CsF-promoted carboxylation of aryl(hetaryl) terminal alkynes with atmospheric CO2 at room temperature

Article abstract of DOI:10.1039/c7nj01779k

A CsF-promoted carboxylation of aryl(hetaryl) terminal alkynes with atmospheric CO₂ in the presence of trimethylsilylacetylene was developed to give functionalized propiolic acid products at room temperature. A wide range of propiolic acids bearing functional groups was successfully obtained in good to excellent yields. Mechanistic studies demonstrate that in the carboxylation process the alkynylsilane intermediate was first in situ generated, which was then trapped by CO₂, giving rise to the corresponding functionalized propiolic acids after acidification. The advantages of this approach include avoiding use of transition-metal catalysts, wide substrate scope together with excellent functional group tolerance, ambient conditions and a facile work-up procedure.

Full text of DOI:10.1039/c7nj01779k

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January 2016 Pages 1–846
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ISSN 1144-0546
PAPER
Jason B. Benedict et al.
The role of atropisomers on the photo-reactivity and fatigue of
diarylethene-based metal–organic frameworks
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CsF-Promoted Carboxylation of Aryl(Hetaryl) Terminal Alkynes
with Atmospheric CO at Room Temperature†
2
Received 00th January 20xx,
Accepted 00th January 20xx
a
a,b
a,b
a
a
a
, a,b
B. Yu, P. Yang, X. Gao, Z. Z. Yang, Y. F. Zhao, H. Y. Zhang and Z. M. Liu*
DOI: 10.1039/x0xx00000x
2
A CsF-promoted carboxylation of aryl(hetaryl) terminal alkynes with atmospheric CO in the presence of
trimethylsilylacetylene has been developed to give functionalized propiolic acids products at room temperature. A wide
range of propiolic acids bearing functional groups was successfully obtained in good to excellent yields. Mechanistic
studies demonstrate that in the carboxylation process alkynylsilane intermediate was first in situ generated, which was
www.rsc.org/
2
then trapped by CO , giving rise to the corresponding functionalized propiolic acids after acidification. The advantages of
this approach include avoiding use of transition-metal catalysts, wide substrate scope together with excellent functional
group tolerance, ambient condition and a facile work-up procedure.
Introduction
2
Recently, utilization of CO as a starting material in organic
synthesis has attracted much attention and emerged as a
flourishing research area in terms of sustainable chemistry,
since CO
C1 source. So far, CO
related products and commodity chemicals, such as urea,
2
is an abundant, inexpensive, nontoxic and renewable
1
-4
2
can be converted into many energy-
5
6
7
8
formamidine derivatives,
formic acids,
methanol,
benzimidazoles, aromatic aldehydes and so on. In particular,
carboxylation of terminal alkynes with CO is a promising and
9
10
2
atom-economic way to the synthesis of alkynyl carboxylic
acids. However, as a result of the thermodynamical stability of
CO
2
, high energy substrates, specific catalysts and harsh
transformation, thus
conditions are generally required for CO
2
Scheme 1
Route A, classical synthesis of aryl propiolic acids by reaction of
organometallic species with CO . The organometallic species are typically
. Routes to the synthesis of propiolic acids. a, Reported routes.
its conversion under ambient conditions, especially at room
temperature and atmospheric pressure is still challenging.
2
Aryl(hetaryl) propiolic acids and their derivatives are an prepared by deprotonation of terminal alkynes or by lithium halogen
exchange of alkynyl halides. X’= Cl or Br; Hal, halogen. Route B, transition-
important kind of organic intermediates with versatile
1
1-17
metal-catalyzed carboxylation of terminal alkynes with CO
strained disilane-propoted carboxylation of alkynyl halides with CO
functionalized propiolic acids in an environmentally benign transition-metal-free conditions. Route D, carboxylation of alkynylsilanes
2
. Route C, a
applications in organic synthesis.
The synthesis of such
2
under
with CO
promoted carboxylation of aryl terminal alkynes with atmospheric
CO /trimethylsilylacetylene at room temperature.
