Scope and mechanistic study of the coupling reaction of α,β-unsaturated carbonyl compounds with alkenes: Uncovering electronic effects on alkene insertion vs oxidative coupling pathways

Article abstract of DOI:10.1021/om201190v

The cationic ruthenium-hydride complex [(C₆H₆) (PCy₃)(CO)RuH]⁺BF₄^- (1) was found to be a highly effective catalyst for the intermolecular conjugate addition of simple alkenes to α,β-unsatur

Full text of DOI:10.1021/om201190v

Article
pubs.acs.org/Organometallics
Scope and Mechanistic Study of the Coupling Reaction of α,β-
Unsaturated Carbonyl Compounds with Alkenes: Uncovering
Electronic Effects on Alkene Insertion vs Oxidative Coupling
Pathways
Ki-Hyeok Kwon, Do W. Lee, and Chae S. Yi*
Department of Chemistry, Marquette University, Milwaukee, Wisconsin 53201-1881 United States
S
* Supporting Information
ABSTRACT: The cationic ruthenium-hydride complex [(C6H6)(PCy3)(CO)RuH]+BF4− (1) was found to be a highly effective
catalyst for the intermolecular conjugate addition of simple alkenes to α,β-unsaturated carbonyl compounds to give (Z)-selective
tetrasubstituted olefin products. The analogous coupling reaction of cinnamides with electron-deficient olefins led to the
oxidative coupling of two olefinic C−H bonds in forming (E)-selective diene products. The intramolecular version of the
coupling reaction efficiently produced indene and bicyclic fulvene derivatives. The empirical rate law for the coupling reaction of
ethyl cinnamate with propene was determined as follows: rate = k[1]1[propene]0[cinnamate]−1. A negligible deuterium kinetic
isotope effect (kH/kD = 1.1
0.1) was measured from both (E)-C6H5CHC(CH3)CONHCH3 and (E)-C6H5CD
C(CH3)CONHCH3 with styrene. In contrast, a significant normal isotope effect (kH/kD = 1.7 0.1) was observed from the
reaction of (E)-C6H5CHC(CH3)CONHCH3 with styrene and styrene-d8. A pronounced carbon isotope effect was measured
from the coupling reaction of (E)-C6H5CHCHCO2Et with propene (13C(recovered)/13C(virgin) at Cβ = 1.019(6)), while a
negligible carbon isotope effect (13C(recovered)/13C(virgin) at Cβ = 0.999(4)) was obtained from the reaction of (E)-
C6H5CHC(CH3)CONHCH3 with styrene. Hammett plots from the correlation of para-substituted p-X-C6H4CHCHCO2Et
(X = OCH3, CH3, H, F, Cl, CO2Me, CF3) with propene and from the treatment of (E)-C6H5CHCHCO2Et with a series of
para-substituted styrenes p-Y-C6H4CHCH2 (Y = OCH3, CH3, H, F, Cl, CF3) gave the positive slopes for both cases (ρ = +1.1
0.1 and +1.5 0.1, respectively). Eyring analysis of the coupling reaction led to the thermodynamic parameters, ΔH⧧ = 20
2
kcal mol−1 and ΔS⧧ = −42 5 eu. Two separate mechanistic pathways for the coupling reaction have been proposed on the basis
of these kinetic and spectroscopic studies.
