Transition metal-free stereoselective α-vinylation of cyclic ketones with arylacetylenes in the superbasic catalytic triad potassium hydroxide/tert-butyl alcohol/dimethyl sulfoxide

Article abstract of DOI:10.1002/adsc.201200210

A stereoselective α-vinylation of cycloaliphatic ketones with arylacetylenes under the transition metal-free conditions has been developed. The reaction is promoted by the superbasic catalytic triad potassium hydroxide/tert-butyl alcohol/dimethyl sulfoxide (80-110 °C, 1-2 h) to afford mainly (E)-β,γ-ethylenic ketones, their (E)-α,β-isomers being minor products, in up to 83% total yield. Copyright

Full text of DOI:10.1002/adsc.201200210

UPDATES
DOI: 10.1002/adsc.201200210
Transition Metal-Free Stereoselective a-Vinylation of Cyclic
Ketones with Arylacetylenes in the Superbasic Catalytic Triad
Potassium Hydroxide/tert-Butyl Alcohol/Dimethyl Sulfoxide
Boris A. Trofimov,a,* Elena Yu. Schmidt,a Nadezhda V. Zorina,a Elena V. Ivanova,a
Igorꢀ A. Ushakov,a and Al’bina I. Mikhalevaa
a
A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch, Russian Academy of Sciences, 1 Favorsky Str., 664033
Irkutsk, Russia
Fax : (+7)-3952-41-93-49; e-mail: boris_trofimov@irioch.irk.ru
Received: March 13, 2012; Revised: April 28, 2012; Published online: June 5, 2012
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200210.
Abstract: A stereoselective a-vinylation of cycloali-
phatic ketones with arylacetylenes under the transi-
tion metal-free conditions has been developed. The
reaction is promoted by the superbasic catalytic
triad potassium hydroxide/tert-butyl alcohol/dimeth-
yl sulfoxide (80–1108C, 1–2 h) to afford mainly (E)-
b,g-ethylenic ketones, their (E)-a,b-isomers being
minor products, in up to 83% total yield.
sophisticated ligands.[4] For instance, the a-alkenyla-
tion of cyclic ketones was performed via cyclic a-io-
doenones and a-triflyloxyenones which were cross-
coupled with alkenylzinc in the presence of palladium
complexes [Pd
CAHUTGTNRENNGU(PPh3)4 or Cl2PdACHTUNTGRENN(GUN PPh3)2 +2n-BuLi]
with further reduction of the resulting dienone with
LiAlHACTHUNTGRNE(UNG OMe)3, the total yield over all the steps being
fairly modest[5] (Scheme 1, A). Substituted cyclopen-
tanones and cyclohexanones were vinylated with hal-
oalkenes in the presence of Pd2ACTHNUTRGNE(UNG dba)3/aminophos-
À
Keywords: acetylenes; C C bond formation; ke-
tones; superbases; vinylation
phine ligand/NaO-t-Bu to produce the corresponding
vinyl ketones in high yields and enantioselectivity[6]
(Scheme 1, B). Later, a catalytic system [PdPACHTUNGTRENNUNG(t-
Bu)3Br]2/lithium hexamethyldisilazine was employed
3
2
À
The search for new sp -sp C C bond-forming reac-
tions remains a standing challenge in the organic
chemistry. In particular, such reactions might repre-
sent an important contribution to the synthesis of eth-
ylenic cycloaliphatic ketones, which are versatile syn-
thetic building blocks and key intermediates in drug
design.[1] Therefore, straightforward catalytic methods
for introducing an E- or Z-alkenyl group in an a-posi-
tion of ketones with control of regiochemistry has
been a subject of the research activity for a long
time.[2] A special interest is directed to the b,g-ethyl-
enic carbonyl moiety as a highly reactive and chemi-
cally flexible structural unit.[3] The importance of the
a-vinylation reactions of ketones stems not only from
frequent appearance of the C=C double bond-carbon-
yl entities in natural products and biologically active
compounds but also from the rich and well-studied
chemistry of a,b- and b,g-ethylenic ketones that ena-
bles expedient syntheses of complex structures. How-
ever, the approaches to such ketones often remain la-
borious and multi-step, requiring hardly accessible
Scheme 1. Literature examples of the a-vinylation of cyclic
starting materials and transition metal catalysts with ketones.