2
mediated by CsF in DMSO. b, Route developed in this work: CsF-
way has become considerable relevance. At present, the most
common approach to construction of alkynyl C-C bond involves
the interception of aromatic lithium or magnesium reagents
2
1
8
based catalysts have been demonstrated to catalyze the
with CO
2
(Scheme 1, a, Route A). However, the high
intermolecular C-H carboxylation of terminal alkynes with CO
1
2
nucleophilicity of lithium and magnesium acetylides limits
functional groups compatibility of this route and requires
prefunctionalization of alkynes. Thus far, the transition-metal-
9-26
(Scheme 1, a, route B).
Although these carboxylation
methods are prominent examples in this field, they rely on
catalysts derived from rare and expensive precious metals,
which can be a significant limitation, particularly for large-scale
syntheses. Transition-metal-free cross-coupling reaction has
offered an attractive surrogate to metal-catalyzed processes to
C-C bond formation due to their low cost, environmentally
2
7-33
benign nature.
Sato and coworkers reported a very mild
using a strained four-
carboxylation of alkyl iodides with CO
2
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membered ring disline and CsF under transition-metal-free Table 1. CsF-promoted carboxylation of phenylacetylene with
3
4
a
conditions (Scheme 1, route C). More recently, Kondo carbon dioxide
reported the direct incorporation of CO into alkynylsilanes
mediated by CsF, affording propiolic acids under ambient
2
3
5
conditions (Scheme 1, route D). However, alkynylsilanes are
usually synthesized via Pd/Cu catalyzed alkynylation of aryl
triflates or halides with alkynes. Though such progress has
been made, expensive and high-energy substrates or metal
catalysts were used, and only limited propiolic acids were
produced. Therefore, general and transition-metal-free
protocols to produce aryl(hetaryl) propiolic acids are highly
desirable.
b
Entry
catalyst system: change from Yield(%)
‘
’standard’’ conditions
1
2
3
4
5
6
7
8
9
none
92
0
no CsF
no Trimethylsilylacetylene
no 18-crown-6
0
47
0
As part of our continuing studies on the transformation of
NEt
3
instead of CsF
instead of CsF
CO into useful chemicals, combined with our interest in the
2
K
2
CO
3
43
85
86
93
65
42
40
23
84
development of new methods for C-C bond formation using
3
6
CO as a C1 source, herein we present a transition-metal-free
KF instead of CsF
t
NaO Bu instead of CsF
t
KO Bu instead of CsF
2
strategy for carboxylation of aryl(hetaryl) terminal alkynes
with CO2 under ambient conditions. In this protocol
trimethylsilylacetylene as a readily available and cheap silane
coupling agent, combined with CsF, was used to promote the
carboxylation (Scheme 1, b). This approach had a wide
substrate scope, and various aryl(hetaryl) propiolic acids
including benzene-1,4-di-propiolic and benzene-1,3,5-tri-
propiolic acids could be obtained in good to excellent yields.
1
1
1
1
0
1
2
3
4
3
CH CN instead of DMSO
THF instead of DMSO
1,4-dioxane instead of DMSO
Toluene instead of DMSO
DMF instead of DMSO
1
a
Reaction conditions: phenylacetylene (1a, 1 mmol), trimethylsilylacetylene
2, 1.1mmol), CsF (1.5 equiv), 18-crown-6 (0.2 equiv), in DMSO (3 ml), at
o
(
b
Moreover, this protocol could be extended to gram scale 30 C for 20h. isolated yield.
production of phenylpropiolic acid. In addition, the
toluene were examined in place of DMSO. It was found that
postreatments on the carboxylated compounds with MeI and
amines could afford the corresponding phenylpropiolic methyl
esters and phenylpropiolic amides.
the absence of the dipolar aprotic solvents led to the decrease
in the yields of 3a under otherwise identical conditions (Table
1
, entries 10-13). In sharp contrast to this result, the dipolar
aprotic solvent, e.g, DMF, improved the 3a yield drastically to
4% (Table 1, entry 14).
Results and discussion
8
Exploration of optimal conditions
Scope of the substrates
At the outset of this investigation, the reaction conditions
were explored using phenylalkyne (1a) as a model substrate,
and the optimal conditions were obtained (for 1 mmol 1a
To demonstrate the general applicability of this protocol, the
carboxylation of various terminal alkynes with CO
2
was
preformed under the optimized reaction conditions. As shown
in Table 2, the products were basically isolated as carboxylic
acids. Interestingly, electron-rich, -neutral, and –deficient as
well as heteroaromatic substrates were all carboxylated,
producing corresponding carboxylic acids in good to excellent
yields after acidification (Table 2, 3a-3v). Notably, the isomers
with the substituent at different positions (ortho-, meta-, and
para positions) in the aryl ring showed similar activity (Table 2,
conversion, 1.1 equiv. of trimethylsilylacetylene, 1.5 equiv. of
o
CsF, 0.2 equiv. of 18-crown-6, DMSO, 1 atm of CO , 30 C, 20h).
