Fluoride-assisted activation of calcium carbide: A simple method for the ethynylation of aldehydes and ketones

Article abstract of DOI:10.1021/acs.orglett.5b01219

The fluoride-assisted ethynylation of ketones and aldehydes is described using commercially available calcium carbide with typically 5 mol % of TBAF·3H₂O as the catalyst in DMSO. Activation of calcium carbide by fluoride is thought to generate an acetylide "ate"-complex that readily adds to carbonyl groups. Aliphatic aldehydes and ketones generally provide high yields, whereas aromatic carbonyls afford propargylic alcohols with moderate to good yields. The use of calcium carbide as a safe acetylide ion source along with economic amounts of TBAF·3H₂O make this procedure a cheap and operationally simple method for the preparation of propargylic alcohols.

Full text of DOI:10.1021/acs.orglett.5b01219

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Letter
pubs.acs.org/OrgLett
Fluoride-Assisted Activation of Calcium Carbide: A Simple Method
for the Ethynylation of Aldehydes and Ketones
Abolfazl Hosseini,⊥ Daniel Seidel,*,‡ Andreas Miska,§ and Peter R. Schreiner*,⊥
⊥Institute of Organic Chemistry, Justus-Liebig University, Heinrich-Buff-Ring 58, 35392 Giessen, Germany
‡Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854,
United States
§Institute of Inorganic and Analytical Chemistry, Justus-Liebig University, Heinrich-Buff-Ring 58, 35392 Giessen, Germany
S
* Supporting Information
ABSTRACT: The fluoride-assisted ethynylation of ketones and aldehydes
is described using commercially available calcium carbide with typically 5
mol % of TBAF·3H2O as the catalyst in DMSO. Activation of calcium
carbide by fluoride is thought to generate an acetylide “ate”-complex that
readily adds to carbonyl groups. Aliphatic aldehydes and ketones generally
provide high yields, whereas aromatic carbonyls afford propargylic alcohols
with moderate to good yields. The use of calcium carbide as a safe acetylide
ion source along with economic amounts of TBAF·3H2O make this procedure a cheap and operationally simple method for the
preparation of propargylic alcohols.
long neglected safe and cheap source for the formation of
2006, Cheng and co-workers reported the synthesis of
symmetric diaryl ethynes from aryl bromides using CaC2.13
Recently, Kuang et al. reported the triazolation of aryl azides
using calcium carbide as the acetylene source, providing 1-
monosubstituted aryl 1,2,3-triazoles in moderate to good
yields.14 Zhang et al. developed several new methods for
utilizing CaC2 in organic synthesis.9,10c,e They suggested that
the addition of small amounts of water can speed up reactions
by increasing the solubility of CaC2. Using this strategy they
synthesized enaminones and propargylic amines through a
three-component coupling reaction of CaC2, aryl aldehydes,
and amines.10a Recently, the same group reported a convenient
method for the preparation of propargyl alcohols by reacting
CaC2 with aldehydes and ketones in the presence of 50 mol %
of cesium carbonate in aqueous DMSO at 60 °C.10c Although
moderate to good yields were obtained, the high cost of
Cs2CO3 and very large amounts of metal contaminated waste
limit the application of such a method. In addition, this method
is not applicable to aromatic aldehydes and requires heating.
Other methods involve the use of super bases, such as KOH/
H2O/DMSO,15 Bu4NBr/KOH/toluene,7c KOH/EtOH/H2O/
DMSO,16 and Bu4NOH/H2O/DMSO,17 for the addition of
acetylides to carbonyls. However, these methods suffer from
low yields, the use of a large excess of acetylene gas, equimolar
or excess amounts of base as well as molecular sieves, and
pretempering of the reaction solutions. We previously reported
the use of phase-transfer conditions, TBABr/fluorobenzene/aq.