pharmaceutical agents such as tamoxifen (antibreast cancer
drug) and rofecoxib (anti-inflammatory drug) as well as for
photoresponsive organic materials.3 Heck- and Suzuki-type Pd-
catalyzed cross-coupling methods have been shown to be highly
effective in forming tetrasubstituted olefins in regio- and
stereoselective fashion.4 A number of Ni- and Rh-catalyzed
exocyclization and nucleophilic coupling methods have been
developed for the synthesis of highly substituted olefins.5 The
ring-closing olefin metathesis strategy has also been successfully
employed for forming tetrasubstituted cyclic olefins.6
Even though conjugate addition of simple alkenes to α,β-
unsaturated carbonyl compounds has long been recognized as a
potentially powerful olefination method, its synthetic potential
has not been fully exploited, in part due to the lack of reactivity
on the olefin substrates coupled with the formation of
homocoupling byproducts. Recently, Jamison and co-workers
INTRODUCTION
■
To stem growing environmental pollution due to wasteful
byproducts, chemical industries in recent years have been
increasingly interested in replacing traditional synthetic
methods with “green” catalytic methods that form desired
products from readily available and renewable feedstocks.1 One
such prominent example is the Wittig-type carbonyl olefination
methods, whose synthetic prowess has been immensely
demonstrated over the years in both laboratory-scale and
industrial processes, but pose debilitating problems especially
for large-scale industrial applications because of the formation
of byproducts resulting from the utilization of stoichiometric
amounts of ylides (or carbanion equivalents).2 Considerable
research efforts have been directed to develop transition metal-
catalyzed olefination methods as a means to increase synthetic
efficacy while reducing the formation of wasteful byproducts.
Designing expeditious catalytic methods for tetrasubstituted
olefins has gained a particular prominence in recent years, in
part to meet the growing needs for the synthesis of
Received: November 29, 2011
Published: December 14, 2011
© 2011 American Chemical Society
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a
Table 1. Conjugate Addition Reaction of Simple Alkenes to α-Substituted α,β-Unsaturated Carbonyl Compounds
a
b
Reaction conditions: carbonyl compound (0.6 mmol), alkene (3.0 mmol), 1 (3 mol %), CH2Cl2 (3 mL). Due to low conversion, the product yield
was determined by GC.
successfully developed catalytic conjugate addition and allylic
substitution methods in forming substituted olefins.7 Ogoshi
and co-workers reported a similar direct conjugate addition of
simple alkenes to enones by using a Ni(0)/PR3 catalyst.8
Chelate-assisted C−H insertion methods have been successfully
extended to the catalytic couplings of enones with simple
alkenes.9 Bergman and Toste’s group recently reported cobalt-
catalyzed intramolecular conjugate addition of vinylic C−H
bonds to enones in forming tetrasubstituted cyclic com-
pounds.10
Transition metal-catalyzed oxidative C−H coupling methods
have also emerged as an expedient olefination protocol for
arene compounds.11 Compared to the traditional catalytic
olefination methods such as Heck and Suzuki coupling
reactions, these oxidative C−H coupling methods directly
introduce olefinic groups without employing any reactive
reagents. Since Fagnou’s seminal report on the C−H oxidative
coupling of two different arene substrates,12 considerable
progress has been made in the area of catalytic C−H
alkenylation of arene compounds. For example, Kakiuchi
successfully developed chelate-assisted direct ortho-C−H
alkenylation of arene compounds by using a Ru catalyst.13
Glorius's and Yu’s research groups reported a series of
regioselective C−H olefination of arene compounds using
carbonyl directing groups.14,15 Following Milstein's and Ishii’s
work on the catalytic oxidative coupling reactions of arenes to
acrylic substrates,16 a number of research groups reported
chelate-assisted C−H alkenylation of arene compounds.17
Ackermann also reported a number of chelate-assisted
alkenylations and arylations of arenes by using Ru catalysts.18
These catalytic C−H alkenylation methods typically require a
stoichiometric amount of oxidants or additives, and the
substrate scope is generally limited to arene sp2 C−H
bonds,19 although an olefination to an sp3 C−H bond has
recently been achieved.11a,20 Detailed mechanistic insights as
well as on the factors influencing these catalytic C−H oxidative
coupling reactions still remain to be established.
We recently disclosed that the cationic ruthenium-hydride
complex [(C6H6)(CO)(PCy3)RuH]+BF4 (1) is a highly
−
effective catalyst precursor for a number of coupling reactions
involving vinyl C−H activation.21 We observed an unusual
selectivity pattern of the catalyst 1 in mediating these coupling
reactions in that C−H and CO olefination products directly
result from the coupling of aryl ketones with alkenes,21c instead
of the ortho-arene C−H insertion products typically observed in
Ru-catalyzed C−H activation reactions.22 We have been able to
extend the synthetic utility of the C−H olefination method to
the conjugate addition reaction of α,β-unsaturated carbonyl
compounds in affording tetrasubstituted olefins.23 This report
delineates full details on the scope as well mechanistic insights
for the coupling reaction of α,β-unsaturated carbonyl
compounds with alkenes.
