One-pot synthesis of unsymmetrical 1,3-butadiyne derivatives and their application in the synthesis of unsymmetrical 2,5-diarylthiophenes

Article abstract of DOI:10.1002/ejoc.201801242

A one-pot protocol was developed for the synthesis of unsymmetrical 1,3-butadiynes. The procedure is based on two sequential reactions: deprotection of R–C≡C–C≡C– C(Me)₂OH derivatives in a retro-Favorskii reaction to furnish a terminal 1,3-butadiyne compound, which reacted with aryl iod-ides in a Sonogashira-type cross-coupling reaction catalyzed by Pd(PPh₃)₄ and CuI, using TBAOH as activator and toluene as solvent under reflux for 10 min. We also studied in situ thiocycli-zation of 1,3-butadiynes, leading to unsymmetrical 2,5-diaryl-thiophenes. The principal features of this method are operational simplicity, good substrate scope, very fast reaction, and high yields.

Full text of DOI:10.1002/ejoc.201801242

A Journal of
Accepted Article
Title: One-pot synthesis of unsymmetrical 1,3-butadiyne derivatives
and their application in the synthesis of unsymmetrical 2,5-
diarylthiophenes
Authors: Camila B Andrade, Diego B Carvalho, Ozildeia S. Trefzger,
Najla Kassab, Palimécio G. Guerrero Jr., Sandro Barbosa,
Cristiane Y. K. Shiguemoto, and Adriano Baroni
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201801242
Link to VoR: http://dx.doi.org/10.1002/ejoc.201801242
Supported by

10.1002/ejoc.201801242
European Journal of Organic Chemistry
FULL PAPER
One-pot synthesis of unsymmetrical 1,3-butadiyne derivatives
and their application in the synthesis of unsymmetrical 2,5-
diarylthiophenes
Camila B. Andrade,[a] Diego B. Carvalho,[a] Ozildéia S. Trefzger,[a] Najla M. Kassab,[a] Palimécio G.
Guerrero Jr.,[b] Sandro L. Barbosa,[c] Cristiane Y. K. Shiguemoto,[a] Adriano C. M. Baroni*[a]
Abstract: A novel one-pot protocol was developed for the synthesis
of unsymmetrical 1,3-butadiynes. The procedure is based on two
sequential reactions: deprotection of R─C≡C─C≡C─C(Me)2OH
derivatives in a retro-Favorskii reaction to furnish a terminal 1,3-
Also, 1,3-butadiynes are important intermediates for the
preparation of heterocyclic compounds such as pyrroles,4
pyrazoles,5 isoxazoles,6 siloles,7 furans,8 thiophenes,4d,9 3-
halothiophenes,10 and selenophenes,11 among others (Figure 1).
The classical method for the synthesis of symmetrical 1,3-
butadiynes, oxidative coupling of terminal acetylenes in copper-
catalyzed reactions, established decades ago, uses Glaser's
homocoupling12 and its variations, such as the Eglinton13, Hay
reactions,14a-b and one-pot sequential Sonogashira-Glaser
reactions approach.14c This method has been used to synthesize
unsymmetrical 1,3-butadyines, but it requires the use of an
excess of one of the terminal alkynes, and the resulting mixture
of unsymmetrical and symmetrical 1,3-butadiynes is a drawback
of this reaction.15
butadiyne compound, which reacted with aryl iodides in
a
Sonogashira-type cross-coupling reaction catalyzed by Pd(PPh3)4
and CuI, using TBAOH as activator and toluene as solvent under
reflux for 10 min. We also studied in situ thiocyclization of 1,3-
butadiynes, leading to unsymmetrical 2,5-diarylthiophenes. The
principal features of this method are operational simplicity, good
substrate scope, very fast reaction, and high yields.
Introduction
On the other hand, Cadiot-Chodkiewicz coupling has been
widely used to synthesize unsymmetrical 1,3-butadyines.16 This
consists of a cross-coupling reaction of terminal acetylenes with
1-haloalkynes, using copper and suitable amines. The
advantages of this reaction are good yields, a variety of
substrates, mild conditions, and the low cost of the catalysts.
However, the electronic properties of terminal acetylenes and
haloalkyne substituents can affect the selectivity of the reaction,
with the formation of homocoupling by-products that complicate
the purification of the unsymmetrical 1,3-butadyines, leading to a
decrease in yields.1,16 Variations of the Cadiot-Chodkiewicz
reaction were described by Wang et al.,17 employing CuI (10
mol%)/P(o-Tol)3/K2CO3 and EtOH as a solvent. This protocol
gave good results with high selectivity. However,
bromoacetylene derivatives are toxic, lachrymators, volatile, and
air- and photosensitive.18
1,3-diynes are important building blocks in organic synthesis,
used as starting materials to synthesize natural products1 and
new electronic2 and optical materials (Figure 1).3
Rao et al. circumvented this drawback by generating
bromoacetylene in situ from the reaction of 1,1-dibromo alkenes
and terminal acetylenes, using the CuI/K3PO4/TBAA and DMF
catalytic system at 90 °C in 4 h of reaction.19 However, the
preparation of 1,1-dibromo alkenes is problematic due to use of
the air sensitive Schwartz's reagent, or because of the tedious
and laborious extractions and purifications of phosphorus by-
products in the Wittig-type protocol.20
Figure 1. Synthesis of heterocycles from 1,3-butadiynes.
Recently, Li et al.21 developed an attractive alternative method
for the synthesis of unsymmetrical 1,3-butadiynes, based on
gold-catalyzed Cadiot-Chodkiewics-type cross-coupling, using
terminal alkynes and alkynyl hypervalent iodine reagents. The
main drawback is the difficulty of preparing hypervalent iodine.
In another strategy, Fiandanese et al.22 employed 1,4-
bis(trimethylsilyl)-1,3-bytadiyne as the starting material.
Monodesilylation with MeLi-LiBr, followed by the Sonogashira
cross-coupling reaction of buta-1,3-diyn-1-yl-trimethylsilane with
aryl iodides, provided unsymmetrical 1,3-butadiynes. However,
the handling of moisture-sensitive reagents and the volatility of
buta-1,3-diyn-1-yl-trimethylsilane, which hinders its isolation, are
disadvantages of this method.
[a]
Faculdade de Ciências Farmacêuticas, Alimentos e Nutrição
Universidade Federal de Mato Grosso do Sul - UFMS
Av. Costa e Silva, s.n., Campo Grande, MS, 79070900, Brazil
E-mail: adriano.baroni@ufms.br; adrianobaroni@hotmail.com
https://sien.ufms.br/docentes/view/2414
[b]
[c]
Departamento de Química e Biologia, DAQBi
Universidade Tecnológica Federal do Paraná, UTFPR,
R. Pedro Gusso, 2671, Curitiba, PR, 81020430, Brazil
Department of Pharmacy
Universidade Federal dos Vales do Jequitinhonha e Mucuri, UFVJM,
R. da Glória, 187, Diamantina, MG, 39100000, Brazil
Supporting information for this article is given via a link at the end of
the document.
As an alternative, terminal 1,3-butadiynes can be generated
from suitable starting materials and react with aryl halides via
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801242
European Journal of Organic Chemistry
FULL PAPER
acetylene
unsymmetrical 1,3-butadiynes.23
In addition, suitable starting material for obtaining
zipper-Sonogashira
reactions
to
provide
Further, this strategy has also been used for construction more
complex triynes, or high oligoynes.24b
Bryce et al.25 employed this approach to synthesize terminal 1,3-
a
unsymmetrical 1,3-butadiynes is the Ar─C≡C─C≡C─C(Me)2OH
derivatives, which react with strong bases such as NaOH or
KOH under reflux in solvents such as toluene or benzene in
retro-Favorskii conditions to eliminate the acetone compound,
furnishing the terminal 1,3-butadiynes, which could be employed
butadiynes
from
2-methyl-6-phenyl-hexa-3,5-diyn-2-ol
derivatives, and isolated eight compounds with the aim of
showing their relative stability and applicability in the
Sonogashira cross-coupling reaction. However, Bryce and co-
workers obtained only one coupling product after 18 h of
reaction, in 75% yield.
in
cross-coupling
reactions.
