Ni-Catalyzed Alkenylation of Ketone Enolates under Mild Conditions: Catalyst Identification and Optimization

Article abstract of DOI:10.1021/jacs.5b02945

A procedure for Ni-catalyzed cross-coupling of ketone enolates with alkenyl halides has been developed. Intermolecular coupling of aromatic and aliphatic ketone lithium enolates with a variety of alkenyl halides is achieved in the presence of Ni(cod)₂ catalyst (5 mol %), an N-heterocyclic carbene (NHC) ligand, and LiI (10 mol %) at 6-22 °C for 0.5-12 h with yields of up to 90%. During the initial development of this reaction, a misleading result with respect to the actual active catalyst was obtained using commercially available Q-Phos ligand, which was found to contain a trace of Pd metal contaminant sufficient to catalyze the reaction. However, under the final conditions optimized for Ni(cod)₂ in the presence of an NHC ligand, Pd was incompetent as a catalyst.

Full text of DOI:10.1021/jacs.5b02945

Communication
pubs.acs.org/JACS
Ni-Catalyzed Alkenylation of Ketone Enolates under Mild Conditions:
Catalyst Identification and Optimization
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
§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
compounds,4 and the many possible manipulations of the
ABSTRACT: A procedure for Ni-catalyzed cross-cou-
pling of ketone enolates with alkenyl halides has been
developed. Intermolecular coupling of aromatic and
aliphatic ketone lithium enolates with a variety of alkenyl
halides is achieved in the presence of Ni(cod)2 catalyst (5
mol %), an N-heterocyclic carbene (NHC) ligand, and LiI
(10 mol %) at 6−22 °C for 0.5−12 h with yields of up to
90%. During the initial development of this reaction, a
misleading result with respect to the actual active catalyst
was obtained using commercially available Q-Phos ligand,
which was found to contain a trace of Pd metal
contaminant sufficient to catalyze the reaction. However,
under the final conditions optimized for Ni(cod)2 in the
presence of an NHC ligand, Pd was incompetent as a
catalyst.
carbonyl and alkene moieties present an attractive platform for
synthetic diversity that has been utilized in a number of total
syntheses.3,5 The α-alkenylation reaction remains at an early
stage of development compared with the related α-arylation
reaction with aryl halides.6 For instance, while procedures for
both reactions are dominated by Pd catalysts, alternative
catalysts have been developed for the α-arylation reaction,
including ones based on Cu7 and Ni.8 The use of Ni in the α-
alkenylation reaction has been limited to a procedure reported
by Rathke in 1977 in which a ligandless Ni species was
employed in stoichiometric or near-stoichiometric quantities
for optimum results.9 This procedure was applied in the total
synthesis of quadrone by Wender in 1985.10 While the arylation
and alkenylation of enolates are considered to be similar
reactions, the alkenylation presents additional challenges.
Under basic conditions, issues arise with stereofidelity of
secondary and tertiary α-alkenylated products, in which cis/
trans isomerization or isomerization to an α,β-unsaturated
compound can occur.11 These complications are nonexistent
for the arylation reaction. Here we describe the development of
a new, efficient Ni-catalyzed α-alkenylation procedure that is
able to accomplish cross-coupling of ketone enolates with
alkenyl bromides under mild conditions, allowing high
regiocontrol of the resulting alkene and providing a major
cost advantage over the corresponding use of Pd. Our protocol
is unique for the alkenylation reaction in that when aryl
bromides are employed under the same conditions, no
significant amounts of arylation products are obtained.
