Transition-Metal-Free α-Vinylation of Enolizable Ketones with β-Bromostyrenes

Article abstract of DOI:10.1021/acs.orglett.8b04004

An α-vinylation of enolizable ketones has been developed by using β-bromostyrenes and a KOtBu/NMP system. β,γ-Unsaturated ketones of E configuration were obtained in excellent yield and selectivity. Further synthetic possibilities are highlighted by one-pot functionalization via trapping of intermediate dienolates with alkyl, allyl, benzyl, and propargyl halides to generate quaternary centers. The reported transformation is believed to involve phenylacetylene and propargylic alcohol derivatives.

Full text of DOI:10.1021/acs.orglett.8b04004

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Transition-Metal-Free α‑Vinylation of Enolizable Ketones with
β‑Bromostyrenes
§,∥
†
Yassir Zaid,‡,§,∥ Cleve Dionel Mboyi, Martin Pichette Drapeau,†,§,∥ Lea Radal,
̀
́
Fouad Ouazzani Chahdi,‡ Youssef Kandri Rodi,‡ Thierry Ollevier,*,† and Marc Taillefer*,§
†
́
́
́
́
́
Departement de chimie, Universite Laval, 1045 avenue de la Medecine, Quebec (Quebec), G1V 0A6, Canada
‡
́
̀
̀
Laboratoire de Chimie Organique Appliquee, FST Fes BP 2202, 30000 Fes, Morocco
§
́
CNRS, UMR 5253, AM2N, Institut Charles Gerhardt Montpellier ENSCM, 8 rue de l’Ecole Normale, F-34296 Montpellier Cedex
5, France
S
* Supporting Information
ABSTRACT: An α-vinylation of enolizable ketones has been developed by using β-bromostyrenes and a KOtBu/NMP system.
β,γ-Unsaturated ketones of E configuration were obtained in excellent yield and selectivity. Further synthetic possibilities are
highlighted by one-pot functionalization via trapping of intermediate dienolates with alkyl, allyl, benzyl, and propargyl halides to
generate quaternary centers. The reported transformation is believed to involve phenylacetylene and propargylic alcohol
derivatives.
he regio- and stereoselective synthesis of β,γ-unsaturated
selectivities; however, isomerization into their α,β-unsaturated
Tcarbonyl compounds is an important transformation in ketones derivatives could not be avoided (minimally 5−10%).
We recently developed a transition-metal-free protocol for the
α-arylation of enolizable ketones with aryl halides using a
mixture of KOtBu and DMF.10 Since the reactions of aryl
iodides proceed at room temperature under these conditions,
we believed that the development of a very mild α-vinylation of
enolizable ketones was feasible. Our main goal was to achieve
complete selectivity for β,γ-unsaturated ketone isomers of E
configuration at low temperatures.
To start our investigation, we reacted propiophenone 1a
with β-bromostyrene 2a11 in DMF for 1 h at 70 °C in the
presence of KOtBu as base (Table 1). Under these conditions,
addition of 3 equiv of the latter gave the expected β,γ-
unsaturated ketone 3a in 66% yield, along with 16% of enone
4a (entry 1). Switching the solvent to DMSO or NMP
furnished 3a in 72% and 93% yields, respectively, along with
trace amounts of the isomerized enone 4a when NMP was
employed (entries 2 and 3). The yields of 3a decreased to 61%
and 22% by using only 2 and 1 equiv of KOtBu (entries 4 and
5). The use of NaOtBu gave a low yield (entry 6), while
LiOtBu proved to be totally unsuitable since phenylacetylene
5a and propargylic alcohol 6a were generated in 11% and 72%
yields, respectively (entry 7). Other potassium bases, such as
KOH or K2CO3, also gave disappointing results (entries 8, 9),
and reactions at room temperature only led to 39% and 52%
yields, after 1 and 24 h, respectively (entry 10). Moreover,
organic chemistry since these units are present in many natural
products and serve as building blocks to access complex
structures.1 The search for efficient and selective methods to
yield allylic carbonyl compounds has a long history. With an
objective of alleviating the intrinsic limitation of prototropic
rearrangement of β,γ-unsaturated carbonyl compounds into
their α,β-unsaturated counterparts,2 many syntheses have been
developed based on the use of organometallic reagents,3 metal-
