A solid acetylene reagent with enhanced reactivity: Fluoride-mediated functionalization of alcohols and phenols

Article abstract of DOI:10.1039/c7gc00724h

The direct vinylation of an OH group in alcohols and phenols was carried out utilizing a novel CaC₂/KF solid acetylene reagent in a simple K₂CO₃/KOH/DMSO system. The functionalization of a series of hydroxyl-group-containing substrates and the post-modification of biologically active molecules were successfully performed using standard laboratory equipment, providing straightforward access to the corresponding vinyl ethers. The overall process developed involves an atom-economical addition reaction employing only inorganic reagents, which significantly simplifies the reaction set-up and the isolation of products. A mechanistic study revealed a dual role of the F^- additive, which both mediates the surface etching/renewal of the calcium carbide particles and activates the CC bond towards the addition reaction. The development of the fluoride-mediated nucleophilic addition of alcohols eliminates the need for strong bases and may substantially extend the areas of application of this attractive synthetic methodology due to increasing functional group tolerance. As a replacement for dangerous and difficult to handle high-pressure acetylene, we propose the solid reagent CaC₂/KF, which is easy to handle, does not require dedicated laboratory equipment and demonstrates enhanced reactivity of the acetylenic triple bond. Theoretical calculations have shown that fluoride-mediated activation of the hydroxyl group towards nucleophilic addition significantly reduces the activation barrier and facilitates the reaction.

Full text of DOI:10.1039/c7gc00724h

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A solid acetylene reagent with enhanced reactivity:
fluoride-mediated functionalization of alcohols
and phenols†
Cite this: DOI: 10.1039/c7gc00724h
Georg Werner,a Konstantin S. Rodygin,a Anton A. Kostin,a Evgeniy G. Gordeev,b
a,b
Alexey S. Kashinb and Valentine P. Ananikov
*
The direct vinylation of an OH group in alcohols and phenols was carried out utilizing a novel CaC2/KF
solid acetylene reagent in a simple K2CO3/KOH/DMSO system. The functionalization of a series of
hydroxyl-group-containing substrates and the post-modification of biologically active molecules were
successfully performed using standard laboratory equipment, providing straightforward access to the
corresponding vinyl ethers. The overall process developed involves an atom-economical addition reaction
employing only inorganic reagents, which significantly simplifies the reaction set-up and the isolation of
products. A mechanistic study revealed a dual role of the F− additive, which both mediates the surface
etching/renewal of the calcium carbide particles and activates the CuC bond towards the addition reac-
tion. The development of the fluoride-mediated nucleophilic addition of alcohols eliminates the need for
strong bases and may substantially extend the areas of application of this attractive synthetic methodology
due to increasing functional group tolerance. As a replacement for dangerous and difficult to handle
high-pressure acetylene, we propose the solid reagent CaC2/KF, which is easy to handle, does not require
dedicated laboratory equipment and demonstrates enhanced reactivity of the acetylenic triple bond.
Theoretical calculations have shown that fluoride-mediated activation of the hydroxyl group towards
nucleophilic addition significantly reduces the activation barrier and facilitates the reaction.
Received 9th March 2017,
Accepted 2nd May 2017
DOI: 10.1039/c7gc00724h
rsc.li/greenchem
Introduction
The post-modification of complex molecules is becoming an
urgent topic due to the high-cost and time-consuming total
syntheses of pharmaceutical substances, biologically active
compounds and smart material building blocks.1 Indeed, in
the case of a multistep synthesis (Fig. 1A), the incorporation of
a new functionality into complex molecules would require the
repetition of the whole procedure using a modified starting
reagent (Fig. 1B). Late-stage functionalization is an alternative
approach, which gives access to the desired product from the
available molecule in a single step, avoiding de novo prepa-
ration (Fig. 1C). This flexible concept opens up new possibili-
ties to a range of modified complex molecules.
Fig. 1 Preparation of vinyl derivatives: common multistep synthesis vs.
late-stage modification.
The hydroxyl functional group represents one of the most
essential building blocks for a diverse range of biologically
aSaint Petersburg State University, Universitetsky pr. 26, Stary Petergof 198504,
Russia
bZelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky pr.
