Unprecedented Multicomponent Organocatalytic Synthesis of Propargylic Esters via CO2 Activation

Article abstract of DOI:10.1002/cctc.201900207

An efficient and straightforward organocatalytic method for the direct, multicomponent carboxylation of terminal alkynes with CO₂ and organochlorides, towards propargylic esters, is reported for the first time. 1,3-Di-tert-butyl-1H-imidazol-3-ium chloride, a simple, widely-available, stable, and cost-efficient N-heterocyclic carbene (NHC) precursor salt was used as the (pre)catalyst. A wide range of phenylacetylenes, bearing electron-withdrawing or electron-donating substituents, react with allyl-chlorides, benzyl chlorides, or 2-chloroacetates, providing the corresponding propargylic esters in low to excellent yields. DFT calculations on the mechanism of this transformation indicate that the reaction is initiated with the formation of an NHC-carboxylate, by addition of the carbene to a molecule of CO₂. Then, the nucleophilic addition of this species to the corresponding chlorides has been computed to be the rate limiting step of the process.

Full text of DOI:10.1002/cctc.201900207

Accepted Article
Title: Unprecedented multicomponent organocatalytic synthesis of
propargylic esters via CO2 activation
Authors: Argyro T. Papastavrou, Martin Pauze, Enrique Gómez-
Bengoa, and Georgios C. Vougioukalakis
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10.1002/cctc.201900207
ChemCatChem
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Unprecedented multicomponent organocatalytic synthesis of
propargylic esters via CO2 activation
Argyro T. Papastavrou,[a] Martin Pauze,[b] Enrique Gómez-Bengoa[b] and Georgios C. Vougioukalakis*[a]
Abstract: An efficient and straightforward organocatalytic method for
the direct, multicomponent carboxylation of terminal alkynes with CO2
and organochlorides, towards propargylic esters, is reported for the
first time. 1,3-Di-tert-butyl-1H-imidazol-3-ium chloride, a simple,
widely-available, stable, and cost-efficient N-heterocyclic carbene
(NHC) precursor salt was used as the (pre)catalyst. A wide range of
phenylacetylenes, bearing electron-withdrawing or electron-donating
substituents, react with allyl-chlorides, benzyl chlorides, or 2-
chloroacetates, providing the corresponding propargylic esters in low
to excellent yields. DFT calculations on the mechanism of this
transformation indicate that the reaction is initiated with the formation
of an NHC-carboxylate, by addition of the carbene to a molecule of
CO2. Then, the nucleophilic addition of this species to the
corresponding chlorides has been computed to be the rate limiting
step of the process.
amino substituent.3 The nitrogen atom at this position
thermodynamically stabilizes the carbenic center of a singlet
carbene, both due to its π-electron donating and σ-electron
withdrawing character (Figure 1).4
Figure 1. Some frequently encountered types of NHCs and the visualization of
the stabilization of singlet carbenes originating from the α-amino substituent(s).
Introduction
Among others, NHCs have been studied as ligands that can
substitute phosphines in metal complexes. Indeed, many metal
complexes of NHCs efficiently catalyze a plethora of reactions,
including olefin metathesis and cross-couplings.5Moreover,
catalytic systems of “green” metals, such as copper and iron, with
NHCs as ligands find numerous applications in sustainable
catalytic systems.6 Equally important, NHCs serve as excellent
organocatalysts in many organic transformations. The benzoin
reaction is one of the earliest known carbon-carbon bond-forming
reactions catalyzed by N-heterocyclic carbenes.7Ever since,
NHCs organocatalysis has been employed in many different
transformations. In addition to the benzoin reaction,8 these include
the Stetter reaction,9 Heck-type reactions,10 NHC-catalyzed
umpolung of imines for intramolecular reactions, as well as many
other valuable transformations employing NHCs’ peculiar
behavior and balance between nucleophilicity and electrophilicity
(Scheme 1).11
Carbenes are neutral compounds bearing a divalent carbon atom
having six valence electrons. Due to the fact that the number of
carbene electrons deviates from the ‘‘octet rule’’, carbenes were
initially considered to be non-isolable. The distribution of the
carbenes’ electrons in their orbitals is the factor that defines their
ground state, characteristics, and reactivity. More specifically,
carbenes are of singlet or triplet ground state. In singlet carbenes,
the two electrons that do not participate in σ-bonds occupy the
highest occupied molecular orbital (HOMO) of the carbon atom.
Therefore, the carbenic carbon’s pπ orbital is empty. This
distribution of valence electrons makes singlet carbenes both
nucleophilic and electrophilic at the same time. In contrast, triplet
carbenes carry a single electron in each pχ and pψ orbital and
behave as biradicaloid species.1N-heterocyclic carbenes (NHCs)
were successfully isolated and characterized for the first time by
Arduengo in 1991.2 The term NHC is used to describe molecules
bearing the carbenic carbon in a ring containing at least one α-
[a]
[b]
A. T. Papastavrou, Prof. Dr. G. C. Vougioukalakis
Laboratory of Organic Chemistry, Department of Chemistry
National and Kapodistrian University of Athens
Athens GR-15771, Greece
E-mail: vougiouk@chem.uoa.gr
M. Pauze, Prof. Dr. E. Gómez-Bengoa
Department of Organic Chemistry I, Faculty of Chemistry
University of the Basque Country
UPV-EHU, 20018 Donostia - San Sebastian, Spain
Scheme 1. Examples of useful organic transformations catalyzed by NHCs.
