Phase-Vanishing Method with Acetylene Evolution and Its Utilization in Several Organic Syntheses

Article abstract of DOI:10.1021/acs.orglett.5b00827

A novel quadraphasic phase-vanishing system in which acetylene is evolved from calcium carbide and directly applied in situ to the Sonogashira coupling reaction was developed. This method, which provides a safe, convenient, and one-pot means to utilize gaseous reagents without special equipment, was also applied to a Cu-catalyzed azide-alkyne cycloaddition (CuAAC) reaction and a three-component aldehyde-alkyne-amine (A³) coupling reaction with excellent results. (Figure Presented).

Full text of DOI:10.1021/acs.orglett.5b00827

Letter
pubs.acs.org/OrgLett
Phase-Vanishing Method with Acetylene Evolution and Its Utilization
in Several Organic Syntheses
Ryosuke Matake, Yuki Niwa, and Hiroshi Matsubara*
Department of Chemistry, Graduate School of Science, Osaka Prefecture University, Sakai, Osaka 599-8531, Japan
S
* Supporting Information
ABSTRACT: A novel quadraphasic phase-vanishing system in which
acetylene is evolved from calcium carbide and directly applied in situ to
the Sonogashira coupling reaction was developed. This method, which
provides a safe, convenient, and one-pot means to utilize gaseous
reagents without special equipment, was also applied to a Cu-catalyzed
azide−alkyne cycloaddition (CuAAC) reaction and a three-component
aldehyde−alkyne−amine (A3) coupling reaction with excellent results.
ighly fluorinated compounds are generally immiscible with
most organic solvents and water and typically have
common test tube without the need for cooling equipment and
dropping funnels. Typical reagents utilized in PV systems are
denser than fluorous media (ρ > 1.7 g cm−3) and include Br2,
BBr3, SnCl4, and CH2I2. Most of the reagents employed in PV
systems are liquids as, with few exceptions,8 the utilization of
gaseous or solid reagents has been unsuccessful. Consequently,
we now focus on the study on the use of calcium carbide (CaC2),
which reacts with water to evolve acetylene gas.
Acetylene, the simplest alkyne, is a gaseous reagent and has
become widely used as a feedstock in the chemical industry in
recent decades. It is known to show versatile reactivity, including
dimerization, oligomerization, and polymerization,9,10 and
undergoes not only electrophilic additions to its triple bond
with various electrophiles such as molecular bromine or
hydrogen bromide but also nucleophilic reactions utilizing the
acidic terminal hydrogen.
Acetylene is a dangerous gas. Its ignition point is only 305 °C,
and air mixtures containing as little as 2.5 vol % are potentially
explosive.11 Thus, extreme caution is required in its use.
Generally speaking, although gaseous reagents are often used
in chemical laboratories, handling them is not easy, and much
caution is required. Gaseous reagents are usually stored in gas
cylinders, and special apparatus such as autoclaves and regulators
is usually needed to use them in reactions. In addition, when
poisonous gases are employed, extra safety precautions, such as
the use of detectors, must be taken.
H
densities higher than those of organic liquids. Over the past
two decades, researchers have utilized these features of fluorous
compounds to develop methods for the simplification of
postreaction treatments such as quick separation of products
and reagents and recovery of reagents and catalysts.1 Work in our
laboratories has been concerned with the design and application
of fluorous compounds with the aim of developing novel
synthetic methodologies. To this end, we have developed a
triphasic phase-vanishing (PV) method, in which the fluorous
medium acts as a liquid membrane to steadily transport reagents
to a substrate-bearing organic layer.2
Since the viability of the PV method was first demonstrated by
the bromination of alkenes with molecular bromine,3 this
method has been used to carry out various reactions.4,5 For
example, in a photoirradiative PV method,4e hydrogen bromide
was efficiently generated in a PV system comprising an alkane,
perfluorohexanes, and molecular bromine, and it was sub-
sequently reacted with 1-alkenes to afford terminal bromides in
high yields. Recently, we carried out Grignard-type reactions
using a quadraphasic PV system comprising a 1:1 mixture of
Galden HT135 and HT200 (Figure 1),6 iodomethane (or
Herein, we report a novel PV system, where acetylene gas is
evolved in situ from CaC2 and water and reacted with substrates
in the organic layer (Scheme 1). Three types of reactions were
carried out using this PV method: a Sonogashira coupling, a
preparation of a triazole from an azide, and a copper-catalyzed
three-component coupling reaction.
