3
ing to the general procedure described above, the reaction of
,3-dibromothiophene 1 >0.10 g, 0.41 mmol) with pent-4-
yn-1-ol 2d >0.03 g, 0.45mmol), in the presence of
2
114.9 >s), 121.5>s), 12 5. 7 >d), 129.8 >d); IR >KBr, ®lm)
n
3600±3100 >br, O±H), 3107 >w, vC±H), 2937 >s, C±H),
2861 >m, C±H), 2226 >w, CuC), 1508 >w), 1428 >m), 1347
>m), 1150 >w), 1048 >m), 863 >s), 709 >s), 606 >m); MS m/z
Pd>PPh ) Cl >1.2 mg, 0.002 mmol), PPh3 >0.6 mg,
3
0
6
2
2
.002 mmol) and CuI >0.6 mg, 0.003 mmol), for 3 h at
08C, afforded 0.06 g >60%) of alkynol 3d as a yellow oil
1
81
1 79
>%) 274 >M [ Br], 46), 272 >M [ Br], 46), 228 >41), 203
>38), 201 >97), 199 >98), 193 >66), 190 >44), 188 >42), 177
>59), 175 >58), 160 >42), 149 >39), 148 >41), 147 >81), 135
>71), 134 >59), 122 >100), 121 >52), 120 >67), 115 >29), 97
and 12 mg >32%) of a colorless solid >mp 458C, CH Cl )
2
2
1
identi®ed as deca-4,6-diyn-1,10-diol >4d). Data for 3d: H
NMR >400 MHz, CDCl ) d 1.67 >br s, 1H, OH), 1.86 >app.
3
8
1
quintuplet, Jˆ6.5Hz, 2H, 2H2), 2. 58 >t, Jˆ6.9 Hz, 2H,
>61), 89 >28); HRMS calcd for C H BrOS 273.9850 and
11 13
7
9
2
1
>
H3), 3.82 >t, Jˆ6.1 Hz, 2H, 2H1), 6.90 >d, Jˆ5.4 Hz,
C H BrOS 271.9870, found 273.9837 and 271.9862.
11 13
0
100 MHz, CDCl ) d 16.3 >t, C2), 31.0 >t, C3), 61.5>t,
0
13
H, H4 ), 7.09 >d, Jˆ5.4 Hz, 1H, H5 ); C NMR
1
Data for 4f: H NMR >400 MHz, CDCl ) d 1.25>br s,
3
2H, 2£OH), 1.4±1.6 >m, 12H, 2H212H312H412H111
3
C1), 72.8 >s), 97.8 >s), 115.1 >s), 121.3 >s), 125.9 >d),
29.7 >d); IR >KBr, ®lm) n 3500±3100 >br, O±H), 3107
m, vC±H), 2949 >s, C±H), 2226 >m, CuC), 1506 >m),
429 >s), 1348 >s), 1151 >m), 1056 >s), 939 >m), 863 >s), 708
2H1212H13), 2.25>t, Jˆ6.7 Hz, 4H, 2H512H10), 3.63
1
3
1
>
1
>
[
2
1
1
2
2
>t, Jˆ6.0 Hz, 4H, 2H112H14); C NMR >100 MHz,
CD Cl ) d 19.4 >t, 2£), 25.4 >t, 2£), 28.5>t, 2 £), 32.6 >t,
2
2
2£), 62.9 >t, 2£, C11C14), 65.6 >s, 2£), 77.7 >s, 2£); IR
>KBr, ®lm) n 3500±3100 >br, O±H), 2936 >s, C±H), 2860
>s, C±H), 1459 >m), 1053 >s), 627 >w); MS m/z >%) 222
1
81
1
s), 607 >m); MS m/z >%) 247 >[M11] [ Br], 10), 246 >M
81 79 79
Br], 100), 245>[M 11] [ Br], 17), 244 >M [ Br], 98),
1
1
1
1
01 >50), 199 >50), 190 >67), 188 >67), 177 >30), 175 >28),
65>78), 147 > 52 ), 137 >23), 135>23), 134 >40), 123 >70),
22 >55), 121 >60), 97 >21); HRMS calcd for C H BrOS
>M , 0.3), 221 >[M21] , 1), 150 >27), 149 >82), 135 >23),
131>39), 129 >34), 128 >26), 119 >36), 117 >84), 116 >26),
115>48), 107 >27), 105>78), 103 >33), 93 >31), 91 >100), 81
>32), 79 >77), 77 >68), 67 >51), 65 >26); HRMS calcd for
C H O 222.1620, found 222.1621.
8
9
1
9
7
9
45.9537 and C H9 BrOS 243.9557, found 245.9525 and
9
43.9547.
1
4
22
2
4
.1.8. 6- 3-Bromothien-2-yl)hex-5-yn-1-ol 3e). In accor-
dance to the general procedure for the Sonogashira
4.1.10. 8- 3-Bromothien-2-yl)oct-7-yn-1-ol 3g). In accor-
dance to the general procedure, treatment of 2,3-di-
bromothiophene 1 >0.10 g, 0.41 mmol) with oct-7-yn-1-ol
coupling, treatment of 2,3-dibromothiophene 1 >0.10 g,

R. Pereira et al. / Tetrahedron 57 +2001) 7871±7881
7877
2
g >0.05g, 0.45mmol), in the presence of Pd>PPh ) Cl
2
2£), 33.2 >t, 2£), 63.1 >t, 2£, C11C18), 65.5 >s, 2£), 77.9 >s,
2£); IR >KBr, ®lm) n 3500±3100 >br, O±H), 2931 >s, C±H),
2853 >s, C±H), 1464 >m), 1352 >w), 1061 >m), 1021 >w), 983
3
2
>
1.2 mg, 0.002 mmol), PPh3 >0.6 mg, 0.002 mmol) and
CuI >0.6 mg, 0.003 mmol), for 3 h at 608C, afforded 0.02 g
20%) of alkynol 3g as a yellow oil and 0.03 g >55%) of a
colorless solid >mp 44.58C, CH Cl ) identi®ed as hexadeca-
1
>
>w), 726 >w), 623 >w); MS m/z >%) 278 >M , 3), 177 >21),
145 >32), 133 >30), 131 >50), 119 >63), 117 >52), 107 >24),
106 >25), 105 >62), 95 >25), 93 >48), 92 >33), 91 >100), 81
>55), 80 >34), 79 >62), 78 >30), 77 >34), 67 >50); HRMS calcd
for C H O 278.2246, found 278.2237.