47, Moscow 119991, Russia. E-mail: val@ioc.ac.ru; http://AnanikovLab.ru
†Electronic supplementary information (ESI) available. CCDC 1444527 and
1444530. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c7gc00724h
and pharmacologically active substances. Consequently, the
late-stage functionalization of an OH group is of great impor-
tance for turning on/off a direct interaction with an OH group
and for adjusting the hydrophilic/hydrophobic properties of
molecules (Fig. 1C). In addition, the facile preparation of well-
defined and multifunctional polymers is of paramount signifi-
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cance for the development of polymer-based drug carriers group towards nucleophilic addition was revealed by joint
(Fig. 1D). This type of a polymer with enhanced biocompatibil- experimental and theoretical studies.
ity, biodegradability and structural versatility contains attrac-
tive potential candidates for theranostic applications.2
Since vinyl ethers are common cationically polymerizable
Results and discussion
monomers and can undergo living polymerization to form
well-defined polymers with desired molecular weights, modi-
fied drugs bearing O-vinyl groups can serve as suitable build-
For the optimization of the reaction conditions, we have
chosen 3,5-dimethylphenol as a model compound for a vinyla-
ing blocks to attain this goal.3
tion procedure with CaC2. As expected, the reaction did not
The reaction of alcohols and phenols with gaseous acety-
take place under regular conditions (entries 1–4, Table 1). The
lene is a direct route for the generation of O-vinyl ethers. This
employment of different solvents (entries 1–3, Table 1) and
could be a promising practical methodology, which utilizes
bases (entry 4, Table 1) did not result in product formation.
atom-economical transformations of alkynes in synthetic
The addition of TBAF·3H2O facilitated the transformation and
conversions.4–7 However, the need for harsh reaction con-
delivered product 2a in 10% yield using K2CO3 as a base (entry
ditions, expensive equipment and special safety requirements
6, Table 1). A series of experiments emphasized the key role of
for handling acetylene under high pressure make this
the F− anion in the studied vinylation reaction (entries 8–12,
approach difficult for application in research laboratories.8
The use of strong bases and high temperature to activate alco-
hols towards nucleophilic addition6 imposes drastic limit-
ations on the reaction scope and reduces functional group tol-
Table 1 Optimization of reaction conditions in the vinylation of 3,5-
dimethylphenola
erance (Fig. 2). Another drawback of the existing base-
mediated reactions originates from a side-reaction of rapid oli-
gomerization of the vinyl ethers during the synthesis, resulting
in a significant drop in the product yield. Gaseous and in situ
generated acetylene have been used in synthetic transform-
ations of reactive thiols and simple alcohols,8–12 where
Entry
Solvent
Base
Additive
Yieldb (%)
phenols were found less reactive12 and TBAF-mediated reac-
tion resulted in the OH group remaining intact.10 Overall, it
should be noted that standard superbasic conditions typically
require a strong base, high temperature and long reaction
time, which decrease the green chemistry potential of this
atom-economical transformation due to lower selectivity and
the formation of by-products.
In this work, we report a solid acetylene reagent CaC2/KF
for the vinylation of aliphatic alcohols and phenols, which has
a number of important advantages (Fig. 2). The practical appli-
cation of the developed procedure allows the synthesis of
important vinyl monomers as well as the late-stage vinylation
of a range of complex functionalized molecules. From a funda-
mental point of view, the dual role of F− in the etching of the
calcium carbide surface and the activation of the hydroxyl
1
2
3
4
5
6
7
8
DMF
KOH
KOH
KOH
K2CO3
KOH
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
—
—
—
—
NR
NR
NR
NR
NR
10
NR
32
70
70
65
50
45
Dioxane
DMSO
DMSO
DMSO
DMSO
DMF
Dioxane
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
TBAF·3H2O
TBAF·3H2O
KF
KF
KF
CsF
NaF
LiF
KCl
KBr
KI
9
10
11
12
13
14
15
30
21
a Conditions: 1a (1.0 mmol), CaC2 (2.0 mmol), additive (4.0 mmol),
H2O (4.0 mmol), base (0.5 mmol), solvent (1.5 mL), 130 °C, 3 h.
b Isolated yields.
