Organocatalytic alkynylation of aldehydes and ketones under phase-transfer catalytic conditions

Article abstract of DOI:10.1002/ejoc.200500064

We developed alkynylations of various aldehydes and ketones under practical phase-transfer conditions at room temperature. The straightforward methodology combines one-pot synthesis and simple workup with good to excellent yields for propargylic alcohols derived from aliphatic aldehydes and ketones. Even aromatic aldehydes and ketones, could be transformed to the corresponding propargylic alcohols in somewhat lower yields. The yield depending on the amount of PT catalyst and NaOH concentration was also determined. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005).

Full text of DOI:10.1002/ejoc.200500064

SHORT COMMUNICATION
Organocatalytic Alkynylation of Aldehydes and Ketones under Phase-Transfer
Catalytic Conditions
[
a]
[a]
Torsten Weil and Peter R. Schreiner*
Keywords: Alkynylation / C–C coupling / Organocatalysis / Phase-transfer catalysis / Propargylic alcohols
We developed alkynylations of various aldehydes and
ketones under practical phase-transfer conditions at room
temperature. The straightforward methodology combines
one-pot synthesis and simple workup with good to excellent
yields for propargylic alcohols derived from aliphatic alde-
hydes and ketones. Even aromatic aldehydes and ketones
could be transformed to the corresponding propargylic
alcohols in somewhat lower yields. The yield depending on
the amount of PT catalyst and NaOH concentration was also
determined.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
Introduction
preparation of ammonium bases should simplify this pro-
cedure by not having to use DMSO as the solvent (from
which the dimsyl anion may be generated in situ) and by
having a straightforward two-phase separation, we envi-
sioned a phase-transfer catalytic (PTC) protocol for this re-
action.
The nucleophilic addition of alkynes to aldehydes and
ketones is an essential organic C–C coupling reaction that
provides propargylic alcohols as versatile intermediates for
[
1,2]
organic synthesis.
Metal-catalyzed additions of alkynes
to carbonyl compounds with stoichiometric amounts of or-
ganometallics (e.g., organolithium, Grignard reagents) are
typically employed. Only a few reports demonstrate the
Results and Discussion
catalytic activation of an alkyne derivative and subsequent
addition to a carbonyl compound.[
3–7]
These alternative
The use of strong alkaline bases for the title reaction is
not new. The original report on this type of transforma-
routes involve either acid-base reactions of strong alkaline
bases, or transition metal complexes with the deployed al-
kyne. Virtually none of the published protocols are univer-
sally applicable to aliphatic as well as aromatic aldehydes
and ketones. Using potassium tert-butoxide, only aliphatic
ketones can be transformed to the corresponding propar-
gylic alcohols with moderate to good yields,[ whereas alky-
tion – often referred to as the “Favorskii reaction”– utilizes
[9,10]
KOH.
This reaction does not involve an acid–base equi-
librium involving a potassium acetylide; the reaction is as-
sumed to proceed through the formation of a potassium
[10]
hydroxide–acetylene complex. Knochel et al. showed that
7]
[4]
the more soluble CsOH·H O can also be utilized. Neither
2
nylations, using zinc reagents, are limited to aldehydes, but
approach utilizes the PTC concept, and NaOH was deemed
give good to excellent yields.[
5,6,8]
CsOH·H O as the base
2
[10]
unsuitable as the base for this purpose. Since we did not
can be used to transform aliphatic aldehydes and ketones
into the resulting ynols also with good to excellent yields.
foresee any obvious problems with the use of NaOH as the
inorganic base, in combination with a tetraalkyl ammonium
salt as the PT catalyst, we put our proposal to test. Utilizing
a two-phase system consisting of an aqueous sodium hy-
droxide layer, an organic layer with fluorobenzene and a
quaternary ammonium salt as the PT catalyst, we devel-
oped a mild and efficient method for the organocatalytic
alkynylation of a variety of aliphatic aldehydes and ketones
[
4]
While zinc derivatives in conjunction with chiral ligands af-
fect enantioselective alkynylations, reactions with alkali or
earth alkali bases generally cannot be conducted in a
stereoselective fashion.
A possible way to overcome these limitations has been
the use of a nonmetallic ammonium base (triton B) as cata-
lyst by Saito and coworkers: a variety of aldehydes and
ketones were transformed into propargylic alcohols with
moderate to good yields; propargylic alcohols derived from
aromatic aldehydes showed significant base-catalyzed re-
arrangement to the respective chalcones.[ As the in situ
(Scheme 1).
The two-phase reaction conditions with relatively low
base concentration in the organic layer reduce the forma-
tion of by-products resulting from aldol condensations or
Cannizzaro reactions. Various aliphatic aldehydes as well as
ketones (1a–1f) react cleanly with different alkynes (2a–2c)
to give the corresponding propargylic alcohols (3a–3k,
Table 1). Two slightly different methods A and B were em-
3]
[
a] Justus-Liebig-Universität, Institut für Organische Chemie,
Heinrich-Buff-Ring 58, 35392 Giessen, Germany
E-mail: prs@org.chemie.uni-giessen.de
Eur. J. Org. Chem. 2005, 2213–2217
DOI: 10.1002/ejoc.200500064
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2213