2
2
1
7
CDCl ) d 1.4±1.7 >m, 8H, 2H212H312H412H5), 2.46 >t,
,9-diyn-1,16-diol >4g). Data for 3g: H NMR >400 MHz,
3
Jˆ6.9 Hz, 2H, 2H6), 3.64 >t, Jˆ6.6 Hz, 2H, 2H1), 6.90 >d,
1
8
30
2
0
100 MHz, CDCl ) d 19.7 >t), 25.2 >t), 28.3 >t), 28.5 >t), 32.6
t), 62.9 >t, C1), 72.4 >s), 98.7 >s), 114.9 >s), 121.6 >s), 125.7
d), 129.8 >d); IR >KBr, ®lm) n 3500±3100 >br, O±H), 3108
w, vC±H), 2933 >s, C±H), 2858 >m, C±H), 2226 >w,
0
13
Jˆ5.4 Hz, 1H, H4 ), 7.09 >d, Jˆ5.4 Hz, 1H, H5 ); C NMR
>
>
>
>
4.1.12. tert-Butyldimethylsilyl 6- 3-bromothien-2-yl)hex-
5-yn-1-yl ether 3i). Following the general procedure
described above, treatment of 2,3-dibromothiophene 1
>0.10 g, 0.41 mmol) with tert-butyldimethylsilyl hex-5-yn-
1-yl ether 2i >0.10 g, 0.45mmol), in the presence of
Pd>PPh ) Cl >1.2 mg, 0.002 mmol), PPh3 >0.6 mg,
3
CuC), 1507 >w), 1428 >m), 1347 >m), 1150 >w), 1054
1
>
[
>
>
>
m), 863 >s), 708 >s), 606 >w); MS m/z >%) 288 >M
Br], 41), 286 >M [ Br], 40), 216 >75), 214 >75), 212
27), 203 >52), 201 >81), 199 >86), 190 >28), 188 >27), 177
29), 175 >29), 161 >39), 148 >55), 147 >55), 135 >86), 134
29), 123 >25), 122 >100), 121 >38), 120 >48), 97 >28); HRMS
3
2
2
8
1
1
79
0.002 mmol) and CuI >0.6 mg, 0.003 mmol), for 3 h at
608C, afforded, after puri®cation by chromatography
>SiO , 85:15±70:30 hexane/CH Cl ), 0.06 g >42%) of
2
2
2
compound 3i as a yellow oil and 0.04 g >40%) of a colorless
oil identi®ed as 1,12-bis>tert-butyldimethylsilyloxy)dodeca-
8
1
79
calcd for C H BrOS 288.0006 and C H BrOS
12 15
2
1
2
15
1
86.0027, found 287.9999 and 286.0021. Data for 4g: H
1
5,7-diyne >4i). Data for 3i: H NMR >400 MHz, CDCl ) d
3
NMR >400 MHz, CDCl ) d 1.25>br s, 2H, 2 £OH), 1.2±1.7
0.08 >s, 6H, Si>CH ) ), 0.92 >s, 9H, SiC>CH ) ), 1.7±1.8 >m,
3 2
3
3 3
>
m, 16H, 2H212H312H412H512H1212H1312H141
4H, 2H212H3), 2.52 >t, Jˆ6.6 Hz, 2H, 2H4), 3.69 >t, Jˆ
0
2
6
1
2
H15), 2.24 >t, Jˆ6.8 Hz, 4H, 2H612H11), 3.62 >t, Jˆ
6.0 Hz, 2H, 2H1), 6.93 >d, Jˆ5.4 Hz, 1H, H4 ), 7.12 >d,
1
.3 Hz, 4H, 2H112H16); C NMR >100 MHz, CD Cl ) d
3
0
13
Jˆ5.4 Hz, 1H, H5 ); C NMR >100 MHz, CDCl ) d 25.3
2
2
3
9.4 >t, 2£), 25.6 >t, 2£), 28.7 >t, 2£), 29.0 >t, 2£), 33.1 >t,
>q, 2£, Si>CH ) ), 18.3 >s, SiC>CH ) ), 19.6 >t), 24.9 >t), 25.9
3
2
3 3
£), 63.0 >t, 2£, C11C16), 65.5 >s, 2£), 77.8 >s, 2£); IR
>q, 3£, SiC>CH ) ), 31.8 >t), 62.6 >t, C1), 72.4 >s), 98.6 >s),
3
3
>
KBr, ®lm) n 3500±3100 >br, O±H), 2934 >s, C±H), 2859
114.9 >s), 121.6 >s), 125.7 >d), 129.7 >d); IR >NaCl, ®lm) n
3108 >w, vC±H), 2952 >s, C±H), 2929 >s, C±H), 2857 >s,
C±H), 2229 >w, CuC), 1471 >m), 1254 >s), 1106 >s), 836
>s, C±H), 1460 >m), 1427 >m), 1055 >m), 725 >w), 542 >w);
MS >FAB ) m/z >%) 252 >[M12] , 12), 251 >[M11] , 71);
1
1
1
1
1
HRMS >FAB ) >[M1H] ) calcd for C H O 251.2011,
1 81
>s), 776 >s); MS m/z >%) 318 >[M11-tBu] [ Br], 19), 317
81 79
1
6
27
2
1
1
found 251.2011.
>[M2tBu] [ Br], 100), 316 >[M11-tBu] [ Br], 19), 315
79
1
[M2tBu] [ Br], 93), 241 >51), 162 >24), 75 >67); HRMS
>
1
81
4
.1.11. 9- 3-Bromothien-2-yl)non-8-yn-1-ol 3h). Accord-
>[M2tBu] ) calcd for C H BrOSSi 316.9854 and
12 16
79
ing to the general procedure for the Sonogashira coupling,
the reaction of 2,3-dibromothiophene 1 >0.10 g, 0.41 mmol)
with non-8-yn-1-ol 2h >0.06 g, 0.45mmol), in the presence
of Pd>PPh ) Cl >1.2 mg, 0.002 mmol), PPh3 >0.6 mg,
C H BrOSSi 314.9874, found 316.9839 and 314.9883.
12 16
1
Data for 4i: H NMR >400 MHz, CDCl ) d 0.02 >s, 12H,
3
2£Si>CH ) ), 0.86 >s, 18H, 2£Si±tBu), 1.5±1.6 >m, 8H,
3
2
2H212H312H1012H11), 2.25>t, Jˆ6.5Hz, 4H, 2H4 1
3
2
2
1
3
0
6
.002 mmol) and CuI >0.6 mg, 0.003 mmol), for 3 h at
08C, provided 0.05g >42%) of compound 3h as a yellow
2H9), 3.59 >t, Jˆ5.9 Hz, 4H, 2H112H12); C NMR
>100 MHz, CD Cl ) d 25.2 >q, 4£, 2£Si>CH ) ), 18.6 >s,
2
2
3 2
oil and 0.03 g >43%) of a colorless solid >mp 66.68C,
CH Cl ) identi®ed as octadeca-8,10-diyn-1,18-diol >4h).