Supporting information for this article is given via a link at the end of
the document.
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Recently-reported transformations, catalyzed by NHCs, deal with
the utilization of nitroalkenes to prepare three- to five-carbon-
utilized to investigate the scope of the reaction. 18 different
propargylic esters were synthesized and isolated, with isolated
yields ranging from 25 to 97%. Finally, DFT studies were carried
out to clarify the mechanism of the transformation. These studies
suggest that the NHC moiety is crucial for the activation of CO2 at
the outset of the reaction, forming an NHC-carboxylate, which is
then esterified with the allyl halide. In the last step, the NHC acts
as an efficient leaving group, leading to the final adducts upon
attack of the potassium acetylide. Thus, NHC is acting as a
catalytic activator of CO2, enhancing its nucleophilicity in the first
step and its electrophilicity during the final alkyne attack.
atom
building
blocks,12
the
synthesis
of
4-
difluoromethylquinolines,13 polymerization reactions,14 1,6-
conjugate addition reactions,15 Michael additions,16 and various
enantioselective functionalizations.17
On a different note, propargylic esters can be prepared via several
synthetic pathways. One of the simplest methods involves the
esterification of the corresponding propiolic acid. The desired
propiolic acid has to be synthesized first, which is then coupled
with the corresponding alcohol.18 Propargylic esters can be also
obtained from the transformation of lithium phenylacetylide, as
demonstrated in the synthesis of Taxoids.19 Other propargylic
esters synthetic methods utilize carbon monoxide as the carbonyl
source of the final molecule.20 However, carbon monoxide is
highly toxic and dangerous. Alternatively, carbon dioxide can be
used as the source of the carbonyl group of the desired
compounds. Besides leading to a highly useful family of organic
synthons, these CO2 monetization methodologies utilize one of
the most harmful pollutants, the main “greenhouse effect” gas,
transforming it into useful organic compounds.21 Catalytic
systems that are known to achieve the direct preparation of
propargylic esters via CO2 activation are currently based on rather
complicated copper complexes or silver salts.22,23 Note that
propargylic esters are invaluable organic synthons, among others
utilized in the preparation of arylnaphthalenes, via intramolecular
dehydro Diels−Alder reactions (Scheme 2). Arylnaphthalenes and
their dihydro- and tetrahydronaphthalene derivatives are
Results and Discussion
To determine which NHC catalyzes the reaction most efficiently,
a number of NHC salts precursors with variable structural
characteristics were screened in the reaction between
phenylacetylene (1a), CO2 (2), and cinnamyl chloride (3a)
towards propargylic ester 4a (Scheme 3). K2CO3 was used as the
base and DMF as the solvent, at 60oC and under 14.8 Atm of CO2
pressure. NHC precursors utilized bear saturated (8-12) or
unsaturated (5-7) NHC backbones, are of symmetrical (5-7 and
11, 12) or unsymmetrical (8-10) nature with regards to their
exocyclic substituents, have aliphatic (5, 6), aromatic (7 and 9-12)
or both aliphatic and aromatic exocyclic substituents (8), or even
exocyclic substituents bearing heteroatoms able to act as base
and/or nucleophile when appropriately rotated close to the
carbenic center (9, 10).NHC precursors bearing the aliphatic,
bulky, electron-donating exocyclic substituents tert-butyl (5) and
cyclohexyl (6) groups afforded the desired product in66 and 21%
yields, respectively. The rest of the NHC precursors utilized,
afforded very low yields of the targeted propargylic ester (7-8), or
no product at all (9-12). Therefore, among the NHC salts tested
in the model reaction, 1,3-di-tert-butyl-1H-imidazol-3-ium chloride
(5) exhibits the optimum catalytic behavior. This was the NHC
precursor we utilized in the rest of our studies.
compounds of medicinal interest, with
a wide range of
pharmacological activity. For example, diphyllin and justicidin B
are both cytotoxic compounds and demonstrate anticancer,
antiparasitic, and antiviral activities.18d
Scheme 2. Propargylic esters as valuable intermediates in organic synthesis.
18d
Herein, we report a novel, straightforward organocatalytic
approach for the multicomponent conjugation of terminal alkynes,
carbon dioxide and organochlorides, affording propargylic esters
with variable structural characteristics in a single step.1,3-Di-tert-
butyl-1H-imidazol-3-ium chloride, a simple, widely-available,
stable, and cost-efficient NHC precursor salt was used as the
(pre)catalyst. The reaction between phenylacetylene, cinnamyl
chloride and CO2was the model reaction employed to probe the
activity of a series of NHC salts as (pre)catalysts, as well as in
order to determine the optimum reaction conditions. Then, a
series of phenyl acetylene derivatives and organohalides were
Scheme 3. Investigation of the catalytic activity of N-heterocyclic carbene salt
precursors. (Experimental conditions: NHC precursor 15 mol%,
phenylacetylene 0.5 mmol, cinnamyl chloride 0.75 mmol, carbon dioxide 14.8
Atm, K2CO3 1 mmol, DMF 4 mL, temperature 60oC, reaction time 24h.Yields
were measured by GC/MS.)
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With the most efficient NHC salt (pre)catalyst in hand, we
investigated the influence of the other reaction parameters. More
specifically, we investigated the influence of the base used, the
solvent of the reaction, the catalytic amount of the NHC precursor,
and the reaction temperature (Table 1). Among the bases used,
in DMF, potassium carbonate provided the best results (Entry 3).
