Base-catalyzed stereoselective vinylation of ketones with arylacetylenes: A new C(sp3)-C(sp2) bond-forming reaction

Article abstract of DOI:10.1002/chem.201000227

Alkylaryl- and alkylheteroarylketones, including those with condensed aromatic moieties, are readily vinylated with arylacetylenes (KOH/DMSO, 100°C, 1 h) to give regio- and stereoselectively the (E)-β-γ- ethylenic ketones ((E)-3-buten-1-ones) in 61-84% yi

Full text of DOI:10.1002/chem.201000227

DOI: 10.1002/chem.201000227
Base-Catalyzed Stereoselective Vinylation of Ketones with Arylacetylenes:
3
(sp2) Bond-Forming Reaction
À
A New C
(sp ) C
Boris A. Trofimov,* Elena Yu. Schmidt, Igorꢀ A. Ushakov, Nadezhda V. Zorina,
Elena V. Skitalꢀtseva, Nadezhda I. Protsuk, and Alꢀbina I. Mikhaleva[a]
Abstract: Alkylaryl- and alkylheteroarylketones, including those with condensed
aromatic moieties, are readily vinylated with arylacetylenes (KOH/DMSO, 1008C,
1 h) to give regio- and stereoselectively the (E)-b-g-ethylenic ketones ((E)-3-
À
Keywords: alkynes · C C bond for-
mation · ketones · superbases ·
vinylation
buten-1-ones) in 61–84% yields and with approximately 100% stereoselectivity.
3
À
This vinylation represents a new C
thetic potential.
(sp ) C
(sp2) bond-forming reaction of high syn-
Introduction
was the iridium-catalyzed cyclization of alkene–amides in
3
À
the cross-coupling reaction of an sp C H bond with an
alkene moiety.[5]
À
C C bond-forming reactions constitute the core of organic
chemistry. Further progress in this area will profoundly con-
tribute to the overall synthetic toolkit. Therefore, the efforts
to discover new reactions of this type or improve known
ones continue to gain pace. In recent years, particular atten-
Over the last few years, another series of papers devoted
3
À
to C
G
(sp2) bond-forming reactions, this time by the
addition of 1,3-dicarbonyl compounds to acetylenes in the
presence of InACTHNUTRGNEUNG
(OTf)3, appeared.[6] The intramolecular cycli-
À
À
tion has focused on the addition of the C H moiety to C C
multiple bonds.
zation of acetylenes, which have similar strong CH-acid moi-
À
eties, for example H C
N
Most recently, the addition of cyclic ethers to arylacety-
lenes in the presence of a tert-butyl hydroperoxide/CuBr
system has been reported.[1] This work was preceded by a
(nBuLi)[7] or SnCl4/Et3N (TiCl4/Et3N)[8] was described.
In 1999, it was found that the superbase-catalyzed
(CsOH·H2O/N-methylpyrrolidinone) addition of phenylace-
tonitrile carbanions to phenylacetylene led to a mixture of
E/Z isomers of the adducts.[9] Previously, vinylation of simi-
lar CH-acids (2-phenylbutyronitrile[10] and N-(benzylidene)-
glycinonitrile[11]) with acetylenes under basic phase-transfer
conditions was performed. Earlier, stronger CH-acids, such
as malonic nitriles and esters, were vinylated at the carbon
atom with acetylene in the presence of cadmium and zinc
stearates at high temperature (185–1958C).[12] In the KOH/
DMSO superbase system, 2-nitropropane and nitrocyclohex-
ane added to acetylene to give the corresponding nitroal-
kenes.[13] In the sixties, base-catalyzed additions of polynitro-
fluoroalkanes to activated acetylenes, for example propy-
noates, were realized.[14]
communication about the ruthenium-catalyzed addition to
alkenes of sp3 C H bonds adjacent to a nitrogen atom.
