Regioselective ketone α-alkylation with simple olefins via dual activation

Article abstract of DOI:10.1126/science.1254465

Alkylation of carbonyl compounds is a commonly used carbon-carbon bond-forming reaction. However, the conventional enolate alkylation approach remains problematic due to lack of regioselectivity, risk of overalkylation, and the need for strongly basic conditions and expensive alkyl halide reagents. Here, we describe development of a ketone-alkylation strategy using simple olefins as the alkylating agents. This strategy employs a bifunctional catalyst comprising a secondary amine and a low-valent rhodium complex capable of activating ketones and olefins simultaneously. Both cyclic and acyclic ketones can be mono-a-alkylated with simple terminal olefins, such as ethylene, propylene, 1-hexene, and styrene, selectively at the less hindered site; a large number of functional groups are tolerated.The pH/redox neutral and byproduct-free nature of this dual-activation approach shows promise for large-scale syntheses.

Full text of DOI:10.1126/science.1254465

Regioselective ketone α-alkylation with simple olefins via dual
activation
Fanyang Mo and Guangbin Dong
Science 345, 68 (2014);
DOI: 10.1126/science.1254465
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REFERENCES AND NOTES
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FP-PEOPLE-2012-IEF-331095. We thank S. Paniagua for help
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ACKNOWLEDGMENTS
The data used in this research are stored in the public archives
of the international space observatories involved: XMM-Newton,
HST, Swift, NuSTAR, INTEGRAL, and Chandra. We acknowledge
support by the International Space Science Institute in Bern; the
Netherlands Organization for Scientific Research; NASA HST
program 13184 from the Space Telescope Science Institute, which
is operated by Association of Universities for Research in
Astronomy, Incorporated, under NASA contract NAS5-26555; the UK
Science and Technology Facilities Council; the French Centre National
d’Etudes Spatiales, CNRS/Project International de Coopération
Scientific and CNRS/Programme National Hautes Énergies;
SUPPLEMENTARY MATERIALS
www.sciencemag.org/content/345/6192/64/suppl/DC1
Materials and Methods
Figs. S1 to S4
Tables S1 to S3
References (21–38)
Movie S1
24 March 2014; accepted 9 June 2014
Published online 19 June 2014;
10.1126/science.1253787
Vicerrectoría de Investigación y Desarrollo Tecnológico (Chile);
Israel’s Ministry of Science, Technology, and Space, Israel Science
coupling, known as the Conia-ene reaction (12),
requires high temperature (>250°C), giving mod-
erate yields with limited functional-group toler-
ance; the catalytic version was first reported by
Widenhoefer (13) using palladium and recently
by Che (14) using gold. In contrast, intermolecular
ketone-olefin couplings are rare and mainly in-
volve addition of stoichiometric metal enolates or
enamides across olefins (8, 15, 16). To our knowl-
edge, base-catalyzed additions of metal enolates
to styrene derivatives (likely facilitated by forma-
tion of delocalized charges) (17, 18) and a Mn/Co-
initiated oxidative radical process for nonaromatic
olefins (19) are the only approaches reported to
date. Recently, enamine radical cation-mediated
couplings with olefins emerged as an attractive
catalytic strategy for a-functionalization of car-
bonyl compounds, albeit requiring oxidative con-
ditions (20, 21). Therefore, a general activation
mode for coupling of simple ketones and un-
activated olefins remains to be developed. Here,
we describe our development of a catalytic dual-
activation strategy for addition of normal ketone
a-C–H bonds across unactivated olefins, which al-
lows for direct ketone alkylation by simple olefins
under both pH- and redox-neutral conditions.