Data for 3h: H NMR >400 MHz, CDCl ) d 1.2±1.7 >m,
2£, 2£SiC>CH ) ), 19.3 >t, 2£), 25.3 >t, 2£), 26.1 >q, 6£,
3
3
2£SiC>CH ) ), 32.3 >t, 2£), 62.8 >t, 2£, C11C12), 65.7 >s,
3 3
2
2
1
2£), 77.8 >s, 2£); IR >KBr, ®lm) n 2954 >s, C±H), 2932 >s,
3
1
2
5
0H, 2H212H312H412H512H6), 2.44 >t, Jˆ7.0 Hz,
C±H), 2859 >s, C±H), 1469 >m), 1254 >s), 1107 >s), 837 >s),
1
1
H, 2H7), 3.63 >t, Jˆ6.6 Hz, 2H, 2H1), 6.90 >d, Jˆ
776 >s); MS m/z >%) 423 >[M11] , 1), 422 >M , 1), 365
>42), 233 >28), 159 >52), 148 >21), 147 >100), 131 >34), 117
>32), 91 >31), 75>80), 73 >75); HRMS calcd for C 24H O Si
0
0
13
.4 Hz, 1H, H4 ), 7.09 >d, Jˆ5.4 Hz, 1H, H5 ); C NMR
>
>
>
100 MHz, CDCl ) d 19.7 >t), 25.6 >t), 28.2 >t), 28.7 >t), 28.8
3
t), 32.7 >t), 63.0 >t, C1), 72.3 >s), 98.8 >s), 114.8 >s), 121.6
s), 125.6 >d), 129.7 >d); IR >KBr, ®lm) n 3500±3100 >br,
46
2
2
422.3036, found 422.3048.
O±H), 3107 >w, vC±H), 2932 >s, C±H), 2856 >s, C±H),
4.1.13. 3-Bromo-2- hex-1-yn-1-yl)thiophene 3j). Accord-
ing to the general procedure for the Sonogashira reaction,
treatment of 2,3-dibromothiophene 1 >0.10 g, 0.41 mmol)
2
1
226 >w, CuC), 1507 >w), 1429 >m), 1348 >m), 1150 >w),
057 >m), 863 >s), 707 >s), 607 >m); MS m/z >%) 302 >M
1
8
1
1 79
Br], 37), 300 >M [ Br], 36), 229 >27), 227 >27), 216
[
>
>
>
>
with 1-hexyne 2j >0.04 g, 0.45mmol) in iPr NH >2 mL),
2
55), 214 >53), 203 >57), 201 >68), 199 >71), 190 >26), 188
24), 177 >28), 175 >29), 162 >25), 161 >29), 148 >50), 147
45), 135 >90), 134 >32), 123 >25), 122 >100), 121 >39), 120
in the presence of Pd>PPh ) Cl >1.2 mg, 0.002 mmol),
3
2
2
PPh3 >0.6 mg, 0.002 mmol) and CuI >0.6 mg, 0.003
mmol), for 2 h at 848C, afforded an inseparable mixture of
2,3-dibromothiophene 1, C2-substituted product 3j and
8
17
1
38); HRMS calcd for C H BrOS 302.0163 and
1
3
7
9
1
C H BrOS 300.0183, found 302.0150 and 300.0173.
1
alkyne dimer 4j. Integration of its H NMR spectrum
showed a 4:1:2 1/3j/4j ratio.
3
17
1
Data for 4h: H NMR >400 MHz, CDCl ) d 1.2±1.6 >m,
3
2
2
0H,2H212H312H412H512H612H1312H1412H151
H1612H17), 2.23 >t, Jˆ6.9 Hz, 4H, 2H712H12), 3.62 >t,
4.1.14. 2E,4E)-5- 3-Bromothien-2-yl)-3-methylpenta-
2,4-dien-1-ol 7a). Procedure A for the Stille reaction. To
1
3
Jˆ6.3 Hz, 4H, 2H112H18); C NMR >100 MHz, CD Cl )
2
2
d 19.4 >t, 2£), 26.0 >t, 2£), 28.7 >t, 2£), 29.1 >t, 2£), 29.2 >t,
a solution of Pd >dba) >11 mg, 0.01 mmol) in NMP >1 mL)
2
3

7878
R. Pereira et al. / Tetrahedron 57 +2001) 7871±7881
was added, in one portion, AsPh >25mg, 0.08 mmol).
3
tion mixture was stirred at 258C for 2 h. It was then diluted
with TBME and ®ltered through a plug of silica gel. After
evaporation of the solvent, the residue was puri®ed by
Degassing of the solution was accomplished by bubbling
an Ar current through the mixture for 5min. A previously
degassed solution of 2,3-dibromothiophene 1 >0.10 g,
chromatography >SiO , hexane), to yield 0.03 g >72%) of
2
0
.41 mmol) in NMP >1 mL) was then added, dropwise.
After stirring at 258C for 10 min, a degassed solution of
2E,4E)-5->tri-n-butylstannyl)-3-methylpenta-2,4-dien-1-ol
>0.24 g, 0.62 mmol) in NMP >1 mL) was added and the
nal mixture was heated to 458C for 90 min. After cooling
compound 7b as a colorless oil and 5mg >11%) of a color-
less oil identi®ed as 1,3-bis>fur-2-yl)thiophene >8b). Data
1
>
5
®
for 7b: H NMR >400 MHz, CDCl ) d 6.52 >dd, Jˆ3.5,
3
0
1.8 Hz, 1H, H4), 7.02 >d, Jˆ5.3 Hz,1H, H4 ), 7.08 >dd,
0
Jˆ3.5, 0.5 Hz, 1H, H3), 7.22 >d, Jˆ5.3 Hz, 1H, H5 ), 7.46
1
3
down to 258C, a KF saturated solution >4 mL) was added
and the mixture was stirred for 30 min. It was then extracted
with TBME >3£5mL). The combined organic extracts were
>dd, Jˆ1.8, 0.5Hz, 1H, H 5) ; C NMR >100 MHz, CDCl ) d
3
106.0 >s), 107.7 >d), 111.7 >d), 124.2 >d), 128.9 >s), 131.5
>d), 141.8 >d), 147.6 >s); IR >KBr, ®lm) n 3110 >m, vC±H),
2926 >m, C±H), 1487 >s), 1344 >m), 865>s), 735>s), 708 >s);
washed with H O >2£15mL) and KF saturated solution
2
1
81
1 81
>15mL), dried >Na SO ) and evaporated. Puri®cation of
the residue by chromatography >SiO , 75:25±50:50
MS m/z >%) 231 >[M11] [ Br], 9), 230 >M [ Br], 100),
79 79
229 >[M11] [ Br], 10), 228 >M [ Br], 98), 201 >21), 199
2
4
1
1
2
hexane/AcOEt) afforded 0.07 g >70%) of a yellow solid
>
>21), 191 >24), 189 >23), 121 >81); HRMS calcd for
8
1
79
mp 85.38C, CH Cl /hexane) identi®ed as >2E,4E)-5->3-
2
C H BrOS 229.9224 and C H BrOS 227.9244, found
8 5 8 5
2
1
229.9218 and 227.9242. Data for 8b: H NMR >400 MHz,
bromothien-2-yl)-3-methylpenta-2,4-dien-1-ol >7a) and
.02 g of a mixture which was further puri®ed by HPLC
0
00
00
0
CD Cl ) d 6.4±6.5>m, 3H, H4 1H3 1H4 ), 6.62 >dd, Jˆ
2
2
w
0
>
MeOH, 4.4 mL/min, 13 min) to afford 10 mg >9%) of
Waters Spherisorb S5NH , 10£250 mm; 97:3 CH Cl /
3.3, 0.6 Hz, 1H, H3 ), 7.28 >d, Jˆ5.3 Hz, 1H, H4 or H5),
2
2
2
7.31 >d, Jˆ5.3 Hz, 1H, H5 or H4), 7.46 >dd, Jˆ1.8, 0.6 Hz,
00
0
0
00
a yellow solid >mp 131.48C, CH C ) identi®ed as
2
1H, H5 or H5 ), 7.48 >dd, Jˆ1.6, 0.6 Hz, 1H, H5 or H5 );
C NMR >100 MHz, CD Cl ) d 108.1 >d), 109.2 >d), 111.7
2 2
2
1
3
2
>
,3-bis[>1E,3E)-3-methylpenta-1,3-dien-5-ol-1-yl]thiophene
8a). Data for 7a: H NMR >400 MHz, CDCl ) d 1.28 >t,
1
>d), 112.1 >d), 125.3 >d), 127.7 >s), 128.3 >s), 128.4 >d),
141.9 >d), 142.6 >d), 148.1 >s), 150.2 >s); IR >KBr, ®lm) n
3115>w, vC±H), 1484 >w), 1019 >m), 855 >m), 734 >s); MS
3
Jˆ5.6 Hz, 1H, OH), 1.89 >s, 3H, C3±CH ), 4.31 >app. t,
3
Jˆ6.2 Hz, 2H, 2H1), 5.79 >t, Jˆ6.8 Hz, 1H, H2), 6.64 >d,
1
1
J
ˆ16.0 Hz, 1H, H4 or H5), 6.69 >d, J ˆ16.0 Hz, 1H, H5
m/z >%) 217 >[M11] , 15), 216 >M , 100), 187 >40), 115
>22), 68 >29); HRMS calcd for C H O S 216.0245, found
216.0234.