uring recent decades, transition-metal-catalyzed cross-
Dcouplings have proven to be essential to modern
synthetic chemistry.1 Palladium has dominated as the catalyst
of choice, whereas nickel, the “impoverished younger sibling of
palladium”,2 has been developed to a lesser extent. Ni is a more
economical substitute for Pd, as it is about 3000 times less
expensive on a molar basis, although the cost of ligands can
offset this factor. Significant differences in reactivity of the two
metals can also be important in catalyst selection. Con-
sequently, investigations of Ni-catalyzed cross-couplings have
increased considerably over the past decade.2
During our initial attempts to use Ni, we uncovered an
unanticipated metal contamination of a commercial ligand that
led to a misleading result, which emphasizes the need for
careful control experiments in catalysis development.12 In our
previous synthesis of trichostatin A, a Pd/phosphine catalyst
was employed to couple a zinc enolate with an alkenyl bromide
in high yield.13 When catalytic quantities of Ni(cod)2 were
employed with Q-Phos as a phosphine ligand, a moderate yield
of product was obtained. In the presence of Q-Phos, the
coupling of the zinc enolate of propiophenone (1a) with 1-
bromo-2-methylpropene (2a) was very efficient with Pd(dba)2,
The transition-metal-catalyzed alkenylation of enolates is a
strategy to mediate C−C bond formation between enolates and
alkenyl halides to produce β,γ-unsaturated compounds (Figure
1).3 This functionality occurs in some biologically important
Received: March 20, 2015
Figure 1. Transition-metal-catalyzed alkenylation of enolates.
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.5b02945
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Journal of the American Chemical Society
Communication
but surprisingly, it also gave a high yield with Ni(cod)2 as well
as with Cu(acac)2, Fe(acac)2, or Fe(acac)3 or even no metal
additive (Figure 2). However, upon pretreatment of the
Table 1. N-Heterocyclic Carbene Screen
Figure 2. Trace-Pd-catalyzed alkenylation of enolates. aThe
commercial Q-Phos used in this example was determined to contain
b
0.6 wt % Pd. Isolated yield.
commercial Q-Phos ligand with a metal scavenger, QuadraPure
TU,14 the alkenylation failed in the absence of added metal or
in the presence of added Ni, Cu, or Fe, but it proceeded upon
addition of as little as 0.1 mol % Pd(dba)2. Analysis of the
commercial Q-Phos ligand by inductively coupled plasma
optical emission spectroscopy and X-ray photoelectron spec-
troscopy indeed showed the presence of 0.6 and 0.7 wt % Pd,
respectively, presumably remaining from the synthesis of Q-
Phos.15 The development of optimum conditions for Pd
catalysis provided a satisfactory protocol,16 but our results
suggest that investigators using Q-Phos with catalysts other
than Pd must proceed with careful scrutiny.
To reach our goal of developing a Ni-catalyzed alkenylation
of enolates, we continued our attempts to use metal-scavenged
Q-Phos. We found that the coupling of lithium enolates could
be effected by Ni(cod)2, but only stoichiometrically because of
precipitation of elemental Ni. We therefore recognized the
need for an appropriate ligand to retain the Ni in solution,
which prompted us to examine N-heterocyclic carbenes
(NHCs) as supporting ligands.17
a
entry
NHC
conversion (%)
1
2
3
4
5
6
4
15
b
5a
5b
6a
6b
5c
7a
7b
75 (60)
76
77
b
85 (60)
64
c
7
c
83
8
77
Reactions were conducted on a 0.5 mmol scale relative to 1a.
Conversions of ketone based on NMR analysis using an internal
standard. Isolated yield in parentheses. 120 mol % LiHMDS.
a
b
c
Preliminary screening employing imidazolium salts as
precursors of NHCs demonstrated the need for moderate
steric hindrance close to the reaction center (Table 1, entries 1
and 2). Only minor differences were found when the
Table 2. Screen of Reaction Conditions
counterion was changed from Cl− to BF4 (entries 2 and 3),
−
when a saturated carbene (entries 4 and 5) or more extensive
branching (entries 6 and 7) was used, or when a preformed free
carbene (purchased or prepared separately) was employed
(entries 7 and 8). We selected IPrHCl (5a) and SIPrHBF4 (6b)
for further studies because of their ready availability, high
conversions of 1, and high product yields. In all cases
employing NHCs, the Ni was retained in solution in catalytic
quantities throughout the reaction. Different bases and solvents
were also examined, with LiHMDS and THF found to be the
best combination (see the Supporting Information).