We targeted a bifunctional catalyst capable of
activating the ketone a-C–H bonds and the ole-
fin simultaneously, which would incorporate
a secondary amine and a low-valent transition
metal complex. Seminal work by Jun and co-
workers showed that metal-organic cooperative
catalysis enables activation of aldehyde ipso-
C−H bonds through imine formation with a
bifunctional primary amine, i.e., 2-amino-3-
picoline (22). We hypothesized that, by using a
secondary amine, the ketone a-C–H bonds would
instead be activated by enamine formation. As
depicted in Fig. 2, first, the catalyst would bind
the ketone substrate to form an enamine (step a),
which would consequently convert the ketone a
sp3 C–H bond into a sp2 C–H bond, thus en-
hancing the reactivity toward oxidative addition
by a low-valent transition metal (23, 24). Mean-
while, if a proper directing group (DG) were linked
to the amine domain, the DG could facilitate
insertion of a low-valent transition metal (e.g.,
RhI) into the resulting enamine C–H bonds, giving
C–H BOND ACTIVATION
Regioselective ketone a-alkylation
with simple olefins via
dual activation
Fanyang Mo and Guangbin Dong*
Alkylation of carbonyl compounds is a commonly used carbon-carbon bond–forming
reaction. However, the conventional enolate alkylation approach remains problematic
due to lack of regioselectivity, risk of overalkylation, and the need for strongly basic
conditions and expensive alkyl halide reagents. Here, we describe development of a
ketone-alkylation strategy using simple olefins as the alkylating agents. This strategy
employs a bifunctional catalyst comprising a secondary amine and a low-valent
rhodium complex capable of activating ketones and olefins simultaneously. Both cyclic
and acyclic ketones can be mono-a-alkylated with simple terminal olefins, such as
ethylene, propylene, 1-hexene, and styrene, selectively at the less hindered site; a large
number of functional groups are tolerated. The pH/redox neutral and byproduct-free nature
of this dual-activation approach shows promise for large-scale syntheses.
he a-alkylation of carbonyl compounds, an
old but fundamental organic transforma-
tion, is still widely used in complex molecule
syntheses (1). Conventionally, carbonyl alkyl-
ation involves generation of metal enolates
hand, the Stork enamine reaction (5, 6) (Fig. 1B)
affords monoalkylation with high regioselectivity
at the less hindered a carbons under less basic
conditions; however, use of reactive alkylating
agents (alkyl halides or Michael acceptors) is still
required due to the reduced nucleophilicity of
enamines versus metal enolates.
We foresaw substantial advantages in the pro-
spective use of simple unactivated olefins as
alkylating agents (Fig. 1C). Adding the ketone
a-C–H bond across a C–C double bond under
neutral conditions would furnish no byproducts
and tolerate a broad range of functionality. This
approach would also have economic advantages
because olefins are much cheaper and more readily
available feedstock than the corresponding alkyl
halides (Fig. 1D); in fact, most terminal alkyl
halides are ultimately prepared from olefins (4, 7).
Although adding a-C−H bonds of activated
methylene compounds across olefins and alkynes
has been established (8–11), there are fewer exam-
ples of direct coupling of simple ketones and unac-
tivated olefins. The intramolecular ketone-olefin
T
followed by addition of an alkylating agent, often
alkyl halides (Fig. 1A). Although effective, as doc-
umented in almost all organic chemistry text-
books, this enolate alkylation approach suffers
from many drawbacks (1), including (i) the need
for stoichiometric strong metallic bases (e.g.,
lithium diisopropylamide) and cryogenic con-
ditions (to avoid homolytic couplings); (ii) the
challenge in controlling regioselectivity for unsym-
metrical ketones and curtailing overalkylation to
di- or trisubstituted products ; (iii) the expense of
alkyl halide reagents (2–4); and (iv) the formation
of stoichiometric metal halides and conjugate
acids of the bases as byproducts. On the other
Department of Chemistry, University of Texas at Austin,
Austin, TX 78712, USA.
*Corresponding author. E-mail: gbdong@cm.utexas.edu
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metal hydride species (M–H, step b). Upon olefin
coordination to the metal, subsequent M–H mi-
gratory insertion (step c) and reductive elimination
(step d) would provide an alkylated enamine, which
upon hydrolysis would lead to a-alkylation and
catalyst regeneration (step e).
site of ketones; thus, this bifunctional catalyst
would be expected to provide high regiocontrol
for monoalkylation of unsymmetrical ketones.
Moreover, as documented in enamine catalysis
(25), enamine formation and hydrolysis can exist in
equilibrium, but the less-hindered ketone (starting
material) preferentially forms enamine over the
more-hindered ketone (product), and thus pro-
duct inhibition can be avoided. In addition,
enamine formation/hydrolysis is known to be
compatible with the RhI to RhIII catalytic cycle
(26). Therefore, both the amine and the metal
components can be employed catalytically. [For
our preliminary study of alkylation with 1,2-cyclic
diketones using stoichiometric aminopyridine
as the cofactor, see (27).]