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RESULTS AND DISCUSSION
Table 2. Oxidative C−H Coupling Reaction of α,β-
Unsaturated Carbonyl Compounds with Arylalkenes
■
a
Reaction Scope. We recently reported a novel catalytic
synthesis of (Z)-selective tetrasubstituted olefins from the
intermolecular conjugate addition of simple alkenes to α,β-
unsaturated carbonyl compounds.23 Among initially screened
metal catalysts, the cationic ruthenium hydride complex 1 was
found to exhibit distinctively high activity in yielding the
coupling products. In a typical setting, the treatment of ethyl
cinnamate (3 mmol) with propene (2.9 mmol) in the presence
of the ruthenium catalyst 1 (3 mol %) at 70 °C in CH2Cl2 led
to the exclusive formation of the tetrasubstituted olefin product
2 (eq 1). Both 1- and 2-alkenes gave the same coupling
product, indicating a rapid rate of olefin isomerization prior to
the coupling reaction. The cationic nature of the ruthenium-
hydride complex 1 was found to be critical for the catalytic
activity, since the neutral ruthenium catalysts showed no
activity for the coupling reaction under similar conditions.
In an effort to extend the scope of the coupling reaction, we
examined the substituent effect of the α,β-unsaturated carbonyl
compounds on the coupling reaction (Table 1). In general, α-
substituted cinnamic esters and amides were found to undergo
the coupling reaction with 1-alkenes to give the corresponding
olefin products 3a−3o. Both α-methyl- and α-phenylcinna-
mides with propene gave the coupling products 3d−3g in
excellent yields (entries 4−7), but a sterically demanding N,N-
disubstituted cinnamide failed to give the coupling product
under similar conditions (entry 8). A E/Z mixture of the
coupling products was formed from an α-substituted cinnamide
with ethylene, while the coupling reaction with both 1-butene
and 2-butenes gave the same product 3j in a highly (Z)-
selective fashion (entries 9−11). The alkene stereochemistry of
3j was assigned from the observation of NOE signals between
phenyl and the methyl triplet peaks (δ 7.24 (Ph) ↔ 0.84
(CH3)) and between the CH proton and the methyl singlet
peaks (δ 3.59 (CH) ↔ 1.82 (CH3)), as analyzed by the
NOESY NMR. Sterically less demanding α-olefins such as 1-
hexene and 4-phenyl-1-butene also yielded (Z)-selective
tetrasubstituted olefin products 3k and 3l (entries 12, 13).
The coupling reaction of α-methyl cinnamide with cyclo-
pentene gave diastereoselective coupling products 3m and 3n
(7:2), in which three different chiral centers are created in one
step (entry 14). The relative stereochemistry of 3m and 3n was
a
Reaction conditions: carbonyl compound (0.6 mmol), alkene (3.0
b
mmol), 1 (5 mol %), CH2Cl2 (3 mL), 50 °C, 12−14 h. Due to low
conversion, the product yield was determined from GC analysis. A
complex mixture of the insertion products 3p and 3q was formed
(55% combined yield).
c
and branched insertion products 3p and 3q predominantly
(entry 6). Styrenes with an electron-donating group were found
to promote the oxidative C−H coupling reaction in yielding
(E)-diene products 4g and 4h (entries 7, 8). 2-Vinyl-
naphthalenes were also found to be suitable substrates for
giving the oxidative coupling products 4j and 4k (entries 10,
11). Unlike other catalytic C−H oxidative coupling methods,
which typically require stoichiometric oxidants,14−17 our
catalytic method does not require any external oxidants, as
the alkene substrate is effectively serving as the hydrogen
acceptor.