[2]
À
This pioneering publication was followed by more recent
studies that showed that sp C H bonds adjacent to a heter-
oatom (nitrogen, oxygen, or sulfur) were more reactive than
those next to a carbon atom and diverse catalytic systems
were suggested for sp C H bond cleavage. In this period,
the catalytic oxidative cross-coupling of active methylene
3
À
3
[3]
À
3
(sp2)
À
compounds with alkenes and alkynes to form C
(sp ) C
3
[4]
À
and C
(sp ) C(sp) bonds was developed. Also published
[a] Prof. B. A. Trofimov, Dr. E. Y. Schmidt, Dr. I. A. Ushakov,
Dr. N. V. Zorina, E. V. Skitalꢀtseva, Dr. N. I. Protsuk,
Prof. A. I. Mikhaleva
Our scrutinized search of the literature gave not one hit
concerning the direct base-catalyzed vinylation of ketones
with acetylenes. The only report was a brief letter in the six-
ties on the radical-catalyzed addition of cyclohexanone to
acetylene (di-tert-butyl peroxide, 1508C, 10 atm) to afford 2-
vinylcyclohexanone in a negligible yield (2.6%) character-
ized by just the Raman spectrum.[15]
A. E. Favorsky Irkutsk Institute of Chemistry
Siberian Branch, Russian Academy of Sciences
1 Favorsky Str., 664033 Irkutsk (Russia)
Fax : (+7)3952-419346
E-mail: boris_trofimov@irioch.irk.ru
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201000227.
8516
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FULL PAPER
The reasons why the base-catalyzed vinylation of such a
large and fundamental class of organic compounds as ke-
tones remains so far unattained are of both theoretical and
experimental nature. It is commonly accepted that an eno-
late anion is unreactive towards unactivated multiple bonds
on thermodynamic and kinetic grounds, the major concern
being the unfavorable thermodynamics due to the formation
of less stable carbanions from more stable oxygen-centered
(enolate) anions.[6c] Among the experimental arguments
against ketone vinylation with acetylene in the presence of a
base are the smooth base-catalyzed ethynylation of ketones
to yield acetylenic alcohols (Favorsky reaction),[16] the easy
autocondensation of ketones, and the deprotonation of ter-
minal acetylenes, such as CH-acids, to generate carbanions.
Meanwhile, these considerations disregard the role of alkali-
metal cations, which may exert electrophilic assistance and
stabilize emerging carbanions. Quantum chemical calcula-
tions[17] confirm that alkali-metal cations facilitate nucleo-
As expected, as shown in the example of ketone 1 and
acetylene 9, at 08C (all other conditions as given in Table 1),
the reaction gave the Favorsky acetylenic alcohol (2,4-di-
phenyl-3-butyn-2-ol) only, whereas at room temperature, a
mixture of this alcohol and adduct 13 (E/Zꢁ1:1) in a ratio
1
of 4:1 (as determined by H NMR spectroscopy monitoring)
had already formed, the conversion of ketone 1 not exceed-
ing 60%. In accordance with the above considerations
(Scheme 1), at 608C only adduct 13 (E/Zꢁ3:2) was detected
in the reaction mixture, the conversion of ketone 1 reaching
70%.
The KOH/reactant molar ratio has a key effect on the re-
action results: with 10 mol% of KOH no products were de-
tected (1008C, 1 h), whereas with 50 mol% of KOH, the
conversion of 1 was 25% and solely adduct 13 was discerni-
1
ble (by H NMR spectroscopy monitoring).
Apparently, the reaction proceeds through the intermedi-
ate dienolates A, which upon aqueous workup afford ad-
ducts 13–24. With 4-nitrophenylacetylene (12), 2-(4-nitro-
phenyl)-5-phenylfuran (25) and 2-(4-nitrophenyl)-5-naph-
thylfuran (26) were isolated instead of the anticipated ad-
ducts. Obviously, in this case, the corresponding intermedi-
ates A cyclize to dihydrofurans B that are further oxidized
(likely by 12) to furans 25 and 26 (Scheme 2).