The
high
polarity
of
Ar─C≡C─C≡C─C(Me)2OH derivatives compared to the terminal
butadiynes lead to easy separation and purification of unreacted
precursor. Ar─C≡C─C≡C─C(Me)2OH derivatives can be
prepared by the use of different terminal acetylenes and 4-
bromo-2-methyl-3-butyn-2-ol, in the same Cadiot-Chodkiewicz
cross-coupling strategy.24a Therefore, this approach shows to be
more suitable because is simple, furnish excellent yields,
product is easy to purify, 4-bromo-2-methyl-3-butyn-2-ol is non
lachrymator, stable in low temperatures, and its use avoids the
synthesis of several other bromoacetylene derivatives, which
have disadvantages as described prior.18 2-methyl-3-butyn-2-ol
used to prepare 4-bromo-2-methyl-3-butyn-2-ol is abundant,
inexpensive, demonstrating great advantage over other starting
materials.
Balova et al.26 used the same strategy for the synthesis of
several unsymmetrical diaryldiacetylenes. However, Ar─C≡C─
C ≡ CH was filtered to remove NaOH and held in toluene
solution before the Sonogashira-type cross-coupling reaction.
Unless a bulky terminal aryl group is attached to terminal 1,3-
butadiynes,27a-b the instability of these compounds remains a
drawback for the use of these two methods.27c-d
Considering the instability of the terminal 1,3-butadiynes, we
explored the possibility of performing this reaction using Ar─C≡
C─C≡C─C(Me)2OH as the starting material in a one-pot
reaction, avoiding the manipulation of the unstable terminal 1,3-
butadiyne outside of an inert atmosphere (Scheme 1).
Scheme 1. Procedures used for the synthesis of unsymmetrical 1,3-butadiynes.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801242
European Journal of Organic Chemistry
FULL PAPER
A
one-pot method via deprotection and cross-coupling
In order to improve the reaction yields, the catalytic system
Pd(PPh3)4 / CuI 10% was tested, using NaOH (4.5 equiv.) as a
base, and the product was obtained in 53% yield, contaminated
with homocoupling by-product 4a (Table 1, entry 2) and other
by-products. Considering that the amount of base can affect the
reaction yields,29 we used NaOH (3 equiv.) in order to determine
the appropriate proportion of base to promote the retro-Favorski
reaction and at the same time promote the cross-coupling
reaction with efficiency and with the formation of fewer by-
products (Table 1, entry 3). Product 3a was obtained in 80%
sequential reactions for the synthesis of diarylethynes from Ph─
C≡C─C(Me)2OH is known,28 but to the best of our knowledge,
this approach has not yet been used for the synthesis of
unsymmetrical 1,3-butadiynes. We also decided to explore the
synthesis of 2,5-diarylthiophene through in situ thiocyclization of
1,3-butadiynes generated in a one-pot procedure.
Results and Discussion
yield after 30 min of reaction, with
a small amount of
homocoupling by-product 4a (5%). Also, purification of 1,3-
butadiyne of this reaction is very difficult in the chromatographic
column, due to contamination with unknown impurities.
In recent years, TBAOH has been used by our research group
and others as an activator in Sonogashira cross-coupling
reactions30 and as a base in the synthesis of symmetrical and
unsymmetrical (Z)-thiobutenynes.31 Recently, TBAOH was used
in deprotection of alkynyl carbinols.32 Thus, tetrabutylammonium
In order to optimize the protocol conditions, the reaction of 2-
methyl-6-phenyl-hexa-3,5-diyn-2-ol 1a with 4-iodoanisole 2a was
performed, in the presence of the catalyst system PdCl2(PPh3)2
5% / CuI 10% and NaOH (4.5 equiv.) as a base at 110 °C. First,
a retro-Favorskii reaction occurs between Ar─C≡C─C≡C─
C(Me)2OH and NaOH. Next, the Ar─C≡C─C≡CH formed in
situ reacts with 4-iodoanisole in a Sonogashira cross-coupling
reaction (Scheme 1). Thus, the NaOH acts as a base in these
two sequential reactions. Although NaOH is not a usual base in
Sonogashira cross-coupling reactions, it was observed after 30
min of reaction, and the terminal 1,3-butadiyne 3a was obtained
in 40% yield, with the formation of a small amount of
homocoupling product 4a. Furthermore, 4-iodoanisole 2a was
not fully consumed in these reaction conditions (Table 1, entry 1).
hydroxide appears to be
a more suitable alternative to
synthesize unsymmetrical 1,3-butadiynes in a one-pot procedure
from Ar─C≡C─C≡C─C(Me)2OH derivatives. Therefore, we
decided to use TBAOH as a base to substitute the NaOH in this
reaction.
In the first attempt, we used the catalyst system Pd(PPh3)4 5% /
CuI 10% in TBAOH 40% in H2O (3.0 equiv.) under reflux (90–
95 °C). The reaction was monitored by thin-layer
chromatography, and work-up occurred after 5 min. The product
was obtained in 51% yield, and homocoupling product 4a was
isolated in 10% yield (Table 1, entry 4), with no observation of
the formation of other by-products. Although the yield was not
good, the reaction was cleaner than that using NaOH.
Table 1. Optimization of coupling reaction of 1,3-butadiyne 1a with 4-
iodoanisole 2a.
When we reduced the amount of 2-methyl-6-phenyl-hexa-3,5-
diyn-2-ol 1a to 1.5 equiv. and the amount of TBAOH to 2.0
equiv., the product was obtained in 73% yield, and
homocoupling compound 4a in 5% yield (Table 1, entry 5).
The analysis of the results showed that the use of NaOH 4.5
equiv. (Table 1, entries 1 and 2) caused the deprotection of 1a
to Ar─C≡C─C≡C─H in only 5 min (TLC monitoring), while
the use of NaOH 3 equiv. caused total deprotection in 15 min
(monitored by TLC). However, for the coupling reaction to occur
efficiently, an additional 15 min reaction time was necessary
(Table 1, entry 3). On the other hand, all reaction conditions
mediated by TBAOH were much faster, and the overall reaction
occurred in only 5 min to furnish product 3a (Table 1, entries 4–
5).
The smaller amounts of NaOH (Table 1, entry 3) and TBAOH
(Table 1, entry 6) gave the best yields of the desired product,
with less formation of the homocoupling by-product 4a. We
speculate that the rapid formation of the intermediate in the
reaction medium promoted the homocoupling reaction (Table 1,
entries 1–5); while the decrease in the rate of formation of Ar─C
≡C─C≡C─H, favoring cross-coupling with 4-iodoanisole 2a,
which is in a proportionately higher concentration in the reaction
medium, promoted the formation of unsymmetrical 1,3-butadiyne.
Therefore, we decided to modify the experimental procedure
adopted. Initially, for the reactions performed up to then, all the
Entry
Reaction
Catalyst
Time
Yield 3a
Yield 4a
conditions[a]
(%)[b]
(%)[b]
1
2
3
4
5
6
A
A
B
C
D
E
PdCl2(PPh3)2
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
30
30
30
5
40
53
80
51
73
95
10
10
5
10
5
5
10
0
[a] Reaction conditions – A: 1a (2.0 mmol), 2a (1.0 mmol), NaOH (4.0
equiv.), toluene (5 mL), 110 C. B: 1a (2.0 mmol), 2a (1 mmol), NaOH (3.0
equiv.), toluene (5 mL), 110 C. C: 1a (2.0 mmol), 2a (1 mmol), TBAOH 40%
in H2O (3.0 equiv.), toluene (5 mL), 90–95 C. D: 1a (1.5 mmol), 2a (1
mmol), TBAOH (2.0 mmol), toluene (5 mL), 90–95 C. E: 1a (1.5 mmol),
solubilized in toluene (15 mL) was added dropwise in a solution of 2a (1
mmol), TBAOH (2.0 mmol) in toluene (5 mL), 90–95 C. [b] Yields after
purification by chromatographic column.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801242
European Journal of Organic Chemistry
FULL PAPER
reagents were added to the reaction flask, and then TBAOH in
H2O 40% was added rapidly, and the reaction mixture was
refluxed at 90 °C (Table 1, entries 4–5). In the new procedure,
Ar─C≡C─C≡C─C(Me)2OH 1a in toluene (15 mL) was added
Different palladium catalysts (PdCl2(PPh3)2 and PdCl2(MeCN)2, a
decrease in the amount of Ar─C≡C─C≡C─C(Me)2OH 1a to
1.2 equiv., as well as reduction of the temperature to 75 °C were
also tested. However, none of these conditions increased the
dropwise (5 min) to a solution of 4-iodoanisole 2a, Pd(PPh3)4 5%, efficiency of the Sonogashira cross-coupling reaction.