2
The coupling reaction of 1a and CO afforded 3a in an isolated
2
yield of 92% at 100% conversion of 1a under the optimized
conditions (Table 1, entry 1). In the absence of either of CsF or
trimethylsilylacetylene, no reaction took place (Entries 2, 3),
indicating that both the base and trimethylsilylacetylene were
indispensable. The absence of 18-crown-6 resulted in the
reduction in the 3a yield to 47% (Entry 4). As known, 18-
crown-6 can coordinate with potassium cation, thus it may
enhance the nucleophilicity of fluoride anion and the solubility
of the catalyst. For comparison, other bases instead of CsF
3d-3f, 3h-3j), suggesting the substitution in the aryl ring had
little impact on the activation of alkyne C-H bond. Remarkably,
the reaction of heteroaromatic alkynes (i.e. 2-ethynylthiophen
and 3-ethynylthiophen) with CO
affording the corresponding products in high yields (Table 2,
and 3r). However, 2-ethynylpyridine and 3-ehtynylpyridine
2
also proceeded well,
were tested. It was indicated that NEt
reaction (Entry 5), while KF, K CO and sodium tertbutoxide
NaO Bu) gave rise to the desired product in declined yields
3
was ineffective for the
3q
2
3
did not give the desired products under standard conditions,
possibly because the newly formed propiolic acids were not
stable. Instead, methyl ester products could be produced via
treating the reaction solutions with MeI (Supporting
Information, Scheme S1).
t
(
(
t
Entries 6-8). Excitingly, potassium tertbutoxides (KO Bu) was
very effective for this reaction, affording 3a in a yield of 93%
t
Entry 9), comparable to CsF. Notably, it was found that KO Bu
(
could give rise to 3a in a yield of 92% even in the absence of
trimethylsilylacetylene. In the next set of experiments, other
solvents including DMF, acetonitrile, 1,4-dioxane, THF, and
Applications of the protocol
2
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Table 2. CsF-promoted coupling of various terminal alkynes materials, and good product yields were obtained (Scheme 2,
with carbon dioxide in DMSO
a,b
c).
a
Reaction conditions: terminal alkynes (1a, 1 mmol), trimethylsilylacetylene
(2, 1.1mmol), CsF (1.5 equiv), 18-crown-6 (0.2 equiv), in DMSO (3 ml), at
o
0 C for 20h. isolated yield. Reaction time: 24h.
b
C
Scheme 2. Applications of the trimethylsilylacetylene/CsF-
promoted carboxylation of terminal alkynes.
3
The above protocol is practical and scalable since a satisfactory
product yield (88%) was obtained when the carboxylation of
Control experiments
phenylacetylene 1a with CO
2
was performed on a 1.0 g scale
To understand the nature of this trimethylsilylacetylene-
involved carboxylation process and to gain insight into the
possible reaction pathway, several control experiments were
carried out as illustrated in Scheme 3. First, the reaction was
(
Scheme 2, a). Since propiolic acids are known to be capable of
7-43
3
undergoing versatile transformations
, the carboxylated
could also
products from the reactions of alkyneswith CO
2
1
3
readily transform into other kinds of value-added chemicals, as
illustrated in Scheme 2. For example, methyl ether product
was obtained in an isolated yield of 90% via treating the
carboxylated compound with methyl iodide (Scheme 2, b).