sodium hydroxide as an organocatalytic system for the
alkynylation of aldehydes and ketones.18 We now report a
A
sp−sp3 carbon bonds derives from the use of calcium
carbide (CaC2) through the addition of acetylides to carbonyl
compounds. Although this strategy has been widely explored
since the first preparations of propargyl alcohols in 19001 using
the base-mediated addition of acetylene to carbonyl com-
pounds,2 further developments would be desirable in view of
the ubiquitous availability of CaC2 at industrial scale. Propargyl
alcohols are valuable intermediates in organic synthesis. They
have been widely used to prepare natural products3 and
biologically active compounds4 and to obtain valuable
intermediates through coupling reactions,5 additions to triple
bonds,6 and many more. Of the many available methods for
their preparation, metal acetylides have been recognized as
being particularly useful. Although metal acetylides readily add
to carbonyl compounds, this approach often requires the use of
1 equiv of a strong base, low temperatures, dry solvents, and a
deprotection step when, for instance, commonly employed
trimethylsilyl acetylene is used, which makes such trans-
formations less desirable at large scale.5,7
CaC2 on the other hand is an acetylide source that was
prepared first by Wohler in 1862.8 It was used in carbide lamps,
̈
welding, and early automobile headlights.9 Due to the low
solubility of CaC2 in organic solvents and, consequently, its
poor reactivity,10 it is mainly used for the production of
acetylene gas and as a drying agent in organic synthesis. The
low reactivity of solid CaC2 can be attributed to its insolubility
deriving from its highly stable lattice structure. “Monomerized”
calcium acetylide, prepared by dissolving calcium metal and
acetylene in liquid ammonia, readily reacts with a variety of
electrophiles to give the corresponding adducts;11 however,
only a few examples have been described.12 Similarly, there are
only a few reports on the use of CaC2 for synthetic purposes. In
Received: April 26, 2015
© XXXX American Chemical Society
A
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Letter
novel method for the mild alkynylation of various aldehydes
and ketones, utilizing commercial calcium carbide (97% purity)
in combination with a fluoride source in DMSO/water.
Initially, cyclohexanone was used as a model substrate to
optimize the reaction conditions (Table 1). In the absence of
2a using Cs2CO3 (0.5 equiv),10c TBAF·3H2O appears to be a
superior catalyst in this reaction (Table 1, entry 19).
Encouraged by these results, we further optimized the reaction
conditions (Table S1, Supporting Information (SI)). With the
optimized reaction conditions in hand (termed method A), the
scope and limitation of the reaction were examined (Table 2).
Table 1. Evaluation of Reaction Conditions for the
Ethynylation of Cyclohexanone
a
Table 2. Alkynylation of Aldehydes and Ketones Using
TBAF·3H2O and Calcium Carbide As Acetylene Source in
a
DMSO
c
b
no.
1
conv (%)
t [h]
water (equiv)
additive (equiv)
d
NR
22
22
22
3
3.34
3.34
3.34
3.34
−
−
−
e
2
NR
5
3
KF (0.50)
f
4
57
KF (3.00)
5
NR
99
12
2
KF (3.00)
6
3.34
3.34
3.34
3.34
3.34
2.10
0.60
3.34
3.34
3.34
3.34
3.34
3.34
3.34
CsF (0.50)
7
29
3.5
2
CsF (0.05)
8
NR
NR
NR
99
ZnF2 (0.05)
9
2
CaF2 (0.05)
10
11
12
13
14
15
16
17
18
19
2
CaF2 (1.00)
3
TBAF·3H2O (0.70)
TBAF·3H2O (0.20)
TBAF·3H2O (0.20)
TBAF·3H2O (0.05)
TBACl (0.05)
TBABr (0.05)
TBAI (0.05)
71
8
99
1
95
2
NR
NR
trace
7
17
45
45
17
3
TBAAc (0.05)
Cs2CO3 (0.50)
26
a
Reaction conditions: 1a (1 mmol), CaC2 (3 mmol), DMSO (3 mL).
b
c
Total amount of water (from TBAF·3H2O and added water). GC
d
e
analysis (conversion of starting material). No reaction. Reaction
performed at 60 °C. Average of three runs.
f
a
Method A: substrate (1 mmol), CaC2 (2.7 mmol), water (2.27
additives, no product (2a) was obtained after 22 h, even at 60
°C (Table 1, entries 1 and 2). Upon adding KF (50 mol %), the
desired product 2a was obtained with a conversion of 5%
(Table 1, entry 3). The conversion to product 2a could be
improved to over 50% by using 3 equiv of KF, but the reaction
was not always reproducible (Table 1, entry 4), owing to the
low solubility of potassium fluoride in DMSO.19 It should be
noted that the reaction did not proceed in the absence of added
water even after long reaction times (Table 1, entry 5). With
0.5 equiv of CsF as the fluoride source, the reaction proceeded
efficiently to furnish the desired product 2a with excellent
conversion (Table 1, entry 6). However, in the case of using a
considerably more economic amount of CsF (5 mol %), 2a was
obtained with low conversion (Table 1, entry 7). Several other
fluoride salts were subsequently tested (Table 1, entries 8−14).