AB
AB
0
H5 ); C NMR >100 MHz, CDCl ) d 12.5>q, C3±CH ),
or H4), 6.91 >d, Jˆ5.3 Hz, 1H, H4 ), 7.09 >d, Jˆ5.3 Hz, 1H,
1
2
8
2
0
5.4 >t, C1), 110.5>s), 119.5>d), 123.7 >d), 130.7 >d),
13
3
3
9
1
3
9
2
1
32.0 >d), 134.4 >d), 135.8 >s), 137.2 >s); IR >KBr, ®lm) n
500±3100 >br, O±H), 2920 >m, C±H), 1433 >m), 997 >m),
4.1.16. 3-Bromo-2-phenylthiophene 12a). Procedure A
for the Suzuki reaction. To a stirred solution of 2,3-di-
bromothiophene 1 >0.20 g, 0.83 mmol) and Pd>PPh3)4
>0.09 g, 0.07 mmol) in dioxane >10 mL) were added phenyl-
boronic acid 10 >0.11 g, 0.91 mmol) and 2 M Na CO
1 81
45>s), 875>m), 704 >s); MS m/z >%) 260 >M [ Br], 49),
1
79
58 >M [ Br], 50), 190 >35), 188 >34), 179 >33), 177 >49),
75>47), 149 >l00), 136 >43), 135>36), 134 >34); HRMS
2
3
8
11
1
79
calcd for C H BrOS 259.9693 and C H BrOS
1
>1.7 mL, 3.31 mmol). The mixture was heated to 1008C
for 4 h. After cooling down to 258C, it was diluted with
0
10 11
1
57.9714, found 259.9686 and 257.9717. Data for 8a: H
2
NMR >400 MHz, CD COCD ) d 1.82 >s, 6H, C3 ±CH 1
0
TBME, poured into H O and extracted with TBME >3£).
3
3
3
2
0
0
C3 ±CH ), 3.6 >m, 2H, 2£OH), 4.20 >t, Jˆ6.0 Hz, 4H,
The combined organic extracts were washed with a NaCl
saturated solution >3£), dried >Na SO ) and evaporated.
3
0
00
0
00
2
H5 12H5 ), 5.73 >t, Jˆ6.4 Hz, 2H, H4 1H4 ), 6.58 >d,
2
4
0
0
00
00
Jˆ15.7 Hz, 1H, H2 or H1 or H2 or H1 ), 6.72 >d,
Puri®cation by chromatography >SiO , hexane) afforded
2
0
0
0
00
00
J
ˆ16.1 Hz, 1H, H2 or H1 or H2 or H1 ), 6.75>d,
0.16 g >81%) of compound 12a as a colorless oil, and
4 mg >2%) of a colorless solid >mp 83.78C, hexane) identi-
®ed as 2,3-diphenylthiophene >13a). Data for 12a: H NMR
AB
0
00
JABˆ16.1 Hz, 1H, H2 or H1 or H2 or H1 ), 6.92 >d,
0
0
00
00
1
Jˆ15.7 Hz, 1H, H2 or H1 or H2 or H1 ), 7.18 >d,
1
3
Jˆ5.4 Hz, 1H, H4), 7.24 >d, Jˆ5.4 Hz, 1H, H5);
C
NMR >100 MHz, CD COCD ) d 12.6 >q), 12.7 >q), 59.4
>400 MHz, CD Cl ) d 7.07 >d, Jˆ5.3 Hz, 1H, H4), 7.32 >d,
2
2
Jˆ5.3 Hz, 1H, H5), 7.4±7.5 >m, 3H, ArH), 7.6±7.7 >m, 2H,
ArH); C NMR >100 MHz, CD Cl ) d 107.8 >s, C3), 125.6
2 2
3
3
1
3
>
t), 59.5 >t), 119.3 >d), 120.2 >d), 124.6 >d), 126.9 >d),
1
1
34.4 >d, 2£), 134.7 >d), 135.1 >s), 135.2 >d), 135.3 >s),
>d), 128.6 >d), 128.9 >d, 2£), 129.3 >d, 2£), 131.9 >d), 133.1
>s), 138.5>s); IR >KBr, ®lm) n 3108 >m, vC±H), 2924 >m,
C±H), 1484 >m), 1445>m), 1147 >m), 864 >s), 7 57 >s), 692
37.8 >s), 138.8 >s); IR >KBr, ®lm) n 3500±3100 >br,
O±H), 2923 >m, C±H), 2854 >m, C±H), 1249 >w), 995
>
1
m), 952 >m), 721 >w); MS m/z >%) 277 >[M11] , 17),
1
81
1 81
>s); MS m/z >%) 241 >[M11] [ Br], 11), 240 >M [ Br],
100), 239 >[M11] [ Br], 11), 238 >M [ Br], 96), 115
1
1
79
1
79
2
76 >M , 100), 245> 53 ), 227 >24), 187 >29), 175>27),
61 >47), 149 >22), 148 >28), 135>21); HRMS calcd for
81
7
1
C H O S 276.1184, found 276.1178.
>68), 114 >10); HRMS calcd for C H BrS 239.9431 and
1
0
7
9
C H BrS 237.9452, found 239.9425 and 237.9443.