We next pursued an intramolecular version of the coupling
reaction to further demonstrate its synthetic utility. Both 1,2-
disubstituted arene and cycloalkene substrates were employed
to examine the conformational effects on the insertion vs the
oxidative coupling products. These substrates were readily
synthesized in two or three steps by using Wittig and Suzuki
coupling protocols (Scheme S1, Supporting Information).24
The coupling reaction of ortho-alkenylated cinnamate substrates
proceeded smoothly to give the 1,2-disubstituted indene
products 5a and 5b (Table 3, entries 1−3). Both allyl- and
homoallyl-substituted substrates gave the same indene product
5b, and this is in line with the previously observed rapid olefin
isomerization rate prior to the coupling reaction.25 The
analogous coupling reaction with 1,2-disubstituted cycloalkenes
led to the oxidative C−H coupling reaction to form bicyclic
fulvene products 6a−6f (entries 4−9). The (Z)-stereo-
chemistry of the exo-acrylate moiety on the fulvene product
was established from the NOESY NMR analysis, where a strong
correlation has been observed between α-vinyl hydrogen and
the CH2 group of the product 6. In these cases, ca. 5−10% of
side products including the hydrogenated substrate were also
detected in the crude mixture. These results suggest that the
conformational orientation between two acrylic and alkene
1
definitively assigned from the H NMR spectroscopic data by
examining vicinal coupling of the diastereotopic protons. A
furan-substituted acrylic substrate with propene rapidly yielded
the corresponding tetrasubstituted olefin product 3o (entry
15).
The analogous coupling reaction with aryl-substituted
alkenes led to the selective formation of the oxidative C−H
coupling products 4a−4k (Table 2). Among initially screened
cinnamic acid derivatives, only α-methylcinnamide with styrene
led to a significant amount of the coupling product 4e (entry
5). Both steric and electronic environments on the carbonyl
substrate seem to be important in effecting the oxidative
coupling reaction, since neither cinnamic esters nor sterically
demanding N,N-disubstituted cinnamides yielded any signifi-
cant amount of the coupling products (entries 1−4). Also, an
electron-deficient p-chlorostyrene gave only 10% of the
oxidative coupling product 4f, resulting in a mixture of linear
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Table 3. Intramolecular Coupling Reaction of α,β-
a
Unsaturated Carbonyl Compounds
Figure 1. Plot of the rate vs catalyst concentration (2.1−34 mM) for
the coupling reaction of (E)-C6H5CHCHCO2Et and propene.
a
Reaction conditions: carbonyl substrate (0.6 mmol), 1 (5 mol %),
CH2Cl2 (3 mL), 50 °C, 12−14 h.
units is important in modulating the formation of the indene
products 5 (insertion pathway) vs the fulvene products 6
(oxidative coupling pathway).
Because of their unique physicochemical properties, fulvene
derivatives have long been utilized in a broad range of material
science and medicinal applications, but the traditional synthetic
methods to such compounds often require multiple steps and
reactive stoichiometric reagents.26 Catalytic methods to
fulvenes and related benzocyclic compounds have not been
extensively developed, although this group and others have
recently reported catalytic C−H coupling methods to
synthesize fulvene and structurally related indene derivative-
s.21a,27 From a synthetic point of view, one of the most salient
features of our intramolecular coupling method is that
synthetically valuable indene and fulvene derivatives are
efficiently constructed without employing any reactive reagents
or additives.
Figure 2. Plot of the rate vs propene concentration (0.6−1.8 M) for
the coupling reaction of (E)-C6H5CHCHCO2Et and propene.
Kinetics and Mechanistic Study: Determination of the
Empirical Rate Law. In an effort to establish the reaction
mechanism, we sought to deduce an empirical rate law from the
coupling reaction of ethyl cinnamate with propene. The
reaction rate of ethyl cinnamate (70 μmol) and propene (5
equiv) in CD2Cl2 (0.5 mL) at 20 °C was monitored as a
function of the catalyst concentration of 1 (2.1−34 mM). The
initial rate was determined from a first-order plot of the product
2 vs time at each concentration of 1. The linear plot of the
reaction rate as a function of the catalyst concentration
established the first-order dependence on [1] (Figure 1).