Fig. 2 Nucleophilic addition of alcohols to acetylene: typical limitations and dual activation approach described in the present study.
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Table 1), with the best results achieved using KF and CsF O-vinylated product (2e) was observed, as confirmed by NMR
(entries 9 and 10, Table 1). Interestingly, other halogen anions spectra (see the ESI†). In the functionalization of a highly reac-
also facilitated the reaction (entries 13–15, Table 1), although tive symmetrical aliphatic diol, both OH groups were vinylated
in a less efficient manner compared to F− (entry 9, Table 1).
(2f), regardless of the amount of calcium carbide added.
Under optimized conditions, the reaction proceeded
Among the studied phenols, the highest yield was
smoothly and gave product 2a in 70% yield. Both KF and CsF obtained for 3,5-dimethylphenol, probably due to the favor-
can be used to activate CaC2 in order to mediate the reaction able inductive effects of its two methyl groups (2a). For a
of interest. For better cost-efficiency, further reactions were similar reason, the yields with electron-rich substrates (2a
performed using KF as an additive.13
and 2k) were significantly higher than that of the unsubsti-
The substrate scope of the developed vinylation reaction tuted phenyl vinyl ether 2l. In the challenging case of 2p,
involving calcium carbide was investigated for a number of which contains a p-Cl substituent as an electron-withdrawing
phenols and naphthols (2a, 2j–2p), substituted aliphatic alco- group, the formation of the corresponding product was still
hols (2b–2i), benzylic alcohol (2q), and functionalized biologi- observed (cf. to 2a). To confirm the influence of the electron-
cally active and organometallic molecules 2s–2w and 2z withdrawing group, 4-nitrophenol was studied, and indeed,
(Fig. 3).
no product was detected due to the reduced nucleophilicity
The vinylation of aliphatic and cycloaliphatic alcohols, of the corresponding alkoxide (2r). Even the sterically
including cyclohexanol and menthol, delivered excellent demanding o-Ph-substituted phenol reacted in the studied
product yields (2b–2i). Primary as well as secondary alcohols system and furnished the formation of 2-(vinyloxy)-1,1′-biphe-
were functionalized in the developed system in >80% yields nyl (2o). Naphthalene derivatives represent another difficult
(2g and 2h).
substrate class due to their higher affinity for thermal
The complete conversion and highest yield were obtained polymerization compared to other phenyl vinyl ethers.14
by the vinylation of N-methyl-2,2,6,6-tetramethyl piperidinol Nevertheless, the formation of 1-(vinyloxy)-naphthalene (2j)
(2d). In the case of 2,2,6,6-tetramethyl piperidinol, only the was observed in the studied system.
Fig. 3 Scope of OH bond functionalization with CaC2 for different substrates (experimental conditions for the synthesis of 2b–2i, 2q and 2z: CaC2
(2.0 mmol), substrate (1.0 mmol), KOH (1.0 mmol), KF (4.0 mmol), H2O (4.0 mmol), 130 °C, 3 h; 2a, 2j–2p: CaC2 (2.0 mmol), substrate (1.0 mmol),
K2CO3 (0.5 mmol), KF (4.0 mmol), H2O (4.0 mmol), 130 °C, 3 h; 2s, 2t, 2v, 2w: CaC2 (2.0 mmol), substrate (50 mg), KOH (1.0 mmol), KF (4.0 mmol),
H2O (4.0 mmol); 2u: CaC2 (2.0 mmol), substrate (50 mg), KOH (1.0 mmol), H2O (4.0 mmol); freshly powdered calcium carbide was used in all cases.
NMR yields and isolated yields (in parenthesis) are shown; for compounds 2j–2n modified sequential vinylation was applied to improve isolated yields
(see the ESI† for details); for 2f the amount of substrate was 0.5 mmol. Single-crystal X-ray structures of 2s and 2t are shown.