10 7
1
6
20
2
4
.1.15. 2- 3-Bromothien-2-yl)furane 7b). Procedure B
4.1.17. 5E)-6- 3-Bromothien-2-yl)hex-5-en-1-ol 12b).
Procedure B for the Suzuki reaction. Argon was bubbled
through a solution of boronic acid 11 >0.07 g, 0.52 mmol) in
THF >1 mL) for 10 min. A previously degassed 10%
aqueous TlOH solution >2.3 mL, 1.05mmol) was then
added. After stirring at 258C for 10 min, this mixture was
slowly added, via cannula, over a degassed solution
of 2,3-dibromothiophene 1 >50 mg, 0.21 mmol) and
for the Stille reaction. To a stirred solution of 2,3-di-
bromothiophene 1 >50 mg, 0.21 mmol) and Pd >dba)
>2.8 mg, 0.003 mmol) in dioxane >1 mL) was added, via
cannula, a solution of PtBu >2.5mg, 0.01 mmol) in dioxane
>1 mL). After stirring at 258C for 10 min, 2->tri-n-butyl-
stannyl)furane 6 >0.08 g, 0.23 mmol) in dioxane >1 mL)
was added, followed by CsF >0.07 g, 0.45mmol). The reac-
2
3
3

R. Pereira et al. / Tetrahedron 57 +2001) 7871±7881
7879
Pd>PPh ) >24 mg, 0.02 mmol) in THF >1 mL). The reaction
3
>SiO , 70:30±40:60 hexane/AcOEt) afforded 0.03 g >64%)
2
4
mixture was stirred at 258C for 6 h. It was then diluted with
AcOEt and ®ltered through a plug of Celite . The ®ltrate
of 12b and 14 mg of a mixture which was further puri®ed by
w
w
HPLC >Waters Spherisorb S5NH , 10£250 mm; 97:3
2
was dried >Na SO ) and evaporated. Puri®cation of the
2
CH Cl /MeOH, 4.4 mL/min, 18 min) to afford 7 mg >12%)
2
4
2
residue by chromatography >70:30±50:50 hexane/AcOEt)
afforded 0.03 g >51%) of 12b as a yellow oil and 11 mg
of a yellow oil identi®ed as 2,3-bis[>1E)hex-1-en-6-ol-1-yl]-
thiophene >13b). Data for 13b: H NMR >400 MHz, CDCl )
d 1.5±1.6 >m, 8H, 2H4 12H5 12H4 12H5 ), 2.22 >qd,
1
3
0
0
00
00
>21%) of a colorless solid >mp 68.48C, hexane/AcOEt)
identi®ed as >5E,7E)-dodeca-5,7-dien-1,12-diol >14b).
3
4
0
00
Jˆ7.1, 1.2 Hz, 4H, 2H3 12H3 ), 3.66 >t, Jˆ6.4 Hz, 4H,
1
Data for 12b: H NMR >400 MHz, CDCl ) d 1.3 >br s,
0
0
0
0
2H6 12H6 ), 5.99 >dtd, Jˆ15.7, 7.0, 2.0 Hz, 2H, H2 1
3
0
0
0
0
0
1
2
7
H, OH), 1.5±1.7 >m, 4H, 2H212H3), 2.2±2.3 >m, 2H,
H4), 3.66 >t, Jˆ6.3 Hz, 2H, 2H1), 6.11 >dt, Jˆ15.8,
.0 Hz, 1H, H5), 6.54 >d, Jˆ15.8 Hz, 1H, H6), 6.88 >d,
H2 ), 6.46 >d, Jˆ15.7 Hz, 1H, H1 or H1 ), 6.62 >d, Jˆ
00 0
15.7 Hz, 1H, H1 or H1 ), 6.96 >d, Jˆ5.3 Hz, 1H, H4),
1
3
7.04 >d, Jˆ5.3 Hz, 1H, H5); C NMR >100 MHz, CDCl )
3
0
0
13
Jˆ5.3 Hz, 1H, H4 ), 7.04 >d, Jˆ5.3 Hz, 1H, H5 );
C
d 25.3 >t), 25.4 >t), 32.0 >t, 2£), 32.7 >t), 32.8 >t), 62.3 >t),
62.4 >t), 121.3 >d), 122.4 >d, 2£), 125.6 >d), 131.0 >d), 131.1
>d), 135.1 >s), 136.5 >s); IR >KBr, ®lm) n 3600±3100 >br,
O±H), 3024 >w, vC±H), 2933 >s, C±H), 2861 >s, C±H),
1657 >m), 1434 >m), 1063 >s), 958 >s), 718 >m); MS m/z >%)
NMR >100 MHz, CDCl ) d 25.2 >t), 32.2 >t), 32.7 >t), 62.7
3
0
d), 137.1 >s, C2 ); IR >KBr, ®lm) n 3500±3100 >br, O±H),
>
>
t, C1), 108.7 >s, C3 ), 121.9 >d), 122.9 >d), 130.4 >d), 132.9
0
933 >s, C±H), 2860 >s, C±H), 1436 >m), 1347 >w), 1060
2
>
1 81
m), 955 >s), 868 >s), 699 >s); MS m/z >%) 262 >M [ Br],
1
280 >M , 23), 210 >25), 148 >20), 147 >51), 137 >100), 135
>36), 123 >21), 85>29), 69 >28); HRMS calcd for C H O S
280.1497, found 280.1502.
1 79
9), 260 >M [ Br], 19), 192 >34), 191 >51), 190 >30), 189
1
1
6
24
2
>
>
47), 181 >32), 177 >33), 175>32), 163 >18), 135>44), 122
100), 97 >29), 85>63); HRMS calcd for C 10H13 BrOS
8
1
7
9
61.9850 and C H BrOS 259.9870, found 261.9855
2
and 259.9881. Data for 14b: H NMR >400 MHz, CDCl )
4.1.20. tert-Butyldimethylsilyl 6- thien-2-yl)hex-5-yn-1-
yl ether 16). To a cooled >08C) solution of tert-butyl-
dimethylsilyl 6->3-bromothien-2-yl)hex-5-yn-1-yl ether 3i
>50 mg, 0.13 mmol) in THF >1 mL) was added dropwise
sec-BuLi >0.12 mL, 1.3 M in cyclohexane, 0.16 mmol).
After stirring at 08C for 30 min, MeOH >0.05mL, 1.33
mmol) was added and the resulting mixture was stirred at
258C for 30 min. Water was then added and the mixture was
1
0
13
1
3
d 1.4±1.6 >m, 8H, 2H212H312H1012H11), 2.07 >app. q,
Jˆ7.1 Hz, 4H, 2H412H9), 3.62 >t, Jˆ6.5Hz, 4H, 2H1 1
2
H12), 5.5±5.6 >m, 2H, H51H8), 5.9±6.0 >m, 2H, H61
13
H7); C NMR >100 MHz, CDCl ) d 25.4 >t, 2£), 32.2 >t,
3
4
£), 62.8 >t, 2£, C11C12), 130.6 >d, 2£), 132.0 >d, 2£); IR
>
KBr, ®lm) n 3500±3100 >br, O±H), 3014 >m, vC±H),
2
1
9
8
933 >s, C±H), 1434 >w), 1060 >m), 987 >s); MS m/z >%)
extracted with Et O >3£). The combined organic layers were
2
1
98 >M , 3), 180 >42), 121 >25), 107 >21), 98 >51), 97 >23),
washed with H O >3£), dried >Na SO ) and evaporated.