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Boris A. Trofimov et al.
UPDATES
for the successful a-vinylation cyclic ketones such as reaction of cyclic ketones and arylacetylenes on the
2-methyl-2,3-dihydroinden-1-one, 1-tetralone and 2- yield of ethylenic ketones to minimize the formation
methyl-1-tetralone[7] (Scheme 1, C). Among the of the Favorsky product (Scheme 2). The Favorsky re-
recent publications devoted to the synthesis of b,g-
ethylenic ketones (although acyclic ones), the enan-
tioselective a-vinylation of ketones via nickel-cata-
lyzed cross-coupling of a-bromo ketones with organo-
zirconium reagents deserves attention[8] (Scheme 1,
D).
The base-catalyzed nucleophilic addition of eno-
lates to acetylenes might provide another direct entry
to the chemistry of ethylenic ketones. But such an ad-
dition seemed to be precluded because, in the pres-
ence of basic catalysts, the formation of propargylic
alcohols usually took place (Favorsky reaction).[9]
However, recently, contrary to this common knowl-
edge, alkyl aryl and alkyl hetaryl ketones were shown
to be capable of regio- and stereoselective vinylation
by acetylenes in the superbasic heterogeneous catalyt-
Scheme 2. Anticipated reaction of cyclic ketones with aryl-
AHCTUNGTREGaNNNU cetylenes in the presence of alkaline metal hydroxides.
ic system MOH/DMSO (M=Na, K, Cs) to give the action itself as applied to cyclic ketones did not need
b,g-ethylenic ketones.[10] Later, while describing the improvement due to almost quantitative yields of the
tandem assembling of methylene dispirocyclic ketals tertiary propargylic alcohols commonly achieved
from cyclohexanones and arylacetylenes in the KOH/ under optimal conditions.[13]
DMSO suspension, we also briefly mentioned about
the formation of unsaturated ketones during this reac- of this synthesis over the cyclic ketones turned out to
tion.[11]
be disappointing. For instance, with the published cat-
However, our first experiments toward expansion
In the light of the above considerations, the possi- alytic systems, the yields of ethylenic ketones from cy-
bility of the base-catalyzed vinylation of cyclic ke- clopentanone, cycloheptanone, cyclododecanone and
tones with acetylenes until recently seemed fuzzy. phenylacetylene did not exceed 12%, generally being
First of all, the major obstacle for realization of this in the range 1–10%. Eventually, the screening of su-
reaction would be due to the fact that the ketones perbasic catalytic systems allowed us to arrive at a spe-
readily added acetylide anions across the polar C=O cific superbasic catalytic triad KOH/t-BuOH/DMSO
bond to furnish propargylic alcohols.[9] Moreover, it securing fairly good preparative results, which are re-
was commonly accepted that enolate anions were un- ported here.
reactive as C-nucleophiles towards the unactivated
We have found that in the presence of the above
multiple bonds on the basis of thermodynamic and ki- triad, cyclic ketones 1–6 added to arylacetylenes 7–12
netic grounds, for example, the formation of less ther- (80–1108C, 1-2 h, ketone:arylacetylene:KOH:t-BuOH
modynamically favorable carbanions from more molar ratio=1:1:1:1) to furnish b,g- (13a–23a, 16b)
stable oxygen-centered (enolate) anions.[12] Among and a,b- (13b–15b, 16c, 17b–23b) ethylenic ketones,
the experimental hurdles interfering in ketone vinyla- both of E configuration, with the latter being minor
tion with acetylene in the presence of bases were, products (on average 10% of the products mixture),
apart from the aforementioned facile formation of in up to 83% total yield (Table 1).