Alkynylamides is a kind of valuable intermediates with multiple
conducted with isotopically labled CO
2
as the carboxylative
1
3
reagent (Scheme 3, (a)). C labled phenylpropiolic acid was
1
3
obtained in a yield of 90% confirmed by C NMR (Figure 1),
suggesting that CO involved the formation of the carboxylated
2
product. Considering that without trimethylsilylacetylene the
reaction did not occur (Table 1, entry 3; Scheme 3, (b)), the
4
4-46
usages.
phenylacetylenes with CO
alkynylamides via their reactions with amines. For instance,
the treatment of phenylacetylene, CO with morpholine in
The
carboxylated
compounds
from
2
could be further converted into
stoichiometric
trimethylsilylacetylene was performed in the presence of N
replacing CO and 1-phenyl-2-trimethylsilyacetylene
intermediate was only obtained in an isolated yield of 95%
Scheme 3, (c)). With this intermediate as a starting material,
bubbling CO into the reaction solution under the optimized
reaction
of
phenylacetylene
and
2
2
,
2
one-pot reaction under mild conditions afforded alkynylamide
in 56% isolated yield, demonstrating the compatibility of our
method with amine molecules of potential pharmaceutical
importance.
(
2
conditions resulted in the production of 3a in an isolated yield
of 94% (Scheme 3, (d)). These results suggest that 1-phenyl-2-
trimethylsilyacetylene intermediate was in situ generated
under the experimental conditions, which could further
Aromatic polycarboxylic acids, especially those with
unsaturated bonds (i.e., -C=C- and -C≡C- ), are promising
feedstocks for the synthesis of advanced materials such as
metal organic frameworks and functional polymers. However,
their synthesis is challenging. Excitingly, the protocol
presented in this work was successfully applied in the
synthesis of benzene-1,4-di-propiolic and benzene-1,3,5-tri-
propiolic acids that are useful building blocks of functional
nucleophilically attack CO
2
, providing 3a after acidification.
47-48
Base on the above and previous studies
, a possible
reaction pathway was proposed as illustrated in Scheme 4.
This carboxylation may in principle proceed in two steps.
Firstly, the fluoride anion reacts with trimethylsilylacetylene to
afford the hypervalent silicon intermediate I, thus reacting
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with phenylalkyne to form the crucial intermediates 1-phenyl- spectrometer. Their peak frequencies were referenced versus
1
-trimethylsilyacetylene 4a. Subsequently, a fluoride anion an internal standard (TMS) shifts at 0 ppm for H NMR and
2
1
3
attacks silicon atom of 4a to afford carbanion of phenylalkyne, against the solvent (CDCl
3
,
77.0 ppm
)
for
C NMR,
which in situ attacks to CO
2
, affording the cesium carboxylate respectively.
5a. After acidification of 5a, phenyl propiolic acid 3a is finally
obtained.
Scheme 4. Proposed reaction pathway for carboxylation of
terminal alkynes.
Multiplicity abbreviations: s = singlet, d = doublet, t = triplet, q
=
quartet, m = multiplet. Coupling constants (J, Hz).
General procedure for carboxylation of terminal alkynes
The reaction was performed in a 10 mL Schlenk tube with a
magnetic stirring bar. Typically, terminal alkyne (1.0 mmol),
trimethylsilylacetylene (1.1 mmol), CsF (1.5 mmol) and 18-
crown-6 (0.2 mmol) were added into dry DMSO (2 ml) loaded
1
3
Figure 1.
phenylacetylene with CO
C NMR spectrum of the carboxylated product from
1
3
2
in the reactor. After purged with CO
was connected to a CO ballon and moved to a water bath of
C. After being stirred for 20h, the reaction mixture was
diluted with water (30 mL), and was extracted with CH Cl (3
0 mL). The aqueous phase was acidified with HCl aqueous
solution (6 M) and then extracted with diethyl ether (5 20
mL). The combined organic extracts were dried over Na SO
and concentrated under vacuum to give the pure propiolic acid
for example, compound 3a: 92%). The obtained product was
2
for 3 times, the reactor
2
30°
2
2
⨯
1
⨯
2
4
(
weighed by a mass balacne, and identified by NMR analysis.
For example, 3-phenylpropiolic acid (3a), white solid, 133.3
1
mg, isolated yield of 92%. H NMR (400 MHz, DMSO) δ 7.68 –
1
3
7
.62 (m, 2H), 7.55 (d, J = 7.4 Hz, 1H), 7.49 (t, J = 7.4 Hz, 2H).
NMR (101 MHz, DMSO) δ 154.81, 133.07, 131.36, 129.50,
19.53, 119.51, 85.03, 81.68.