The analogous procedure was used to obtain the rate
dependence on both cinnamate and propene substrates. Two
separate linear plots of the rate vs [cinnamate] and with
[propene] revealed that the rate is independent of [propene] in
the range 0.6−1.8 M (Figure 2), but exhibited an inverse
dependence on [cinnamate] (Figure 3). The inverse rate
dependence on [cinnamate] suggests that the second
Figure 3. Plot of the rate vs (E)-C6H5CHCHCO2Et (0.12−0.36 M)
for the coupling reaction of (E)-C6H5CHCHCO2Et and propene.
cinnamate substrate is serving as an effective inhibitior. To
further demonstrate zero-order dependence of [alkene] under
preparatory-scale reaction conditions, we separately measured
the product conversion from the coupling reaction of N-methyl
cinnamide with different amounts of styrene (3−10 equiv)
under otherwise similar conditions. In all cases, exactly the
same product conversion (10%) resulted after 30 min at 50 °C.
By combining these experimental results, the empirical rate law
of the reaction has been deduced as shown in eq 2.
1
0
−1
rate = k[1] [propene] [cinnamate]
(2)
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Deuterium Labeling Study. We previously observed that
the coupling reaction of (E)-C6D5CDCDCONMe2 with an
excess amount of propene led to the selective H/D exchange
on the α-methylene position of the product (55% D), but only
with 5% D on the δ-methyl positions.23 To examine the H/D
exchange pattern of the oxidative coupling reaction, the
treatment of (E)-C6H5CDC(CH3)CONHCH3 (70 μmol,
99% D) with an excess amount of styrene (5 equiv) in the
presence of 1 (2 mg, 5 mol %) in CD2Cl2 was monitored by
NMR (eq 3). After 15 h at 20 °C, a significant H/D exchange
Figure 4. First-order plots of −ln([cinnamide]t/[cinnamide]0) vs time
for the coupling reaction of (E)-C6H5CHC(CH3)CONHCH3 with
styrene (◆) and styrene-d8 (●).
between the vinyl hydrogen of the cinnamide (75% D) and
styrene (4% D) substrates was observed without forming the
1
2
coupling product 3q, as analyzed by H and H NMR (Figure
S1, Supporting Information). A relatively facile H/D exchange
pattern is consistent with a reversible vinyl C−H bond
activation of the cinnamide substrate and further suggests
that the vinyl C−H bond activation step is not rate-limiting for
the oxidative coupling reaction.
Kinetic Isotope Effects. We next measured the deuterium
kinetic isotope effect from the coupling reaction of cinnamic
acid derivatives with alkenes. As for the formation of insertion
products, we separately measured the rate from the treatment
of (E)-C6H5CHCHCO2Et with ethylene and with ethylene-
d4 at 60 °C in CD2Cl2, which led to a negligible kinetic isotope
effect of kH/kD = 1.1
0.1 (Figure S2, Supporting
reinforced the notion that the styrenyl C−H activation is the
rate-limiting step in forming the oxidative coupling product 4.
To demonstrate the propensity of the carbon isotope effect
in determining the rate-determining step, we measured the
analogous carbon isotope effect from the coupling reaction of
an α-substituted cinnamide with 4-chlorostyrene, which was
found to yield the insertion product 3p predominantly as
described in Table 2 (eq 5). In this case, a definitive carbon
Information). We also measured the deuterium isotope effect
from both (E)-C6H5CHC(CH3)CONHCH3 and (E)-
C6H5CDC(CH3)CONHCH3 with styrene under the same
reaction conditions in forming the oxidative coupling product
4e. The pseudo-first-order plots from both (E)-C6H5CH
C(CH3)CONHCH3 and (E)-C6H5CDC(CH3)CONHCH3
with styrene led to kobs = 9.2 × 10−2 h−1 and kobs = 8.8 × 10−2
h−1, respectively, which translated to a negligible isotope effect
of kH/kD = 1.1
0.1 (Figure S3, Supporting Information).
These results further support that the vinyl C−H bond
activation of the cinnamic acid derivative is not the rate-limiting
step in forming the oxidative coupling product 4.