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The efficiency of this process allowed for the direct vinyla- product separation were possible. In most of the studied cases,
tion of OH-containing pharmacologically active substances, product losses were minimized, so that a small difference
such as steroids and drugs, in good to high yields. Again, the between the NMR yields and isolated yields was observed
crucial role of fluoride is reflected in the vinylation of estra- (Fig. 3).
diol. Using KF as an additive, estradiol was vinylated at both
To reveal the reaction mechanism we have first confirmed
OH groups, delivering the corresponding divinylated estradiol the involvement of acetylene in the studied system. The reac-
(2s) in good yield. In the absence of KF, the process provides tion was carried out using gaseous acetylene (instead of CaC2)
solely the monovinylated product 2u with an aliphatic O-vinyl and the formation of the vinylation product was observed in
ether group. The structure of 2u was confirmed by HMBC and the presence of KF/K2CO3. To confirm the proposed mechanis-
NOESY experiments, and the structures of 2s and 2t were con- tic assumption we have also detected acetylene in situ in the
firmed by NMR and X-ray analyses (Fig. 3). The treatment of reaction with CaC2. The reaction was carried out in the NMR
cholesterol with CaC2 gave the vinylation product in a 91% iso- tube and acetylene was detected in the 1H NMR spectrum
lated yield (2t).
which is in total agreement with the proposed mechanism. In
To further explore the possibilities of late-stage functionali- addition, carrying out the reaction with D2O (instead of H2O)
zation, we also vinylated metoprolol (a selective β1 receptor in DMSO-d6 resulted in >80% incorporation of deuterium in
blocker, marketed under the trade name Lopressor®)15 and the vinylation product (approximate ratio of D : H ∼ 5 : 1 in the
hydroxyzine (a tranquilizer, marketed as Atarax®).16 Hydroxyzine vinyl groups). This experiment required the preliminary con-
was vinylated with CaC2, and the corresponding product was iso- version of the ROH substrate to ROD to avoid deuterium
lated in 85% yield (2w). Metoprolol was vinylated with CaC2 at scrambling (the presence of residual exchangeable protons in
both oxygen and nitrogen atoms with an 89% overall yield and a the substrate and base leads to some amount of the non-deute-
good 5 : 1 selectivity between the O-vinylated product 2v and rated product).
N-vinylated product. The structure of 2v was confirmed by
It is of great interest to reveal the nature of the activating
HMBC, HMQC and NOESY experiments.
effect of the fluorine anion. In the first step, it is expected that
The key advantage of the developed system is the utilization the reaction of CaC2 with water generates acetylene and is
of transition metal free inorganic reagents (CaC2, KF and in- accompanied by the formation of Ca(OH)2 as an inorganic
organic base K2CO3 or KOH) and water to carry out the trans- phase. Unexpectedly, the experiment showed that the in-
formation. Thus, a simplified reaction set-up and an easy organic component was precipitated as insoluble calcium fluo-
Fig. 4 Scanning electron microscopy images of initial calcium carbide (A and B) and the inorganic residue isolated after the reaction (C and D),
shown at low (A), medium (B, C) and high (D) magnifications.
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ride after the reaction (Fig. 4). To trace the transformations of
calcium carbide, the solid residue in the model reaction of the
vinylation of 3,5-dimethylphenol was subjected to field-emis-
sion scanning electron microscopy (FE-SEM) and EDS ana-
lyses. Electron microscopy showed that the calcium carbide
initially consisted of aggregated flaky particles with character-
istic sizes of approximately several micrometers for individual
particles and tens of micrometers for aggregates (Fig. 4A and
4B). After the reaction, the morphology of the solid phase iso-
lated from the reaction mixture changed drastically. The par-
ticles had a nearly round shape and sizes from several tens to
hundreds of nanometers (Fig. 4A and 4B). X-ray microanalysis
by EDS-SEM and X-ray powder diffraction (XPD) studies con-
Fig. 6 Plausible mechanism for the vinylation of alcohols and phenols
in the CaC2/KF system.
firmed the transition of fluorine from solution into the solid Therefore, the presence of the fluoride anion also facilitates
phase and the formation of CaF2 (see the ESI†). The analysis the reaction between acetylene and the hydroxyl group in solu-
of the solid sample isolated after the reaction showed that tion (in addition to the transformation of inorganic com-
approximately 90–95% of the calcium in the studied sample ponents into calcium fluoride).