Figure 1. General structure of Galden.
iodoethane), magnesium, ether, and carbonyl compounds. In
this method, alkyl magnesium iodide reagents were successfully
generated in situ and reacted with carbonyl compounds,
affording the desired products in good yields.7
We started our investigation of the gas evolution PV method
by applying it to the Sonogashira coupling.12,13 CaC2 (ρ = 2.22 g
In PV methods, the fluorous phase regulates the transport of
reagents by passive diffusion. Thus, it is a simple and easy method
for controlling heat evolution in exothermic reactions using a
Received: March 20, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b00827
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Scheme 1. Acetylene Gas Evolution PV System
cm−3, 4 equiv) was used as the reagent phase (bottom layer), and
THF (ρ = 0.89 g cm−3) was employed as the organic phase (top
layer). Galden HT135 (ρ = 1.72 g cm−3) was used as the fluorous
phase, and water (12 equiv) was placed onto it. It should be
noted that the order of addition of the components is important
in safely carrying out the PV method. Careless addition of water
to CaC2 causes intense evolution of acetylene, which is a
potentially hazardous situation. The appropriate aryl halide (2
mmol), Pd(PPh3)4 (5 mol %), CuI (5 mol %), and triethylamine
(Et3N, 2 equiv) were added to the top layer, and then the air in
the test tube was removed by a syringe.14 The bottom layer was
gently stirred at room temperature, taking care not to mix the
four layers (Figure 2, left). However, the CaC2 did not react with
a
Table 1. Sonogashira Coupling Using the PV Method with
Acetylene Evolution
entry
1
R
X
2
isolated yield (%)
1
2
3
4
5
6
7
1a
H
I
2a
2b
2c
2c
2d
2e
2e
94
78
95
<1
97
96
53
1b
1c
OMe
Me
Me
F
I
I
1c′
1d
1e
Br
I
CF3
CF3
I
1e′
Br
a
Reaction conditions: substrate (2 mmol), Pd(PPh3)4 (5 mol %), CuI
(5 mol %), Et3N (4 mmol), CaC2 (8 mmol), THF (4 mL), Galden
HT135 (2 mL), H2O (24 mmol), 55 °C, 20 h.
Aryl iodides with electron-donating/withdrawing groups under-
went Sonogashira coupling to afford the diphenylacetylene
derivatives in good yield (Table 1, entries 3, 5, and 6), while 1-
iodo-4-methoxybenzene gave the coupling product in a some-
what lower yield (Table 1, entry 2). However, the yields for aryl
bromides were significantly lower than those of aryl iodides
(Table 1, entries 4 and 7), and 1-bromo-4-methylbenzene did
not undergo the coupling reaction at all (Table 1, entry 4).
We also investigated a copper-catalyzed azide−alkyne cyclo-
addition (CuAAC)15,16 using the PV method with acetylene
evolution, as shown in Table 2. Employing a similar PV system as
that used for the Sonogashira coupling, we replaced the THF in
the organic phase with Et3N (ρ = 0.73 g cm−3), to which benzyl
azide (1 mmol) and CuI (10 mol %) were added. After the air in
the test tube was removed, the bottom layer was gently stirred at
55 °C. After 20 h, the reagent phase (CaC2) and water phase
disappeared, and following aqueous workup and column
chromatography on silica gel with hexane/ethyl acetate (1:1)
as an eluent, the desired triazole was obtained from the organic
phase in 85% yield (Table 2, entry 1). The yield of the CuAAC
reaction using the PV method was almost equal to that of the
Figure 2. PV Sonogashira coupling of iodobenzene with acetylene. The
arrows indicate the interface of the phase. (a) Quadraphasic system:
CaC2, Galden HT135, water, THF solution of iodobenzene, Et3N, and
catalysts (from the bottom). (b) After completion of the reaction (55
°C, 20 h), the CaC2 layer and aqueous layer disappeared, affording two
phases: Galden HT135 and THF phase (from the bottom).
the water, and no acetylene evolution was observed in the test
tube, indicating that water does not diffuse into the fluorous
phase at room temperature. Consequently, the test tube was
heated to 55 °C using an oil bath. Continuous acetylene gas
evolution was observed, and after 20 h, the reagent phase (CaC2)
and water phase had vanished (Figure 2, right). The organic layer
and inorganic salts were then taken, washed with brine, dried
over Na2SO4, and concentrated. After column chromatography
on silica gel with hexane as an eluent, diphenylacetylene (2a) was
obtained in 94% yield (Table 1, entry 1).