In the Stork enamine reaction (5, 6), enamine
formation is regioselective for the less-hindered
To examine the feasibility of the proposed
strategy, we tested 3-phenylcyclopentanone (1a)
and ethylene (2a) as model substrates. A variety
of rhodium precatalysts/dative ligands, bifunc-
tional ligands, solvents, additives, and pressure
of ethylene were examined (see table S1). Given
the crucial role of the bifunctional ligands in the
proposed catalytic cycle, seven secondary amine
compounds (L1 to L7 in table S1) containing an
adjacent DG were designed and explored under the
ethylation conditions. To our delight, 7-azaindoline
(L1) exhibited unique and high catalytic activi-
ties, whereas others were inactive. In the presence
of 2.5 mole percent (mol %) chlorobis(cyclooctene)
rhodium(I) dimer {[Rh(coe)2Cl]2}, 5 mol % 1,3-
bis(2,4,6-trimethylphenyl)imidazol-2-ylidene (IMes)
ligand, 10 mol % p-toluenesulfonic acid mono-
hydrate (TsOH·H2O), and 25 mol % L1 in toluene,
the desired ethyl-substituted product 3a was
isolated in 82% yield using ethylene gas as the
alkylating agent (table S1, entry 4). Subsequently,
the role of each reactant was investigated through
a series of control experiments. The absence of
the RhI complex or bifunctional ligand L1 com-
pletely eliminates the reactivity (table S1, entries
5 and 6), supporting our hypothesis that enamine
formation and low-valent metal are key for the
C–H/olefin coupling reaction. To promote en-
amine formation, 10 mol % TsOH·H2O was pur-
posely employed as an acid catalyst; indeed,
without this additive, no desired alkylation pro-
duct was observed (table S1, entry 7). The bulky
electron-rich N-heterocyclic carbene (NHC) lig-
and (IMes) was used to promote oxidative addi-
tion of enamine C–H bonds to Rh and subsequent
olefin insertion (28). Considerably diminished
yields were found in the absence of this ligand
or using Wilkinson’s catalyst instead (table S1,
entries 8 and 20). The reaction exhibited complete
regioselectivity for the less-hindered 5 position
of cyclopentanone; neither alkylation at the 2
position nor multiple alkylations was observed
for ketone 1a. Moreover, while the reaction re-
quires 2 days at toluene reflux temperature
when 2.5 mol % [Rh(coe)2Cl]2, 5 mol % IMes,
and 25 mol % L1 were employed, increasing the
catalyst loading can result in a full conversion
within 12 to 24 hours (table S1, entries 1 and 2).
With the optimized conditions in hand, we
examined the substrate scope. A wide range of
different functional groups were tolerated under
the alkylation conditions (Fig. 3A). Ethers, aryl
bromides, carboxylic esters, methylenedioxys,
nitriles, and thioethers proved compatible (3b
to 3h). Substrates containing competitive alkylation
sites, such as secondary amides (3i), malonates
(3j) and aliphatic esters (3k and 3t), gave chemo-
and regioselective ethylation exclusively at the
ketone C5 position. Furthermore, reactive functional
Fig. 1. Different approaches to ketone alkylation. (A) Enolate alkylation. (B) Stock enamine
reaction. (C) Simple olefins as alkylating agents. (D) Cost of alkylating agents.
Fig. 2. Design of a bifunctional catalyst and proposed catalytic cycle. (a) Enamine formation;
(b) Oxidative addition of enamine C–H bond; (c) Migratory insertion into olefins; (d) Reductive
elimination to form C–C bond; (e) Enamine hydrolysis.
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groups, including free tertiary and primary al-
cohols (3l and 3m), free phenols (3n), unpro-
tected indoles (3o), and amines (3p), survived,
giving moderate to high yields of ketone-alkylation
products. Acid-sensitive substrates, such as those
containing a tert-butyldimethyl silyl (TBS) ether
(3q), a tertiary alcohol (3l), and a trimethylsilyl
(TMS) group (3ad in Fig. 3C), were also suitable
for this transformation. Furthermore, enolizable
preexisting stereocenters were preserved dur-
ing the reaction (3t) because no strong base was
involved. Thus, this method provides comple-
mentary compatibility to the conventional eno-
late alkylation chemistry.
On a 2-mmol scale (2.0 M), the reaction of ketone
1a provided full conversion and 96% isolated yield
with a lower catalyst loading (versus the 0.2-mmol
scale). In addition, using 10 mmol (0.98 g) 3-methyl-
cyclopentanone as the starting material, we ob-
tained the desired ethylation product (3s) in nearly
quantitative yield [determined by 1H nuclear
Fig. 3. Regioselective ketone a-alkylation with simple olefins. (A) Ethyl-
ation of various cyclopentanones. Unless otherwise mentioned, the reactions
were run on a 0.2-mmol scale; the data are reported as percent isolated yield.