acetylenic alcohols, the autocondensation of ketones
The minor regioisomers of ethylenic ketones 13–23,
and acetylide generation from terminal acetylenes. that is, a,b-ethylenic ketones 13b–15b, 16c, 17b–23b,
However, these rationalizations did not account for expectedly resulted from a partial 1,3-prototropic
the expected electrophilic assistance from alkaline shift of the double bond toward the carbonyl moiety.
metal cations in stabilizing the emerging carbanions. The formation of
a tertiary acetylenic alcohol
Indeed, quantum chemical evaluation[13] showed that (common product of the Favorsky reaction,[9] which
alkaline metal cations did facilitate nucleophilic might be anticipated here also) was not observed in
ꢀ
attack at the C C triple bond. Experimentally, com- this case.
plexes of alkaline metal hydroxides with acetylenes
The E configuration of b,g-ethylenic ketones was
3
(known as Tedeschi complexes)[14] were isolated and confirmed by J values (15.8–16.3 Hz) between pro-
characterized. All this allows the superbase-induced tons at the double bond. The E configuration of
reactions of acetylenes to be qualified as having es- minor a,b-ethylenic ketones was supported by the
sentially a metallocomplex character.
presence of characteristic cross-peaks in their
Having all this in mind, we systematically scruti- NOESY spectra (Figure 1).
nized the influence of experimental conditions for the
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Transition Metal-Free Stereoselective a-Vinylation of Cyclic Ketones with Arylacetylenes
Table 1. Reaction of cyclic ketones 1–6 with arylacetylenes 7–12 in the superbasic catalytic triad KOH/t-BuOH/DMSO.
Ketone
Arylacetylene
Conditions
Product (isomer ratio)
Total yield [%][a]
808C, 2 h
25
1008C, 1 h
1008C, 1 h
83
51
1008C, 1 h
1008C, 2 h
57
38
1108C, 2 h
38
1008C, 1 h
1008C, 1 h
48
54
1008C, 1 h
52
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Boris A. Trofimov et al.
UPDATES
Table 1. (Continued)
Ketone
Arylacetylene
Conditions
Product (isomer ratio)
Total yield [%][a]
1008C, 1 h
45
1008C, 1 h
43
[a]
Isolated yield after column chromatography.
method here developed should not be underrated
since it possesses clear beneficial preparative features
such as high E stereoselectivity and a one-pot transi-
tion metal-free protocol using entirely accessible and
inexpensive starting materials.
Thus, the key to the success of the vinylation of
cyclic ketones is the introduction of a certain amount
of t-BuOH as an active component of the catalytic
Figure 1. Characteristic NOESY correlations of a,b-ethylen-
ic ketones.
The E configuration of the adducts 13–23 is unusual system. The activating effect of t-BuOH makes it an
for a nucleophilic addition to monosubstituted acety- important partner of the catalytic triad KOH/t-
lenes which is known to proceed as a concerted trans- BuOH/DMSO that may be understood in terms of
addition leading to Z adducts.[15] Here, the uncommon homogenizing the reaction mixture (vs. the KOH/
stereochemistry can be explained by the fact that the DMSO heterogeneous suspension previously em-
kinetic products of the Z configuration undergo ployed)[10] and hence increasing the concentration of
a rapid post-formation isomerization to the adducts of the strongly basic catalyst in the solution.
E configuration. A probable cause for the higher ther-
Another role of t-BuOH as a co-catalyst is likely to
modynamic stability of the E isomers may lie in the be as a mild proton-transfer agent, which reduces the
enolization of b,g-ethylenic ketones in the presence of concentration of acetylenic carbanions, inactive
a base. In a dienolate of the E configuration, the con- toward the nucleophilic attack by the ketone carban-
jugation is assumed to be more effective, while in a Z ion [Eq. (1)].
dienolate, the steric repulsion of hydrogen atoms
should destabilize this isomer.