T. Weil, P. R. Schreiner
SHORT COMMUNICATION
factors, namely the concentration dependence of the PTC-
catalyst and base in these reactions.
Scheme 1. General alkynylation conditions.
Scheme 3. Proposed PTC alkynylation mechanism.
ployed; method A is typically used for aliphatic carbonyl
compounds and acetophenones, whereas method B is more
advantageous for aromatic aldehydes.
Generally, the propargylic alcohols derived from ali-
phatic aldehydes and ketones with phenylacetylene were ob-
tained in good yields; methods A and B gave similar results.
As expected, aliphatic aldehydes react faster than aliphatic
ketones; non-enolizable 1d was converted fully after 24 h
The model reaction of cyclohexanone and phenylacety-
lene (entry 1) was optimized by varying parameters such
as catalyst concentration (Figure 1, left), concentration of
sodium hydroxide (Figure 1, right), reaction time, solvent,
ratio of carbonyl compound and alkyne, and mode of ad-
dition. Using dichloromethane instead of fluorobenzene for
entry 1 gave only 25% of 3a. Fluorobenzene and toluene
[
17]
are suitable solvents for PTC reactions.
In our experi-
(at 100% catalyst loading). Even enolizable carbonyl com-
ence, the higher dipole moment of fluorobenzene facilitates
the extraction of the ammonium compound into the or-
ganic phase; it also does not display many of the typical
side reactions often observed in dichloromethane. Figure 1
pounds showed no significant aldol condensation, with iso-
butyraldehyde being the only exception where we could iso-
late a by-product, identified as 6 (Scheme 2) in negligible
amounts (Ϸ 3%). Deactivated cyclopropyl ketones (4 and
(left) demonstrates that the overall reaction is phase-trans-
5) showed little (20%) or no conversion, respectively.
fer catalytic: while a minimum concentration of about 10
mol-% is required for satisfactory yields within 24 h, it is
noteworthy that the reactions do run to completion at any
catalyst concentration (at the expense of longer reaction
times). Apparently up to a catalyst concentration of about
10–15 mol-% the rate-limiting step is the transport of OH
Scheme 2. Deactivated cyclopropyl ketones and by-product.
into the organic phase promoted by the PT catalyst. Higher
catalyst concentrations result in a change of mechanism;
THP-protected propargylic alcohols as the alkyne com- the rate-limiting step is now likely to be the nucleophilic
ponent can also be utilized but give somewhat lower yields addition of the acetylide anion to the carbonyl compound.
(
entries 7–9). The resulting protected ynols with an ad- From this point on an increase of catalyst concentration
ditional functional group are also useful building blocks for has only little effect.
organic synthesis. 1-Hexyne reacted slightly more effectively A practical protocol therefore utilizes 15–20 mol-% PTC-
entries 10 and 11). catalyst and adjustable reaction times. As the in situ genera-
(
Aromatic ketones and aldehydes gave propargylic tion of the ammonium hydroxide takes place in form of
alcohols in moderate yields (entries 12–14), although this is equilibrium reactions at the phase boundary (Scheme 3),[
not a problem of reactivity. Rather we found that under its relative concentration in the organic phase depends on
these conditions significant amounts of polymers and un- the absolute concentration of aqueous sodium hydroxide.
18]
identified and inseparable by-products form.
This is evident from the yield dependence of 3a on the
Surprisingly little is known about phase-transfer catalytic NaOH concentration (Figure 1, right) that must exceed 30
mechanisms, probably owing to the fact that multicompo- mass-% for an efficient reaction to occur. For this purpose
nent mixtures are difficult to analyze.[13–16] As a working we determined the pH and thus the relative concentration
mechanistic hypothesis, we refer to Scheme 3 that shows the of hydroxide anions in the organic phase with a simple ex-
deprotonation of the alkyne, coordination to the PT-cata- periment. We simulated the reaction conditions by stirring
lyst, and subsequent reaction with the carbonyl compound. 10 mL of fluorobenzene, 10 mL 50% aqueous sodium hy-
With the available data we cannot distinguish between ex- droxide, and 15 mmol of TBABr for two hours to reach
traction and interphase mechanisms. The carbanion-ammo- equilibrium. Then we separated the organic layer and ex-
nium ion pairs were also proposed in the reactions with tracted the dissolved salts with 10 mL of distilled water.
[
3]
triton B; our present work lends further evidence to this Measuring the pH (12.51–13.05± 0.05) and the volume of
mechanistic suggestion. We therefore addressed two key the resulting aqueous phase (including the former in-
2214
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2005, 2213–2217