Diastereomeric ratio (dr) was determined by 1H NMR. *[Rh(coe)2Cl]2 (1 mol %),
IMes (2 mol %), TsOH·H2O (5 mol %), toluene 1 mL (2.0 M). †[Rh(coe)2Cl]2
(0.5 mol %), IMes (1 mol %), TsOH·H2O (2 mol %), L1 (15 mol %), toluene 3.0 mL
(3.3 M). (B) Ethylation of various ketones. ‡Condition A: ketone 1 mL, ethylene
300 pounds per square inch, L1 (0.2 mmol), [Rh(coe)2Cl]2 (0.005 mmol),
IMes (0.01 mmol), TsOH·H2O (0.02 mmol), 2,4,4-trimethylpentan-2-amine
(0.1 mmol), neat, 130°C, 48 hours. The TON are based on [Rh] monomer, which
are determined by GC with dodecane as an internal standard. §No 2,4,4-
trimethylpentan-2-amine, but with H2O (10 mL); 2,5-diethyl-cyclopentanones
were also obtained (TON 29). ||180°C. (C) Alkylation of cyclopentanone with
various olefins. ¶Condition B: cyclopentanone (0.5 mL), olefin (0.5 mL, propene
~1 mL), L1 (0.2 mmol), [Rh(coe)2Cl]2 (0.005 mmol), IMes (0.01 mmol),
TsOH·H2O (0.02 mmol), 2,4,4-trimethylpentan-2-amine (0.1 mmol), H2O (10 mL),
neat, 130°C, 48 hours. The TON are based on [Rh] monomer, which are
determined by GC with dodecane as an internal standard.
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magnetic resonance (NMR)] with only 0.5 mol %
of the Rh-dimer catalyst and 15 mol % of L1 (75%
isolated yield due to the volatility of 3s). This
reaction can tolerate a range of concentrations
(from 0.2 M to 3.3 M), which can be critical for
large-scale applications. Structures of the products
were unambiguously characterized by 1H/13C
NMR, infrared (IR), and high-resolution mass
spectrometry (HRMS); x-ray structures of sev-
eral hydrazone derivatives were also obtained. For
all substrates, the products were obtained as a pair
of diastereoisomers with the cis-isomer predom-
inating. It is likely that in the last step (enamine
hydrolysis), the proton preferentially attacks
the less-hindered face of the enamine, resulting
in cis disposition of the two substituents. The di-
astereomeric ratio (dr) of the alkylation product
can be enhanced by conversion to the correspond-
ing silyl enol ether followed by treatment with a
chiral Lewis acid (supplementary materials).
cies toward enamine formation (29). By further in-
vestigating the reaction conditions, we discovered
that a catalytic amount of an additional amine,
such as triethylamine, 1,4-diazabicyclo[2.2.2]octane
(DABCO), or 2,4,4-trimethylpentan-2-amine, could
increase the efficiency of the ketone a-alkylation.
Although the exact reason remains unclear, with
the help of the amine additive, simple aliphatic
ketones, such as acetone and 2-pentanone, coupled
with ethylene to afford the desired monoalkylation
products. It is well established that aromatic ke-
tones, such as acetophenone, can undergo metal-
catalyzed C–H/olefin couplings through activation
of the ortho aromatic C–H bond, initially reported
by Murai and co-workers (30). In contrast, our strat-
egy completely switched the chemoselectivity from
the normal aromatic C–H bond to the ketone
a-C–H bond, providing homologated ketone 3y.
Using cyclopentanone as the ketone substrate,
different classes of terminal olefins were also ex-
plored. All these a-olefins provided the desired mono-
alkylation products with complete regioselectivity for
the anti-Markovnikov addition products. Sterically
hindered and less-hindered, isomerizable and non-
isomerizable, aliphatic and aromatic olefins all
reacted, suggesting a broad scope of this method-
ology. Through this investigation, dialkylation
was only observed when coupling the unsubsti-
tuted cyclopentanone (1u) with ethylene (Fig.
3B); however, we discovered that simply adding
water to the reaction enhanced the selectivity
for monoalkylation (supplementary materials).
For examples exhibited in Fig. 3, B and C, the
ketones were employed as the solvents for op-
timal performance, and the turnover numbers
(TON) based on the Rh monomer were used to
measure the efficiency of these reactions. Given
the volatility of these alkylation products, their
accurate yields were determined by gas chro-
matography (GC) or 1H NMR analysis; a portion
of the pure products could be isolated via silica
gel chromatography and fully characterized (sup-
plementary materials), although compounds 3w
and 3x were identified by comparison of their
crude 1H NMR, GC, and GC–mass spectrometry
data with authentic samples.