existed in the form of CaF2.17
The overall mechanism would involve the generation of
This finding can be rationalized by taking into account the acetylene by the reaction of calcium carbide with KF/H2O as an
difference in solubility: 1.73 g L−1 for Ca(OH)2 and only initial step (Fig. 6). Next, the nucleophilic addition of the
0.016 g L−1 for CaF2 (in water).18 Because solubility data in hydroxyl group to the triple bond of the alkyne may be further
DMSO were not available, we carried out two control experi- enhanced by the formation of an intermediate complex invol-
ments to confirm the nature of the process. First, a mixture of ving the fluoride anion. The complexes and clusters between
Ca(OH)2 and KF was heated in DMSO for 3 h. Indeed, Ca(OH)2 halogen anions and acetylene are known, and hydrogen
was completely converted into CaF2 upon the reaction with KF bonding between fluoride anions and a relatively acidic acety-
in DMSO (eqn (1), Fig. 5). To model the reaction conditions, a lenic proton may also be anticipated in aprotic media.19,20 The
three-component mixture with CaC2 was studied and showed interaction of F− with alcohols has been reported and applied
the formation of CaF2 as a solid precipitate (eqn (2), Fig. 5).
in sensor applications.21 In this case, an intermediate complex
These findings highlight one of the key roles of F− in the would geometrically pre-activate the substrates towards the
studied system. Under standard conditions (without F−), the desired addition reaction (Fig. 6) as well as enhance the reac-
reaction of solid particles of CaC2 with water leads to the cover- tivity via electron density delocalization. If the assumption is
age of the calcium carbide particle surface with amorphous correct, then larger and less electronegative halogen atoms
Ca(OH)2. The presence of fluorine anions results in a continuous (Cl−, Br− and I−) may also exhibit a similar effect, although to
etching on the surface of CaC2, leading to an efficient surface a lesser extent. Indeed, the observed experimental findings are
renewal and a controllable rate of acetylene evolution. The con- in good agreement with the proposed mechanism (entries 9
version to crystalline CaF2 prevents the coverage of the carbide and 13–15; Table 1).
particles with amorphous calcium hydroxide.
To reveal the nature of the observed activating effect of the
However, the role of fluoride is not limited to the solid-state fluoride anion, we carried out a series of theoretical calcu-
process. We carried out a set of control experiments under lations at the CCSD(T)/6-311++G(d,p) level and accounted for
1 atm acetylene pressure for 3,5-dimethylphenol and benzyl the DMSO solvent effect with the SMD method (Fig. 7 and 8).
alcohol (the reaction was carried out using gaseous acetylene A direct reaction of an alcohol (ROH, R = CH3 for model
instead of CaC2). In the absence of KF, 3,5-dimethylphenol did system) with the triple bond of acetylene (I → II-TS → III)
not react with acetylene, while in the presence of KF, the for- requires overcoming a high activation barrier of ΔE‡
=
mation of the vinylation product was detected. The more reac- 48.6 kcal mol−1 (Fig. 7A).
tive benzyl alcohol reacted with acetylene in the absence of KF,
Theoretical calculations have shown that both reagents
although a higher yield was obtained in the presence of KF. (ROH and acetylene) indeed do coordinate to the fluoride
anion (Fig. 7). Hydrogen bonding with the hydroxyl group and
the acetylenic proton resulted in the formation of the linear
intermediate complex I-F. Starting from the compound I-F, a
computational study has revealed two possible pathways
(Fig. 7B): (1) the reaction with the fluoride anion remaining co-
ordinated to the acetylenic proton (II-TS-F); and (2) the reac-
tion involving the interaction of the fluoride anion with the
hydroxyl group (IV-TS-F). In the first case, the activation
barrier of the I-F → II-TS-F → III-F transformation was
increased to ΔE‡ = 55.4 kcal mol−1, reflecting an increase in
Fig. 5 Fluoride-mediated activation of calcium carbide: formation of
CaF2 in two- and three-component reactions with KF in DMSO.