Puri®cation by chromatography >SiO ±C , 100%
2 18
2
2
4
5 >47), 94 >35), 93 >57), 91 >40), 84 >25), 82 >27), 81 >50),
0 >60), 79 >100), 77 >31), 68 >27), 67 >42); HRMS calcd for
1
CH CN) afforded 35mg >92%) of 16 as a yellow oil. H
3
C H O 198.1620, found 198.1625.
1
NMR >400 MHz, CDCl ) d 0.08 >s, 6H, Si>CH ) ), 0.92 >s,
3
2
22
3 2
9
H, tBu), 1.6±1.7 >m, 4H, 2H212H3), 2.47 >t, Jˆ6.6 Hz,
4.1.18. 3-Bromo-2-phenylthiophene 12a). Procedure C
for the Suzuki reaction. The mixture of Pd>OAc) >0.5mg,
2H, 2H4), 3.68 >t, Jˆ5.7 Hz, 2H, 2H1), 6.94 >dd, Jˆ4.9,
0
0
0
4.9 Hz, 1H, H5 ); C NMR >100 MHz, CDCl ) d 25.3 >q,
3.6 Hz, 1H, H4 ), 7.12 >d, Jˆ3.6 Hz, 1H, H3 ), 7.17 >d, Jˆ
2
13
0
mg, 0.004 mmol), phenyl boronic acid 10 >38 mg, 0.31
.002 mmol), 2->di-tert-butylphosphino)biphenyl 15 >1.2
3
2£, Si>CH ) ), 18.3 >s, SiC>CH ) ), 19.5 >t), 25.0 >t), 25.9 >q,
3
2
3 3
mmol) and K PO >0.09 g, 0.41 mmol) was degassed by
3
3£, SiC>CH ) ), 32.0 >t), 62.6 >t, C1), 73.8 >s), 94.2 >s),
3 3
4
means of 3 vacuum-Ar cycles. To this mixture was added
a previously degassed solution of 2,3-dibromothiophene 1
124.1 >s), 125.8 >d), 126.7 >d), 130.9 >d); IR >KBr, ®lm) n
2929 >s, C±H), 2857 >s, C±H), 1361 >m), 1256 >s), 1107 >s),
1
836 >s), 775>s), 696 >s); MS m/z >%) 238 >[M11-tBu] , 19),
>
50 mg, 0.21 mmol) in toluene >1 mL) and the ®nal solution
1
237 >[M2tBu] , 90), 171 >25), 164 >20), 163 >100), 121
was heated to 1008C for 4 h. After cooling down to 258C,
TBME was added, the mixture was poured into a 1 M NaOH
solution and it was extracted with TBME >3£5mL). The
combined organic extracts were dried >Na SO ) and evapo-
>19), 97 >14), 75>36); HRMS calcd for C H OSSi
1
6
26
294.1474, found 294.1471.
2
4
rated. Puri®cation by chromatography >SiO , hexane)
2
afforded 0.02 g >40%) of 12a and 4 mg >8%) of 13a.
4.1.21. 2- Hex-1-yn-6-ol-1-yl)-3-[ 1E,3E)-3-methylpenta-
1,3-dien-5-ol-1-yl]thiophene 17). In accordance to pro-
cedure B for the Stille coupling, the reaction of 6->3-
bromothien-2-yl)hex-5-yn-1-ol 3e >0.05g, 0.19 mmol)
with >2E,4E)-5->tri-n-butylstannyl)-3-methylpenta-2,4-dien-
1-ol 5 >0.11 g, 0.29 mmol), in the presence of Pd >dba)
4.1.19. 5E)-6- 3-Bromothien-2-yl)hex-5-en-1-ol 12b).
Procedure D for the Suzuki reaction. The mixture of
Pd>OAc) >0.5mg, 0.002 mmol), 2->di- tert-butylphosphino)-
2
2
3
biphenyl 15 >1.2 mg, 0.004 mmol), boronic acid 11 >75mg,
0
>2.6 mg, 0.003 mmol), PtBu3 >2.3 mg, 0.01 mmol) and
CsF >0.06 g, 0.42 mmol), for 2 h at 808C, afforded, after
puri®cation by chromatography >Al O , CH Cl ±97:3
.52 mmol) and KF >0.04 g, 0.62 mmol) was degassed by
means of three vacuum-Ar cycles. To this mixture was
added a previously degassed solution of 2,3-dibromo-
thiophene 1 >50 mg, 0.21 mmol) in dioxane >1 mL) and
the ®nal solution was heated to 908C for 5h. After cooling
down to 258C, AcOEt was added, the mixture was poured
into a 1 M NaOH solution and it was extracted with AcOEt
2
3
2
2
CH Cl /MeOH), 0.04 g >76%) of thiophene 17 as a yellow
2
2
solid >mp 66.58C, CH Cl ) and 7 mg >20%) of a yellow oil
2
2
3
identi®ed as 6->thien-2-yl)hex-5-yn-1-ol >18). Data for 17:
5
1
0
H NMR >400 MHz, CD Cl ) d 1.5±1.8 >m, 6H, 2H4 1
2
2
0
00
2H5 12£OH), 1.89 >s, 3H, C3 ±CH ), 2.55 >t, Jˆ6.6 Hz,
3
0
0
>
>
3£5mL). The combined organic extracts were dried
2H, 2H3 ), 3.66 >t, Jˆ6.0 Hz, 2H, 2H6 ), 4.30 >d, Jˆ6.7 Hz,
00 00
AB
Na SO ) and evaporated. Puri®cation by chromatography
2
2H, 2H5 ), 5.79 >t, Jˆ6.7 Hz, 1H, H4 ), 6.73 >d, J ˆ
4

7880
R. Pereira et al. / Tetrahedron 57 +2001) 7871±7881
0
0
00
00
1
6.2 Hz, 1H, H1 or H2 ), 6.81 >d, J ˆ16.2 Hz, 1H, H2
References
AB
00
or H1 ), 7.11 >d, Jˆ5.4 Hz, 1H, H4 or H5), 7.14 >d, Jˆ
1
.4 Hz, 1H, H5 or H4); C NMR >100 MHz, CD Cl ) d
3
5
1
6
1
1. Horn, D. H. S.; Lamberton, J. A. Aust. J. Chem. 1963, 16,
475±479.