In sharp contrast, a normal deuterium isotope effect was
measured from the coupling reaction of (E)-C6H5CH
C(CH3)CONHCH3 with styrene and styrene-d8 at 40 °C in
CH2Cl2. The pseudo-first-order plots from the reaction of (E)-
C6H5CHC(CH3)CONHCH3 with both styrene and styrene-
d8 led to kobs = 9.2 × 10−2 and 5.3 × 10−2 h−1, respectively,
which translated to a normal deuterium isotope effect of kH/kD
= 1.7
0.1 (Figure 4). The results clearly indicate that the
isotope effect was observed on the β-carbon of the cinnamide
substrate, when the 13C ratio of recovered (E)-C6H5CH
C(CH3)CONHCH3 at 80% and 82% conversion was compared
to that of the virgin sample (13C(recovered)/13C(virgin) at Cβ
= 1.017(7); average of two runs) (Table S2 and Figure S5,
Supporting Information). Previously, we also observed similar
results from the coupling reaction of (E)-C6H5CHCHCO2Et
with propene in forming the insertion product 2.23 It should be
mentioned that the coupling reaction of (E)-C6H5CH
C(CH3)CONHCH3 with an electron-deficient alkene such as
4-chlorostyrene led to a mixture of linear and branched
insertion products 3p and 3q and the oxidative coupling
product 4f ((3p + 3q):4f = 85:15), and we observed the
styrenyl C−H bond cleavage is the most likely turnover-
limiting step in forming the oxidative coupling product 4.
To further discern the rate-limiting step of the oxidative
coupling reaction, the 12C/13C carbon isotope effect was
measured from the coupling reaction of an α-substituted
cinnamide with styrene by employing Singleton’s high-
precision NMR technique (eq 4).28 No significant carbon
isotope effect on the β-carbon of the cinnamide substrate was
observed from the coupling reaction of (E)-C6H5CH
C(CH3)CONHCH3 with styrene (13C(recovered)/13C(virgin)
of Cβ = 0.999(4); average of two runs at 70% conversion)
(Table S1 and Figure S4, Supporting Information). The results
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Figure 5. Hammett plots of the coupling reaction of para-substituted p-X-C6H4CHCHCO2Et (X = OCH3, CH3, H, F, Cl, CO2Me, CF3) with
propene (A) and (E)-C6H4CHCHCO2Et with para-substituted p-Y-C6H4CHCH2 (Y = OCH3, CH3, H, Cl, CF3) (B).
Scheme 1
noticeable carbon isotope effect only from the insertion
products 3p and 3q.
nearly 1:1 mixture of the linear and branched insertion
products along with other minor double bond isomers as well
as the oxidative coupling product 4 was observed in the crude
reaction mixture (combined insertion products 2:4 = 4:1 to
5:1). The product ratio for these reactions was determined by
NMR.
For the coupling reaction of the α-substituted cinnamide
(E)-C6H5CHC(CH3)CONHCH3 with para-substituted styr-
enes p-Y-C6H4CHCH2 (Y = OCH3, CH3, H, F, Cl, CF3), the
electronic nature of the para-substituent group was found to be
the dominant factor in modulating the product selectivity
(Scheme 1). Thus, the coupling reaction of (E)-C6H5CH
C(CH3)CONHCH3 with styrenes with a para-electron-
donating group (Y = OCH3, CH3, H) yielded the oxidative
coupling products 4 over the insertion products 3 (3:4 = 1:2.5
to 1:8). In contrast, the analogous coupling reaction with
styrenes having a para-electron-deficient group (Y = F, Cl,
CF3) resulted in a mixture of the branched and linear insertion
products 3 predominantly (3:4 = 3:1 to 5.5:1).
