Synthesis of Terminal Ethynyl Aryl Selenides and Sulfides Based on the Retro-Favorskii Reaction of Hydroxypropargyl Precursors

Article abstract of DOI:10.1002/chem.201702493

The retro-Favorskii reaction is an excellent way to achieve terminal alkynes. Methodologies that connect the synthesis of terminal alkynes and organochalcogen motifs are important for the construction of novel compounds. Fourteen new terminal alkynes containing either C_sp?S or C_sp?Se bonds were selectively prepared through the retro-Favorskii reaction from the respective carbinol precursors. It was discovered that terminal chalcogen alkynes were stable for weeks if stored as a solution in hexanes.

Full text of DOI:10.1002/chem.201702493

A Journal of
Accepted Article
Title: Synthesis of terminal ethynyl aryl selenides and sulfides based
on the retro-Favorskii reaction of hydroxypropargyl precursors
Authors: Eric Francis Lopes, Bianca T Dalberto, Gelson Perin, Diego
Alves, Thiago Barcellos, and Eder Joao Lenardao
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To be cited as: Chem. Eur. J. 10.1002/chem.201702493
Link to VoR: http://dx.doi.org/10.1002/chem.201702493
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Synthesis of terminal ethynyl aryl selenides and sulfides based
on the retro-Favorskii reaction of hydroxypropargyl precursors
Eric F. Lopes[a], Bianca T. Dalberto[a], Gelson Perin[a], Diego Alves[a], Thiago Barcellos[b] and Eder J.
Lenardão*[a]
Abstract: The retro-Favorskii reaction is an excellent way to achieve
terminal alkynes. Methodologies that connect the synthesis of
terminal alkynes and organochalcogen motifs are important for the
construction of novel compounds. Fourteen new terminal alkynes
containing either Csp-S or Csp-Se bonds were selectively prepared via
the retro-Favorskii reaction from the respective carbinol precursors. It
was discovered that terminal chalcogen alkynes are stable for weeks
if stored as a hexanes solution.
Introduction
The base-catalyzed ethynylation of aldehydes and ketones
to prepare propargylic alcohols is known as Favorskii reaction.[1]
Besides a useful tool in organic synthesis, Favorskii reaction is a
convenient way to protect unstable and volatile terminal alkynes,
which can be easily recovered by treatment with a base.[2] It is
remarkable to notice that with such a simple classical procedure
many possibilities can be achieved, such as, the synthesis of
Scheme 1. Synthetic applications of ethynyl(phenyl) sulfides.
polyfunctional alkynes bearing the incredible application of a
nanomechanical switch,[3] or ranging from building blocks[4] to
The selenium analogues however, were much less explored,
complex natural products,[5] or even synthons in the synthesis of
both in terms of their use in organic synthesis and their biological
biological active molecules.[6]
activities.[12] This marginal position is probably due to the
Organochalcogen compounds are interesting molecules
limitations in the synthetic protocols to obtain them,[13] which
both due their participation as intermediate in many selective
include the use of air-sensitive organometallic reagents at low
reactions[7] and their large number of biological properties.[8]
temperature,[13a,d] highly flammable acetylene gas and metal
When a chalcogen atom is directly connected to the Csp of
sodium,[13a-c] besides the use of hazardous species, like
a triple bond, as in the case of organochalcogen alkynes, they can
selenocyanate[13c] (Scheme 2).
generate interesting products or act as intermediates for more
It is also described that this kind of compounds are relatively
complex molecules.[9] Terminal organochalcogen alkynes,
unstable at room temperature, changing color quickly and
notably sulfenyl alkynes, have a plethora of applications, some of
suffering disproportionation due their base-sensitivity.[14] The
them are showed in Scheme 1.[10] The high number of
reactivity order to suffer disproportionation was determined as
applications is associated with an equally high number of methods
being RSC≡CH> RSeC≡CH> RTeC≡CH.[15]
to prepare organosulfenyl alkynes.[11]
[a]
[b]
E. F. Lopes, B. T. Dalberto, Prof. G. Perin, Prof. D. Alves and Prof.
E. J. Lenardão
Centro de Ciências Químicas, Farmacêuticas e de Alimentos
Universidade Federal de Pelotas - UFPel
P. O. box 354, CEP: 96010-900, Pelotas, RS - Brazil
E-mail: lenardao@ufpel.edu.br
Prof. T. Barcellos
Laboratory of Biotechnology of Natural and Synthetic Products
Universidade de Caxias do Sul – UCS
Caxias do Sul, RS - Brazil.
