Palladium-catalyzed alkenylation of ketone enolates under mild conditions

Article abstract of DOI:10.1021/ol5017965

A protocol for a mild, catalytic, intermolecular alkenylation of ketone enolates has been developed using a Pd/Q-Phos catalyst. Efficient intermolecular coupling of a variety of ketones with alkenyl bromides was achieved with a slight excess of LiHMDS and temperatures down to 0 °C.

Full text of DOI:10.1021/ol5017965

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed Alkenylation of Ketone Enolates under Mild
Conditions
Michael Grigalunas,† Tobias Ankner,‡ Per-Ola Norrby,§,∥ Olaf Wiest,†, ⊥ and Paul Helquist*,†
†Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States
‡Department of Biochemistry and Organic Chemistry, Uppsala University, Box 576 BMC, SE-751 23 Uppsala, Sweden
§Department of Chemistry and Molecular Biology, University of Gothenburg, Kemigarden 4, SE-412 96 Goteborg, Sweden
̊
̈
∥Pharmaceutical Development, Global Medicines Development, AstraZeneca, Pepparedsleden 1, SE-431 83 Molndal, Sweden
̈
⊥Lab of Computational Chemistry and Drug Design, School of Chemical Biology and Biotechnology, Peking University, Shenzhen
Graduate School, Shenzhen 518055, China
S
* Supporting Information
ABSTRACT: A protocol for a mild, catalytic, intermolecular alkenyla-
tion of ketone enolates has been developed using a Pd/Q-Phos catalyst.
Efficient intermolecular coupling of a variety of ketones with alkenyl
bromides was achieved with a slight excess of LiHMDS and temperatures
down to 0 °C.
β,γ-Unsaturated carbonyls are structural features present in a
number of important compounds.1 From a synthetic chemist’s
perspective, the carbonyl and alkene moieties also provide an
attractive platform to access a diverse range of complex
structures2 by further transformations of these two functional
groups. Several synthetic approaches have been developed en
route to β,γ-unsaturated compounds including transition-metal-
catalyzed methods to mediate C−C bond formation between
metal enolates and alkenyl halides (Scheme 1).3 Both inter- and
performed at 80 °C with a large excess of base (250 mol %),6
although lower temperatures have been reported in select
cases.3 Here we report a protocol for intermolecular
alkenylations that is efficient at lower temperatures with a
nearly stoichiometric amount of base. These mild conditions
minimize the undesired side reactions discussed above.
Our studies began with a screening of bases together with a
palladium catalyst and a bulky ferrocenylphosphine ligand,
starting from conditions used in prior work in our laboratory.7
Several synthetic procedures, including Negishi couplings,8
Reformatsky reactions,9 and α-arylations10 have utilized more
mildly basic Zn derivatives as opposed to harsher alkali metal
species. With this factor in mind, our initial conditions
employed Zn(TMP)2 as the base to couple 1 and 2 in the
presence of Pd(dba)2 (2.5 mol %) and Q-Phos (3a, 5 mol %) in
THF at 22 °C. Compared to the less basic Zn enolates (Table
1, entry 1), further base screenings revealed that Li enolates
(entries 2 and 4) reacted faster and resulted in higher yields
without observation of unwanted side reactions. Screenings
using Na and K bases led to the formation of unidentified
precipitates and lower yields (entries 3, 5, and 6). The use of
Cs2CO3 resulted in no reaction (entry 7). With Li bases
performing best, LiHMDS was chosen for use in further
studies. An evaluation of solvents showed that both THF and
toluene gave comparable results (entries 2 and 8), whereas
more polar solvents resulted in lower yields (entries 9 and 10).
During the screening for optimum conditions, two different
protocols were employed. Procedure A involved having a base,
ligand, and catalyst present, then adding a ketone to generate
an enolate, followed by addition of the alkenyl halide. In
procedure B, a preformed enolate was added to a solution of
Scheme 1. Transition-Metal-Catalyzed Alkenylation of
Enolates
intramolecular versions of these reactions have been reported.
However, compared to related arylation reactions with aryl
halides,4 these alkenylations remain at an early stage of
development with ample opportunity for improvement.