Besides, t-BuOH as a controlled source of protons
should facilitate the quenching of intermediate car-
banions in a concerted manner [Eq. (2)].
Notably, the major adducts of ketones to arylacety-
lenes have the structure of substituted styrenes
(Table 1), that is, the double bond remains conjugated
with the aromatic moiety despite the possibility of its
migration toward the carbonyl group. This implies
that conjugation in the styrene fragment is stronger
than the competitive conjugation in the a,b-enone
counterpart.
Fundamentally, the acidity of ketones is commonly
It is worthy to underline that, despite the modest to known to be several orders higher as compared to
good isolated yields of a-vinylated cyclic ketones, the that of acetylenes. For example, the pKa values of ace-
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Transition Metal-Free Stereoselective a-Vinylation of Cyclic Ketones with Arylacetylenes
tone, acetophenone and phenylacetylene measured in b just in 25% yield, the conversion of ketone 1 being
DMSO by Bordwell are 24.3[16], 22.5[16] and 26.5,[17] re- complete (seemingly, due to the base-catalyzed auto-
spectively. Consequently, the concentration of depro- condensation). With a higher t-BuOH content (up to
tonated ketones exceeds sizeably that of neutral mol- 3.0 equivalents relative to ketone 1), the yield of eth-
ecules of acetylenes thus favoring the nucleophilic ad- ylenic ketones 13a and b was not improved. At
dition under study.
a longer reaction time (808C, 3 h) and a higher tem-
In the presence of the obviously more basic perature (1008C, 1 h), a full tarring occurred, neither
NaOMe/DMSO catalytic system, the reaction of cy- starting materials nor the anticipated products of C-
clohexanone 2 with phenylacetylene 7 led to ~1:1 vinylation of ketone 1 were detected in the reaction
mixture of the expected a-vinylated ketone 14a and mixture (1H NMR).
a side product, (Z)-1-(2-methoxyvinyl)benzene 24, the
Generally, one of the major hurdles for the a-vinyl-
conversion of the starting ketone 2 being incomplete ation of cyclic ketones with arylacetylenes is the com-
(~50%):
petitive based-catalyzed self-condensation of the
former that remains a fundamental challenge that still
needs to be overcome.
The larger ring-size ketones 5 and 6 afforded with
phenylacetylene 7 the corresponding ethylenic ke-
tones 17a and b and 18a and b in a better yield (38%,
Table 1), although still lower than that in the case of
cyclohexanones 2–4.
It follows that methanol, released upon deprotona-
At a lower temperature (808C, 2 h) the yield of
tion of the ketone, undergoes competitive vinylation adduct 17a dropped to 7%, and the major reaction
with phenylacetylene:
product became the corresponding tertiary propargyl-
ic alcohol 25 resulting from the Favorsky reaction
(42% yield, Scheme 3).
The substitution in the benzene ring of arylacety-
lenes (3-F, 3-Me, 2,5-Me2, 4-Ph) has no significant
effect on the yield of the ethylenic ketones (Table 1).
It was shown (for the examples of ethylenic ketones
14a, 15a, 17a and 22a) that b,g-ethylenic ketones can
be isolated as pure isomers (without the correspond-
ing a,b-ethylenic ketone admixtures) the column
chromatography (SiO2, eluent hexane-benzene with
Therefore, this competitive reaction is assumed to gradient from 1:0 to 0:1).
accompany (more or less) the a-vinylation of cyclic
In summary, a straightforward transition metal-free,
ketones in the presence of any alkaline metal alkox- stereoselective a-vinylation of cycloaliphatic ketones
ide, thus complicating the isolation of the target prod- with arylacetylenes in the presence of the superbasic
ucts.
homogeneous catalytic triad KOH/t-BuOH/DMSO to
The yield of ethylenic ketones 13–23 was strongly afford mainly b,g-ethylenic ketones of the E configu-
dependent on the size of the cycle and the substitu- ration has been developed. The advantages of this
3
2
À
ents therein. The best results were attained for cyclo- new sp -sp C C bond-forming reaction are its high E
hexanones 2–4, the most representative and syntheti- stereoselectivity and use of the easily accessible super-
cally meaningful family of cycloaliphatic ketones. 3- basic catalytic system. The resulting styryl ketones
Methylcyclohexanone 4 was vinylated with phenylace- (major products) are versatile and reactive, in-
tylene 7 under the same conditions (KOH/t-BuOH/
DMSO, 1008C, 1 h) to afford, along with a-ethylenic
ketone 16a, products of the a’-vinylation 16b and 16c.