Special attention should be drawn to the high E stereose-
lectivity of the reaction. Normally, nucleophilic addition to
monosubstituted acetylenes is a trans-concerted process
leading to Z adducts.[22] As mentioned above, CsOH cata-
lyzed addition of phenylacetonitriles to phenylacetylene was
not stereoselective,[9] whereas a similar reaction with 1-pro-
pynyl benzene under the action of cesium alkoxides was
found to be E stereoselective,[23] though no mechanistic ex-
planation was given to this fact. Notably, our reaction, when
conducted with CsOH, also lost its stereoselectivity
(Table 2). Table 2 shows that
ꢀ
philic attack at the C C triple bond and the isolable com-
plexes of alkali-metal hydroxides with acetylenes (Tedeschi
complexes)[18] are known. Therefore, the reactions of acety-
lenes in the presence of alkali-metal hydroxides can be con-
sidered as having essentially metallocomplex character.
After weighing up all the pros and cons, we have challenged
the conventional wisdom (that based-catalyzed reactions of
terminal acetylenes with ketones always give acetylenic al-
cohols) and have screened the conditions of the reaction of
ketones with terminal arylacetylenes in the alkali-metal hy-
droxide/DMSO superbase system.[19] At low temperatures
(0–308C),[17,20] this reaction is known to yield acetylenic al-
cohols,[16] which at higher temperature dissociate back to the
starting materials (retro-Favorsky reaction)[21] and hence at
elevated temperatures the addition reaction of ketone car-
banions to acetylene might be competitive (Scheme 1).
the reaction is sensitive towards
the nature of the alkali-metal
cation.
Indeed, the effect of the
alkali-metal cation in MOH on
the ketone conversion and ste-
reochemistry is crucial. The re-
action is most stereoselective
Scheme 1. Anticipated reaction of ketones with acetylenes in the presence of alkali-metal hydroxides.
when conducted in the KOH/
DMSO suspension, whereas
with LiOH/DMSO no reaction
Results and Discussion
occurs at all. Less effective and stereodirective is the system
NaOH/DMSO. The CsOH/DMSO system, though it ensures
full conversion of the ketone, appears to be the least stereo-
directive. LiOH is known to represent a tight ion pair and
possesses a low basicity, whereas NaOH is intermediate (in
the basicity and ion pair contact term) between that of lithi-
um and potassium and hence is not as effective in the depro-
tonation of ketones as KOH. On the contrary, CsOH is
commonly known to be a looser (solvent separated) ion pair
and therefore, in this case, the hydroxide anion becomes a
stronger base and consequently a more effective deprotonat-
We found that in a KOH/DMSO suspension, alkylaryl- and
alkylheteroarylketones 1–8, including those with condensed
aromatic moieties, added readily to arylacetylenes 9–12
(1008C, 1 h) to deliver stereoselectively the products of C-
vinylation of the ketones with the acetylenes, (E)-3-buten-1-
ones 13–24 in 61–84% yields and with about 100% E ste-
reoselectivity (Table 1). Upon heating to 1008C, the KOH/
DMSO suspension became homogeneous due to enolate for-
mation.
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B. A. Trofimov et al.
Table 1. Stereoselective C-vinylation of ketones 1–8 with arylacetylenes 9–12 in the KOH/DMSO suspension.[a]
Ketone (R1, R2)
Acetylene (R3)
Product
Yield [%][b]
83
9
9
79[c]
84
9
9
71
82
9
82
9
9
83
81[c]
1
3
70
10
83
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Base-Catalyzed Stereoselective Vinylation of Ketones
Table 1. (Continued)
FULL PAPER
Ketone (R1, R2)
Acetylene (R3)
Product
Yield [%][b]
1
61[d]
6
11
63[d]
1
6
22[e]
26[e]
12
[a] Reaction conditions: ketone 1–8 (10 mmol), arylacetylene 9–12 (10 mmol), KOH·0.5H2O (10 mmol) in DMSO (30 mL), 1008C, 1 h. [b] Yield of the
isolated product. [c] Total yield, isomer ratio 4:1. [d] Ketone/acetylene molar ratio=2:1. [e] The products resulted from further transformation of the ad-
ducts (Scheme 2).