Supporting information for this article is given via a link at the end of
the document.
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10.1002/chem.201702493
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carbinols 3i and 3m. In our hands, however, alkynes 3n-o could
not be obtained (Table 1, entries 14-15).
Table 1: Synthesis of chalcogen-containing carbinols 3.a
Entry Ch
Product
Yield (%)b
95 (98)c
1
2
3
4
5
6
7
Se
Se
Se
Se
Se
Se
Se
93
99
92
93
93
92
Scheme 2. Procedures to prepare ethynyl(aryl) selenides.
In our studies on the synthesis of chalcogen alkenes, it was
necessary to prepare a series of terminal alkynyl selenides with
high purity grade. At that moment, we faced with the limitations of
the current protocols: no systematic studies on the preparation,
isolation and characterization of alkynyl selenides and sulfides as
well a lack of full experimental details.
In view of all the possibilities of this class of
organochalcogen compounds, it is important that novel
methodologies exist, either to increase the studies of their
physical chemical properties and their role as synthetic
intermediates or in biological assays. It is noteworthy that until
now, to the best of our knowledge, the retro-Favorskii reaction has
never been combined with organochalcogen motifs to prepare
terminal organochalcogen alkynes in a systematic way. In a
strategy that joins classical protocols with contemporary synthetic
organic chemistry, we report herein the synthesis of arylselanyl
and arylsulfenyl alkynes using the retro-Favorskii reaction of the
respective alkynyl carbinols (Scheme 2).
8
Se
91
9
S
S
94
92
94
95
88
10
11
12
13
14
S
S
Te
S
Results and discussion
d
First of all, our studies were focused in the synthesis of the
carbinols 3, necessary for the retro-Favorskii reaction. A search
in the literature for general methods to prepare chalcogen-
containing carbinols 3 faced us with an unexpected picture: the
lack of a suitable and general method to access this class of
compounds. Despite their use as intermediate in organic
synthesis has largely been described, the number of works to
prepare them is limited, once they are normally used in situ and
no isolation or quantification are reported in most of cases. Among
the several methods to prepare alkynyl chalcogenides,[16] the
more robust probably is the copper-catalyzed coupling between
terminal alkynes and dichalcogenides, developed by Bieber and
co-workers.[17] By using this protocol, we prepared twelve alkynyl
carbinols 3a-l containing either Csp-S or Csp-Se bonds and one
alkynyl telluride 3m (Table 1). As can be seen in Table 1, excellent
yields were obtained in all examples, except when the electron-
rich disulfides 1n and 1o were used as starting materials. In the
original work from Bieber,[17] only diphenyl dichalcogenides 1a, 1i
and 1m were used. For diphenyl disulfide 1i and ditelluride 1m,
authors used as base NaHCO3 to achieve the respective
-
15
S
N.R.e
a The reactions were carried out using different scales, the stoichiometry being
always the same of the Bieber’s procedure, according ref. 17. Yields after
purification by column chromatography. Multi-gram scale: used 40 mmol of
diphenyl diselenide 1a and 80 mmol of 2-methylbut-3-yn-2-ol 2. A complex
mixture of products was obtained, among a small amount (ca. 5%) of 3n. e The
b
c
d
starting diaryl disulfide was recovered.
In
a
multi-gram
scale
synthesis,
2-methyl-4-
(phenylselanyl)but-3-yn-2-ol 3a was obtained in 98% yield after
24 h by the reaction between diphenyl diselenide 1a (40 mmol)
and 2-methylbut-3-yn-2-ol 2 (80 mmol) (Table 1, entry 1).