C
1
1
3
Experiment of isotopically labled CO
2
Sheme 3. Control experiments for mechanistic studies.
Experimental
1
The carboxylation of phenylalkyne with CO
3
2
was performed
under the standard conditions, and the procedure was similar
to the general one. The desired product was obtained in an
1
3
isolated yield of 90%. The product was then analyzed by
NMR spectroscopy as shown in Figure 1.
C
General information
Alkynes, trimethylsilylacetylene and other chemicals were
purchased from J&K or Innochem. Carbon dioxide (99.999%),
Synthesis of 4a
1
3
13 18
C-labled carbon dioxide (purity>99.9%, C 99%, O<1%),
Phenylacetylene (1.0 mmol) was added to a DMSO solution of
trimethylsilylacetylene (1.1 mmol), CsF (1.5 mmol) and 18-
crown-6 (0.2 mmol) in a 10 mL Schlenk tube with a magnetic
terminal alkynes, and other reagents were used without
further purification. All reactions were monitored by thin-layer
chromatography (TLC) using UV light as cisualizing agent.
Column chromatography was performed with 230-300 mesh
stirring bar. The Schlenk tube was purged with N
and connected to a N ballon, which was then moved to a
water bath of 30 C. After being stirred for 20h, the reaction
2
for 3 times,
2
1
13
silica gel. H and C NMR spectra were recorded on a Bruker
1 13
AvanceII 400M type ( H NMR, 400 MHz; C NMR, 101 MHz)
°
mixture was diluted with water (30 mL), and was extracted
4
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with CH
2
Cl
2
(3
⨯
10 mL). The combined organic extracts were under vacuum to give the crude mixture, which was purified by
and concentrated under vacuum to give the silica gel flash column chromatography (petroleum
as light yellow powder in 56%
column chromatography (petroleum ether) to give the desired yield. The resultant product was identified by NMR analysis.
dried over Na
2
SO
4
crude mixture. The residue was purified by silica gel flash ether/EtOAc 5:1), giving pure
7
5
0
1
product as a yellow liquid in 95% yield. The as-obtained
H NMR (400 MHz, CDCl
3
) δ 7.52 – 7.48 (m, 2H), 7.35 (ddd, J =
1
product was identified by NMR analysis. H NMR (400 MHz, 16.0, 11.7, 4.5 Hz, 3H), 3.83 – 3.79 (m, 2H), 3.75 – 3.70 (m, 2H),
1
3
3 3
CDCl ) δ 7.52 (dd, J = 6.5, 3.2 Hz, 2H), 7.33 (dd, J = 5.1, 1.8 Hz, 3.67 (s, 4H). C NMR (101 MHz, CDCl ) δ 153.22, 132.35,
1
3
3
H), 0.32 (s, 9H). C NMR (101 MHz, CDCl
28.19, 123.22, 105.21, 94.05, 0.00.
3
) δ 131.96, 128.46, 130.16, 128.52, 120.25, 91.23, 80.74, 47.32, 41.99.
1
Synthesis of 3u and 3v
Synthesis of 3a in gram scale
1,4-Diethynylbenzene or 1,3,5-triethynylbenzene (1.0 mmol)
Phenylacetylene (10.0 mmol) was added to a DMSO solution of was added to a DMSO solution of trimethylsilylacetylene (1.1
trimethylsilylacetylene (11 mmol), CsF (15 mmol) and 18- equiv.), CsF (1.5 equiv.) and 18-crown-6 (0.2 equiv.) in a 10 mL
crown-6 (2 mmol) in a 100 mL Schlenk tube with a magnetic Schlenk tube with a magnetic stirring bar. The Schlenk tube
stirring bar. The reactor was purged with CO
connected to a CO ballon, which was then moved to a water ballon, which was then moved to a water bath of 30
bath of 30 C. After being stirred for 20h, the reaction mixture being stirred for 20h, the reaction mixture was diluted with
was diluted with water (200 mL), and was extracted with water (30 mL), and was extracted with CH
CH Cl (3
aqueous HCl solution (6 M) and then extracted with diethyl and then extracted with diethyl ether (5
2
for 3 times, and was purged with CO
2
for 3 times, and connected to a CO
2
2
°C. After
°
2
Cl
2
(3
⨯ 20 mL). The
2
2
⨯ 50 mL). The aqueous phase was acidified with aqueous phase was acidified with aqueous HCl solution (6 M)
⨯
20 mL). The
SO and
and concentrated under vacuum to give the pure concentrated under vacuum, giving pure products in 75% (3u
ether (5
over Na
⨯
SO
50 mL). The combined organic extracts were dried combined organic extracts were dried over Na
2
4
2
4
)
4
9
3a
in an isolated yield of 88%.