One potential complication using enolate nucleophiles is that
the α-hydrogens of the alkenylation products are more acidic
than those of the starting ketones due to allylic resonance in the
enolates formed from the products. Consequently, several side
reactions can occur due to (1) quenching of the starting ketone
enolate by the product, resulting in low conversions, (2)
dialkenylations, and/or (3) rearrangement of the initial
products to αβ-unsaturated carbonyl compounds.5 The
majority of previously reported ketone enolate alkenylations
employ elevated temperatures. As an example, one of the more
recently developed procedures of relevance to our studies is
Received: June 21, 2014
Published: July 17, 2014
© 2014 American Chemical Society
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a
Table 1. Base and Solvent Screen
Table 2. Ligand Screen*
b
entry
base
solvent
time (h)
yield (%)
1
2
Zn(TMP)2
LiHMDS
KHMDS
LiOtBu
THF
6
0.5
24
0.5
52
24
24
0.5
24
24
47
85
50
87
24
45
0
THF
3
THF
4
THF
5
NaOtBu
KOtBu
THF
6
THF
7
Cs2CO3
THF
8
LiHMDS
LiHMDS
LiHMDS
toluene
DMF
CH3CN
88
14
0
9
10
a
Procedure A: Ketone was added to Pd source, ligand, and base in
b
solution followed by addition of alkenyl halide. Isolated yield.
ligand, catalyst, and alkenyl halide. The reactions proceeded ca.
three times faster with procedure B than with procedure A and
with similar yields (Table 2, entries 1 and 2). Our choice of
procedure B for our further studies is in contrast to the use of
conditions that are analogous to procedure A for many prior
cases of enolate alkenylations6,11 and arylations.12
Several ligands varying in electronic and steric properties
were screened using Pd(dba)2 (2.5 mol %) and LiHMDS (1.1
equiv) in THF at 22 °C. In these studies, Pd(dba)2 and
Pd(OAc)2 performed comparably well as catalysts (Table 2,
entries 2 and 3). Triarylphosphines (entries 5, 9, and 11) were
inferior to more electron-rich and sterically demanding dialkyl
arylphosphines (entries 3, 4, 6, 7, and 10). Among the
dialkylarylphosphines, those bearing a ferrocene (entries 3 and
4) gave the highest yields. Dialkylferrocenyl monophosphines
outperformed ferrocenyl diphosphines for which a tBu
*
i
Procedure B: Ketone enolate was generated by adding ketone to a
solution of base. The ketone enolate was then added to a Pd source,
substituent led to a modest yield, whereas a cyclohexyl or Pr
substituent led to no reaction (entries 3, 4, and 14−16). The
use of other ligand classes, including a phosphoramidite, a
bis(oxazoline) (BOX) ligand, and an N-heterocyclic carbene,
resulted in low yields (entries 17−19). From the ligand screen,
it was concluded that the bulky, electron-rich monophosphine
Q-Phos (3a) performed best with respect to both yield and
reaction time. This ligand has also found use in enolate
arylations.13
a
b
ligand, and alkenyl halide in solution. Isolated yield. Procedure A
c
d
(see Table 1). Pd(dba)2 instead of Pd(OAc)2. Ligand (3 mol %).
e
130 mol % of LiHMDS.
Table 3. Optimization of Catalyst Loadings and
Temperature
a
The optimal reagents resulting in fast reaction times
permitted the use of lower catalyst loadings and temperatures.
Similar yields were achieved with catalyst loadings as low as
0.67 mol % at 22 °C (Table 3, entry 1). Reducing the
temperature to 0 °C with 3 mol % catalyst consistently gave
high yields and full conversion (entry 4). Upon lowering the
temperature, a significant difference was observed between
procedure A and procedure B. At 0 °C, procedure B resulted in
100% conversion after 40 min, whereas procedure A achieved
only 80% conversion after 10 h (entries 4 and 5). The lower
reactivity in procedure A could be rationalized by the strong
amide base perhaps interacting with the catalyst. Optimal
conditions were achieved using LiHMDS (110 mol %),
b
c
entry
x (mol %)
temp (°C)
time (h)
yield (%)
conv (%)
1
2
3
4
0.67
0.1
2.5
3
22
22
0
3
85
e
100
35
40
1.25
0.66
10
92
97
e
98
0
100
d
e
5
3
0
b
80
a
c
Procedure B (see Table2). Isolated yield. Based on starting ketone.
d
e
Procedure A (see Table1). Not isolated.
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Pd(OAc)2 (3 mol %), and Q-Phos (6 mol %) at 0 °C in THF
following procedure B.