CuI 10% and 40% TBAOH in H2O, in toluene (5 mL) at 90–95 °C. In view of this result (Table 1, entry 6), we decided to investigate
A further 5 min was required to finalize the Sonogashira cross-
coupling, affording 3a in 95% yield, and the homocoupling by-
product was not detected (Table 1, entry 6).
the scope of the reaction, and aryl iodides 2 with different
substituents were reacted with 2-methyl-6-aryl-hexa-3,5-diyn-2-
ol 1 to provide unsymmetrical 1,3-butadiynes 3a-x.
Table 2. Synthesis of unsymmetrical 1,3-butadiynes.[a][b]
[a] Reagents and reaction conditions: Pd(PPh3)4 5 mol%, CuI 10 mol%, aryl iodide 2 (1 mmol, 1.0 equiv.), TBAOH 40% in H2O (2 mmol, 2.0 equiv.) and toluene
(5.0 mL). Then, the reaction mixture was heated to 95 °C, and 1 (1.5 mmol, 1.5 equiv.) solubilized in toluene (15 mL) was added dropwise. Heating was
maintained for 5 min. [b] Yields isolated after column chromatography.
Due to the high interest of our research group in the synthesis of
bioactive derivatives of tetrahydrofuran neoligans such as
Veraguensin, Grandisin, and Machilin G,33 we gave priority to the
iodide, electronic effects influenced the reaction to some degree.
Electron-donor groups attached to the aryl halide provided better
yields (Table 2, compounds 3a-b, 3d-g, 3k-m, 3p-r, and 3u)
preparation of unsymmetrical 1,3-butadiynes containing methoxy, than those with an electron-acceptor substituent (Table 2,
and methylenedioxy substituent patterns (compounds 3e-r).
compounds 3c, 3h-i, 3n-o, 3s-t).
The reaction tolerated a variety of functional groups present in 2-
For instance, product 3g with the electron-donor group -OCH3
was obtained in 89% yield, while the derivative with the electron-
acceptor group -Cl 3h was obtained in 73% yield (Table 2).
Similarly, the methylenedioxy and 3,5-dimethoxy derivatives with
electron-donor groups (Table 2, compounds 3k-m and 3r
respectively) were obtained in higher yields than derivatives with
methyl-6-phenyl-hexa-3,5-diyn-2-ol.
Electron-acceptor
or
electron-donor groups attached to the aromatic ring affected the
reaction yield (compounds 3a-d). An aliphatic carbinol diyne as
starting material was also used, and product 3u was obtained in
good yield. Concerning the substituent attached to the aryl
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801242
European Journal of Organic Chemistry
FULL PAPER
electron-acceptor patterns (Table 2, compounds 3n-o and 3s-t
respectively).
Thus, we decided to extend the reaction time to 24 h. However,
2,5-diarylthiophene was obtained in 58% yield (Table 3, entry 3).
Then, we increased the amount of NaSH.×H2O to 10.0 equiv.,
and the yield of product was 70% (Table 3, entry 4). After
determining the optimal conditions for in situ thiocyclization, we
expanded the scope of this one-pot protocol (Table 4). Our
procedure proved to be general, furnishing different
unsymmetrical 2,5-diarylthiophenes 5a-f in moderate to good
yields.
1,3-butadiynes functionalized with only methylenedioxy
substituents were obtained in very good yields, which is highly
important in organic synthesis since these compounds have not
been described previously (Table 2, compounds 3k-m).
On the other hand, the strength of the electron-acceptor group
also affected the reaction yield. Methylenedioxy 1,3-butadyine
3o synthesized using 1-iodo-4-nitrobenzene was obtained in
57% yield, while the derivative with the chlorine substituent 3n (a
weaker electron acceptor than the nitro group) was obtained in
72% yield.
Table 4. Synthesis of unsymmetrical 2,5-diaryl-thiophenes.
The scope of this reaction was extended to 1,3-butadiynes
substituted with thiophene ring, and compounds 3v-x were
obtained in good yields (Table 2).
Encouraged by the success of this protocol, we explored the
applicability of 1,3-butadiynes to the synthesis of more complex
substances. Based on the literature reports,4d,9,19a,34 we
reasoned that in situ thiocyclisation of unsymmetrical 1,3-
butadiynes would provide a straightforward approach to prepare
unsymmetrical 2,5-diarylthiophenes. For this purpose, we
performed a series of experiments to optimize the thiocyclization
reaction after the formation of 1,3-butadiynes, using only sodium
hydrosulfide in different amounts under different temperatures
and times (Table 3).
Table 3. Optimization of in situ thiocyclization of 1,3-
[a] Step 1: Pd(PPh3)4 5 mol%, CuI 10 mol%, 2 (1 mmol, 1.0 equiv.), TBAOH
40% in H2O and toluene (5.0 mL). Then 1 (1.5 mmol, 1.5 equiv.) solubilized in
toluene (15 mL) was added dropwise and the mixture heated to reflux for 10
min. Step 2: Reaction mixture was cooled to 60 °C, and then NaSH.xH2O (10
mmol, 10 equiv.), 80 °C, 12 h. [b] Yields isolated after column chromatography
and recrystallization with hexane.
butadiynes.[a]
Entry
Amount of
NaSH.×H2O
(equiv.)
Temperature
(°C)
Time
(h)
Yield
(%)[b]
Based on literature reports,35 the overall mechanism proposed is
depicted in Scheme 2. Ar─C≡C─C≡C─C(Me)2OH 1 is
deprotected by a base in a retro-Favorskii reaction to furnish
terminal 1,3-butadiyne 6, which reacts with copper iodide to form
copper acetylide 7.
In the “palladium cycle“, aryl iodide 2 is added to palladium
catalyst in an oxidative addition, and the intermediate 8 is
transformed to 9 after transmetallation with copper acetylide.
The cis/trans isomerization followed by reductive elimination
generates the unsymmetrical 1,3-butadiyne 3, which reacts with
sodium hydrosulfide in the thiocyclization reaction to deliver the
unsymmetrical 2,5-diaryl thiophene 5.
1
2
3
4
5
5
95
80
80
80
12
12
24
12
30
55
58
70
5
10
[a] Reagents and reaction condition: step 1: Pd(PPh3)4 5 mol%, CuI 10 mol%,
2a (1 mmol, 1.0 equiv.), TBAOH 40% in H2O and toluene (5.0 mL). Then 1e
(1.5 mmol, 1.5 equiv.) solubilized in toluene (15 mL) was added dropwise and
the mixture heated to reflux for 10 min. Step 2: Reaction mixture was cooled to
60 °C, and then NaSH.×H2O was added in portions. [b] Yields isolated after
chromatography column and recrystallization with hexane.
Initially, the use of 5.0 equiv. of NaSH.×H2O at 95 °C for 12 h
furnished the product in only 30% yield, and the degradation of
1,3-butadiyne was observed (Table 3, entry 1). When the
temperature was decreased to 80 °C, the product was isolated
in 55% yield (Table 3, entry 2).
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801242
European Journal of Organic Chemistry
FULL PAPER
(CDCl3 1H δ 7.27, 13C δ 77.0) as the internal standard. HR-ESI-MS
measurements were carried out on a quadrupole time-of-flight instrument
(UltrOTOF-Q, BrukerDaltonics, Billerica, MA). Details of the synthesis of
diacetylenic alcohol 1 and NMR data are shown in the Supporting
Information.
One-pot protocol for the preparation of unsymmetrical 1,3-
butadiynes 3a-x
A solution of Pd(OAc)2 (0.05 mmol), PPh3 (0.25 mol) and toluene (5 mL)
was stirred for 15 min at room temperature. Aryl iodide 2 (1.0 mmol, 1.0
equiv.), CuI (0.1 mmol) and TBAOH 40% aqueous solution (2.0 mmol,
2.0 equiv.) were added and the resulting mixture was heated to 95 °C.