Sodium carbonate provided the desired product, albeit with
significantly lower yields (Entries 4 and 9). This result is attributed
to the size and the nature of the counterion of carbonate. Sodium
bicarbonate was found to be an inappropriate base for the
reaction (Entry 1), as also did sodium hydroxide (Entry 5). Besides
DMF, four other solvents were used to carry out the reaction.
Those were toluene, acetonitrile, dichloromethane and
tetrahydrofuran (Entries 6 to 11). When acetonitrile was used as
the solvent (Entries 7 to 9) the targeted propargylic ester was
formed efficiently, but in slightly lower yields than those observed
in the case of DMF. All other solvents either did not yield the
product at all, or the product was formed in traces. By increasing
the NHC (pre)catalyst loading from 15 to 20% (Entry 12),
phenylacetylene is quantitatively converted to the desired product,
as was also observed under 25% catalyst loading (Entry 13). The
reaction also takes place at room temperature (Entry 14) affording
a 55% yield of the propargylic ester, which is, however, lower than
the 99% GC/MS yield obtained at 60oC. In a series of blank tests,
it was found that the presence of base (Entry 17), NHC precursor
(Entry 18) and a high pressure of carbon dioxide (Entry 16) were
all necessary for the three-component reaction to occur.
We then carried out a kinetic study, in order to find the optimum
reaction time. More specifically, we studied the catalytic activity of
our optimized organocatalytic system in the reaction of
phenylacetylene (1a), CO2, and cinnamyl chloride (3a) towards
propargylic ester 4a via GC/MS. The conversion to the product 4a
over time is represented in Figure 2. Interestingly, the reaction has
a relatively long induction period of about 10 hours (about 20%
conversion in the first 10 hours). This long induction period could
be rationalized by the necessity for the formation of an important
intermediate in the catalytic cycle, or by some kind of an off-cycle
process (also see the discussion with regards to the theoretical
calculations below). After the necessary induction period, the
reaction speeds up, reaching completion in about 10 additional
hours, that is, in 20 hours total reaction time.
Table 1. Investigation of the conditions of the three-component coupling of
phenylacetylene, cinnamyl chloride and carbon dioxide towards the
corresponding propargylic ester.
Entry
Base
Solvent
Catalyst
loading
Temperature
Yield[a]
1
NaHCO3
CsF
DMF
15%
15%
15%
15%
15%
15%
15%
20%
15%
15%
15%
20%
25%
20%
20%
20%
20%
-
60oC
60oC
60oC
60oC
60oC
60oC
60oC
60oC
60oC
60oC
60oC
60oC
60oC
r.t.
-
2
DMF
9%
66%
11%
-
3
K2CO3
Na2CO3
NaOH
K2CO3
K2CO3
K2CO3
Na2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
-
DMF
4
DMF
5
DMF
6
Toluene
CH3CN
CH3CN
CH3CN
CH2Cl2
THF
-
7
53%
78%
Trace
Trace
-
8
9
10
11
12
13
14
15[b]
16[c]
17
18
DMF
>99%
>99%
55%
-
DMF
DMF
DMF
60oC
60oC
60oC
60oC
DMF
17%
-
DMF
K2CO3
DMF
-
[a] Experimental conditions:1,3-di-tert-butyl-1H-imidazol-3-ium chloride (NHC
precursor salt), phenylacetylene 0.5 mmol, cinnamyl chloride 0.75 mmol,
carbon dioxide 14.8 Atm, base 1 mmol, solvent 4 mL, reaction time 24h. Yields
were measured by GC/MS.[b] In the absence of CO2. [c] CO2 pressure of
4.9Atm.
Prior to investigating the reaction scope, we also carried out a
series of control experiments towards shedding some light on the
possible role of the NHC in the generation of the acetylide. It is
known that the deprotonation of phenylacetylene readily occurs in
the presence of carbonates to provide the corresponding
acetylide.24 Nevertheless, carbenes have been also shown to be
able to insert into C-H bonds.25 Therefore, we were intrigued to
study whether the in situ generated NHC could somehow increase
the rate of the acetylide formation. Unfortunately, though, despite
Figure 2. Reaction profile of the organocatalytic multicomponent coupling of
phenylacetylene (1a), cinnamyl chloride (3a) and carbon dioxide towards
propargylic ester 4a.
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our efforts to trap the generated acetylide under conditions
analogous to our reaction conditions, our experiments were
inconclusive in this regard.
With the optimum reaction conditions in hand, we investigated the
scope of the organohalides (Scheme 4). The two 2-chloroacetate
esters probed yield the corresponding coupling products 4b and
4c, albeit at relatively low yields. Moreover, organochlorides
bearing the chlorine atom on the carbonyl carbon do not provide
the desired propargyl ester, as found in the case of 4d. On the
contrary, allylic chlorides are very good substrates for this reaction,
leading to propargylic esters 4a, 4e, 4f and 4g in good to excellent
yields. The relatively low yield in the reaction of chloropropene
(leading to propargylic ester 4e) can be attributed to the fact that
this substrate has a relatively low boiling point (46°C, while the
reaction temperature is 60oC). The same rationale can be also
true in the case of propargylic ester 4f (56% yield), given that
chlorobutene has a boiling point of 59°C, also lower that the
reaction temperature. Along these lines, crotyl chloride, with a
boiling point of 85°C, yields the corresponding propargylic ester
4g in an excellent, 96% yield. Benzyl chlorides are also very good
substrates under these conditions, leading to propargylic esters
4h to 4l, in isolated yields ranging from 59 to 84%. Picolyl chloride
does not provide the targeted ester 4m, most probably due to the
existence of the pyridine moiety in its structure. This was shown
during control experiments, in which the reaction of
phenylacetylene with benzylchloride was completely quenched in
the presence of one equivalent (in relation to benzylchloride) of
pyridine - in the absence of pyridine this reaction provides
propargylic ester 4h in 61% isolated yield. Interestingly, in addition
to the parent benzyl chloride (4h), both electron-poor (4j and 4l)
and electron-rich (4i and 4k) benzyl chlorides afford very good
yields, while the co-existence of a second chlorine atom on the
aromatic ring (4j) does not impose any problem to the reaction.