Following, we started our studies aiming to find the best
conditions to prepare terminal alkynyl chalcogenides 4 via the
retro-Favorskii reaction. For that, 2-methyl-4-(phenylselanyl)but-
3-yn-2-ol 3a was chosen as starting material, aiming to prepare
ethynyl(phenyl) selenide 4a (Table 2). To begin this study, the
classic procedure of the retro-Favorskii was used,[4a] with a slight
modification: a mixture of hexanes was used as the solvent
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10.1002/chem.201702493
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instead of toluene. This caution was taken due the volatility of
most of synthesized compounds, which could be carried away by
toluene during the workup and purification step.
withdrawing groups. It can be observed in Table 3 that yields of
respective terminal selanyl alkynes 4b-g ranged from 53 to 93%
(Table 3, entries 2-7).
Table 2: Optimization studies in the synthesis of 4a.a
Table 3: Synthesis of terminal chalcogen alkynes via retro-
Favorskii.a
Entry
Base (equiv)
KOH (1.0)
KOH (1.0)
KOH (1.0)
KOH (1.1)
KOH (1.2)
KOH (1.5)
KOH (2.0)
KOH (1.1)
T (ºC)
25
50
reflux
50
50
50
50
50
Yield (%)b
1
2
3
4
5
6
7
8c
30
80
54
93
90
79
53
75
Time
(h)
Entry
1
Product
Yield (%)
93
1
2
3
4
5
6
1.5
4
82
89
53
83
89
9
KF/Al2O3 30% (1.1)
50
42
10
11d
12e
NaOH(1.1)
KOH (1.1)
KOH (1.1)
50
reflux
50
50
23
60
4
a Reaction processed using 2-methylbut-3-yn-2-ol 2 (1.0 mmol) and base in
4
hexanes (3.0 mL) as the solvent for 1 h. The progress of the reaction was
followed by TLC. Yields after purification by column chromatography. c The
b
reaction time was 2 h. d Petroleum ether (3.0 mL) was the solvent. e CTAB (10
4
mol%) was used as a phase-transfer catalyst and the reaction was stirred for 45
min.
7
8
9
3
3
2
77
53
93
The first attempt was the reaction at room temperature using
1.0 equiv of KOH as the base. After 1 h, the TLC showed
incomplete consumption of starting carbinol 3a, and the desired
product 4a was isolated in only 30% yield (Table 2, entry 1).
Following, the temperature was increased to 50 °C and, for our
delight, the deprotected alkynyl selenide 4a was obtained in 80%
yield (Table 2, entry 2). However, additional increase in the
temperature to 68 °C (refluxing hexanes) has caused a decrease
in the yield of 4a to 54%, with a disproportionation reaction
pathway starting to compete (Table 2, entry 3).
Once KOH is highly hygroscopic, it cannot be weighted
precisely. Then, the amount of base was increased, ranging from
1.1 to 2.0 equiv (Table 2, entries 4-7). Very good outcomes were
obtained using 1.1 and 1.2 equiv of KOH (up to 93% yield), while
the use of a large excess (1.5 or 2.0 equiv) was not so effective
in promoting the reaction (Table 2, entries 4-5 vs. entries 6-7).
Longer reaction time was not effective either, and only 50% yield
of 4a was obtained after 2 h (Table 2, entry 8). Then, other bases,
like solid-supported KF/Al2O3 and NaOH were tested; however,
the results were not satisfactory (Table 2, entries 9-10). Petroleum
ether was also used as the solvent in the presence of KOH, but
product 4a was isolated in only 23% yield after 1 h at reflux (Table
2, entry 11). A positive effect of phase-transfer catalyst (PTC) in
the retro-Favorskii reaction of conjugated dialkynes to prepare
unsymmetrical terminal diynes was observed by one of us.[4a]
Thus, aiming to increase the reactivity of KOH in the reaction
medium, cetyltrimethylammonium bromide (CTAB) was used as
a PTC; however, the yield of 4a was only 60% after 1 h (Table 2,
entry 12).