Then, a solution of diacetylenic alcohol 1 (1.5 mmol, 1.5 equiv.) in
toluene (15 mL) was added dropwise for 10 min. After the addition of
diacetylenic alcohol solution was completed, the reaction mixture was
kept heated for 5 min. The crude mixture was extracted with ethyl acetate
(3 x 60 mL), and the organic phase washed with saturated aqueous
solution NH4Cl (3 × 60 mL), dried over anhydrous MgSO4 and filtered.
The solvent was removed under reduced pressure, and the residue was
purified by flash column chromatography to afford the unsymmetrical 1,3-
butadiynes 3a-x.
1-methoxy-4-(phenylbuta-1,3-diynyl)benzene (3a)36: The product was
obtained as yellow solid in 95% yield. Mp: 92 ºC. 1H NMR (300 MHz,
CDCl3) δ 3.83 (s, 3H), 6.86 (d, J 8.4 Hz, 2H), 7.33-7.35 (m, 3H), 7.47 (d,
J 8.4 Hz, 2H), 7.50-7.54 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 55.3, 72.7,
74.2, 81.0, 81.8, 113.7, 114.2, 122.0, 128.4, 129.0, 132.4, 134.1, 160.4.
HRMS (ESI+) m/z calcd. for C17H12O [M + H] 233.0966; found 233.0970.
Scheme 2. Proposed mechanism for the one-pot synthesis of unsymmetrical
1,3-butadiynes and 2,5-diarylthiophenes.
Conclusions
1,2-dimethoxy-4-(phenylbuta-1,3-diynyl)benzene (3b)36: The product
was obtained as brown solid in 96% yield. 1H NMR (300 MHz, CDCl3): δ
3.88 (s, 3H), 3.90 (s, 3H), 6.82 (d, J 6Hz, 1H), 7.02 (d, J 3 Hz, 1H), 7.16
(dd, J 3 Hz and J 6Hz, 1H), 7.33-7.35 (m, 3H), 7.52 (dd, J 6Hz and J 3
Hz, 2H). 13C NMR (75 MHz, CDCl3): δ 55.9, 72.6, 74.0, 81.1, 81.9, 111.0,
113.8, 115.0, 122.0, 126.2, 128.4, 129.0, 132.4, 148.7, 150.4. HRMS
(ESI+) m/z calcd. for C18H14O2 [M + H] 263.1072; found 263.1072.
In conclusion, we have developed a synthetic protocol to
synthesize
unsymmetrical
1,3-butadiynes
through
the
deprotection of 2-methyl-6-phenyl-hexa-3,5-diyn-2-ol, followed
by a Sonogashira cross-coupling reaction with Ar-I derivatives,
using TBAOH as a base. The protocol developed in this study
has the following advantages: (i) operational simplicity, since it is
a one-pot reaction that generates terminal 1,3-butadiyne in situ
and employs stable and easily manipulable starting materials; (ii)
good substrate scope; (iii) very fast reaction; (iv) products
obtained in good yields; and (v) easy purification of the desired
products because there is no formation of the homocoupling by-
product. Additionally, this method proved to be very useful for
the straightforward synthesis of unsymmetrical 2,5-
diarylthiophenes.
1-(phenylbuta-1,3-diynyl)-3-(trifluoromethyl)benzene
(3c)37
:
The
product was obtained as white solid in 73% yield. 1H NMR (300 MHz,
CDCl3): δ 7.33-7.38 (m, 3H), 7.45 (t, J 7.8 Hz, 1H), 7.51-7.54 (m, 2H),
7.59 (d, J 7.8 Hz, 1H), 7.67 (d, J 7.8 Hz, 1H), 7.76 (s, 1H). 13C NMR (75
MHz, CDCl3): δ 73.4, 75.4, 79.6, 82.5, 121.4, 122.9, 123.5 (q, JF 270.7
Hz), 125.6 (q, JF 3.1 Hz), 128.4, 129.0, 129.2 (q, JF 3.8 Hz), 129.5, 131.1
(q, JF 32.5 Hz), 132.6, 135.4.
1-chloro-4-(4-methoxyphenyl)buta-1,3-diynyl)benzene (3d)36
:
The
product was obtained as pale yellow crystal in 83% yield. Mp: 155-157
oC. 1H NMR (300 MHz, CDCl3): δ 3.81 (s, 3H), 6.84 (d, J 9Hz, 2H), 7.28
(d, J 8.7 Hz, 2H), 7.40-7.47 (m, 4H). 13C NMR (75 MHz, CDCl3): δ 55.3,
72.6, 75.2, 79.8, 82.4, 113.5, 114.2, 120.5, 128.8, 133.6, 134.1, 135.1,
160.5. HRMS (ESI+) m/z calcd. for C17H11ClO [M + H] 267.0577; found
267.0561.
Experimental Section
General
Reactions were carried out under a nitrogen atmosphere and monitored
by TLC using prepared plates (silica gel 60 F254 on aluminum). The
chromatograms were examined under both 254 and 360 nm UV light or
with the developing agent ethanolic vanillin and heat. Flash column
chromatography was performed on silica gel 60 (particle size 200–400
mesh ASTM, purchased from Aldrich, USA). Melting points were
determined using Fisatom 430D equipment. The 1H and 13C NMR
spectra were recorded in CDCl3 solutions using a Brucker 75 MHz or 300
MHz spectrometer, as noted. Chemical shifts (δ) are expressed as parts
per million (ppm) downfield from tetramethylsilane or deuterated solvent
1,2-dimethoxy-4-(4-methoxyphenyl)buta-1,3-diynyl)benzene
(3e):
The product was obtained as yellow crystal in 97% yield. Mp: 106 oC. H
NMR (300 MHz, CDCl3): δ 3.79 (s, 3H), 3.85 (s, 3H), 3.86 (s, 3H), 6.78
(d, J 8.3 Hz, 1H), 6.82 (d, J 8.7 Hz, 2H), 6.98 (d, J 1.6 Hz, 1H), 7.11 (dd,
J 1.6 Hz and 8.3 Hz, 1H), 7.43 (d, J 8.7 Hz, 2H). 13C NMR (75 MHz,
CDCl3): δ 55.3, 55.9, 72.9, 81.3, 81.4, 111.0, 113.8, 113.9, 114.1, 114.8,
126.1, 134.0, 148.6, 150.2, 160.3. HRMS (ESI+) m/z calcd. for C19H16O3
[M + H] 293.1178; found 293.1184.
1
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801242
European Journal of Organic Chemistry
FULL PAPER
1-methoxy-4-(p-tolylbuta-1,3-diynyl)benzene (3f)36: The product was
obtained as pale yellow solid in 71% yield. Mp: 133 oC. 1H NMR (300
MHz, CDCl3): δ 2.34 (s, 3H), 3.81 (s, 3H), 6.85 (d, J 8.2 Hz, 2H), 7.11 (d,
J 7.6 Hz, 2H), 7.39 (d, J 8.2 Hz, 2H), 7.44 (d, J 7.6 Hz, 2H). 13C NMR (75
MHz, CDCl3): δ 21.6, 55.3, 72.8, 73.5, 81.0, 81.8, 113.8, 114.1, 118.8,
3H), 6.93 (d, J 3Hz, 1H), 7.05 (dd, J 9 Hz and J 3 Hz, 1H). 13C NMR (75
MHz, CDCl3): δ 56.1, 61.0, 72.6, 73.2, 81.2, 101.5, 108.6, 109.7, 112.1,
114.6, 116.7, 127.7, 147.5, 149.5, 153.1. HRMS (ESI+) m/z calcd. for
C20H16O5 [M + H] 337.1076; found 337.1064.
129.2, 132.3, 134.1, 139.4, 160.3. HRMS (ESI+) m/z calcd. for C18H14
[M + H] 247.1123; found 247.1135.