Note, finally, that all organobromides probed (results not shown:
Scheme 4. Investigation of the scope of the reaction with regards to the
organochloride. (Experimental conditions: 1,3-di-tert-butyl-1H-imidazol-3-ium
chloride (NHC precursor salt) 20%, phenylacetylene 0.5 mmol, organochloride
0.75 mmol, carbon dioxide 14.8 Atm, K2CO3 1 mmol, DMF 4 mL, reaction time
20h, reaction temperature 60oC. All yields provided are isolated.)
Subsequently, the scope of the multicomponent organocatalytic
coupling towards propargylic esters was investigated with regards
to the terminal alkyne utilized. The results of this study are shown
in Scheme 5. Alkyl-substituted terminal alkynes (results not
shown: 1-pentyne and 3,3-dimethylbut-1-yne) do not afford the
targeted propargylic esters under our protocol’s conditions. The
same is true for a hydroxyl-bearing alkyne we tested (results not
shown: 2-methylbut-3-yn-2-ol), as well as a phenyl acetylene
1-bromobutane,
bromoethene,
1-bromododecane,
3-
bromopropanenitrile, 2-bromo-1-phenylethanone) were found to
be unsuitable substrates for the reaction.
bearing
a
bromide (results not shown: 1-bromo-2-
ethynylbenzene). Moreover, the electron poor, p-NO2-substituted
phenyl acetylene affords the targeted propargylic ester 4n, albeit
in traces. On the other hand, the p-CF3-substituted phenyl
acetylene, which is also electron-poor, gives an excellent isolated
yield of 91% of propargylic ester 4s. This finding suggests the
reaction is not problematic with electron-poor terminal alkynes in
general, but, most probably, it is not compatible with the -NO2
moiety (also see the discussion that follows). Phenylacetylenes
bearing no aromatic substituents or methyl and/or methoxy
moieties on the aromatic ring are excellent substrates under our
protocol, affording the corresponding propargylic esters in very
good to excellent yields (4a, 4o-4r, and 4t-4u).
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We wanted to get information about the energy profile of the
reaction, which is crucial to clarify some important issues about
the mechanism, like: a) the identification of the rate limiting step
of the process, b) the understanding of the origin of the induction
period observed at the outset of the reaction, and c) the
determination of the underlying reasons for the large difference of
reactivity between the different electrophiles, like, for example,
cinammyl chloride 3avspicolyl chloride 3m (Scheme 4). We
assumed that the fundamental steps of the reaction would be the
attack of the NHC catalyst to CO2 (TS1, Figure 3), the SN2-type
nucleopilic substitution of the chloride by the carboxylate (TS2)
and the final introduction of the propargylic system with
concomitant recovery of the catalytic NHC carbene (TS3 and
TS4). For the initial calculations, those substrates affording the
best results were selected, including the di-tertbutylcarbene
catalyst derived from5, cinnamyl chloride 3a, and
phenylacetylene1a.
As previously mentioned, we envisioned that the first step of the
reaction was the attack of NHC carbene to a molecule of CO2
(Figure 3). As described by others,27 this step was computed to
be easy and low in energy (TS1, ΔGǂ = 10.9 kcal/mol), with a very
early transition state that bears a long carbon-carbon bond
distance (2.3 Å). The intermediate formed in this step (II) is fairly
stable and low in energy (-2.7 kcal/mol). These carbene-CO2
adducts are known and extensively studied. Amongst others, they
are used as non-ionic NHC precursors, delivering the free
carbene in the reaction mixture upon thermal decomposition,
circumventing the need for the use of a base.28 The intermediate
formed in step (II) shows kinetic resistance to react with cinnamyl
chloride 3a, as can be inferred from its moderate activation energy
(ΔΔGǂ = 22.1 kcal/mol). This value is perfectly affordable at the
experimental reaction temperature. The structure of the transition
state follows a standard SN2-type nucleophilic displacement of the
chloride anion (see 3D structure in Figure 4), leading to the
second intermediate of the
Scheme 5.Investigationof the scope of the multicomponent organocatalytic
carboxylative coupling of terminal alkynes and organohalides with CO2.
(Experimental conditions: 1,3-di-tert-butyl-1H-imidazol-3-ium chloride (NHC
precursor salt) 20%, terminal alkyne 0.5 mmol, organochloride 0.75 mmol,
carbon dioxide 14.8 Atm, K2CO3 1 mmol, DMF 4 mL, reaction time 20h, reaction
temperature 60oC. All yields provided are isolated.)
Theoretical Calculations
We next turned our attention to the study of the mechanism of the
reaction, by means of DFT methods. The calculations were
carried out with the Gaussian 16 set of programs, using the M06-
2X functional together with the 6-311G(s,p) basis sets for full
structure optimization. An implicit solvent model (IEFPCM,
solvent = dimethyl formamide) was also incorporated to all
calculations.26
reaction (III), which is rather
stable (ΔG = -4.2 kcal/mol).