10
4
88
86
88
11
12
13
4
4
1
b
-
a Reactions were performed using 1.1 mmol of KOH and 3 mL of hexanes at
50°C. The progress of the reactions was followed by TLC. b Diphenyl ditelluride
1m was isolated as the only final product.
There is not an apparent connection between electronic
effects and yields in the reaction, except when the strongly
electronegative fluorine is present, with 4d being obtained in 53%
yield after 4 h (Table 3, entry 4). A similar result was obtained
starting from butylselanyl carbinol 3h (R = C4H9), that afforded the
respective terminal butylselanyl alkyne 4h in 53% yield after 3 h
(Table 3, entry 8). In both cases, RSeCCSeR, the
disproportionation product, was also isolated. Since there are not
studies regarding the stability of these compounds, there is not
much to speculate regarding the role of the group attached to
selenium.
After electing entry 4 of Table 2 as the best condition for the
retro-Favorskii reaction, it was evaluated the generality of the
method, the results are showed in Table 3. We started by varying
the substituents at the aromatic ring of the selanyl alkynes, in
order to verify the influence of electron-donors and electron-
It was also evaluated the influence of other chalcogenides
in this reaction, using sulfur and tellurium instead of selenium
directly bonded to the Csp (Table 3, entries 9-13). Yields of
terminal sulfenyl alkynes ranged from 86 to 93% after 2-4 h of
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reaction (Table 3, entries 9-12). Similarly to the selenium
analogues, it is not possible to infer any influence of electronic
effects in the reactivity of carbinols 3i-l. Unfortunately, the present
protocol was not suitable to prepare the terminal tellanyl alkyne
4m from 3m, even if other Bronsted bases were used, such as
K2CO3 and NaOH, and the only isolated product was diphenyl
ditelluride and unreacted starting alcohol 3m (Table 3, entry 13).
As already mentioned before, it was not a surprise that after
a few hours, products 4 would drastically change color, turning
from a colorless/light yellow to a dark red one. It is reported that
the sulfenyl alkyne 4i can be stored for several months at
temperatures as low as -10 °C, changing its color from a light
yellow/colorless to a strong yellow liquid.6a Since it is reported that
these terminal alkynes can produce unwanted by-products and
change color quickly, regardless the temperature, we decided to
perform a study to verify if compounds 4 could be stored for longer
periods of time as a solution. For that, compound 4a was chosen
as a model and three tests were performed: A: a neat sample at
room temperature; B: a 0.3 mol L-1 solution in hexanes at -10 oC
and C: a 0.3 mol L-1 solution in hexanes at room temperature
(Figure S1, supporting information). It can be observed that after
one week, the neat product acquired a slightly yellow color which,
after one month changed to a dark brown goop, with a black solid
suspension, remaining with this aspect after three months (Figure
S1A, a-c). The 1H-NMR spectrum of sample of Fig. S1Ac
presented the expected signals for 4a, but the integral area for the
hydrogens of the phenyl group was much higher than expected.
Scheme 3. Use of 4a as a precursor of more complex molecules.
Other interesting class of compounds whit a sort of
applications is the 1,2,3-triazoles,20 which can be prepared by the
Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC)
“click” reaction.21 Selanyl alkyne 4a was successfully used in the
CuAAC reaction with 1-azido-4-methoxybenzene 7, giving the
expected 4-phenylseleno 1,2,3-triazole 8 in 60% yield after 6 h at
o
50 C (not optimized) (Scheme 3). The reactions of Scheme 3
show just a few examples of the vast possibilities which arise from
the easy access to terminal selanyl alkynes 4. The methods to
prepare compounds like 6 and 8 are limited,12a,22 in view of the
difficult in preparing the key starting material 4a and analogues
before the present work.
Conclusion
In conclusion, 12 terminal selanyl and sulfenyl alkynes were
easily synthesized in good to excellent yields by the retro-
Favorskii reaction of the respective chalcogen-containing alkynyl
carbinols. Hexanes solutions of terminal chalcogen alkynes can
be stored by up three months without decomposition, opening
new possibilities of using selanyl alkynes as interesting building
blocks. Ethynyl(phenyl) selenide 4a was readily used to form new
C-C and C-N bonds in simple addition reactions.