O
5-(4-chlorophenyl)buta-1,3-diynyl)benzo[d][1,3]dioxole (3n): The
product was obtained as a yellow solid in 72% yield. Mp: 184-186 oC. 1H
NMR (300 MHz, CDCl3): δ 5.98 (s, 2H), 6.75 (d, J 9 Hz, 1H), 6.93 (d, J 3
Hz, 1H), 7.06 (dd, J 9 Hz and J 3 Hz, 1H), 7.28 (d, J 9 Hz, 2H), 7.42 (d, J
9Hz, 2H). 13C NMR (75 MHz, CDCl3): δ 72.3, 75.0, 79.9, 82.2, 101.5,
108.7, 112.1, 114.7, 120.4, 127.8, 128.8, 133.6, 135.2, 147.5, 148.9.
HRMS (ESI+) m/z calcd. for C17H9ClO2 [M + H] 281.0369; found
281.0386.
1,2-dimethoxy-4-(4-methoxyphenyl)buta-1,3-diynyl)benzene
(3g):
The product was obtained as a yellow crystal in 89% yield. Mp: 106 oC.
1H NMR (300 MHz, CDCl3): δ 3.80 (s, 3H), 3.86 (s, 3H), 3.88 (s, 3H),
6.79 (d, J 8.4 Hz, 1 H), 6.83 (d, J 8.7 Hz, 2H), 6.99 (d, J 1.5 Hz, 1H), 7.12
(dd, J 1.5 Hz and 8.4 Hz, 1H), 7.44 (d, J 8.7 Hz, 2H). 13C NMR (75 MHz,
CDCl3): δ 55.3, 55.8, 72.9, 81.4, 81.41, 111.0, 113.7, 113.9, 114.1,
114.7, 126.1, 134.0, 148.6, 150.2, 160.3. HRMS (ESI+) m/z calcd. for
C19H16O3 [M + H] 293.1178; found 293.1159.
5-(4-nitrophenyl)buta-1,3-diynyl)benzo[d][1,3]dioxole
(3o):
The
product was obtained as red solid in 57% yield. Mp: 147-148 oC. 1H NMR
(300 MHz, CDCl3): δ 5.98 (s, 2H), 6.58 (d, J 9 Hz, 2H), 6.74 (d, J 9H,
1H), 6.91 (d, J 3 Hz, 1H), 7.03 (dd, J 3 Hz and 9 Hz, 1 H), 7.30 (d, J 9
Hz, 2H). 13C NMR (75 MHz, CDCl3): δ 72.1, 73.0, 80.8, 82.4, 101.4,
108.6, 110.8, 112.0, 114.6, 115.4, 127.5, 134.2, 147.4, 147.5, 148.5.
HRMS (ESI+) m/z calcd. for C17H9NO4 [M + H] – NO = 262.0630; found
262.0889.
4-(4-chlorophenyl)buta-1,3-diynyl)-1,2-dimethoxybenzene (3h): The
o
product was obtained as pale yellow solid in 73% yield. Mp: 132-134 C.
1H NMR (300 MHz, CDCl3): δ 3.85 (s, 3H), 3.87 (s, 3H), 6.79 (d, J 8.4 Hz,
1H), 6.98 (s, 1H), 7.13 (d, J 8.4 Hz, 1H), 7.28 (d, J 8.1 Hz, 2H), 7.41 (d, J
8.1 Hz, 2H). 13C NMR (75 MHz, CDCl3): δ 55.9, 72.4, 75.1, 79.9, 82.5,
111.1, 113.5, 114.8, 120.5, 126.3, 128.8, 133.6, 135.2, 148.7, 150.5.
HRMS (ESI+) m/z calcd. for C18H13ClO2 [M + H] 297.0682; found
297.0699.
1,2,3-trimethoxy-5-(4-methoxyphenyl)buta-1,3-diynyl)benzene (3p):
The product was obtained as pale yellow crystal in 88% yield. Mp: 122-
123 oC. 1H NMR (300 MHz, CDCl3): δ 3.79 (s, 3H), 3.82 (s, 3H), 3.84 (s,
6H), 6.73 (s, 2H), 6.83 (d, J 8.4 Hz, 2H), 7.43 (d, J 8.4 Hz, 2H). 13C NMR
(75 MHz, CDCl3): δ 55.3, 56.1, 61.0, 72.7, 73.4, 81.1, 81.8, 109.6, 113.7,
114.2, 116.8, 134.1, 139.7, 153.1, 160.4. HRMS (ESI+) m/z calcd. for
C20H18O4 [M + H] 323.1283; found 323.1289.
1,2-dimethoxy-4-(4-nitrophenyl)buta-1,3-diynyl)benzene (3i): The
product was obtained as a tan solid in 60% yield. Mp: 137-139 oC. 1H
NMR (300 MHz, CDCl3): δ 3.87 (s, 3H), 3.89 (s, 3H), 6.60 (d, J 9Hz, 2H),
6.80 (d, J 9 Hz, 1H), 7.00 (d, J 3Hz, 1H), 7.14 (dd, J 3Hz and J 9Hz, 1H),
7.32 (d, J 9 Hz, 2H). 13C NMR (75 MHz, CDCl3): δ 55.3, 81.0, 81.8,
113.7, 114.2, 122.0, 128.4, 129.0, 132.4, 134.1, 160.3. HRMS (ESI+) m/z
calcd. for C18H13NO4 [M + H] – NO = 278.0943; found 278.1164.
5-(3,4-dimethoxyphenyl)buta-1,3-diynyl)-1,2,3-trimethoxybenzene
(3q): The product was obtained as pale yellow crystal in 88% yield. Mp:
114-116 oC. 1H NMR (300 MHz, CDCl3): δ 3.84 (s, 6H), 3.86 (s, 3H), 3.88
(s, 3H), 6.74 (s, 2H), 6.86 (d, J 9Hz, 1H), 6.99 (s, 1H), 7.13 (d, J 9Hz,
1H). 13C NMR (75 MHz, CDCl3): δ 55.9, 56.2, 61.0, 72.6, 73.3, 81.3,
81.9, 109.7, 111.1, 113.9, 114.9, 116.8, 126.2, 139.8, 148.7, 150.0,
153.1. HRMS (ESI+) m/z calcd. for C21H20O5 [M + H] 353.1389; found
353.1379.
5-(phenylbuta-1,3-diynyl)benzo[d][1,3]dioxole (3j): The product was
obtained as pale yellow solid in 77% yield. Mp: 105-106 oC. 1H NMR (300
MHz, CDCl3): δ 5.98 (s, 2H), 6,76 (d, J 9Hz, 1H), 6.94 (d, J 3Hz, 1H),
7.06 (dd, J 9 Hz and J 3 Hz, 1H), 7.31-7.33 (m, 3H), 7.48-7.50 (m, 2H).
13C NMR (75 MHz, CDCl3): δ 72.5, 74.1, 81.2, 81.7, 101.5, 108.7, 112.1,
114.9, 121.9, 127.9, 128.4, 129.1, 132.5, 147.5, 148.8. HRMS (ESI+) m/z
calcd. for C17H10O2 [M + H] 247.0759; found 247.0777.
4-(3,5-dimethoxyphenyl)buta-1,3-diynyl)-1,2-dimethoxybenzene (3r):
The product was obtained as pale yellow crystal in 91% yield. Mp: 101
oC. 1H NMR (300 MHz, CDCl3): δ 3.75 (s, 6H), 3.84 (s, 3H), 3.86 (s, 3H),
6.45 (s, 1H), 6.64 (s, 2H), 6.78 (d, J 8.2 Hz, 1H), 6.98 (s, 1H), 7.12 (d, J
8.2 Hz, 1H). 13C NMR (75 MHz, CDCl3): δ 55.4, 55.9, 72.6, 73.6, 81.2,
82.0, 102.7, 110.1, 111.0, 113.7, 114.8, 123.1, 126.3, 148.7, 150.5,
160.5. HRMS (ESI+) m/z calcd. for C20H18O4 [M + H] 323.1283; found
323.1285.
5-(4-methoxyphenyl)buta-1,3-diynyl)benzo[d][1,3]dioxole (3k): The
o
product was obtained as pale yellow solid in 83% yield. Mp: 129-130 C.