The process continues with
the nucleophilic attack of the
propargylic unit (1a) to
intermediate III through a
classical two-step addition to
the
carbonyl
group
(transition states TS3 and
TS4) with formation of the
tetrahedral intermediate IV.
The addition of the acetylide
in TS3 is higher in energy
(ΔΔG = 20.7 kcal/mol) than
the detachment of the
carbene leaving group in
TS4, which is very fast (ΔΔG
= 5.1 kcal/mol), but both
steps are lower in energy
than TS2.
Figure 3. Energy profile for the catalytic cycle of the reaction
between 1a, 3a, and CO2.
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Thus, the energy profile points to the nucleophilic displacement of Conclusions
the chloride by NHC-carboxylate (TS2) as the rate limiting step of
the process, as it shows the highest energy of the catalytic cycle.
Thus, the comparison of the reactivity of the different substrates
should be done at this point. In fact, we were able to locate the
transition states for the substitution of intermediate II to benzyl
chloride (3h) and picolyl chloride (3m). The computed structures
of TS2h, and TS2i were structurally very similar to that of
cinnamyl chloride TS2a (Figure 4).29 The computed activation
energies show the lowest value (ΔGǂ = 22.1 kcal/mol) for the most
reactive substrate of the three (3a), in agreement with the
experimental results shown in Scheme 4. The activation energy
for the benzyl derivative 3h lies 0.9 kcal/mol higher, which is not
a very significant difference, but enough to explain the decrease
in yield noted experimentally (97% vs 61%, Scheme 4).
Interestingly, the unreactive picolyl derivative 3m shows an
activation energy of ΔGǂ = 24.7 kcal/mol). While this value is 2.6
kcal/mol higher than for 3a, allowing us to explain a significant
decrease in yield for substrate 3m, it does not seem enough to
account for its complete lack of reactivity. Therefore, the presence
of a pyridine moiety has a deleterious effect on the reactivity by
some other undisclosed mechanism. As previously discussed, the
addition of 1 eq of pyridine to the reaction medium quenches the
reaction completely. Finally, the structures of the three transition
states in Figure 4 present forming O-C bond distances between
2.00 Å and 2.09 Å, and breaking C-Cl bond distances between
2.34 Å and 2.44 Å. Interestingly, the distances slightly increase
with the increasing reactivity of the substrates (Figure 4). These
data suggest that the reacting sp3 carbon develops a relative
positive charge during TS2, explaining why electron donating
substituents, like 3k, show higher reactivity than electron
withdrawing groups, like 3l (Scheme 4).
A
novel organocatalytic protocol for the multicomponent
carboxylative coupling of terminal alkynes with organochlorides
and CO2, catalyzed by an in-situ generated NHC derived from the
widely-available, cost-efficient and stable 1,3-di-tert-butyl-1H-
imidazol-3-ium chloride was developed. The protocol is user-
friendly, straightforward and highly efficient against a number of
substrates and functionalities. In addition to the parent
phenylacetylene, a wide range of substituted phenylacetylenes,
bearing electron-withdrawing or electron-donating aromatic
substituents, react with allyl-chlorides, benzyl chlorides, or 2-
chloroacetates, providing the corresponding propargylic esters in
low to excellent yields. DFT calculations on the mechanism of this
transformation indicate that the reaction is initiated with the
addition of the carbene to a molecule of CO2, forming a NHC-
carboxylate. This species is nucleophilic enough to react with
chlorides, although the high activation energy of this process
suggests that it is the rate limiting step. This fact would explain
the large difference in reactivity of the different allyl and benzyl
chlorides and the effect of the substituents.
Experimental Section
General reagent information. Unless otherwise noted, chemicals were
obtained from commercial sources and were purified according to
literature procedures. Solvents were purified according to published
procedures, distilled and stored under argon over 3Å molecular sieves. All
reactions were set up under argon and carried out under carbon dioxide in
sealed, high pressure reactor. The course of the reactions was followed
with GC/MS. The purification of the products was carried out by flash
column chromatography, using silica gel 60 (230-400 mesh).
General analytical information.1H, 13C NMR spectra were measured on
a Varian Mercury 200MHz spectrometer using CDCl3 as the solvent and
its residual solvent peak as a reference. NMR spectroscopic data are given
in the order: chemical shift, multiplicity (s, singlet, br. s, broad singlet, d,
doublet, t, triplet, q, quartet, m, multiplet), coupling constant in Hertz (Hz),
and number of protons. Peaks at 0 and 1.5ppm of spectra are attributed to
impurities of laboratory solvents, organics, and gases in deuterated
solvents.30 HRMS spectra were recorded in a QTOF maxis Impact (Bruker)
spectrometer with Electron Spray Ionization (ESI). The GC/MS spectra
were recorded with a Shimandzu R GCMS-QP2010 Plus Chromatograph
Mass Spectrometer using a MEGAR (MEGA-5, F.T: 0.25μm, I.D.: 0.25mm,
L: 30m, Tmax: 350 oC, Column ID# 11475) column, using n-octane as the
internal standard.
Figure 4. Activation free energies for the substitution step of chloride (TS2) in
the cinnamyl (3a), benzyl (3h) and picolyl substrates (3m).
Synthetic protocols. The synthetic protocols for NHC ligand precursors
5 to 10 are reported in the literature.6b,31 NHC ligand precursors 11 and 12
were purchased and used without any further purification.