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Fig. 7 Mechanistic studies with theoretical calculations: (A) hydroxyl group addition to acetylene and (B) fluoride-mediated hydroxyl group addition
to acetylene (energy calculations at the CCSD(T)/6-311++G(d,p) level, geometry optimization at the PBE1PBE/6-311++G(d,p) level, and solvent
effect accounted for at the SMD level;22 for a visual comparison of activation barriers, the energies of I and I-F were set to 0.0 kcal mol−1 on the
potential energy surfaces (A) and (B); the energy changes ΔE = −40.8 kcal mol−1 for isolated molecules and −8.2 for DMSO medium were calculated
for the reaction: I + F− → I-F (Fig. S5 and S6†); the fluoride-containing anion I-F is regenerated at point III-F by reaction of F− with I. See the ESI† for
the details.
the negative charge of the alkyne unit, which hampered
nucleophilic addition.
After studying a small model system, the calculations
involving phenol as a substrate were carried out using the
Remarkably, the hydrogen bonding between the hydroxyl same theory level (the CCSD(T)/6-311++G(d,p) level for energy
group and the fluoride anion greatly reduces the activation and the SMD method to account for the DMSO solvent
barrier of the I-F → IV-TS-F → III-F transformation to ΔE‡
=
effect). The calculated energy surfaces have revealed the key
33.3 kcal mol−1, likely because of an increase in the nucleophi- trends of the investigated vinylation process (Fig. 8). The
licity of the oxygen atom. The overall process is exothermic by direct reaction between phenol and acetylene (I → II-TS → III)
ΔE‡ = −27.3 kcal mol−1 (Fig. 7B). The same conclusions were required overcoming a much larger activation barrier ΔE‡
=
made upon the analysis of the ΔH and ΔG energy surfaces.22 57.5 kcal mol−1 (Fig. 8A) as compared to the aliphatic alcohol
We also carried out the theoretical modeling of the process ΔE‡ = 48.6 kcal mol−1 (Fig. 7A). Optimized geometries
involving Cl− instead of F− and found the calculated energy showed more efficient interaction of the RO group with an
barrier for the I-Cl → IV-TS-Cl → III-Cl transformation to be acetylene carbon atom in the case of the R = Me substituent
ΔE‡ = 37.1 kcal mol−1. The results agree with the experimental as compared with the R = Ph substituent in the transition
findings, where the activating effect of the chloride anion was state II-TS (the C3–O1 distance is 1.500 Å for R = Me and
observed to be noticeably less than that of the fluoride anion 2.076 Å for R = Ph). The results are in agreement with experi-
(Table 1).
mental findings, where a lower reactivity of phenols as com-
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Fig. 8 Mechanistic studies of acetylene vinylation with phenol using theoretical calculations: (A) addition of a hydroxyl group of phenol to acetylene
and (B) fluoride-mediated addition of a hydroxyl group of phenol to acetylene (energy calculations at the CCSD(T)/6-311++G(d,p) level, geometry
optimization at the PBE1PBE/6-311++G(d,p) level, and the solvent effect accounted for at the SMD level; the energies of I and I-F were set to
0.0 kcal mol−1 for comparative purposes similar to the previous reaction, see caption to Fig. 7.
pared to aliphatic alcohols was observed. The fluoride-
mediated activation of the hydroxyl group significantly
Conclusions
decreased the barrier height to ΔE‡ = 34.2 kcal mol−1 for the To summarize, we have developed an efficient procedure for
I-F → IV-TS-F → III-F pathway (Fig. 8B). Thus, fluoride- the preparation of vinyl ethers from alcohols and phenols
mediated activation makes the process feasible under studied using a simple CaC2/KF system. The procedure allows the
conditions in total agreement with the experimental direct and cost-efficient formation of important H2CvCH–O-
observations.