To gain more mechanistic insight into this bi-
functional catalyst-mediated ketone/olefin coupling,
we conducted several additional experiments
(Fig. 4). First, we isolated a key Rh-enamine
complex (4) from enamine 5 and [Rh(coe)2Cl]2
(Fig. 4A). The x-ray structure of 4 shows that
the azaindoline plane is twisted 62.5° (compared
with the x-ray structure of free enamine 5) to
allow chelation of the metal with the pyridine
and the olefin, suggesting a preactivated confor-
mation for the subsequent C–H insertion (see
step a in Fig. 2). Second, attempts to capture the
metal-hydride intermediate incorporating an IMes
ligand were unfruitful; however, we successfully
isolated and obtained the x-ray structure of Rh–H
complex 6 with PMe3 as the dative ligand (Fig. 4B).
Although complex 6 did not react with ethyl-
ene, it demonstrated the feasibility of insertion
of a low-valent transition metal into enamine
vinyl C–H bonds by oxidative addition (see step
b in Fig. 2). Third, two deuterium-labeling exper-
iments (Fig. 4C) were carried out to examine the
proposed metal-hydride migratory insertion and
reductive elimination steps (see steps c and d in
Fig. 2). Following the proposed sequence, an a
hydrogen of the ketone substrate should be
transferred to the terminal position of the ethyl
substituent of the alkylation product. Indeed,
when the a and a′-deuterated (at the 93% D level)
3-methylcyclopentanone (1s′) was subjected to
the standard reaction conditions, more than 82%
deuterium incorporation was observed at the C2
position of the ethyl group. In addition, a stable
conjugated enamine (8) could be isolated in good
yield through coupling cyclopentanone (1u′ a and
a′-92% deuterated), amine L1, and diphenylace-
tylene. Similarly, significant deuterium incorpo-
ration (68%) was observed at the vinyl hydrogen
of compound 8. X-ray diffraction analysis con-
firmed the E olefin geometry, further supporting a
syn-migratory insertion pathway (see step c in
Fig. 2). The erosion in deuterium incorporation
for both labeling experiments is likely caused by
proton exchange with the NH hydrogen of L1
and/or the protons of TsOH·H2O (for more de-
tails, see the supplementary materials, section 3.6).
Altogether, these results are consistent with our
proposed mechanism in Fig. 2.
We next explored the scope of ketones and
olefins for this transformation. Both cyclic and
acyclic ketones could be directly coupled with
ethylene gas to afford the ethyl-substituted ke-
tones (Fig. 3B). In general, cyclopentanones were
more reactive than cyclohexanones and acyclic
ketones, consistent with the established tenden-
Fig. 4. Preliminary mechanistic studies. (A) Structure of the enamine-Rh complex. (B) Synthesis
of a Rh‒H complex. (C) Deuterium-labeling experiments.
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M
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ACKNOWLEDGMENTS
We thank the University of Texas at Austin and Cancer
Prevention and Research Institute of Texas (R1118) for a start-up
fund and the Welch Foundation (F-1781) and NSF (CAREER:
CHE-1254935) for research grants. A provisional patent based
on this work has been filed by the University of Texas at Austin.
G.D. is a Searle Scholar. We thank V. Lynch for x-ray
crystallography. Metrical parameters for the crystal structures
of compounds S3a to S3g, S3j, S3r, S3s, 4 to 6, and 8 are
available free from the Cambridge Crystallographic Data Centre
under reference numbers CCDC-1003268 to -1003281,
respectively. We thank J. L. Sessler, M. J. Krische, and
D. R. Siegel for loaning chemicals; B. A. Shoulders, S. Sorey, and
A. Spangenberg for NMR advice; Y. Xu for thoughtful suggestions;
A. Dermenci and H. Lim for proofreading the manuscript; and
Z. Dong for checking and repeating the experimental procedure.
SUPPLEMENTARY MATERIALS
1School of Chemistry and Biochemistry, Georgia Institute of
Technology, Atlanta, GA 30332, USA. 2School of Chemical &
Biomolecular Engineering, Georgia Institute of Technology,
Atlanta, GA 30332, USA. 3Department of Chemical and
Biomolecular Engineering, The Ohio State University,
Columbus, OH 43210, USA.
www.sciencemag.org/content/345/6192/68/suppl/DC1
Materials and Methods
Supplementary Text
Table S1
References (31–58)
7 April 2014; accepted 27 May 2014
10.1126/science.1254465
*Corresponding author. E-mail: sankar.nair@chbe.gatech.edu
(S.N.); christopher.jones@chbe.gatech.edu (C.W.J.)
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