and 62%
(3v) isolated yield, respectively. 3, 3’-(1,4-
1
Phenylene)dipropiolic acid (3u), 160.5 mg, pale yellow solid; H
Synthesis of 6
13
NMR (400 MHz, CDCl
Phenylacetylene (1.0 mmol) was added to a DMSO solution of CDCl ) δ 154.44, 133.41, 121.62, 84.29, 83.51. 3, 3’,3’’-(1,3,5-
trimethylsilylacetylene (1.1 mmol), CsF (1.5 mmol) and 18- Phenylene)tripropiolic acid (3v), 174.8 mg, yellow solid;
3
) δ 7.55 (s, 1H). C NMR (101 MHz,
3
1
H
1
3
crown-6 (0.2 mmol) in a 10 mL Schlenk tube with a magnetic NMR (400 MHz, CDCl
stirring bar. The Schlenk tube was purged with CO for 3 times, CDCl ) δ 154.26, 137.97, 121.54, 83.63, 81.65.
and connected to a CO ballon, which was then moved to a
water bath of 30 C. After being stirred for 20h, the solution of
3
) δ 7.95 (s, 3H). C NMR (101 MHz,
2
3
2
°
Conclusions
MeI (1.2 mmol MeI in 2 ml anhydrous DMSO) was added via a
syringe. After 2h, the reaction mixture was diluted with water
In conclusion, we have developed a new approach for
(
30 mL), and was extracted with CH
2
Cl
2
(3
⨯
combined organic extracts were dried over Na
20 mL). The
SO and
2
carboxylation of terminal alkynes with CO under ambient
2
4
conditions, affording the corresponding aromatic propiolic
acids in good to excellent yields. A broad range of substrates
were proved to be well tolerable. This transition-metal-free
protocol provides an alternative convenient and simple
concentrated under vacuum to give the crude mixture.
Subsequently, the mixture was purified by silica gel flash
column chromatography (petroleum ether/EtOAc 10:1) to give
4
9
the pure
product was identified by NMR analysis. H NMR (400 MHz,
CDCl ) δ 7.47 – 7.41 (m, 2H), 7.37 – 7.32 (m, 1H), 7.24 (t, J = 7.4
Hz, 2H), 3.69 (s, 3H). C NMR (101 MHz, CDCl
32.83, 130.60, 128.52, 119.45, 86.27, 80.32, 52.57.
6 as light yellow liquid in 90% yield. The as-obtained
2
strategy for efficient access to construct C-C bond using CO as
1
a C1 source. Further application of this carboxylation
methodology in the synthesis of diverse alkynylamides is
currently under investigation.
3
1
3
3
) δ 154.26,
1
Synthesis of 7
Conflicts of interest
Phenylacetylene (1.0 mmol) was added to a DMSO solution of
trimethylsilylacetylene (1.1 mmol), CsF (1.5 mmol) and 18-
crown-6 (0.2 mmol) in a 10 mL Schlenk tube with a magnetic
There are no conflicts of interest to declare.
stirring bar. The Schlenk tube was purged with CO
and connected to a CO ballon, which was then moved to a
water bath of 30 C. After being stirred for 15 h, the solution of
2
for 3 times,
Acknowledgements
2
This work was supported by the National Natural Science
Foundation of China (No. 21503239, 21533011, 21402208,
°
morpholine (1.1 mmol morpholine and 1.2 mmol HBTU (O-(1H-
benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluoro-
phosphate) in 3ml anhydrous DMF) was added via syringe.
After 5h, the reaction mixture was diluted with water (30 mL),
2
1403252).
References
and was extracted with CH
2
Cl
2
(3
⨯
organic extracts were dried over Na
20 mL). The combined
SO and concentrated
2
4
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A CsF-promoted carboxylation of aryl(hetaryl) terminal alkynes with atmospheric
CO in the presence of trimethylsilylacetylene at room temperature was developed.
2