Table 5. Scope of Alkenyl Halides*
With optimum conditions determined, the scope of coupling
of ketones to 2 was explored. A range of electron-rich and
-deficient secondary aryl ketones reacted rapidly in high yields
(70−97%) at 0 °C (Table 4, entries 1−6). The use of 4′-
a
Table 4. Scope of Ketones
b
c
entry
R1
R2
R3
time
yield (%) conv (%)
1
2
3
4
5
p(NMe2)C6H4
p(OMe)C6H4
C6H5
Me
Me
Me
Me
Me
H
H
H
H
H
H
Me
H
10 min
10 min
40 min
1.5 h
84
87
97
78
78
70
82
22
100
100
100
90
p(Cl)C6H4
p(CF3)C6H4
α-tetralone
p(NMe2)C6H4
C6H5
1.5 h
93
d
6
1 h
86
e
7
Me
H
20 h
100
33
8
30 min
a
b
c
Procedure B (see Table 2). Isolated yield. Based on starting ketone.
d
e
Toluene as solvent. Run at 22 °C.
chloropropiophenone led exclusively to the α-alkenylation
product without any detectable α-arylation (entry 4).
Generation of a quaternary carbon center was possible when
the temperature was elevated to 22 °C (entry 7). The use of an
α-unsubstituted ketone resulted in the desired α-alkenylation
occurring in only 22% yield (entry 8). The highest conversions
and yields are obtained using α-mono- or disubstituted ketones
that give products containing a tertiary or quaternary α-center
without formation of detectable side products.
*
a
b
Procedure B (see Table 2). Isolated yield. Based on starting
c
d
e
ketone. Was not isolated. Run at 22 °C. Toluene as solvent.
f
g
Alkenyl bromide and product were both a 95:5 E:Z mixture. Not
determined due to volatility of the starting ketone.
Next, the scope of alkenyl halides was examined. When
different halides were compared, alkenyl bromides were
superior to analogous alkenyl iodides and chlorides (Table 5,
entries 1−3). Gratifyingly, the conjugated ester-activated
derivatives coupled in moderate to high yields (61% and
78%) despite generating products containing α-protons that are
presumably more acidic than in the other products (entries 4
and 5). Reactions involving more sterically hindered electro-
philes, including use of an alkenyl triflate, resulted in moderate
yields (47−71%) (entries 6 and 7). Electrophiles with trans-1,2-
substitution reacted rapidly to give modest yields in THF.
Changing the solvent from THF to toluene in these cases
resulted in increased yields (entries 7−9). Coupling of the
aliphatic ketone, 3-pentanone, with activated electrophiles
resulted in moderate yields (75 and 50%, Table 5, entries 10
and 11).
As mentioned above, a potential concern for both
alkenylation and arylation of enolates is the increased acidity
of the products’ α-hydrogens, which may lead to further
reactions. In the case of α-alkenylation, steric factors based on
the introduction of a cis-substituted alkene may be considered.
Subsequent deprotonation of the alkenylation product from an
α-substituted ketone may be disfavored due to A-1,3 strain in
the resulting enolate. These considerations may be reflected in
in a comparison of entries 2 and 9 in Table 5, where lower
yields and conversions are observed in the latter case for the
product lacking cis-substitution. This result may be due to the
more facile deprotonation of the non-cis-substituted product by
the starting ketone enolate, resulting in its quenching. Likewise,
when the α-substitution pattern is varied from formation of a
tertiary to a secondary product (entries 3 and 8 in Table 4),
much lower conversions and yields are observed. This possible
effect of A-1,3 strain in inhibiting product deprotonation is
consistent with the protocol being most efficient when
secondary and tertiary ketones are coupled to form cis-
substituted products. Of the factors responsible for A-1,3
strain, the absence of a cis-alkene substituent is not as
unfavorable as using an α-unsubstituted ketone. Another result
that may be expected to arise from deprotonation of the α-
alkenylation products would be isomerization of the initial
products to produce conjugated 2-alkenones. This outcome was
not observed in our systems, although it has been observed
under previously reported conditions.5
In summary, we have developed a procedure for Pd-catalyzed
alkenylation of enolates that has been applied to synthesize β,γ-
unsaturated ketones under mild conditions. A range of ketones
readily undergo coupling with alkenyl bromides varying in
steric and electronic properties in good to excellent yields. With
this combination of conditions and a variety of substrates now
established, we are exploring the mechanistic details and the
possibility of developing an enantioselective version of this
procedure.
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Letter
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Experimental procedures, H, 13C, and 19F NMR spectra, and
characterization data of all compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: phelquis@nd.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge the National Science Foundation (CHE-
1058075 and CHE-1261033), the Research Council of Sweden,
the Shenzhen Peacock Program (KQTD201103), and
AstraZeneca for support of this research.
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