1H NMR (300 MHz, CDCl3): δ 3.76 (s, 3H), 6.74 (d, J 9 Hz, 1H), 6.84 (d, J
9 Hz, 2H), 6.92 (s, 1H), 7.04 (d, J 9Hz, 1H), 7.44 (d, J 9 Hz, 2H). 13C
NMR (75 MHz, CDCl3): δ 55.3, 72.7, 72.8, 81.1, 81.4, 101.5, 108.6,
112.1, 113,7, 114.1, 115.1, 127.6, 134.1, 147.4, 148.7, 160.3. HRMS
(ESI+) m/z calcd. for C18H12O3 [M + H] 277.0865; found 277.0856.
1-(4-fluorophenyl)buta-1,3-diynyl)-3,5-dimethoxybenzene (3s): The
product was obtained as yellow solid in 71% yield. Mp: 150 oC. 1H NMR
(300 MHz, CDCl3): δ 6.47-6.48 (m, 1H), 6.65-6.66 (m, 2H), 6.99-7.04 (m,
2H), 7.47-7.51 (m, 2H). 13C NMR (75 MHz, CDCl3): δ 55.4, 73.3, 73.6,
80.4, 81.5, 102.9, 110.1, 115.9 (d, JF 22.1 Hz), 117.8 (d, JF 3.6 Hz),
122.9, 134.5 (d, JF 8.5 Hz), 160.5, 163.0 (d, JF 250 Hz). HRMS (ESI+)
m/z calcd. for C18H13FO2 [M + H] 281.0978; found 281.0970.
5-(3,4-dimethoxyphenyl)buta-1,3-diynyl)benzo[d][1,3]dioxole
(3l):
The product was obtained as yellow solid in 85% yield. Mp: 149-151 oC.
1H NMR (300 MHz, CDCl3): δ 3.86 (s, 3H), 3.88 (s, 3H), 5.97 (s, 2H),
6.74 (d, J 9 Hz, 1H), 6.80 (d, J 9 Hz, 1H), 6.92 (d, J 3Hz, 1H), 6.99 (d, J
1.5Hz, 1H), 7.04 (dd, J 9 Hz and J 3.0 Hz), 7.12 (dd, J 1.5Hz and J 9 Hz,
1H). 13C NMR (75 MHz, CDCl3): δ 55.9, 72.6, 72.7, 81.2, 81.5, 101.5,
108.6, 111.0, 112.1; 113.8, 115.0, 126.2, 127.6, 148.6, 147.4, 148.7,
150.2. HRMS (ESI+) m/z calcd. for C19H14O4 [M + H] 307.0970; found
307.0965.
1,3-dimethoxy-5-(3-(trifluoromethyl)phenyl)buta-1,3-diynyl)benzene
(3t): The product was obtained as yellow solid in 71% yield. Mp: 36 oC.
1H NMR (300 MHz, CDCl3): δ 3.76 (s, 6H), 6.49 (s, 1H), 6.66 (s, 2H), (m,
2H), 7,44 (t, J 7.8 Hz, 1H), 7.59 (d, J 7.7 Hz, 1H), 7.65 (d, J 7.7 Hz, 1H),
7,75 (s, 1H). 13C NMR (75 MHz, CDCl3): 55.2, 72.9, 75.4, 79.6, 82.5,
103.1, 110.2, 122.6, 122.8, 123.4 (q, JF 270.9 Hz), 125.8 (q, JF 3.9 Hz),
5-(3,4,5-trimethoxyphenyl)buta-1,3-diynyl)benzo[d][1,3]dioxole (3m):
The product was obtained as dark yellow solid in 98% yield. Mp: 175-177
oC. 1H NMR (300 MHz, CDCl3): δ 3.85 (s, 9H), 5.98 (s, 2H), 6.74-6.77 (m,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801242
European Journal of Organic Chemistry
FULL PAPER
129.0, 129.2 (q, JF 3.8 Hz), 131.1 (q, JF 32.6 Hz), 135.5, 160.6. HRMS
(ESI+) m/z calcd. for C19H13F3O2 [M + H] 331.0946; found 331.0941.
108.7, 119.5, 123.3, 123.9, 125.5, 127.4, 128.7, 128.9, 134.3, 142.8,
143.5, 147.2, 148.2. HRMS (ESI+) m/z calcd. for C17H12O2S [M + H]
281.0636; found 281.0638.
1,2-dimethoxy-4-(octa-1,3-diynyl)benzene (3u): The product was
obtained as yellow solid in 93% yield. Mp: 47-49 oC. 1H NMR (300 MHz,
CDCl3): δ 0.84 (t, J 7.1 Hz, 3H), 1.29-1.46 (m, 4H), 2.24 (t, J 6.7 Hz, 2H),
3.73 (s, 3H), 3.74 (s, 3H), 6.65 (d, J 8.3 Hz, 1H), 6.83 (s, 1H), 6.95 (d, J
8.3 Hz, 1H). 13C NMR (75 MHz, CDCl3): δ 13.5, 19.2, 21.9, 30.3, 55.7,
65.2, 73.1, 74.8, 84.2, 110.9, 113.9, 114.7, 125.9, 148.5, 149.9. HRMS
(ESI+) m/z calcd. for C16H18O2 [M + H] 243.1385; found 243.1385.
5-(5-(4-methoxyphenyl)thiophen-2-yl)benzo[d][1,3]dioxole (5d): The
product was obtained as white solid in 70% yield. Mp: 169-170 oC. 1H
NMR (300 MHz, CDCl3): δ 3.82 (s, 3H), 5.97 (s, 2H), 6.81 (d, J 8.6 Hz,
2H), 6.90 (d, J 8.8 Hz, 2H), 7.12-7.07 (m, 4H), 7.52 (d, J 8.8 Hz, 2H). 13
C
NMR (75 MHz, CDCl3): 55.4, 101.2, 106.2, 108.6, 114.3, 119.3, 122.8,
123.3, 126.8, 127.2, 128.8, 142.5, 142.8, 147,1, 148.1, 159.2. HRMS
(ESI+) m/z calcd. for C18H14O3S [M+] 310.0664; found 310.0659.
2-(3,4-dimethoxyphenyl)buta-1,3-diynyl)thiophene (3v): The product
was obtained as yellow viscous liquid in 75% yield. 1H NMR (300 MHz,
CDCl3): δ 3.86 (s, 3H), 3.88 (s, 3H), 6.79 (d, J 8.4 Hz, 1H), 6.95-6.98 (m,
2H), 7.13 (dd, J 8.4 Hz and J 1.8 Hz, 1H), 7.27-7.31 (m, 2H). 13C NMR
(75 MHz, CDCl3): δ 55.9, 72.5, 74.2, 78.1, 84.0, 111.0, 113.6, 122.2,
126.2, 127.2, 128.5, 134.1, 148.6, 150.5. HRMS (ESI+) m/z calcd. for
C16H12O2S [M + H] 269.0636; found 269.0647.
2-(3,4-dimethoxyphenyl)-5-(4-methoxyphenyl)thiophene (5e): The
product was obtained as white solid in 67% yield. Mp: 151-153 oC. 1H
NMR (300 MHz, CDCl3): δ 3.81 (s, 3H), 3.89 (s, 3H), 3.93 (s, 3H), 6.84-
6.91 (m, 3 H), 7.10-7.17 (m, 4 H), 7.53 (d, J 8.7 Hz, 2H). 13C NMR (75
MHz, CDCl3): δ 55.3, 55.94, 55.98, 109.0, 111.5, 114.3, 118.2, 122.9,
123.1, 126.8, 127.2, 127.6, 142.6, 142.7, 148.7, 149.1, 159.1. HRMS
(ESI+) m/z calcd. for C19H18O3S [M + H] 327.1055; found 327.1054.
5-(thiophen-2-ylbuta-1,3-diynyl)benzo[d][1,3]dioxole
(3x):
The
product was obtained as yellow solid in 70% yield. Mp: 94-96 oC. 1H
NMR (300 MHz, CDCl3): δ 5.98 (s, 2H), 6.76 (d, J 9Hz, 1H), 6.92 (d, J
3Hz, 1H), 6.97 (t, J 6Hz, 1H), 7.05 (dd, J 9 Hz and J 3 Hz, 1H), 7.28-7.31
(m, 2H). 13C NMR (75 MHz, CDCl3): δ 72.3, 74.2, 78.2, 83.7, 101.5,
108.7, 112.1, 114.8, 112.2, 127.1, 127.7, 128.5, 134.1, 147.5, 148.9.