a
b
b
b
b
c
entry
X
Y
5a
Z
LiI
T (°C) t (h) conv. (%)
1
2
3
4
5
6
7
Br
I
10
10
10
10
5
20
20
20
20
5
140
140
140
120
105
105
105
0
22
22
22
22
22
0
5
75
78
84
90
95
84
95
0
40
40
20
10
10
0.5
0.5
0.5
0.5
7
Br
Br
Br
Br
Br
5
5
d
5
5
6
2
We next turned our attention to the choice of the alkenyl
halide. Exchanging the bromide 2a for the corresponding iodide
resulted in higher conversion in a shorter time (Table 2, entries
1 and 2). Gratifyingly, even better results were obtained when
bromide 2a was combined with 40 mol % LiI at 22 °C (entry
3). Further improvements were obtained using a minimal
amount of base (120 mol %), which was just sufficient to
deprotonate both the ketone and NHC precursor 5a (entry 4).
Decreasing the catalyst, ligand, and additive loadings resulted in
the highest conversion of 95% (entry 5). The same result could
be obtained at 6 °C with a slight increase in reaction time
(entry 7). We note that the corresponding Pd-catalyzed
a
Reactions were conducted on a 0.5 mmol scale relative to 1a. 130 mol
% alkenyl halide was used in entries 1−6 and 110 mol % in entry 7.
b
c
Reported in mol %. Conversion of ketone based on NMR analysis
using an internal standard. Only 3aa was observed as the product.
d
Dry ice/cyclohexane bath.
reaction employs 250 mol % base because of the increased
acidity of the product α-hydrogens,18 but this problem does not
appear to arise with Ni, thus allowing milder, less basic
conditions. One possible explanation is that Ni functions as a
more active catalyst, resulting in the starting ketone enolate
B
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Communication
being converted to product faster than proton exchange
between the starting ketone enolate and product.
Reaction with a cyclic ketone was achieved but in much lower
yield (3da). Generation of a quaternary α-center proceeded
well, but required a temperature of 22 °C (3ea). An
unsymmetrical aliphatic ketone could also be coupled readily
at 22 °C to form 3fa regioselectively. Our protocol was
applicable to scale-up, producing 1.5 g (83% isolated yield) of
3aa. Attempts to employ a methyl ketone resulted in low yields
because of further reaction of the initially formed product.
Amides and esters were investigated as potential nucleophiles
but led to no reaction under our conditions.
The reaction conducted at ambient temperature (Table 2,
entry 5) allowed us to isolate the product in 89% yield. To
verify the role of Ni, we performed control experiments without
metal and with Ni replaced by 5 mol % Pd(OAc)2 or 2.5 mol %
Pd2(dba)3, which gave yields of 0%, 5%, and 6%, respectively
(see the Supporting Information). Thus, Pd is inferior as a
catalyst under the conditions optimized for Ni.
Under the optimized low-temperature conditions (Table 2,
entry 7), the ketone scope was explored using alkenyl bromide
2a (Figure 3). Electron-neutral and -rich aryl ketones
underwent coupling in high yields (3aa and 3ba), while an
electron-deficient aryl ketone resulted in a lower yield (3ca).
Next, a range of alkenyl bromides was coupled with ketone
1a. A trans-alkenyl bromide reacted faster than its cis analogue,
but the cis product was obtained in higher yields (3ab and 3ac).