Finally, we were intrigued by the long induction period that we
observed in our reactions (Figure 2). In fact, nothing, in the
computed cycle shown in Figure 3, points to the existence of such
an initial delay, which has to be related to some off-cycle process.
One hypothesis is that the initial formation of the active NHC
carbene from the imidazolium precursor in the presence of a base
could be slow in the reaction scale, and, therefore, the necessary
concentration of NHC carbene (I) would need some time to evolve.
Unless otherwise mentioned, the following procedure was used for the
synthesis of all products: A flame-dried vial with a stirring bar and a rubber
septum was charged with 20 mol% of 1,3-di-tert-butyl-1H-imidazol-3-ium
chloride (0.1 mmol), K2CO3 (1mmol) and DMF (4mL). Under a flow of
argon, the terminal alkyne (0.5 mmol) and organohalide (0.75 mmol) were
added and the mixture was placed in the pressure reactor. The reactor
was purged three times with carbon dioxide, the pressure was finally fixed
to 14.8 Atm and the reaction was allowed to stir in an oil bath, preheated
at 60oC, for 20 hours. After this time, the pressure reactor was cooled to
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10.1002/cctc.201900207
ChemCatChem
FULL PAPER
room temperature and ventilated carefully. Water was added to the
reaction mixture and was extracted with ethyl acetate (3x5 ml). The organic
phase was dried with MgSO4 and the solvent was removed under reduced
pressure to afford the crude mixture of the reaction. Gradient column
chromatography with ethyl acetate/petroleum ether furnished the desired
product. Products prepared for the first time were characterized by 1H
NMR, 13C NMR, and HRMS, which are all in agreement with the assigned
structures. Known compounds were characterized by 1H NMR and 13C
NMR with all their spectroscopic characteristics in agreement with those
reported in the literature.
NMR (50 MHz, CDCl3) δ 154.1, 135.1, 133.2, 130.9, 128.9, 128.9, 128.8,
128.8, 119.7, 86.9, 80.8, 67.9.
4-Methylbenzyl 3-phenylpropiolate (4i):22i Prepared according to the
general procedure and obtained in 73% yield (91 mg,0.365 mmol).1H NMR
(CDCl3) δ 7.63 – 7.55 (m, 2H), 7.46 – 7.32 (m, 4H), 7.22 (d, J=7.9, 2H),
5.25 (s, 2H), 2.38 (s, 3H).13C NMR (CDCl3) δ 154.20, 138.80, 133.25,
132.18, 130.93, 129.61, 129.08, 128.83, 119.81, 86.82, 80.86, 67.96,
21.52.
4-Chlorobenzyl 3-phenylpropiolate (4j):22i Prepared according to the
general procedure and obtained in 75% yield (101 mg, 0.375 mmol).1H
1-(2,6-Diisopropylphenyl)-3-(quinolin-8-yl)-4,5-dihydro-1H-imidazol-3-ium
chloride (10): 1H NMR (200 MHz, CDCl3) δ 9.62 (s, 1H), 8.74 (s, 1H), 8.28
(d, J = 7.9 Hz, 1H), 7.99 (d, J = 7.4 Hz, 1H), 7.79 (d, J = 8.1 Hz, 1H), 7.66
– 7.36 (m, 3H), 7.24 (d, J = 7.6 Hz, 2H), 5.24 (t, J = 10.5 Hz, 2H), 4.57 (t,
J = 10.5 Hz, 2H), 3.17 (hept, J = 13.2, 6.9 Hz, 2H), 1.26 (t, J = 6.9 Hz, 12H).
13C NMR (50 MHz, CDCl3) δ 158.36, 150.58, 146.73, 140.17, 137.79,
131.80, 131.72, 130.20, 129.42, 128.06, 127.01, 125.34, 122.84, 122.27,
53.35, 29.07, 25.48, 24.44. HRMS (ESI) m/z calculated for C12H10O4Na
[Μ]+ requires m/z 358.5085. Found m/z: 358.2321.
NMR (CDCl3) δ 7.61 – 7.51 (m, 2H), 7.50 – 7.31 (m, 7H), 5.22 (s, 2H).13
C
NMR (CDCl3) δ 153.5, 134.4, 133.3, 132.8, 130.6, 129.8, 128.7, 128.4,
119.2, 86.8, 80.2, 66.6.
4-Methoxybenzyl 3-phenylpropiolate (4k):22i Prepared according to the
general procedure and obtained in 84% yield (112 mg, 0.42 mmol).1H
NMR (200 MHz, CDCl3) δ 7.77 – 7.45 (m, 2H), 7.46 – 7.28 (m, 5H), 6.98 –
6.86 (m, 2H), 5.21 (s, 2H), 3.81 (s, 3H).13C NMR (50 MHz, CDCl3) δ 160.16,
154.22, 133.23, 130.92, 130.84, 128.81, 127.23, 119.77, 114.26, 86.75,
80.84, 67.86, 55.54.
Cinnamyl 3-phenylpropiolate (4a):22c Prepared according to the general
procedure and obtained in 97% yield (127 mg, 0.485mmol).1H NMR (200
MHz, CDCl3) δ 7.70 – 7.52 (m, 2H), 7.51 – 7.16 (m, 8H), 6.74 (d, J = 15.8
Hz, 1H), 6.34 (dt, J = 15.9, 6.5 Hz, 1H), 4.90 (d, J = 6.5 Hz, 2H).13C NMR
(50 MHz, CDCl3) δ 154.0, 136.2, 135.5, 133.2, 130.9, 128.8, 128.8, 128.5,
126.9, 122.3, 119.7, 86.8, 80.7, 66.7.