2-(4-chlorophenyl)-5-(3,4-dimethoxyphenyl)thiophene
(5f):
The
product was obtained as pale yellow solid in 60% yield. Mp: 153-155 oC.
1H NMR (300 MHz, CDCl3): δ 3.89 (s, 3H), 3.93 (s, 3H), 6.86 (d, J 9 Hz,
1H), 7.09-7.20 (m, 4 H), 7.31 (d, J 9 Hz, 2H), 7.51 (d, J 9 Hz, 2 H). 13C
NMR (75 MHz, CDCl3): δ 55.96, 55.99, 109.1, 111.5, 118.3, 123.2,
124.3, 126.6, 127.2, 129.0, 132.9, 133.0, 141.3,144.1, 148.9, 149.2.
HRMS (ESI+) m/z calcd. for C18H15ClO2S [M + H] 331.0560; found
331.0603.
HRMS (ESI+) m/z calcd. for C15H8O2S [M
253.0353.
+ H] 253.0323; found
One-pot protocol for the preparation of unsymmetrical 2,5-
disubstituted thiophene 5a-f
Acknowledgments
The one-pot protocol to the synthesis of unsymmetrical 1,3-butadiynes
given above was followed in the first step. After the formation of 1,3-
butadiyne, the reaction mixture was cooled to 60 °C, and NaSH.×H2O
was added in portions. Then, the reaction mixture was heated at 80 °C
for 12 h. The crude mixture was extracted with ethyl acetate (3 x 60 mL),
and the organic phase washed with saturated aqueous solution NH4Cl (3
x 60 mL), dried over anhydrous MgSO4 and filtered. The solvent was
removed under reduced pressure, and the residue was purified by flash
column chromatography followed by recrystallization using hexane, to
afford the unsymmetrical 2,5-disubstituted thiophene 5a-f.
This study was supported by grants from FUNDECT-MS
(Process Number 59/300.151/2016), PROPP-UFMS, CNPq, and
CAPES. Special thanks to the Laboratory of Natural Products
and Mass Spectrometry (LaPNEM) of the Federal University of
Mato Grosso do Sul for the HPLC-DAD-MS/MS analysis.
Keywords: cross-coupling • unsymmetrical 1,3-butadiynes •
one-pot • cyclization • sulfur heterocycles
2-(4-methoxyphenyl)-5-phenylthiophene (5a)38
: The product was
obtained as yellow solid in 80% yield. 1H NMR (300 MHz, CDCl3): δ 3.83
(s, 3H), 6.92 (d, J 8.7Hz, 2H), 7.16 (d, J 3.6 Hz, 1H), 7.24-7.27 (m, 2H),
7.39 (t, J 7.5 Hz, 2H), 7.56 (d, J 8.7Hz, 2H), 7.61 (d, J 7.5 Hz, 2H). 13C
NMR (75 MHz, CDCl3): δ 55.4, 114.3, 122.9, 123.9, 125.5, 126.9, 127.2,
127.3, 128.9, 134.4, 142.6, 143.6, 159.3. HRMS (ESI+) m/z calcd. for
C17H14OS [M + H] 267.0844; found 267.0854.
[1]
[2]
[3]
a) A. L. K. S. Shun, R. R. Tywinski, Angew. Chem. Int. Ed. 2006, 45,
1034-1057; b) S. F. Mayer, A. Steinreiber, R. V. A. Orru, K. Faber, J.
Org. Chem. 2002, 67, 9115-9121.
a) J.-E. Lee, J. Yang, D. Kim, Faraday Discuss. 2012, 155, 277-288; b)
F. Cataldo, L. Ravagnan, E. Cinquanta, I. E. Castelli, N. Manini, G.
Onida, P. Milani, J. Phys. Chem. B 2010, 114, 14834-14841.
2-phenyl-5-(3-(trifluoromethyl)phenyl)thiophene (5b): The product
was obtained as pale yellow solid in 53% yield. Mp: 129-130 oC. 1H NMR
(300 MHz, CDCl3): δ 7.28-7.34 (m, 3H), 7.40 (t, J 6 Hz, 2H), 7.46-7.54 (m,
2 H), 7.63 (d, J 6 Hz, 2 H), 7.77 (d, J 6 Hz, 1 H), 7.85 (s, 1 H). 13C NMR
(75 MHz, CDCl3): δ 122.2 (q, JF 3.6 Hz), 123.9 (q, JF 3.7 Hz), 124.1,
125.0, 125.7, 127.9, 128.7, 129.0, 129.4, 131.1 (q, JF 32.1 Hz), 133.9,
135.1, 141.6, 144.8 HRMS (ESI+) m/z calcd. for C17H11F3S [M + H]
305.0612; found 305.0661.
a) T. Ide, S. Sakamoto, D. Takeuchi, K. Osakada, S. Machida, J. Org.
Chem. 2012 77, 4837-4841; b) T.-H. Doan, I. Talbi, J.-F. Lohier, S.
Touil, C. Alayrac, B. J. Witulski, J. Mol. Struct. 2016, 116, 127-134; c) I.
Hisaki, S. Hiroto, K. S. Kim, S. B. Noh, D. Kim, H. Shinokubo, A. Osuka,
Angew. Chem. Int. Ed. 2007 46, 5125-5128; d) J. G. Rodríguez, A.
Lafuente, L. Rubio, Tetrahedron Lett. 2004, 45, 5685-5688.
[4]
a) P. Nun, S. Dupuy, S. Gaillard, A. Poater, L. Cavallo, S. P. Nolan, Cat.
Sci. Technol. 2011, 1, 58-61; b) S. Kramer, J. L. H. Madsen, M.
Rottlander, T. Skrydstrup, Org. Lett. 2010, 12, 2758-2761; c) Q. Zheng,
5-(5-phenylthiophen-2-yl)benzo[d][1,3]dioxole (5c): The product was
obtained as white solid in 77% yield. Mp: 128-129 oC. 1H NMR (300 MHz,
CDCl3): δ 5.98 (s, 2H), 7,10-7.14 (m, 3H), 7.23-7.29 (m, 2H), 7.35-7.40
(m, 2H), 7.59-7.62 (m, 2H). 13C NMR (75 MHz, CDCl3): δ 101.3, 106.3,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801242
European Journal of Organic Chemistry
FULL PAPER
R. Hua, Tetrahedron Lett. 2010, 51, 4512-4514; d) Q. Zheng, R. Hua, J.
Jiang, L. Zhang, Tetrahedron 2014, 70, 8252-8256.
E. Kulyashova, V. N. Sorokoumov, V. V. Popik, I. A. Balova,
Tetrahedron Lett., 2013, 54, 2235-2238; c) E. Negishi, M. Hata, C. Xu,
Org. Lett., 2000, 2, 3687-3689.
[5]
[6]
a) L. Wang, X. Yu, X. Feng, M. Bao, J. Org. Chem. 2013, 78, 1693-
1698; b) M. M. Bassaco, M. P. Fortes, T. S. Kaufman, C. C. Silveira,
RSC Adv. 2015, 5, 21112-21124; c) X. Yu, N. Huang, X. Feng, Y.
Yamamoto, M. Bao, Synthesis 2014, 46, 2422-2429.
[24] a) M. J. Dabdoub, A C. M. Baroni, E. J. Lenardão, T. R. Gianeti, G. R.
Hurtado, Tetrahedron, 2001, 57, 4271-4276. b) B. Witulski, T.
Schweikert, D. Schollmeyer, N. A. Nemkovich Chem. Commun. 2010,
46, 2953-2955.
a) L. Wang, X. Yu, X. Feng, M. Bao, Org. Lett., 2012, 14, 2418-2421; b)
Naveen, S. A. Babu, G. Kaur, N. A. Aslam, M. Karanam, RSC Adv.
2014, 4, 18904-18916; c) M. M. Bassaco, M. P. Fortes, D. F. Back, T. S.
Kaufman, C. C. Silveira, RSC Adv. 2014, 4, 60785-60797.
T. Matsuda, S. Kadowaki, M. Murakami, Chem. Commun., 2007, 2627-
2629.
[25] K. West, C. Wang, A. S. Batsanov, M. R. Bryce, J. Org. Chem. 2006,
71, 8541-8544.