For these and subsequent examples, the β,γ-unsaturated
products were formed stereospecifically and were stable
under the reaction conditions; no formation of α,β-unsaturated
products was observed. The hindered α-styryl bromide gave a
low yield of 3ad, which may be attributed to added steric
hindrance of the electrophile at the α-styryl position. A silyl
protecting group was partially removed, resulting in only a
moderate yield of 3ae along with desilylated material. trans-β-
Bromostyrene gave only low yields with 1a (3af) but reacted
well with a more electron-rich ketone (3bf). To demonstrate
the utility of our Ni-catalyzed protocol compared with the
previously utilized Pd catalyst,13 we constructed the carbon
backbone of trichostatin A in comparably high yield (3bg). No
reaction was observed between 1a and alkenyl chlorides,
alkenyl triflates, or bromobenzene under the present mild
conditions. For bromobenzene, increasing the reaction temper-
ature to 40 °C for 24 h gave only a 32% yield of the arylation
product. Consistent with the lower reactivity of bromobenzene,
we found that 2h containing both alkenyl bromide and aryl
bromide moieties could be chemoselectively coupled with 1e at
6 °C to afford the α-alkenylated product 3eh in 71% isolated
yield; no α-arylation product was detected in the crude mixture
1
by H NMR analysis.
In related Pd-catalyzed alkenylations, large excesses of base
and reactant, high temperatures, and/or long reaction times
have been employed to form quaternary α-centers,18,19 with the
exception of our recent Pd protocol.16 With our Ni-catalyzed
procedure, high yields were achieved under relatively mild
conditions (6 °C) with short reaction times (1−4 h) to
generate quaternary ketones when the alkenyl halide has
exclusively trans substitution (3eh, 3gf, 3hf, 3eb). Alkenyl
halides having a cis substituent could be coupled in moderate to
good yields (3ea, 3ei) but required a higher temperature (22
°C) and a longer reaction time (12 h).
We further investigated the beneficial effects of LiI. There
have been several reports of Ni- and Pd-catalyzed sp2 halide
exchanges of both alkenyl halides20 and aryl halides,21 which
would also be possible in our protocol. To test whether a
similar exchange occurs in our system, alkenyl halide 2i was
subjected to LiI (120 mol %) in the presence of a Ni/IPrHCl
catalyst. After 2 h, a 4:5 ratio of 2i and the corresponding
alkenyl iodide was observed. Similarly, trans-β-bromostyrene
underwent this halide exchange. In the absence of Ni(cod)2, no
alkenyl iodides were formed. Therefore, it appears that a Ni-
catalyzed halide exchange occurs in the presence of LiI under
the conditions of our alkenylation reaction, although other
potential effects of LiI cannot be ruled out at this point.
In summary, we have described the development of a Ni-
catalyzed alkenylation of ketone enolates. Secondary and
tertiary ketones were readily coupled by a Ni/NHC catalyst
Figure 3. Substrate scope. Isolated yields (averages of two runs) are
shown. Reactions were conducted on a 0.5 mmol scale relative to 1.
The first letter in the alphanumeric product designators refers to the
starting ketone, and the second letter identifies the alkenyl halide.
aConducted on an 8 mmol scale relative to 1a. bReaction was run at 22
c
°C. Conducted on a 0.25 mmol scale relative to 1b.
C
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Journal of the American Chemical Society
Communication
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ASSOCIATED CONTENT
■
S
* Supporting Information
1
Experimental procedures, H, 13C, and 19F NMR spectra, and
characterization of all compounds. The Supporting Information
is available free of charge on the ACS Publications website at
DOI: 10.1021/jacs.5b02945.
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P. Org. Lett. 2014, 16, 3970.
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AUTHOR INFORMATION
Corresponding Author
*phelquis@nd.edu
■
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Science Foundation
(CHE-1058075 and CHE-1261033), the Research Council of
Sweden, the Shenzhen Peacock Program (KQTD201103), and
AstraZeneca. We thank Prof. Dr. K. Henderson (Notre Dame)
for sharing equipment and Prof. Dr. P. Andersson (Stockholm
University) for providing laboratory facilities during a research
visit by M.G.
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