4-(Trifluoromethyl)benzyl 3-phenylpropiolate (4l):20 Prepared according to
1
the general procedure and obtained in 59% yield (89 mg, 0.29 mmol). H
NMR (CDCl3) δ 7.68 – 7.62 (d, J = 8.1 Hz, 2H), 7.62 – 7.57 (m, 2H), 7.56
– 7.52 (d, J = 8.1 Hz, 2H), 7.49 – 7.43 (m, 1H), 7.41 – 7.35 (m, 2H), 5.31
(s, 2H). 13C NMR (CDCl3) δ 153.8, 139.1, 133.3, 131.1, 128.7, 125.8, 119.5,
87.5, 80.4, 66.8.
2-Methoxy-2-oxoethyl 3-phenylpropiolate (4b): Prepared according to the
general procedure and obtained in 25% yield (27 mg, 0.125mmol).1H NMR
(200 MHz, CDCl3) δ 7.65 – 7.56 (m, 2H), 7.48 – 7.32 (m, 3H), 4.76 (s, 2H),
3.80 (s, 3H).13C NMR (50 MHz, CDCl3) δ 167.7, 153.4, 133.4, 131.2, 128.8,
119.3, 88.4, 79.9, 61.7, 52.8. HRMS (ESI) m/z calculated for C12H10O4Na
[Μ+Na]+ requires m/z 241.0579. Found m/z: 241.0472.
Cinnamyl 3-(p-tolyl)propiolate (4o):22c Prepared according to the general
procedure and obtained in 83% yield (115 mg, 0.41 mmol). 1H NMR
(CDCl3) δ 7.48 (d, J = 7.9 Hz, 2H), 7.41 – 7.24 (m, 5H), 7.16 (d, J = 7.9 Hz,
2H), 6.71 (d, J = 15.9 Hz, 1H), 6.32 (dt, J = 15.9, 6.6 Hz, 1H), 4.87 (d, J =
6.6 Hz, 2H), 2.36 (s, 3H). 13C NMR (CDCl3) δ 153.9, 141.3, 136.0, 135.2,
133.0, 129.4, 128.6, 128.2, 126.7, 122.1, 116.4, 87.2, 80.2, 66.4, 21.7.
2-Ethoxy-2-oxoethyl 3-phenylpropiolate (4c):22c Prepared according to the
general procedure and obtained in 28% yield (32 mg, 0.14 mmol).1H NMR
(CDCl3) δ 7.68 – 7.55 (m, 2H), 7.51 – 7.31 (m, 3H), 4.74 (s, 2H), 4.27 (q,
J = 7.1 Hz, 2H), 1.31 (t, J = 7.1 Hz, 3H).13C NMR (CDCl3) δ 167.1, 153.4,
133.3, 131.1, 128.8, 119.4, 88.3, 79.9, 61.9, 61.8.
Cinnamyl 3-(m-tolyl)propiolate (4p): Prepared according to the general
procedure and obtained in 82% yield (113 mg, 0.41 mmol). 1H NMR (200
MHz, CDCl3) δ 7.73 – 7.08 (m, 9H), 6.74 (d, J = 15.9 Hz, 1H), 6.34 (dt, J =
15.9, 6.5 Hz, 1H), 4.90 (d, J = 6.5 Hz, 2H), 2.35 (s, 3H). 13C NMR (50 MHz,
CDCl3) δ 154.1, 138.6, 136.2, 135.5, 133.7, 131.9, 130.4, 128.9, 128.7,
128.5, 126.9, 122.3, 119.5, 87.2, 80.4, 66.7, 21.4. HRMS (ESI) m/z
calculated for C19H16O2Na+ [Μ+Na]+ requires 299.1150. Found m/z:
299.1047.
Allyl 3-phenylpropiolate (4e):22c Prepared according to the general
procedure and obtained in 42% yield (39 mg, 0.21 mmol). 1H NMR (CDCl3)
δ 7.65 – 7.52 (m, 2H), 7.50 – 7.30 (m, 3H), 5.97 (m, 1H), 5.41 (dd, J = 17.2,
1.4 Hz, 1H), 5.32 (dd, J = 10.3, 1.2 Hz, 1H), 4.73 (d, J = 5.9 Hz, 2H). 13C
NMR (CDCl3) δ 153.9, 133.2, 131.3, 130.9, 128.8, 119.7, 119.6, 86.7, 80.6,
66.8.
Cinnamyl 3-(4-methoxyphenyl)propiolate (4q):22c Prepared according to
the general procedure and obtained in 87% yield (123 mg, 0.43 mmol). 1H
NMR (200 MHz, CDCl3) δ 7.54 (d, J = 8.9 Hz, 2H), 7.47 – 7.23 (m, 5H),
7.01 – 6.81 (m, 2H), 6.79 – 6.66 (m, 1H), 6.33 (dt, 1H), 4.88 (d, J = 6.5 Hz,
2H), 3.80 (s, 3H). 13C NMR (50 MHz, CDCl3) δ 161.8, 154.3, 136.2, 135.4,
135.2, 128.9, 128.5, 126.9, 122.4, 114.5, 111.4, 87.7, 80.2, 66.6, 55.6.