Hammett ρ values were measured for the coupling reaction
with these para-substituted styrene derivatives to further probe
electronic effects of the alkene substrate on the product
selectivity. Interestingly, the Hammett correlation from the
reaction of (E)-C6H5CHC(CH3)CONHCH3 with a series of
para-substituted styrene p-Y-C6H4CHCH2 (Y = OCH3,
CH3, H, F, Cl, CF3) in the presence 1 (5 mol %) at 50 °C in
CH2Cl2 led to positive ρ values for both electron-donating and
Hammett Study. To probe electronic effects on the
product formation, we determined the Hammett ρ values
from the coupling reaction of α,β-unsaturated carbonyl
compounds with alkenes.29 The correlation of the relative
rate with σp for a series of para-substituted p-X-C6H4CH
CHCO2Et (X = OCH3, CH3, H, F, Cl, CO2Me, CF3) with
propene in the presence of 1 (3 mol %) at 20 °C led to a
positive ρ value (ρ = +1.1
0.1) in forming the insertion
products 2 (Figure 5A). The promotional effect by an electron-
withdrawing group as indicated by a positive slope is consistent
with a decreasing positive charge on the β-carbon of a
cinnamate substrate during the alkene insertion step. The
observed Hammett ρ value is well within the range of other
Michael-type conjugate additions of nucleophiles to acrylic
substrates.30
An analogous correlation from the reaction of (E)-
C6H5CHCHCO2Et with a series of para-substituted styrene
derivatives p-Y-C6H4CHCH2 (Y = OCH3, CH3, H, Cl, CF3)
at 50 °C in CH2Cl2 resulted in a substantially higher Hammett
ρ value (ρ = +1.5
0.1) for the formation of the insertion
products 2 (Figure 5B). In this case, a strong promotional effect
by an electron-withdrawing group of styrene can be readily
rationalized by invoking the formation of a cationic Ru-vinyl
species Ru−CHCHAr. A higher +ρ value compared to the
insertion reaction suggests a considerable buildup of ionic
character on the cationic Ru-vinyl species, and a linear
Hammett correlation also indicates the same operating
mechanism for these cinnamate and styrene derivatives.
While overall conversion is relatively high, the coupling
reaction with styrene derivatives generally led to a lower
selectivity toward the insertion product 2; the formation of a
electron-withdrawing groups (ρ = +1.1
0.1 with electron-
donating group; ρ = +0.9 0.1 with electron-withdrawing
group) (Figure 6). The results suggest that two opposing
electronic factors promote the product selectivity. Thus, for the
styrene derivatives having an electron-withdrawing group, the
formation of the conjugate addition product 3 is promoted by a
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Scheme 2. Proposed Mechanism for the Conjugate Addition
Reaction of α,β-Unsaturated Carbonyl Compounds with
Simple Alkenes
Figure 6. Hammett plots for the coupling reaction of (E)-C6H4CH
C(CH3)CONHCH3 with para-substituted styrenes p-Y-C6H4CH
CH2 (Y = OCH3, CH3, H (●) and Y = F, Cl, CF3 (◆)).
facile olefin insertion resulting from increasing olefinic bond
polarity. On the other hand, for styrenes with an electron-
donating group, the predominant formation of the oxidative
coupling product 4 can be rationalized by invoking a
promotional effect from the styrenyl C−H activation.
Thermodynamic Parameters. The thermodynamic pa-
rameters were successfully obtained from measuring the rates of
the coupling reaction as a function of the temperature. The
reaction rate was measured from the treatment of (E)-
C6H4CHCHCO2Et (0.12 mmol) with an excess amount of
propene (0.60 mmol) and the catalyst 1 (3 mol %) in the
temperature range 20−40 at 5 °C intervals by using the
standard VT NMR technique. Excess propene concentration
was employed to maintain a pseudo zero-order [propene],
which minimized the cinnamate inhibition during the reaction.
The thermodynamic parameters, ΔH⧧ = 20.3 2.2 kcal/mol
and ΔS⧧ = −42 5 eu, were obtained from the standard Eyring
analysis (Figure 7).29 A relatively large negative ΔS⧧ value is
the formation of the insertion product 3, we propose a
mechanistic pathway via the cationic Ru-alkene-alkyl species 8,
which is formed from the chelate-directed regioselective alkene
insertion. The zero-order dependence on [alkene] indicates
that the alkene coordination step is quite facile in the presence
of excess [alkene]. On the other hand, the inverse dependence
on [cinnamate] suggests that the cinnamate substrate inhibits
competitively by binding to the metal center, where an excess
[alkene] would be needed to overcome the competitive
inhibition from the cinnamate substrate.