mediated coupling reactions,4 and transition-metal catalyzed α-
vinylation reactions of enolates.5 In contrast, there have been
few reports for the synthesis of allylic carbonyl compounds that
do not require transition metals.6 In early investigations on
radical-chain transformations, Bunnett reported the photo-
stimulated reaction between potassium acetonate and vinyl
halides.7 An observation made by Galli in 1993 showed that a
competing elimination−addition pathway via acetylene inter-
mediates was involved under certain conditions.8 The presence
of propargylic alcohols hinted at an ionic mechanism involving
Favorsky-type reactions. Multiple contributions by Galli,
Rappoport, and Rossi later hinted that an unequivocal SRN1
ketone α-vinylation reaction occurred only for triphenylvinyl
bromide, highlighting the rich mechanistic world of vinylic
substitution reactions. Recently, Trofimov developed on Galli’s
initial observation by developing a general base-mediated
synthesis of β,γ-unsaturated ketones by the reaction of
enolizable ketones and arylacetylenes at temperatures ≥80
°C.9 The reactions proceed in the presence of either KOH or
KOtBu in DMSO to provide β,γ-unsaturated ketones in good
Received: December 14, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b04004
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. α-Styrylation of Propiophenone 1a with β-Bromostyrene 2a: Reaction Conditions
entry
base
solvent
temp (°C)
3a (%)
4a (%)
5a (%)
6a (%)
1
2
3
4
5
6
7
8
9
10
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
NaOtBu
LiOtBu
KOH
DMF
DMSO
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
70
70
70
70
70
70
70
70
70
25
66
72
93
61
22
46
4
8
0
16
23
2
2
5
5
0
4
0
0
0
2
6
0
11
4
0
0
0
0
0
0
72
0
0
b
c
d
K2CO3
KOtBu
0
0
39 (52)
7 (8)
6 (5)
38 (36)
a
1
Reaction conditions: propiophenone 1a (2 mmol), β-bromostyrene 2a (1 mmol), base (3 mmol), solvent (9 mmol). Yields calculated by H
b
NMR using hexamethylbenzene as an internal standard. Yields in parentheses were calculated after 24 h. 70% from the β-iodostyrene and 28% for
the β-chlorostyrene. 2 mmol. 1 mmol.
c
d
a
lower 3a/4a ratios were obtained at 25 °C than at 70 °C.
Under the optimal conditions, ketones were thus reacted with
β-bromostyrenes in the presence of 3 equiv of KOtBu in NMP
at 70 °C for 1 h (entry 3).
Scheme 1. Substrate Scope of the α-Vinylation of Ketones
We subsequently turned our attention to the scope of the
reaction (Scheme 1). In addition to propiophenone,
acetophenone undergoes vinylation to give 3b in a very good
81% yield without the double vinylation product being
detected. In contrast, butyrophenone only led to a low 31%
yield of 3c. Electron-withdrawing and -donating substituents
are well tolerated at the para position of propiophenones,
giving 3d−3f in good to excellent yields. Cycloheptanone also
undergoes vinylation to give 3g in 59% yield and the reaction
also tolerated a p-tert-butyl substituent on the styrene partner,
yielding 77% of α-vinylketone 3h. Reactions of electron-rich or
-poor aryl ketones with various β-bromostyrenes substituted at
all positions (o, m, p) with methyl, tert-butyl, methoxy, and
naphthyl groups provided the desired compounds 3i−3u in
yields ranging from 49% to 95% (Scheme 1). Selectivity for
β,γ- vs α,β-unsaturated ketones is almost complete in all cases,
the lower yields being caused by incomplete conversions. In all
cases, β,γ-unsaturated ketones were obtained with complete
selectivity for E stereoisomers.
To further highlight the synthetic potential of this base-
mediated α-vinylation of ketones, we performed one-pot
trapping of intermediate dienolates with carbon-based electro-
philes (Scheme 2). As expected, β,γ-unsaturated ketones 7
bearing all-carbon quaternary centers at the α-position could
be isolated in good 60−71% yields, except for 7b leading to a
low 35% yield (Scheme 2).
Beyond iodoalkanes, this method enables efficient one-pot
procedures using allyl, benzyl, and propargyl bromides.