3-Methylbut-2-en-1-yl 3-phenylpropiolate (4f):22c Prepared according to
the general procedure and obtained in 56% yield (60 mg, 0.28 mmol).1H
NMR (CDCl3) δ 7.58 – 7.30 (m, 5H), 5.44 – 5.40 (m, 1H), 4.73 (d, J = 7.4
Hz, 2H), 1.79 (s, 3H), 1.75 (s, 3H). 13C NMR (CDCl3) δ 154.3, 140.8, 133.2,
130.8, 128.7, 119.8, 117.8, 86.3, 80.8, 63.1, 26.0, 18.3.
Cinnamyl
3-(4-methoxy-2-methylphenyl)propiolate
(4r):
Prepared
(E)-But-2-en-1-yl 3-phenylpropiolate (4g):32 Prepared according to the
general procedure and obtained in 94% yield (94 mg, 0.47 mmol).1H NMR
(CDCl3) δ 7.65 – 7.50 (m, 2H), 7.48 – 7.27 (m, 3H), 6.01 – 5.72 (m, 1H),
5.71 – 5.51 (m, 1H), 4.63 (d, 2H), 1.72 (d, J = 6.3 Hz, 3H).13C NMR (CDCl3)
δ 154.0, 133.1, 133.0, 130.8, 128.7, 124.4, 119.8, 86.4, 80.8, 66.9, 18.0.
according to the general procedure and in 91% yield (136 mg, 0.45mmol).
1H NMR (200 MHz, CDCl3) δ 7.50 (d, J = 8.4 Hz, 1H), 7.46 – 7.21 (m, 5H),
6.82 – 6.63 (m, 3H), 6.34 (dt, J = 15.9, 6.5 Hz, 1H), 4.89 (dd, J = 6.5, 1.1
Hz, 2H), 3.80 (s, 3H), 2.48 (s, 3H). 13C NMR (50 MHz, CDCl3) δ 161.6,
154.4, 144.8, 136.2, 135.5, 135.3, 128.8, 128.4, 126.9, 122.5, 115.6, 111.9,
111.5, 86.8, 83.8, 66.6, 55.5, 21.1. HRMS (ESI) m/z calculated for
C20H18O3Na+ [Μ+Na]+ requires 329.1256. Found m/z: 329.1158.
Benzyl 3-phenylpropiolate (4h):22i Prepared according to the general
procedure and obtained in 61% yield (72 mg, 0.30 mmol).1H NMR (200
MHz, CDCl3) δ 7.66 – 7.55 (m, 2H), 7.50 – 7.31 (m, 8H), 5.29 (s, 2H).13
C
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10.1002/cctc.201900207
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FULL PAPER
Cinnamyl 3-(4-(trifluoromethyl)phenyl)propiolate (4s):22c Prepared
K. Stamatopoulos, A. T. Papastavrou, A. Pinaka, G. C. Vougioukalakis,
European J. Org. Chem. 2018, in press; c) S. Nolan, Acc. Chem.
Res.2010, 44, 91-100; d) K. Riener, S. Haslinger, A. Raba, M. Högerl, M.
Cokoja, W. Herrmann, F. Kühn, Chem. Rev. 2014, 114, 5215-5272; e) Y.
Zhang, J. Chan, Energy Environ. Sci. 2010, 3, 408-417.
according to the general procedure and obtained in 91% yield (150 mg,
1
0.45 mmol). H NMR (CDCl3) δ 7.67 (d, J = 8.2 Hz, 2H), 7.61 (d, J = 8.2
Hz, 2H), 7.41 – 7.23 (m, 5H), 6.72 (d, J = 15.9 Hz, 1H), 6.32 (dt, J = 15.9,
6.6 Hz, 1H), 4.90 (d, J = 6.6 Hz, 2H). 13C NMR (CDCl3) δ 153.4, 135.9,
135.7, 133.2, 132.2, 128.7, 128.4, 126.8, 125.6, 123.4, 121.9, 121.8, 84.3,
82.1, 66.9.
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Prepared
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(CDCl3) δ 7.46 (d, J=8.5 Hz, 2H), 7.15 (d, J=8.5 Hz, 2H), 5.85 (dq, J=15.0,
7.0 Hz, 1H), 5.64 (tq, J=15.0, 7.0 Hz, 1H), 4.63 (d, J=7.0 Hz, 2H), 2.36 (s,
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Computational details. The computational details of the calculations
carried out are provided at the supporting information of this article.
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We acknowledge the contribution of COST Action CA15106 (C-H
Activation in Organic Synthesis – CHAOS). The Special Account
for Research Grants of the National and Kapodistrian University
of Athens is also gratefully acknowledged for funding (Research
Program 70/3/14872). Moreover, we are thankful for the technical
and human support provided by IZO-SGI SGIker of UPV/EHU,
and the European Funding Horizon 2020-MSCA (ITN-EJD
CATMEC 14/06-721223).
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Keywords: NHCs • organocatalysis • propargylic esters• CO2 •
multicomponent
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10.1002/cctc.201900207
ChemCatChem
FULL PAPER
FULL PAPER
Argyro T. Papastavrou, Martin Pauze,
Enrique Gómez-Bengoa and Georgios
C. Vougioukalakis*
Page No. – Page No.
Unprecedented multicomponent
organocatalytic synthesis of
propargylic esters via CO2 activation
A straightforward organocatalytic method for the direct carboxylation of terminal
alkynes towards propargylic esters, is reported. A simple, widely-available, stable,
and cost-efficient N-heterocyclic carbene precursor salt was used as the
(pre)catalyst.
This article is protected by copyright. All rights reserved.