However, only tetrabutylammonium fluoride showed enhanced
activity compared to other fluoride sources (Table 1, entries
11−14). The reaction provided nearly quantitative access to 2a
using 70 mol % of TBAF·3H2O after 3 h without additional
water. The amount of TBAF·3H2O could readily be reduced to
5 mol % when water was added (95% of 2a, entry 14). No
catalytic activity was observed when other tetrabutylammonium
halides were employed, and only low conversion was reached
when tetrabutylammonium acetate was used as the catalyst
(Table 1, entries 15−18). In comparison to the preparation of
mmol), TBAF·3H2O (0.05 equiv), and DMSO (3 mL) at room
b
temperature. Isolated product yield (values in parentheses refer to
c
gram scale isolated yields). pKa of corresponding carbonyl substrate in
d
DMSO. dr: 2:1 (the diastereomeric ratio was determined by 1H
e
f
NMR). Not available. Isolated product yield after single recrystalliza-
tion.
The reaction of cyclohexyl aldehydes and ketones (1 equiv),
CaC2 (2.7 equiv), and water (2.27 equiv) in 3 mL of DMSO
with 0.05 equiv of TBAF·3H2O (0.5 M in DMSO) at room
temperature for 2 h afforded the corresponding ethynyl
alcohols 2a−c in high yields (>90%) (Table 2, entries 1−3).
No aldol products were observed in these cases according to
GC-MS analysis.
Upon scale-up, the ethylynation of 1a−c occurred cleanly
with a 5 mol % catalyst loading to give the corresponding
propargyl alcohols in high yields. Under the same reaction
conditions cyclopentanone failed to give the desired product
and the reaction afforded the aldol product instead. Although
the difference between the pKa values of cyclohexanone (26.4)
and cyclopentanone (25.8) in DMSO is small, we considered
the pKa of 26.4 for the carbonyl component as a lower limit to
avoid aldol condensation in the basic medium. It should be
pointed out that other factors might be relevant. For instance, it
is well-known that cyclohexanone reacts much more readily
B
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with nucleophiles than cyclopentanone, possibly because of
strain relief.20 Under the same conditions, the reaction of
aliphatic ketones (pinacolone and 3-pentanone with the pKa
values of 27.7 and 27.1, respectively) gave the ethynyl product
exclusively in good yields (Table 2, entries 4 and 5). The
reaction of 2-adamantanone under the optimal reaction
conditions gave the corresponding propargyl alcohol in 85%
isolated product yield (entry 6). Similarly, norcamphor
produced the desired 2-exo-ethynylbicyclo[2.2.1]heptan-2-ol
product in good yield (entry 7). Even highly unreactive (in
these types of transformations) benzaldehyde gave 1-phenyl-
propargyl alcohol (2h) in 32% isolated product yield (entry 8).
The standard reaction conditions (method A) were ineffective
for the alkynylation of acetophenone, very likely due to rapid
enolization of acetophenone.16,21 Therefore, newly optimized
conditions (method B) using acetophenone as a model
substrate (Table S2, SI) were used for the ethynylation of
carbonyl compounds with pKa values lower than 26. This also
allowed the conversion of cyclopentanone to the corresponding
product (Table 3, entry 2). In the case of 2-phenylpropion-
from estrone 3-methyl ether (cf. SI). Similarly, Stanolone can
be ethnylated with high yield using method A (Scheme 1) that
provides easier and more effective access to the desired product
than previously reported procedures.23 The product structure
was also confirmed by X-ray crystallography.
Scheme 1. Fluoride-Promoted Ethynylation of Steroids
Using Calcium Carbide
Table 3. Alkynylation of Challenging Substrates Using
TBAF·3H2O and Calcium Carbide As Acetylene Source in
a
DMSO
The reactivity of metal acetylides toward nucleophilic
additions is strongly influenced by their solubility, and it has
been demonstrated that addition of chelating agents may
increase their reactivity.24 In terms of mechanism, we note that
although calcium acetylide has been considered a monomeric
compound, its structure has not been firmly elucidated.