2
2
00
2.6 >q, C3 ±CH ), 20.0 >t), 25.4 >t), 32.3 >t), 59.7 >t),
3
2.6 >t), 73.7 >s), 99.1 >s), 121.4 >d), 124.8 >d), 125.7 >d),
32.2 >d), 134.4 >d), 136.2 >s, 2£), 142.6 >s); IR >KBr, ®lm)
2. Cosimelli, B.; Neri, D.; Roncucci, G. Tetrahedron 1996, 52,
11281±11290.
n 3600±3100 >br, O±H), 3106 >w, vC±H), 2939 >s, C±H),
3. Rossi, R.; Carpita, A.; Ciofalo, M.; Lippolis, V. Tetrahedron
1991, 47, 8443±8460 and references cited therein.
4. Gronowitz, S.; Peters, D. Heterocycles 1990, 30, 645±658.
5. Han, Y.; Giroux, A.; L e pine, C.; Lalibert e , F.; Huang, Z.;
Perrier, H.; Bayly, C. I.; Young, R. N. Tetrahedron 1999,
55, 11669±11685.
2
1
2
219 >w, CuC), 1711 >m), 1663 >m), 1429 >m), 1248 >m),
1
060 >m), 833 >m), 755 >s); MS m/z >%) 277 >[M11] , 19),
1
76 >M , 100), 245>68), 187 > 57 ), 185>49), 184 >39), 175
>
37), 171 >47), 161 >58), 147 >46); HRMS calcd for
C H O S 276.1184, found 276.1180. Data for 18: H
1
1
6
20
2
NMR >400 MHz, CDCl ) d 1.6±1.7 >m, 4H, 2H212H3),
3
6. Chou, Y.-M.; Lai, M. C.; Hwang, T.-M.; Ong, C. W. Bioorg.
Med. Chem. Lett. 1999, 9, 2643±2646 and references cited
therein.
2
6
.45>t, Jˆ6.6 Hz, 2H, 2H4), 3.68 >t, Jˆ5.9 Hz, 2H, 2H1),
0
.91 >dd, Jˆ5.1, 3.6 Hz, 1H, H4 ), 7.09 >d, Jˆ3.6 Hz, 1H,
0
CDCl ) d 19.4 >t), 24.8 >t), 31.8 >t), 62.3 >t, C1), 74.0 >s),
0
13
H3 ), 7.15>d, Jˆ5.1 Hz, 1H, H5 ); C NMR >100 MHz,
7. >a) Minato, A.; Tamao, K.; Suzuki, K.; Kumada, M.
Tetrahedron Lett. 1980, 21, 4017±4020. >b) Minato, A.;
Tamao, K.; Hayashi, T.; Suzuki, K.; Kumada, M. Tetrahedron
Lett. 1980, 21, 845±848. >c) Minato, A.; Suzuki, K.; Tamao,
K.; Kumada, M. J. Chem. Soc., Chem. Commun. 1984, 511±
513. >d) Jayasuriya, N.; Kagan, J. Heterocycles 1986, 24,
2261±2264. >e) Rossi, R.; Carpita, A.; Lezzi, A. Tetrahedron
1984, 40, 2773±2779.
3
0
9
3.9 >s), 124.0 >s, C2 ), 125.9 >d), 126.7 >d), 131.0 >d); IR
>
2
>
KBr, ®lm) n 3500±3100 >br, O±H), 3106 >w, vC±H),
939 >s, C±H), 2866 >s, C±H), 2224 >w, CuC), 1428
m), 1239 >w), 1190 >m), 1061 >s), 845>m), 700 >s); MS
1
m/z >%) 180 >M , 43), 162 >33), 136 >37), 135> 57 ), 134
48), 124 >31), 123 >91), 121 >100), 97 >46), 77 >26); HRMS
calcd for C H OS 180.0609, found 180.0604.
>
1
0
12
8. >a) King, A. O.; Negishi, E. J. Org. Chem. 1978, 43, 358±360.
b) Negishi, E.; Xu, C.; Tan, Z.; Kotora, M. Heterocycles
>
4.1.22. 2-Phenyl-3-[ 1E,3E)-3-methylpenta-1,3-dien-5-
ol-1-yl]thiophene 19). According to procedure B for the
Stille reaction, treatment of 3-bromo-2-phenylthiophene
1997, 46, 209±214. >c) Tamao, K.; Nakamura, K.; Ishii, H.;
Yamaguchi, S.; Shiro, M. J. Am. Chem. Soc. 1996, 118,
12469±12470. >d) Karlsson, J. O.; Gronowitz, S.; Frejd, T.
J. Org. Chem. 1982, 47, 374±377.
1
2a >0.05g, 0.21 mmol) with >2 E,4E)-5->tri-n-butyl-
stannyl)-3-methylpenta-2,4-dien-1-ol >0.12 g, 0.31
mmol), in the presence of Pd >dba) >2.9 mg, 0.003
5
9. >a) Carpita, A.; Lezzi, A.; Rossi, R.; Marchetti, F.; Merlino, S.
Tetrahedron 1985, 41, 621±625. >b) Wang, Y.; Koreeda, M.;
Chatterji, T.; Gates, K. S. J. Org. Chem. 1998, 63, 8644±8645.
>c) Pschirer, N. G.; Bunz, U. H. F. Tetrahedron Lett. 1999, 40,
2481±2484.
2
3
mmol), PtBu3 >2.5mg, 0.01 mmol) and CsF >0.07 g,
.46 mmol), for 2 h at 808C, afforded, after puri®cation by
chromatography >SiO , hexane±70:30 hexane/AcOEt),
0
2
0
>
®
.04 g >80%) of thiophene 19 as a yellow oil and 5mg
15%) of a colorless solid >mp 36.68C, EtOH/H O) identi-
10. >a) Bussolari, J. C.; Rehborn, D. C. Org. Lett. 1999, 1, 965±
967. >b) Kodani, T.; Matsuda, K.; Yamada, T.; Kobatake, S.;
Irie, M. J. Am. Chem. Soc. 2000, 122, 9631±9637. >c) Sharp,
M. J.; Snieckus, V. Tetrahedron Lett. 1985, 26, 5997±6000.
>d) Mohanakrishnan, A. K.; Hucke, A.; Lyon, M. A.;
Lakshmikantham, M. V.; Cava, M. P. Tetrahedron 1999, 55,
11745±11754. >e) F uÈ rstner, A.; Nikolakis, K. Liebigs Ann.
1996, 2107±2113.
2
¶
ed as 2-phenylthiophene >20). Data for 19: H NMR
1
0
>
400 MHz, CD COCD ) d 1.75>s, 3H, C3 ±CH ), 3.66 >t,
3
3
3
0
Jˆ5.3 Hz, 1H, OH), 4.25 >t, Jˆ5.9 Hz, 2H, 2H5 ), 5.79 >t,
0
0
0
Jˆ6.4 Hz, 1H, H4 ), 6.64 >d, Jˆ16.1 Hz, 1H, H1 or H2 ),
0
0
6
7
1
.84 >d, Jˆ16.1 Hz, 1H, H2 or H1 ), 7.4±7.5>m, 5H, ArH),
.43 >d, J ˆ5.4 Hz, 1H, H4 or H5), 7.44 >d, J ˆ5.4 Hz,
AB
AB
1
3
H, H5or H4); C NMR >100 MHz, CD COCD ) d 12.5
11. >a) Hucke, A.; Cava, M. P. J. Org. Chem. 1998, 63, 7413±
7417. >b) Bjùrnholm, T.; Greve, D. R.; Reitzel, N.; Hassen-
kam, T.; Kjaer, K.; Howes, P. B.; Larsen, N. B.; Bùgelund, J.;
Jayaraman, M.; Ewbank, P. C.; McCullough;, R. D. J. Am.