Using these reaction conditions, we investigated the substrate
scope of the PV system with a series of aryl halides (Table 1).
traditional methodology reported by Liang16a and Novak 16b
́
.
B
DOI: 10.1021/acs.orglett.5b00827
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a
DMF was used as the organic phase, to which benzaldehyde (1
mmol), pyrrolidine (2 equiv), and CuI (20 mol %) were added.
After the air in the test tube was removed, the bottom layer was
gently stirred at 55 °C, similarly to the previous reactions. After
20 h, the reagent phase (CaC2) and water phase vanished, and
the desired product was afforded in an acceptable yield (Table 3,
entry 1), indicating that the A3 coupling in our PV system
proceeded with results similar to those seen for the traditional
methodology reported by Zhang.19
Table 2. CuAAC Using the PV Method with Acetylene
Evolution
The substrate scope of the PV system was investigated with a
series of aryl aldehydes. As shown in Table 3, aryl aldehydes with
electron-donating groups afforded the corresponding products in
acceptable yields (Table 3, entries 2, 4, and 5), while 4-
(trifluoromethyl)benzaldehyde, an aryl aldehyde with an
electron-withdrawing group, did not undergo the A3 reaction
at all, resulting in a complex mixture (Table 3, entry 3), and
cyclohexanone afforded the coupling product in low yields
(Table 3, entry 6). Generally, the yields observed for the A3
reaction in the PV system were slightly lower20 than those of
Zhang’s work. A possible reason for this is that the reaction tube
for the PV system is sealed by a rubber septum; therefore, some
of the acetylene gas evolved may escape from the test tube before
it can be used in the reaction.
In summary, we have presented a new PV method where
acetylene gas was generated from CaC2 in a test tube. This
method utilized passive diffusion of water into fluorous media as
a driving force for the generation of acetylene gas, which was
well-controlled, steady, and constant. The evolved acetylene was
then successfully applied to the Sonogashira coupling reaction,
CuAAC reaction, and A3 coupling reaction to afford the desired
products in yields similar to those obtained by established
conditions.22 Therefore, this method has an advantage for
reactions where acetylene gas is required, as it avoids the use of
high-pressure apparatus such as regulators and gas cylinders. This
method will be of high value not only to synthetic organic
chemists but also to other scientists that use acetylene gas. The
PV method described here, which employs a simple test tube,
may also be expanded to encompass other gaseous reagents.
Further applications of this method will be reported in due
course.
a
Reaction conditions: substrate (1 mmol), CuI (10 mol %), CaC2 (4
mmol), H2O (12 mmol), Et3N (4 mL), Galden HT135 (2 mL), 55 °C,
20 h.
Consequently, a scope of substrates was investigated, as
summarized in Table 2. Benzyl azides with various substituents
on the phenyl ring underwent cyclization with the evolved
acetylene to afford the corresponding triazoles in good yields
(except xylyl derivatives, entries 2 and 3).
Finally, we performed a three-component aldehyde−alkyne−
amine (A3) coupling reaction using the PV system (Table 3).17,18
a
Table 3. A3 Coupling Using the PV Method with Acetylene
Evolution
ASSOCIATED CONTENT
* Supporting Information
Experimental details and copies of H NMR and 13C NMR
■
S
1
spectra for all compounds. The Supporting Information is
available free of charge on the ACS Publications website at DOI:
10.1021/acs.orglett.5b00827.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: matsu@c.s.osakafu-u.ac.jp.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the Japan Society for the Promotion of Science (JSPS)
for financial support of this work.
■
a
Reaction conditions: substrate (1 mmol), pyrrolidine (2 mmol), CuI
REFERENCES
(20 mol %), CaC2 (4 mmol), H2O (12 mmol), DMF (4 mL), Galden
■
b
1
HT135 (2 mL), 55 °C, 20 h. Yields determined by H NMR using
1,1,2,2-tetrachloroethane as an internal standard are listed in
parentheses.21
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Letter
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D
DOI: 10.1021/acs.orglett.5b00827
Org. Lett. XXXX, XXX, XXX−XXX