However, the use of iodobenzene did not lead to the
corresponding α-arylated ketone, probably due to steric
hindrance.
In order to gain insight into the reaction mechanism, we
reacted β-bromostyrene 2a with 1 equiv of KOtBu and
observed an 86% yield of phenylacetylene 5a in only 10 min at
50 °C (Scheme 3, path a). Under the same reaction conditions,
a
Reaction conditions: ketone 1 (2 mmol), β-bromostyrene 2 (1
mmol), KOtBu (3 mmol), NMP (0.9 mL), 70 °C, 1 h; isolated yields.
propargylic alcohol 6a is obtained in 58% yield and β,γ-
unsaturated ketone 3a (E configuration) in 40% yield when 2
equiv of KOtBu are used and 1 equiv of propiophenone 1a is
added after 10 min in a Favorsky-type reaction (Scheme 3,
path b).12 Both 5a and 6a, which were observed as byproducts
B
DOI: 10.1021/acs.orglett.8b04004
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(entry 4) and galvinoxyl (entry 5) as potential radical
scavengers lowered the yields to 22% and 39%, respectively.
While an effect is observed, one cannot conclude that the
process involves radical intermediates.
Scheme 2. One-Pot Trapping of Dienolate Intermediates for
the Generation of Quaternary Carbon Centers
a
We next investigated the conditions for the transformation
of propargyl alcohol 6a, as another potential intermediate of
the reaction (Scheme 3), into β,γ-unsaturated ketone 3a
(Table 3). In the absence of a base at 100 °C for 24 h, 6a is
Table 3. Base-Mediated Rearrangement of Propargylic
a
Alcohol 6a to β,γ-Unsaturated Ketone 3a
a
Reaction conditions: ketone 1 (2 mmol), β-bromostyrene 2a (1
mmol), KOtBu (3 mmol), NMP (9 mmol), 70 °C, 1 h, then R2−X (1
mmol), 0.5 h; isolated yields.
entry
x
t (h)
temp (°C)
6a (%)
3a (%)
1a (%)
1
2
3
4
5
6
−
1
1
1
2
0.2
24
0.5
0.5
4
4
4
100
25
50
50
50
100
50
16
18
0
0
2
35
40
72
0
0
36
42
26
7
Scheme 3. Generation of Phenylacetylene 5a and
Propargylic Alcohol 6a from β-Bromostyrene 2a
100
76
24
a
Reaction conditions: propargylic alcohol 6a (1 mmol), KOtBu (x
mmol), NMP (0.9 mL). Yields calculated by 1H NMR using
hexamethylbenzene as an internal standard.
recovered quantitatively (entry 1), but the presence of 1 equiv
of KOtBu already leads to 2% of 3a and 36% of 1a via a retro-
Favorsky reaction13 at only room temperature (entry 2). By
increasing the temperature up to 50 °C, 3a was obtained in
35% and 40% yields after 0.5 and 4 h, respectively (entries 3−
4). Complete rearrangement of 6a to 3a was obtained only via
the addition of 2 equiv of KOtBu at 50 °C, leading to 72% of
the desired compound 3a (entry 5). Interestingly, the use of a
catalytic amount of KOtBu (20 mol %) only led to a slight
rearrangement of 6a into 1a without formation of 3a, even at
100 °C (entry 6).
during optimization (see Table 1), are likely reaction
intermediates or side reaction products.
It was then observed that, in the reaction conditions
disclosed herein, the reaction of propiophenone 1a and
phenylacetylene 5a to give 3a is efficient at low temperatures
(Table 2). While a low 7% yield of the latter is observed after 5
Table 2. α-Styrylation of Propiophenone 1a with
a
Phenylacetylene 5a
In light of these results, we propose an ionic mechanism
based on the one postulated by Trofimov for the base-
mediated addition of arylacetylenes to ketones (Scheme 4).9a−c
The arylacetylene and the enolate, in situ generated by β-
entry
additive
t (h)
temp (°C)
3a (%)
b
Scheme 4. Plausible Reaction Mechanism
1
2
3
4
5
−
−
−
0.09
4
24
4
50
50
25
50
50
7
90
91
22
39
hydroquinone
galvinoxyl
4
a
Reaction conditions: propiophenone 1a (2 mmol), phenylacetylene
5a (1 mmol), additive (1 mmol), KOtBu (3 mmol), NMP (0.9 mL).