Organocatalytic Alkynylation of Aldehydes and Ketones under PTC Conditions
Table 1. PTC/organocatalytic alkynylation of selected aldehydes and ketones.
SHORT COMMUNICATION
[
a] Method A: 7 mmol alkyne, 8.4 mmol carbonyl compound, 1.4 mmol [20 mol-%] TBABr; method B: 14 mmol alkyne compound, 7
mmol carbonyl compound, 1.4 mmol [20 mol-%] TBABr. For details see experimental section. [b] 1:1 mixture of diastereomeric propar-
gylic alcohols.
–
terphase) and conversion to the volume of OH gave an NaOH (1 mol/L) deprotonates weak acids up to pKa Ϸ 14–
–
average relative concentration of c[OH ] = 0.11 mol/L. 15, the “naked” hydroxide ion is, owing to loss of its solvat-
These experiments were repeated three times.
ing water molecules, highly activated: extracted into the or-
The hydroxide anion is much more basic in the organic ganic phase it is able to deprotonate reactants up to a pKa
[
17]
phase than in water. Whereas an aqueous solution of of about 35!
www.eurjoc.org
Consequently alkynes with pKa Ϸ 22–26
Eur. J. Org. Chem. 2005, 2213–2217
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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T. Weil, P. R. Schreiner
SHORT COMMUNICATION
Figure 1. (left) Yields of 3a vs. concentration of phase-transfer catalyst TBABr [x mol-%]; 50 mass-% NaOH; reaction time 24 h. (right)
Yields of 3a vs. NaOH concentration [y mass-%]; 100 mol-% catalyst; reaction time 24 h.
phenylacetylene: 23.2–23.7[19]) are easily converted into slightly yellowish oils. All propargylic alcohols prepared are known
in the literature.
(
their corresponding anions that can subsequently act as nu-
–
cleophiles. This remarkably behaviour of OH is driven to Method B: To an intensively stirred mixture consisting of 14 mmol
alkyne compound, 1.4 mmol (20 mol-%) TBABr, 3 mL of fluoro-
extreme in PTC halogenation reactions of alkanes, where it
benzene and 5 mL of aqueous sodium hydroxide (50%), a solution
functions even as electron donor, i.e., as a reduction
agent.
[
17,20–22]
of 7 mmol carbonyl compound in 2 mL of fluorobenzene was
added over a period of 2 hours via an addition funnel. Reaction
time and workup are identical to method A.
Side product (new compound):
Conclusions and Outlook
4
,4,6-Trimethyl-1-phenylhept-1-yne-3,5-diol (6): Colorless solid,
We present a mild and effective organocatalytic PTC pro- m.p. 98.5 °C, R = 0.23 (ethyl acetate/hexane, 1:3), 3% isolated pro-
tocol for the alkynylation of various aldehydes and ketones. duct. H NMR (400 MHz, CDCl ): δ = 7.44 (m, 2 H, CH), 7.32
m, 3 H, CH), 4.55 (s, 1 H, CH), 3.57 (d, J = 2.3 Hz, 1 H, CH),
.73 (br. s, 2 H, OH), 2.03 (m, 1 H, CH), 1.17 (s, 3 H, CH ), 1.05
d, J = 6.8 Hz, 3 H, CH ), 1.03 (s, 3 H, CH ), 0.97 (d, J = 6.8 Hz,
) ppm. C NMR (100 MHz, CDCl ): δ = 131.7, 128.4,
28.3, 122.6, 88.4, 86.2, 82.3, 73.3, 43.1, 29.5, 23.2, 21.7, 16.4, 16.2
f
1
3
(
2
Best results are obtained for aliphatic ketones and non-en-
olizable aldehydes; the alkyne component can be varied
widely and can be aromatic or aliphatic. As the coordina-
tion between the PT-catalyst and the carbanion is implied
in this and other PTC reactions, we also hope to develop
stereoselective alkynylations.[23–25] Experiments in this di-
rection are currently under way and will be reported in due
course.
3
(
3
1
3
3
1
3
H, CH
3
3
ppm. IR (KBr): ν˜ = 3236.3, 2964.3, 2360.9, 1597.0, 1490.8, 1332.8,
–1
1
9
045.8 cm . C16
.18.
22 2
H O : calcd. C 78.01, H 9.00; found C 77.86, H
Acknowledgments
Experimental Section
This work was supported by the Fonds der Chemischen Industrie.
All chemicals were purchased from Acros Organics, Aldrich, and
Lancaster in highest purities available; liquid aldehydes were freshly
distilled through a 10 cm Vigreux column prior use, solid aldehydes
were used without further purification. Reactions were monitored
with a HP 5890 GC spectrometer with a HP 5971 mass selective
detector. 1H-NMR and C-NMR spectra were recorded with a
Bruker AM 400 spectrometer using TMS as internal standard;
chemical shift values are given in ppm. IR spectra were measured
with a Bruker IFS 25 spectrometer. Elemental analysis (CHN) was
determined with a Carlo Erba EA 1106.
[
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2216
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Eur. J. Org. Chem. 2005, 2213–2217

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SHORT COMMUNICATION
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