building blocks under easy to use conditions (without the
Of course, the computational study deals with a model involvement of high pressure acetylene). Two areas of appli-
system and may be subject to some limitations in accuracy. cation have been explored in the present study. First, impor-
Nevertheless, the calculated energy surfaces and the revealed tant vinylic monomers of aliphatic and aromatic alcohols have
relative trends clearly confirm the advantage of the F−- been synthesized (2a–2q), which are of much interest for
mediated addition of the hydroxyl group to an alkyne. The materials science and industrial applications. Second, mild
unique nature of fluoride substantially reduced the energy experimental conditions and a high functional tolerance make
barrier and facilitated the transformation of interest.
the methodology suitable for the post-modification of complex
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biologically active molecules and drugs (2s–2w) using calcium A typical procedure for the vinylation of biologically active
carbide as an easily available reagent. The developed approach molecules (for the synthesis of 2s, 2t, 2v and 2w)
provides a new methodology for the vinylation of biologically
KOH (2.0 mmol, 112 mg), substrate (50 mg), KF (4.0 mmol,
active molecules and pharmaceutical substances, leading to
232 mg) and freshly powdered calcium carbide (2.0 mmol,
the formation of highly demanded vinyl ethers. These pro-
128 mg) were added to a reaction tube (volume: 7 mL) with
ducts are of great interest for the preparation of well-defined
1.5 mL of dry DMSO. After stirring the mixture at room temp-
erature for 5 min, water (4.0 mmol, 72 µL) was added. The
tube was sealed, and the mixture was heated at 130 °C for 3 h
and multifunctional drug-containing polymers.
Two fundamentally important findings were revealed in the
present study: the etching of the calcium carbide surface by
with vigorous stirring. The reaction mixture was cooled to
the fluoride ions and the fluoride-mediated activation of alco-
25 °C and extracted with hexane (3 × 4 mL), and the collected
hols for the nucleophilic transformations. A combination of
hexane layers were dried under vacuum to give a pure product
(see Fig. 3 for the yields).
CaC2/KF can be considered as an efficient replacement of
high-pressure gaseous acetylene, which is difficult to handle in
the laboratory. Moreover, the usage of CaC2/KF as an acetylene
surrogate demonstrated enhanced reactivity of the CuC bond.
Monovinylation of estradiol
KOH (2.0 mmol, 112 mg), estradiol (50 mg), and freshly pow-
dered calcium carbide (2.0 mmol, 128 mg) were added to a
reaction tube (volume: 7 mL) with 1.5 mL of dry DMSO. After
stirring the mixture at room temperature for 5 min, water
(4.0 mmol, 72 µL) was added. The tube was sealed, and the
mixture was heated at 130 °C for 3 h with vigorous stirring.
The reaction mixture was cooled to 25 °C and extracted with
hexane (3 × 4 mL), purified with chromatography and dried
under vacuum to give a pure product. Estradiol monovinyl
ether (2u) was obtained as white crystals (45 mg, 74%).
A mechanistic study involving theoretical calculations has
shown a significant decrease of the activation barrier of the
vinylation reaction in the fluoride-mediated process.
Undoubtedly, these novel findings will open several new
opportunities in synthetic transformations. The application of
an easy to weigh and handle solid “acetylene reagent” (a com-
bination of CaC2 and KF) may introduce a new direction in the
well-known and powerful acetylene chemistry.
Experimental part
A typical procedure for the vinylation of phenols (synthesis of
Further purification of the products
Typically, after evaporation of hexane the vinylated products
were obtained in high purity (see the ESI†). For further purifi-
cation, if required, the products can be distilled under reduced
pressure. In general, purification via column chromatography
on silica is not suggested due to sensitivity of the vinyl ethers
towards undergoing rapid polymerization or degradation
(some products are stable, however, and can be purified by
chromatography, see the ESI†). Several vinyl ethers become
highly unstable in the pure form upon drying and undergo
fast polymerization, such products may be stabilized by
dilution with pentane or hexane and stored in solution.
2a, 2j–2p, 2z)
K2CO3 (0.5 mmol, 69 mg), alcohol (1.0 mmol), KF (4.0 mmol,
232 mg) and freshly powdered calcium carbide (2.0 mmol,
128 mg) were added to a reaction tube (7 mL) with 1.5 mL of
dry DMSO. After stirring at room temperature for 5 min, water
(4.0 mmol, 72 µL) was added, the tube was sealed, and the
mixture was heated at 130 °C for 3 h with vigorous stirring.