Yields calculated by 1H NMR using hexamethylbenzene as an internal
b
standard. 6a is obtained in 81% yield as a byproduct.
min at 50 °C, accompanied by 81% of intermediate 6a,
prolonging the reaction time to 4 h leads to an excellent 90%
yield in 3a (E isomer) (entries 1 and 2). The reaction gives the
same yield after 24 h at room temperature (entry 3). To the
best of our knowledge, the selective formation of β,γ-
unsaturated ketones of E configuration from simple ketones
and arylacetylenes has never been reported at temperatures
lower than 80 °C.9 It is worth noting that reactions performed
in the presence of stoichiometric amounts of hydroquinone
C
DOI: 10.1021/acs.orglett.8b04004
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Tetrahedron 1963, 19, 299. (b) Malhotra, S. K.; Ringold, H. R.
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Kinetics, and Mechanism of the Acid- and Enzymatic-Catalyzed
elimination reaction of the bromostyrene and deprotonation of
the ketone, respectively, would react together by a concerted
trans addition with the assistance of HOtBu to provide the E
dienolate D after base-mediated isomerization of the
intermediate Z allylic ketone C. A Favorsky reaction could
also be envisioned from the attack of the corresponding
acetylide on the ketone.12 A retro-Favorsky reaction from the
corresponding propargylic alcohol A13 could then explain the
results obtained in Scheme 3 and Table 3.
In summary, we have developed a highly regio- and
stereoselective synthesis of β,γ-unsaturated ketones of E
configuration from enolizable ketones and β-bromostyrenes
under transition-metal-free conditions. The reactions can be
performed with KOtBu at room temperature for 24 h in
moderate yields or up to 70 °C for only 1 h without
isomerization into the thermodynamically favored enones. The
observation that radical scavengers did not completely
suppress the transformation, coupled with the successful
trapping of intermediates with carbon-based electrophiles to
generate all-carbon quaternary centers, rather points toward an
ionic mechanism.14
5
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b04004.
Experimental procedures, compound characterization,
1
and copies of H NMR and 13C NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: thierry.ollevier@chm.ulaval.ca.
*E-mail: marc.taillefer@enscm.fr.
ORCID
Thierry Ollevier: 0000-0002-6084-7954
Marc Taillefer: 0000-0003-2991-5418
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Soc. Rev. 1972, 1, 73. (b) Ouaka, M.; Goto, T.; Mukaiyama, T. The
Reaction of π−Allylnickel Halides with 2- Pyridyl Carboxylates a New
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of Olefins with Anhydrides and Zinc Chloride to Give β,γ-
Unsaturated Ketones. J. Am. Chem. Soc. 1980, 102, 3848. (d) Lee,
A. S.-Y.; Lin, L.-S. Synthesis of Allyl Ketone via Lewis Acid Promoted
Barbier-Type Reaction. Tetrahedron Lett. 2000, 41, 8803. (e) Gohain,
M.; Gogoi, B. J.; Prajapati, D.; Sandhu, J. S. Ytterbium Mediated
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(5) For a review, see: (a) Ankner, T.; Cosner, C. C.; Helquist, P.
Palladium- and Nickel-Catalyzed Alkenylation of Enolates. Chem. -
Eur. J. 2013, 19, 1858. For a recent example at room temperature,
see: (b) Grigalunas, M.; Ankner, T.; Norrby, P.-O.; Wiest, O.;
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Author Contributions
∥Y.Z., C.D.M., and M.P.D. contributed equally to this
manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors are thankful to the Natural Sciences and
Engineering Research Council of Canada (NSERC) Agence
Nationale de la Recherche (ANR), Centre National de la
́
Recherche Scientifique (CNRS), and Ecole Nationale Super-
ieure de Chimie de Montpellier (ENSCM) for financial
support. M.P.D. thanks Fonds de Recherche du Quebec
Nature et Technologies (FRQNT) and Centre in Green
Chemistry and Catalysis (CGCC) for doctoral scholarships.
́
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DOI: 10.1021/acs.orglett.8b04004
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