[26] N. A. Danilkina, A. E. Kulyashova, A. F. Khlebnikov, S. Bräse, I. A.
Balova, J. Org. Chem. 2014, 79, 9018−9045.
[7]
[27] a) C. Wang, A. S. Batsanov, K. West, M. R. Bryce, Org. Lett., 2008, 10,
3069-3072. b) C. Wang, L.-O. Palsson, A. S. Batsanov, M. R. Bryce, J.
Am. Chem. Soc., 2006, 128, 3789-3799. c) Y. Morisaki, T. Luu, R. R.
Tykwinski, Organic Lett. 2006, 4, 689-692; d) L. Brandsma, in
Synthesis of Acetylenes, Allenes, and Cumulenes, Elsevier;
Amsterdam, 2004, p 360
[8]
H. Jiang, W. Zeng, Y. Li, W. Wu, L. Huang, W. Fu, J. Org. Chem., 2012,
77, 5179-5183.
[9]
a) J. Tang, X. Zhao, RSC Adv., 2012, 2, 5488-5490; b) G. Zhang, H. Yi,
H. Chen, C. Bian, C. Liu, A. Lei, Org. Lett., 2014, 16, 6156-6159.
A. S. Santana, D. B. Carvalho, N. S. Cassemiro, L. H. Viana, G. R.
Hurtado, M. S. Amaral, N. M. Kassab, P. G. Guerrero Jr, S. L. Barbosa,
M. J. Dabdoub, A. C. M. Baroni, Tetrahedron Lett., 2014, 55, 52-55.
[10]
[28] a) H. Chow, C. Wan, K. Low, Y. Yeung, J. Org. Chem. 2001, 66, 1910-
1913; b) Z. Novák, P. Nemes, A. Kotschy, Org. Letters 2004, 6, 4917-
4920.
[11] D. Alves, C. Luchese, C. W. Nogueira, G. Zeni, J. Org. Chem. 2007, 72,
6726-6734.
[29] E. F. Lopes, B. T. Dalberto, G. Perin, D. Alves, T. Barcellos, E.
Lenardão, Chem. Eur. J. 2017, 23, 13760-13765.
[12] a) P. Siemsen, R. C. Livingston, F. Diederich, Angew. Chem. Int. Ed.
2000, 39, 2632-2657; b) K. S. Sindhu, G. Anilkumar, RSC Adv. 2014, 4,
27867-27887.
[30] C. E. D. Nazario, A. S. Santana, C. Y. Kawasoko, C. A. Carollo, G. R.
Hurtado, L. H. Viana, S. L. Barbosa, P. Guerrero Jr., F. A. Marques, V.
B. Dabdoub, M. J. Dabdoub, A. C. M. Baroni, Tetrahedron Lett. 2011,
52, 4177-4181.
[13] a) G. Eglinton, A. R. Galbraith, Chem. Ind. 1956, 737-738; b) G.
Eglinton, A. R. Galbraith, J. Chem. Soc. 1959, 889-896.
[14] a) A. S. Hay, J. Org. Chem., 1960, 25, 1275-1276; b) A. S. Hay, J. Org.
Chem. 1962, 27, 3320-3321. c) E. Merkul, D. Urselmann, T. J. J. Müller,
Eur. J. Org. Chem., 2011, 238-242.
[31] A. S. Santana, D. B. Carvalho, N. S. Casemiro, G. R. Hurtado, L. H.
Viana, N. M. Kassab, S. L. Barbosa, F. A. Marques, P. Guerrero Jr., A.
C. M. Baroni, Tetrahedron Lett. 2012, 53, 5733-5738.
[15] a) L. Bettanin, G. V. Botteselle, M. Godoi, A. L. Braga, Green Chem.
Lett. and Rev. 2014, 7, 105-112. b) W. Shi, A. Lei. Tetrahedron Lett.,
2014, 55, 2763-2772. c) L. Su, J. Dong, L. Liu, M. Sun, R. Qiu, Y. Zhou,
S.-F. Yin, J. Am. Chem. Soc., 2016, 138, 12348-12351.
[16] K. S. Sindhu, A. P. Thankachan, P. S. Sajitha, G. Anilkumar, Org.
Biomol. Chem., 2015, 13, 6891-6905.
[32] J. Li, P. Huang, Beilstein. J. Org. Chem. 2011, 7, 426-431.
[33] a) T. B. Cassamale, E. C. Costa, D. B. Carvalho, N. S. Cassemiro, C. C.
Tomazela, M. C. S. Marques, M. Ojeda, M. F. C. Matos, S.
Albuquerque, C. C. P. Arruda, A. C. M. Baroni, J. Braz. Chem. Soc.,
2016, 27, 1217-1228. b) E. C. Costa, T. B. Cassamale, D. B. Carvalho,
L. S. S. Bosquiroli, M. Ojeda, T. V. Ximenes, M. F. C. Matos, M. C. T.
Kadri, A. C. M. Baroni, C. C. P. Arruda, Molecules, 2016, 21, 802-813.
[34] a) I. Talbi, C. Alayrac, J.-F. Lohier, S. Touil, B. Witulski, Org. Lett., 2016,
18, 2656-2659. b) D. Urselmann, D. Antovic, T. J. J. Müller, Beilstein J.
Org. Chem, 2011, 7, 1499-1503.
[17] S. Wang, L. Yu, P. Li, L. Meng, L. Wang, Synthesis, 2011, 10, 1541-
1546.
[18] B. Witulski, C. Alayrac, Science of Synthesis, 2006, 24, 905.
[19] a) M. L. N. Rao, S. S. Islam, P. Dasgupta, RSC Adv. 2015, 5, 78090-
78098; b) M. L. N. Rao, P. Dasgupta, B. S. Ramakrishna, V. N. Murty,
Tetrahedron Lett., 2014, 55, 3529-3533.
[35] R. Chinchilla, C. Nájera, Chem. Soc. Rev., 2011, 40, 5084-5121.
[36] M. Yu, D. Pan, W. Jia, W. Chen, N. Jiao, Tetrahedron Lett, 2010, 51,
1287-1290.
[20] M. J. Dabdoub, V. B. Dabdoub, A. C. M. Baroni, J. Am. Chem. Soc.
2001, 123, 9694-9695.
[37] Z. Huang, R. Shang, Z.-R. Zhang, X.-D Tan, X. Xiao, T. Fu, J. Org.
Chem., 2013, 78, 4551-4557.
[21] X. Li, X. Xie, N. Sun, Y. Liu, Angew. Chem. Int. Ed. 2017, 56, 6994-
6998.
[38] S.-C. Yin, Q. Zhou, Q.-W. He, S.-W. Li, P.-C. Qian, L.-X. Shao,
Tetrahedron, 2017, 73, 427-431.
[22] V. Fiandanese, D. Bottalico, G. Marchese, A. Punzi, Tetrahedron Lett.,
2003, 44, 9087-9090.
[23] a) I. A. Balova, V. N. Sorokoumov, S. N. Morozkina, O. V. Vinogradova,
D. W. Knight, S. F. Vasilevsky, Eur. J. Org. Chem., 2006, 882-888; b) A.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801242
European Journal of Organic Chemistry
FULL PAPER
Entry for the Table of Contents (Please choose one layout)
FULL PAPER
Camila B. Andrade, Diego B. Carvalho,
Ozildéia S. Trefzger, Najla M. Kassab,
Palimécio G. Guerrero Jr., Sandro L.
Barbosa, Cristiane Y. K. Shiguemoto,
Adriano C. M. Baroni*
Page No. – Page No.
Novel one-pot, fast and efficient protocol was developed to synthesize
unsymmetrical 1,3-diynes. The procedure involved two sequential reactions: a
retro-Favorskii reaction to furnish terminal diacetylenic compound, and its coupling
with organic iodide in a Sonogashira under reflux in toluene for ten minutes. In
addition, the described protocol was also extended to the synthesis of 2,5-
diarylthiophenes through in situ thiocyclization of 1,3-butadiynes.
One-pot synthesis of unsymmetrical
1,3-butadiyne derivatives and their
application in the synthesis of
unsymmetrical 2,5-diarylthiophenes
Key topic: Synthetic methods
This article is protected by copyright. All rights reserved.