After cooling to 25 °C, the mixture was extracted with hexane
(3 × 4 mL), and the collected hexane layers were concentrated
under reduced pressure (see Fig. 3 for the yields).
A typical procedure for the vinylation of aliphatic and benzylic
alcohols (synthesis of 2b–2i and 2q)
Electron microscopy study
Before the measurements, the samples were mounted on a
25 mm aluminum specimen stub and fixed by conductive
double-sided tape. Coating with a thin film (10 nm) of palla-
dium was performed using the magnetron sputtering method.
The observations were carried out using a Hitachi SU8000
field-emission scanning electron microscope (FE-SEM). Images
were acquired in the secondary electron mode at a 2 kV acceler-
ating voltage and a working distance of 4–5 mm. The mor-
phology of the coated samples was studied, adjusting for the
metal coating surface effects. EDS-SEM studies were carried
out using an Oxford Instruments X-max EDX system, with
spectra acquired at a 10 kV accelerating voltage. For the quanti-
KOH (1.0 mmol, 69 mg), alcohol (1.0 mmol), KF (4.0 mmol,
232 mg) and freshly powdered calcium carbide (2.0 mmol,
128 mg) were added to a reaction tube (7 mL) with 1.5 mL of
dry DMSO. After stirring at room temperature for 5 min, water
(4.0 mmol, 72 µL) was added, the tube was sealed, and the
mixture was heated at 130 °C for 3 h with vigorous stirring.
After cooling to 25 °C, the mixture was extracted with hexane
(3 × 4 mL), and the collected hexane layers were concentrated
under reduced pressure (see Fig. 3 for the yields).
Scaling of the experimental procedure
The procedure was successfully scaled to synthesize 2.72 g of tative analysis, internal standards were used. Before the
product 2q in a single run in 70% yield (see the ESI† for measurements, all samples were coated with a thin film
details).
(15 nm) of carbon using a Cressington 208 carbon coater.
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Computational study
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For all optimized structures, single-point CCSD(T)23 calcu-
lations involving the 6-311++G(d,p) basis set were performed
in a vacuum and in DMSO (the SMD method to account for
the effect of the solvent). All structures were optimized by the
PBE1PBE24 DFT method with the 6-311++G(d,p) basis set25
(Grid = UltraFine). Calculations in DMSO medium were per-
formed by the SMD continuum solvation model.26 Molecular
structures were optimized in DMSO medium. For all mole-
cules, the normal mode analysis was carried out at the DFT
level, and all transition states have one imaginary frequency
corresponding to the hydroalkoxylation reaction. The validity
of all transition states was confirmed by intrinsic reaction
coordinate (IRC) calculations.27 Only the essential narrative of
the calculated data is discussed in the article, see the ESI† for
details. The Gaussian 09 program was used for all
calculations.28
4 W. Reppe, Justus Liebigs Ann. Chem., 1956, 601, 81.
5 Selected recent reviews: (a) B. M. Trost and C.-J. Li, Modern
Alkyne
Chemistry:
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and
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N. B. Kurmankulov, K. B. Yerzhanov and V. M. Dembitsky,
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Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, 2008.
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(a) R. K. Sharma and J. L. Fry, J. Org. Chem., 1983, 48, 2112;
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Competing financial interests
The authors declare no competing financial interests.
Acknowledgements
Synthetic studies were supported by the Russian Science
Foundation (grant 16-13-10301). GW acknowledges Saint
Petersburg State University for a postdoctoral fellowship (No
0.50.1186.2014). The authors also express their gratitude to the
Centre for Magnetic Resonance, X-ray Diffraction Center, the
Centre for Chemical Analysis and Materials Research and the
Interdisciplinary Center for Nanotechnology (Saint Petersburg
State University). Mechanistic studies using theoretical calcu-
lations and microscopy were supported by Russian Science
Foundation (RSF grant 14-50-00126). The authors thank Dr Yan
Zubavichus and Victor Khrustalev for carrying out XPD analysis.
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