that is, the stereochemistry ob-
served is a thermodynamically
controlled process. This may be
caused by more effective conju-
gation in the E isomer of the
Scheme 2. Formation of furans 25 and 26 by the cyclization of intermedi-
ates A, the initial adducts of ketones 1 and 6 with acetylene 12.
intermediate dienolate A and a
steric repulsion of the hydrogen
atoms in the corresponding Z
isomer C.
Table 2. Vinylation of ketone 1 with acetylene 9 in the MOH/DMSO
Kinetically, in the case of CsOH·H2O, the concerted hy-
drogen transfer to quench the emerging carbanionic center
should be most effective due to the looser ion pairing and a
higher concentration of water (a proton transfer agent). Ac-
tually, when the reaction of ketone 1 with acetylene 9 in the
CsOH/DMSO system was carried out with a longer reaction
time (1.5 h instead of 1 h), the isolated product was adduct
13 of E configuration, whereas for a 1 h reaction time a mix-
ture of E/Z=1:1 isomers was formed (Table 2) indicating
the conversion of the kinetic Z adduct to the thermodynam-
ically controlled E isomer. The thermodynamic control of
the E stereochemistry of the ketone vinylation at 1008C also
follows from the temperature dependence of the E/Z ratio
of adduct 13: as shown above, at room temperature the
ratio E/Z=1:1 is obtained, whereas at 608C this ratio
changes in favor of the E isomer (3:2) and finally at 1008C
system: the effect of the alkali-metal cation on the ketone conversion
and the E/Z isomer ratio of adduct 13.
MOH
conversion of 1 [%]
no reaction
E/Z[a] ratio of 13
LiOH
NaOH
70
10:1[b]
KOH·0.5H2O
CsOH·H2O
100
100
only E isomer
1:1[b]
[a] 1H NMR spectroscopy monitoring. [b] For E isomer Jtrans =16.1 Hz,
for Z isomer Jcis =11.4 Hz.
1
ing species. Taking all this into account, the stereochemistry
evolution as dependant of the metal cation nature can be
tentatively rationalized as follows: the kinetic adduct is of Z
configuration in agreement with a trans-concerted addition
of nucleophiles to the triple bond[22] and the E configuration
results from the post isomerization of the kinetic Z isomer,
the Z isomer becomes indiscernible (by H NMR spectros-
copy) in the reaction mixture.
Apparently, the presence of DMSO as a coordinating sol-
vent should be considered in the analysis: the geometry and
coordination modes of MOH, acetylene, and the intermedi-
ate dienolates A and C in DMSO are certainly important.
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B. A. Trofimov et al.
Within the ab initio approach (DFT) the formation of solva-
tion shells of nondissociated alkali-metal hydroxides of the
corresponding cations and the hydroxide ion in DMSO has
recently been studied.[24] Complexes in which the alkali-
metal cation (M+) environment contains the coordinated
acetylene molecule along with a DMSO molecule were
shown to be formed. It was found that the accommodation
of an acetylene molecule into the solvation sphere of non-
dissociated MOH is possible.