We
suspected
that
the
disproportionation
product,
C6H5SeCCSeC6H5, was formed and its presence was confirmed
by the HRMS analysis (see Figures S3-S5 in the SI for HRMS and
NMR spectra).
The results are quite different in comparison to the sample
stored at -10 °C as a solution in hexanes, for which no significant
change in coloration or any form of precipitate were observed,
even after three months (Figure S1B, a-c).
Experimental Section
The reactions were monitored by thin layer chromatography
(TLC) that was performed using Merck silica gel (60 F254), 0.25
mm thickness. For visualization, TLC plates were either placed
under UV light, or stained with iodine vapor, or 5% vanillin in 10%
H2SO4 and heating. Column chromatography was performed
using Merck Silica Gel (230-400 mesh). High resolution mass
spectra (HRMS) were measured on a Bruker MicrOTOF-QII
spectrometer interfaced with APCI source in positive mode. Low-
resolution mass spectra (MS) were measured on a Shimadzu GC-
MS-QP2010 mass spectrometer. NMR spectra were recorded
with Bruker DPX 400 (1H NMR = 400 MHz; 13C NMR = 100 MHz),
DPX 300 (1H NMR = 300 MHz; 13C NMR = 75 MHz) or Bruker
Avance 500 (1H NMR = 500 MHz; 13C NMR = 125 MHz)
instruments, using CDCl3 as solvent and calibrated using
tetramethylsilane (TMS) as internal standard. Coupling constants
(J) are reported in Hertz and chemical shifts (δ) in ppm. The NMR
spectra are found in the Supporting Information. The reagents (2-
methyl-3-butyn-2-ol, selenium powder, diphenyl disulfide,
tellurium powder, Knochel-Hauser base) were purchased from
Sigma-Aldrich.
For our surprise, the stability of the third sample, stored at
room temperature in hexanes, was quite high (Figure S1C). After
one month, it did not change color at all, nor produced any
precipitate, indicating that there was no formation of unwanted
decomposition products. A slight change in color to a light yellow
was observed after the storage completed 2 months, and after
three months it turned into a dark yellow solution (Figure S1C, a-
c). The samples were evaluated by NMR (1H and 13C) to check
for decomposition’s products and it was observed that the stability
of the product in hexanes is quite high, rising our hopes that this
compound can be further studied and used as an interesting
intermediate. The same test was extended to all the synthesized
compounds, and all of them showed to be stable in hexanes at
room temperature for up three months. A similar solvent-
stabilization effect was observed using chloroform and more
details can be seen in the support information (Figure S2).
As an example of the synthetic usefulness of the
synthesized terminal selanyl alkynes, ethynyl(phenyl) selenide 4a
was subjected to two simple transformations to prepare densely
functionalized selenium-containing compounds (Scheme 3). In
the first reaction, 4a was reacted with the turbo-Hauser base,
followed by the addition of 4-chloro benzaldehyde 5, to afford the
desired propargyl alcohol 6 in 78% yield. Propargyl alcohols are
important motifs in organic chemistry, both due their presence in
the structure of several natural compounds18 and their use as
synthetic intermediate for complex molecules.19
General Procedure to prepare alkynes 3a-m: The same
procedure from Bieber was used, with minor changes.17 In a 50
mL round bottomed flask was added diorganoyl dichalcogenide
(1, 2.5 mmol), 2-methyl-3-butyn-2-ol (2, 5.0 mmol, 0.42 g), CuI (10
mol%, 0.5 mmol, 0.095 g) and DMSO (20 mL). After stirring for 24
h at room temperature, the resulting solution was diluted with
EtOAc (10 mL) and quenched with a saturated solution of NH4Cl
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10.1002/chem.201702493
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(20 mL). The aqueous layer was extracted with EtOAc (3x 20 mL)
and the organic layer was washed with water (50 mL) to remove
the DMSO. The organic phase was then dried with MgSO4 and
filtered off. The solvent was evaporated under reduced pressure
and the residue was purified by column chromatography on silica
gel, using a mixture of hexanes and EtOAc as the eluent. For the
sulfur analogues 3i-l, K2CO3 (10.0 mmol, 0.991 g) was used as a
base, while NaHCO3 (20 mmol, 5.04 g) was used to prepare the
alkynyl telluride 3m.