The ratio of ethylenic ketones 16a:16b:16c was 8:1:1
(1H NMR) and their total yield reached 57%
(Table 1). As seen (Table 1), a methyl substituent in
the cyclohexanone ring diminishes the total yield of
vinylation products, assumingly due to the steric (in
the case of ketone 4), conformational and electron-
donating effects of the methyl group, the latter de-
creasing the CH-acidity of the ketonic a-positions.
Cyclopentanone 1 gave with phenylacetylene 7
Scheme 3. Reaction of cycloheptanone 5 with phenylacety-
(808C, 2 h) the expected ethylenic ketones 13a and lene 7 in the KOH/t-BuOH/DMSO system at 808C.
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Boris A. Trofimov et al.
UPDATES
Soc. 2011, 133, 7260–7263; c) H. Yokoe, C. Mitsuhashi,
Y. Matsuoka, T. Yoshimura, M. Yoshida, K. Shishido, J.
Am. Chem. Soc. 2011, 133, 8854–8857; d) F. R. Petroni-
jevic, P. Wipf, J. Am. Chem. Soc. 2011, 133, 7704–7707;
e) T. Diao, S. S. Stahl, J. Am. Chem. Soc. 2011, 133,
14566–14569.
demand building blocks for organic synthesis and
drug design.
Experimental Section
[2] a) E. Negishi, K. Akiyoshi, Chem. Lett. 1987, 1007–
1010; b) M. G. Maloney, J. T. Pinhey, J. Chem. Soc.
Perkin Trans. 1 1988, 2847–2854; c) S. Hashimoto, Y.
Miyazaki, T. Shinoda, S. Ikegami, Tetrahedron Lett.
1989, 30, 7195–7198.
[3] a) M. Gohain, B. J. Gogoi, D. Prajapati, J. S. Sandhu,
New J. Chem. 2003, 27, 1038–1040; b) M. Iwasaki, E.
Morita, M. Uemura, H. Yorimitsu, K. Oshima, Synlett
2007, 167–169.
[4] a) P. Marceau, L. Gautreau, F. Bꢃguin, G. Guillaumet,
J. Organomet. Chem. 1991, 403, 21–27; b) B. Baruah, A.
Boruah, D. Prajapati, J. S. Sandhu, Tetrahedron Lett.
1996, 37, 9087–9088; c) A. S.-Y. Lee, L.-S. Lin, Tetrahe-
dron Lett. 2000, 41, 8803–8806; d) J. S. Yadav, B. V. S.
Reddy, M. S. Reddy, G. Parimala, Synthesis 2003, 2390–
2394; e) Y. Liu, Y. Zhang, Tetrahedron Lett. 2004, 45,
1295–1298.
General Remarks
All chemicals and solvents are commercially available from
Sigma Aldrich Chemie and were used without further purifi-
cation. The elaborated procedure does not require degassing
of DMSO and use of 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%).[18] 1H and 13C NMR spec-
tra were recorded on a 400.13 and 100.61 MHz instrument,
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 the
Bruker standard gradient pulse programs. The assignment of
1
signals in the H NMR spectrum was made using 2D COSY
and NOESY experiments. Resonance signals of carbon
atoms were assigned based on 2D H-13C HSQC and H-13C
1
1
HMBC experiments.
[5] E. Negishi, Z. R. Owezarczyk, D. R. Swanson, Tetrahe-
dron Lett. 1991, 32, 4453–4456.