However, in the case of phenylacetylide, a structurally related
compound, a polymeric structure has been proposed that is
partially soluble and slowly depolymerizes in solution, probably
giving predominantly a dimer.25 At the same time, the ability of
calcium to form complexes with carbonyl compounds is well-
known,26 so it is likely that Ca···OC coordination also plays a
role in the reactions presented here. Second, calcium ate-
complexes bearing, for instance, hexamethyldisilazides have
been used for catalytic intramolecular hydroamination reac-
tions.27 Based on the results presented here and literature
reports, a suggested mechanism is illustrated in Scheme 2. The
reaction of water with solid calcium carbide gives ethynylcal-
cium hydroxide, which is activated with fluoride from TBAF·
3H2O to form the corresponding ate-complex 4. Complex 4
then attacks the carbonyl component (5) to give addition
product 6. Subsequently, the product complex 6 regenerates
a
Method B: substrate (1 mmol), CaC2 (12 mmol), water (25 mmol,
added over 2 h with a syringe pump), TBAF·3H2O (0.3 mmol), and
DMSO (3 mL) at room temperature. Isolated product yield. pKa of
b
c
d
corresponding carbonyl substrate in DMSO. Reaction performed at
e
65 °C. dr: 2:1 (the diastereomeric ratio was determined by 1H NMR).
f
g
Not available. Method C: substrate (1 equiv), CaC2 (2.7 equiv),
water (3.6 equiv), TBAF·3H2O (0.5 equiv), and DMSO (3 mL) at
room temperature.
Scheme 2. Suggested Mechanism for the Fluorine Catalyzed
Ethynylation of Aldehydes and Ketones with CaC2
aldehyde, the reaction required heating to 65 °C (Table 3,
entry 3). Diisopropyl ketone has proven unreactive with
method A, presumably due to significant steric hindrance and
deactivation of the carbonyl group through alkyl substitution.
However, it afforded 30% of the desired product using method
B at 65 °C (Table 3, entry 4).
Benzophenone was the least reactive ketone,22 and methods
A (no reaction) and B (10% conversion) proved unsuitable
even after long reaction times (up to 20 h). However,
increasing the amounts of TBAF·3H2O to 50 mol % provided
a 53% yield of isolated product 2m (Table 3, entry 5).
As a further application of our protocol, we used it for the
synthesis of pharmacologically active steroids. For instance, the
oral contraceptive pro-drug Mestranol can readily be prepared
C
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(f) Wang, J.; Zhu, H.-T.; Li, Y.-X.; Wang, L.-J.; Qiu, Y.-F.; Qiu, Z.-H.;
Zhong, M.-J.; Liu, X.-Y.; Liang, Y.-M. Org. Lett. 2014, 16, 2236.
the catalyst and liberates calcium salt 7 that is hydrolyzed to
produce product 2a upon workup. Importantly, the reaction did
not proceed with acetylene gas instead of calcium carbide with
our two protocols. Phenylacetylene, a more acidic alkyne,28
gave no conversion in the absence of calcium carbide even after
3 h. We thought that it might be possible to perform an acid−
base reaction through anion exchange in complex 4 (Scheme 2)
using phenylacetylene and concomitant release of acetylene gas.
Indeed, addition of cyclohexanone to a solution of phenyl-
acetylene under the conditions of method A afforded 1-
(phenylethynyl)cyclohexanol in 70% isolated product yield (see
SI for more details).
Although catalytic ethynylation of aldehydes and ketones has
previously been achieved, the efficient catalytic system
described here has the advantage of being cost-effective, safe,
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Experimental procedures, characterization data, and spectra for
all compounds, cif file of the X-ray structure of ethynyl-3,17β-
andro-stanediol. The Supporting Information is available free of
charge on the ACS Publications website at DOI: 10.1021/
acs.orglett.5b01219.
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AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: seidel@rutchem.rutgers.edu.
*E-mail: prs@org.chemie.uni-giessen.de.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
This work was supported in part by the U.S. Department of
Energy, Office of Science, Basic Energy Sciences, Materials
Sciences and Engineering Division, under Contract DE-AC02-
76SF00515. D.S. is grateful to the Alexander von Humboldt
Foundation for a research fellowship for experienced
researchers.
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