Keywords: Deprotection • Retro-Favorskii • Selenium • Sulfur •
Terminal alkynes
[1]
[2]
A. Favorskii, J. Russ. Phys. Chem. Soc. 1905, 37, 643.
(a) T. W. Greene, P. G. M. Wuts, in Protective Groups in Organic
Synthesis, 3rd ed., John Wiley & Sons, New York, 1999, pp. 654-659. (b)
Z. Wang, Comprehensive Organic Name Reactions and Reagents, John
Wiley & Sons, New York, 2010, pp 1032-1035.
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S. Gaikwad, M. Schmittel, J. Org. Chem. 2017, 82, 343.
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General Procedure to prepare terminal chalcogen alkynes
4a-l: In a 10 mL Schlenk tube were added the chalcogen carbinol
3 (1.0 mmol) followed by KOH (1.1 mmol, 0.062 g) and hexanes
(3.0 mL). The system was then immersed in a pre-heated oil bath
at 50 °C and stirred at this temperature for the time indicated in
Table 3. The reaction mixture was poured into a chromatography
column containing 6.5 g of silica gel, and a simple filtration using
hexanes as eluent was done. Then, the solvent was evaporated
and the product was obtained as a colorless liquid. After that, dry
hexanes (3.0 mL) was added for storage.
Synthesis of 1-(4-chlorophenyl)-3-(phenylselanyl)prop-2-yn-
1-ol 6: In a 25 mL two-necked round bottomed flask equipped with
a reflux condenser was added a solution of ethynyl(phenyl)
selenide 4a (2.34 mmol, 0.423 g) in hexanes (6.0 mL), followed
by the addition of THF (5.0 mL). The system was then cooled to
around -10 °C and the Knochel-Hauser base (2.4 mmol, 2.4 mL;
1M solution in THF/toluene) was added dropwise. After the
complete addition, the reaction mixture turned dark yellow. The
cooling bath was removed and the reaction was left to react for
20 min at room temperature. Then, 4-chlorobenzaldehyde 5 (2.4
mmol, 0.337 g) in THF (5.0 mL) was added in one portion. The
reaction was left to react for 1 h (followed by TLC) and after that,
a saturated solution of NH4Cl (20 mL) was added. The product
was extracted with EtOAc (3x 20 mL), the organic phase was
dried over MgSO4 and the solvent was removed under reduced
pressure. The final residue was then purified by column
chromatography with silica flash, using hexanes/EtOAc (9:1) as
the eluent. The product 6 was obtained as a yellow oil in 78% yield
(0.587 g).
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1,2,3-triazole 8: In
a 10 mL Schlenk tube was added
ethynyl(phenyl) selenide 4a (0.3 mmol, 0.054 g) followed by 1-
azido-4-methoxybenzene 7 (0.36 mmol, 0.054 g), sodium
ascorbate (10 mol%, 0.03 mmol, 0.006 g), THF (1.0 mL),
Cu(OAc)2‧ H2O (5 mol%, 0.015 mmol, 0.003 g) and water (1.0
mL). The reaction mixture was stirred at 50 °C for 6 h. Then, a
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addition of EtOAc (10 mL). The product was extracted with EtOAc
(3x 10 mL), dried over MgSO4 and the solvent evaporated under
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eluent. The product 8 was isolated as a light orange solid (m.p. =
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CNPq, CAPES and FAPERGS are acknowledged for financial
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selenium and sulfur, alkynes
Eric F. Lopes, Bianca T. Dalberto,
Gelson Perin, Diego Alves, Thiago
Barcellos and Eder J. Lenardão*
Page No. – Page No.
Retro-Favorskii Reaction revisited: selanyl and sulfenyl terminal alkynes made
easy.
Synthesis of terminal ethynyl aryl
selenides and sulfides based on the
retro-Favorskii reaction of
hydroxypropargyl precursors
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