Chem. Soc. 1998, 120, 7643±7644. >c) Hatanaka, Y.; Matsui,
K.; Hiyama, T. Tetrahedron Lett. 1989, 30, 2403±2406.
12. Gozzi, C.; Lavenot, L.; Ilg, K.; Penalva, V.; Lemaire, M.
Tetrahedron Lett. 1997, 38, 8867±8870.
3
3
0 0
q, C3 ±CH ), 59.4 >t, C5 ), 121.3 >d), 125.7 >d), 127.0 >d),
3
>
128.7 >d), 129.7 >d, 2£), 130.2 >d, 2£), 134.1 >d), 135.1 >s),
135.2 >s), 135.3 >d), 136.4 >s), 140.0 >s); IR >KBr, ®lm) n
3600±3100 >br, O±H), 2924 >s, C±H), 1599 >m), 1491 >m),
1445>m), 1386 >w), 1246 >w), 1076 >w), 1002 >m), 960 >m),
835>m), 762 >s), 700 >m), 646 >m); MS m/z >%) 257
1
1
>[M11] , 8), 256 >M , 45), 226 >18), 225 >100), 213
>16), 187 >16), 186 >17), 185>43), 184 >26), 173 >27), 171
>19); HRMS calcd for C H OS 256.0922, found 256.0917.
13. Brandsma, B.; Vasilevsky, S. F.; Verkruijsse, H. D. Applica-
tion of Transition Metal Catalysts in Organic Synthesis;
Springer: Berlin-Heidelberg, 1998; Chapter 10, pp 222±223.
1
6
16
1
4. As a complementary approach, some other dibromothio-
phenes >like 2,5-dibromothiophene, ethyl 4,5-dibromothio-
phene-2-carboxylate or ethyl 2,5-dibromothiophene-3-
carboxylate) have also been regioselectively substituted by
means of halogen±metal exchange reactions: Abarbri, M.;
Thibonnet, J.; B e rillon, L.; Dehmel, F.; Rottl aÈ nder, M.;
Knochel, P. J. Org. Chem. 2000, 65, 4618±4634.
Acknowledgements
We thank MEC >grant SAF98-0143) and Xunta de Galicia
grant PGIDT99PX30105B and fellowship to R. Pereira) for
nancial support, and CACTI >Universidade de Vigo) for
>
®
NMR and mass spectra.
15. Brandsma, B.; Vasilevsky, S. F.; Verkruijsse, H. D. Appli-
cation of Transition Metal Catalysts in Organic Synthesis;
Springer: Berlin-Heidelberg, 1998; Chapter 2, p 26.
¶
2-Phenylthiophene is commercially available.

R. Pereira et al. / Tetrahedron 57 +2001) 7871±7881
7881
1
6. Bach, T.; Kr uÈ ger, L. Eur. J. Org. Chem. 1999, 2045±2057.
7. Sonogashira, K. In Metal-Catalyzed Cross-Coupling
Reactions; Diederich, F., Stang, P. J., Eds.; Wiley-VCH:
Weinheim, 1998; Chapter 5, pp 203±229.
1991, 32, 4243±4246. >c) Roth, G. P.; Farina, V.; Liebeskind,
L. S.; Pe nÄ a-Cabrera, E. Tetrahedron Lett. 1995, 36, 2191±
2194.
1
26. Betzer, J.-F.; Delaloge, F.; Muller, B.; Pancrazi, A.; Prunet, J.
J. Org. Chem. 1997, 62, 7768±7780.
1
8. >a) Paik, S.; Carmeli, S.; Cullingham, J.; Moore, R. E.;
Patterson, G. M. L.; Tius, M. A. J. Am. Chem. Soc. 1994,
27. Brandsma, B.; Vasilevsky, S. F.; Verkruijsse, H. D.
Application of Transition Metal Catalysts in Organic
Synthesis; Springer: Berlin-Heidelberg, 1998; Chapter 1, p 15.
116, 8116±8125. >b) Abrams, S. R. Can. J. Chem. 1984, 62,
1
333±1334. >c) Havr a nek, M.; Dvor a k, D. Synthesis 1998,
1264±1268.
2
8. Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. Engl. 1999, 38,
411±2413.
9. Suzuki, A. In Metal-Catalyzed Cross-Coupling Reactions;
2
1
2
2
2
9. Moody, C. J.; Shah, P. J. Chem. Soc., Perkin Trans. 1 1988,
249±3254.
2
3
Diederich, F., Stang, P. J., Eds.; Wiley-VCH: Weinheim,
1998; Chapter 2, pp 49±97.
0. Roush, W. R.; Kageyama, M.; Riva, R.; Brown, B. B.;
0. Nystr oÈ m, J.-E.; McCanna, T. D.; Helquist, P.; Amouroux, R.
Synthesis 1988, 56±58.
3
1. Lipshutz, B. H. In Organometallics in Synthesis. A Manual;
Schlosser, M., Ed.; Wiley: West Sussex, 1994; p. 286.
2. >a) Thorand, S.; Krause, N. J. Org. Chem. 1998, 63, 85 5 1±
Warmus, J. S.; Moriarty, K. J. J. Org. Chem. 1991, 56,
1
192±1210.
3
3
1. Kato, S.; Ishizaki, M. Japanese Patent No JP 62148480, 1987.
2. Uenishi, J.; Beau, J. M.; Armstrong, R. W.; Kishi, Y. J. Am.
Chem. Soc. 1987, 109, 4756±4758.
8
553. >b) Miller, M. W.; Johnson, C. R. J. Org. Chem. 1997,
2, 1582±1583.
6
2
3. Hundertmark, T.; Littke, A. F.; Buchwald, S. L.; Fu, G. C.
Org. Lett. 2000, 2, 1729±1731.
3
3
3
3. Wolfe, J. P.; Singer, R. A.; Yang, B. H.; Buchwald, S. L. J. Am.
Chem. Soc. 1999, 121, 9550±9561.
4. Kato, J.; Nakamura, K. Japanese Patent No JP 04068002,
2
4. Mitchell, T. N. In Metal-Catalyzed Cross-Coupling Reactions;
Diederich, F., Stang, P. J., Eds.; Wiley-VCH: Weinheim,
1990.
5. Tilley, J. W. European Patent No EP 94080, 1983.
1
998; Chapter 4, pp 167±202.
5. >a) Farina, V.; Krishnan, B. J. Am. Chem. Soc. 1991, 113,
585±9595. >b) Farina, V.; Roth, G. P. Tetrahedron Lett.
2
9