Notably, most of the adducts have the substituted styrene
structure (Table 1), that is, with the ethenyl moiety conjugat-
ed with the benzene ring, in spite of the expected easy base-
catalyzed migration (at least partially) of the double bond
towards the carbonyl group. It follows that in these mole-
cules the conjugation in the styrene unit is much stronger
than the competitive conjugation in the a,b-enone counter-
part. Apparently, the intermediate present before quenching
is the dienolate and after aqueous treatment, the b,g-ketone
is kinetically formed. However, upon heating (1 h), also in
the presence of KOH (10% wt), no isomerization to a,b-ke-
tones was discernible, thus implying that the b,g-ketone is
the thermodynamic product. Nonetheless, this partial
double-bond migration still occurs in the case of adducts 14
and 20, which exist as mixtures of the two structural isomers
14a, 14b and 20a, 20b both sets in a ratio of 4:1 (Scheme 3,
Table 1). This is rationalized in terms of the double bond
stabilization by alkyl substituents.
Conclusion
3
À
We have developed a new C
(sp ) C
(sp2) bond-forming reac-
tion, that is, the MOH/DMSO-catalyzed (M=Na, K, Cs)
stereoselective C-vinylation of alkylaryl- and heteroarylke-
tones with arylacetylenes to afford 1,4-disubstituted 3-buten-
1-ones of E configuration in high yields. Acylated condensed
aromatic compounds and diphenyl derivatives as well as 1,4-
diethynylbenzene tolerate the reaction conditions. The ad-
vantage of the reaction is the wide and practically inexhaus-
tible range of starting materials (acylated aromatic, hetero-
aromatic, and condensed aromatic compounds together with
diversely substituted arylacetylenes), that is, the coverage of
all aromatics has been ensured. High regio- and stereoselec-
tivity, easy product isolation procedures, and scalability are
among the definite merits of the reaction found. Another
advantage of the new synthesis is the simple, accessible, and
transition-metal-free recoverable catalytic system (MOH/
DMSO). The resulting 1,4-disubstituted (E)-3-buten-1-ones
(allylic ketones) are synthetic intermediates for numerous
chemical transformations, drug design, and in the creation
of new optoelectronic materials.
Experimental Section
1H and 13C NMR spectra were recorded on a Bruker AVANCE 400 in-
strument (400.13 and 101.61 MHz respectively) equipped with an inverse
gradient 5 mm probe in CDCl3 with hexamethyldisiloxane (HMDS) as an
internal standard. All 2D NMR spectra were recorded by using a stan-
dard gradient Bruker pulse programs. The procedure does not require
degassing of DMSO or the use of an inert atmosphere and the benefit of
DMSO as a solvent is that it is stable up to 1508C for a long time (24 h,
weight lost 0.1–1.0%).[25] IR spectra were obtained on a Bruker Vertex
70 spectrometer. For full experimental data and spectroscopic data see
the Supporting Information.
The geometry of the isomers 14b and 20b was determined
from 2D NOESY spectra (Scheme 4).
Synthesis of (E)-1,4-diphenyl-3-buten-1-one (13) (typical protocol): A
mixture of acetophenone 1 (1.20 g, 10 mmol), phenylacetylene 9 (1.02 g,
10 mmol), and KOH·0.5H2O (0.65 g, 10 mmol) in DMSO (30 mL) was
heated (1008C) stirred for 1 h. The reaction mixture, after cooling to RT,
was diluted with water (70 mL), neutralized (NH4Cl) and extracted with
diethyl ether (10 mLꢂ4). The obtained organic extract was washed with
water (10 mLꢂ3) and dried (K2CO3) overnight. After removal of the sol-
vent, the crude residue (2.14 g) was obtained. Column chromatography
(basic Al2O3, hexane) gave the pure product 13 (1.84 g, 83%).
Acknowledgements
The work was carried out under financial support of the Russian Founda-
tion of Basic Research (grant no.: 08-03-00002).
Scheme 3. Stability of adducts to the KOH/DMSO-catalyzed isomeriza-
tion.
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Scheme 4. Characteristic NOE correlations of compounds 14b and 20b.
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Base-Catalyzed Stereoselective Vinylation of Ketones
FULL PAPER
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Received: January 27, 2010
Revised: April 2, 2010
Published online: June 16, 2010
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