[6] A. Chieffi, K. Kamikawa, J. Ahman, J. M. Fox, S. L.
Typical Procedure for the Reaction of Cycloaliphatic
Ketones with Arylacetylenes (Reaction of Cyclohex-
anone 2 with Phenylacetylene 7 as Example)
Buchwald, Org.Lett. 2001, 3, 1897–1900.
[7] J. Huang, E. Bunel, M. M. Faul, Org. Lett. 2007, 9,
4343–4346.
[8] S. Lou, G. C. Fu, J. Am. Chem. Soc. 2010, 132, 5010–
5011.
[9] a) A. E. Favorsky, Zh. Ross. Khim. Obshchestva 1906,
37, 643; b) M. Smith, J. March, Marchꢀs Advanced Or-
ganic Chemistry, 6th edn., Wiley, New York, 2007,
p 1360.
[10] B. A. Trofimov, E. Yu. Schmidt, I. A. Ushakov, N. V.
Zorina, E. V. Skital’tseva, N. I. Protsuk, A. I. Mikhale-
va, Chem. Eur. J. 2010, 16, 8516–8521.
A mixture of cyclohexanone 2 (2.00 g, 20.4 mmol), phenyl-
ACHTUNGTRENNUNGacetylene 7 (2.08 g, 20.4 mmol), KOH·0.5H2O (1.33 g,
20.4 mmol) and t-BuOH (0.15 g, 20.4 mmol) in DMSO
(20 mL) was heated (1008C) and stirred for 1 h. The reac-
tion mixture, after cooling (20–258C), was diluted with H2O
(50 mL), neutralized with NH4Cl and extracted with Et2O
(10 mLꢂ4). The organic extract was washed with H2O
(10 mLꢂ3) and dried (K2CO3). After removal of the sol-
vent, a crude residue (3.89 g) was obtained. Column chro-
matography (SiO2, eluent benzene) gave the pure vinyl ke-
tones 14a and b in a 10:1 ratio as a yellow oil; yield: 3.39 g
(83%). Repeated column chromatography (SiO2, eluent
hexane-benzene with gradient from 1:0 to 0:1) gave the
pure vinyl ketone 14a and vinyl ketone 14b with admixture
of ketone 14a.
[11] E. Yu. Schmidt, N. V. Zorina, E. V. Skitaltseva, I. A.
Ushakov, A. I. Mikhaleva, B. A. Trofimov, Tetrahedron
Lett. 2011, 52, 3772–3775.
[12] K. Endo, T. Hatakeyama, M. Nakamura, E. Nakamura,
J. Am. Chem. Soc. 2007, 129, 5264–5271.
[13] B. A. Trofimov, Curr. Org. Chem. 2002, 6, 1121–1162.
[14] R. J. Tedeschi, J. Org. Chem. 1965, 30, 3045–3049.
[15] J. I. Dickstein, S. I. Miller, in: The Chemistry of the
Carbon-Carbon Triple Bond, Part 2, (Ed.: S. Patai),
Wiley, New York, 1978, pp 813–955.
Acknowledgements
The work was carried out under financial support of the Rus-
sian Foundation of Basic Research (Grant 11-03-00270). We
thak Prof. S. F. Vasilevsky for supplying us with the sample
of 4-ethynylisoquinoline.
[16] F. G. Bordwell, W. S. Matthews, J. Am. Chem. Soc.
1974, 96, 1216–1217.
[17] F. G. Bordwell, W. S. Matthews, J. Am. Chem. Soc.
1974, 96, 1214–1216.
[18] Dimethyl sulfoxide (DMSO). Technical Bulletin. Crown
Zellerbach Chemical Products Division, Vancouver
(Orchards), WA 98662, 1985.
References
[1] a) N. S. Radin, Drug Dev. Res. 2008, 69, 15–25; b) S. B.
Herzon, L. Lu, C. M. Woo, S. L. Gholap, J. Am. Chem.
1818
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