Both the observation of the carbon isotope effect on the β-
carbon of α,β-unsaturated carbonyl substrate and a negligible
deuterium isotope effect of kH/kD = 1.1 0.1 from the reaction
with ethylene/ethylene-d4 support the olefin insertion as the
rate-limiting step. The positive Hammett ρ value obtained from
the correlation of para-substituted cinnamate substrates is also
consistent with the formation of the carbonyl-chelated species
8, where an electron-releasing group would promote the
regioselective olefin insertion and β-hydride elimination steps.
It has been well established that both olefin bond polarity and
the chelation of the carbonyl group are important in directing
regioselective insertion of enamides and α,β-unsaturated
carbonyl compounds.31 In light of the recent deuterium
labeling study on the alkene dimerization and isomerization
reactions,25 a facile olefin isomerization step is expected in
forming the tetrasubstituted olefin products 3 and the
regeneration of 7. Previously, we have successfully trapped
and isolated the catalytically relevant ruthenium-allyl species 9,
which provides more supporting evidence for the Ru-alkene-
hydride complex 10.23
Figure 7. Eyring plot for the coupling reaction of (E)-C6H5CH
CHCO2Et with propene.
consistent with an organized transition state formed from
combining two substrate molecules.
Proposed Mechanism. We present two separate mecha-
nistic pathways to explain the formation of the coupling
products 3 and 4. We propose the cationic Ru−H species 7,
which is initially formed from the ligand exchange reaction of 1
with the carbonyl substrate, as the common intermediate
species for both mechanistic pathways (Scheme 2). To explain
We propose an alternative mechanistic pathway involving
vinyl C−H bond activation to explain the formation of the
oxidative coupling product 4 (Scheme 3). The olefin insertion
to the electrophilic Ru−H complex 7 followed by the vinyl C−
H bond activation of the carbonyl substrate and olefin insertion
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Scheme 3. Proposed Mechanism for the Coupling Reaction
of α,β-Unsaturated Carbonyl Compounds with Aryl-
Substituted Alkenes
Table 4. Summary of the Kinetic Data for the Coupling
Reaction of α,β-Unsaturated Carbonyl Compounds with
Alkenes
alkene insertion path oxidative coupling path
a
Hammett ρ value
+1.1 to +1.5
+0.9 to +1.1
b
carbon isotope effect
yes (Cβ = 1.017)
no (kH/kD = 1.1)
alkene insertion
no (Cβ = 0.999)
yes (kH/kD = 1.7)
vinyl C−H activation
c
deuterium isotope effect
rate-limiting step
a
Hammett ρ values obtained from the reaction of (E)-p-X-C6H4CH
b
CHCO2Et with propene and with styrene. 13C ratio (recovered/
virgin) obtained from the reaction of (E)-C6H4CHCHCON(CH3)2
with propene with styrene and from the (E)-C6H4CHCH(CH3)-
c
CONHMe with styrene. Deuterium isotope effect obtained from the
reaction of (E)-C6H4CHCHCO2Et with ethylene/ethylene-d4 and
from the reaction of (E)-C6H4CHCH(CH3)CONHCH3 with
styrene/styrene-d8.
substitutent in forming the alkyl species 8. As illustrated in
Table 3, such conformational flexibility has been successfully
exploited for an intramolecular version of the coupling reaction
to form the fulvene products 6.
Hammett study from the coupling reaction of (E)-
C6H5CHC(CH3)CONHCH3 with para-substituted styrenes
(Figure 6) also revealed that the electronic environment on the
alkene substrate significantly influences the oxidative C−H
coupling pathway. That styrenes with an electron-releasing
group yield the oxidative coupling products 4 suggests that the
olefin insertion is the key step in modulating the product
selectivity by promoting the styrenyl C−H bond activation
while discouraging the olefin insertion pathway.
steps would form the cationic Ru(IV) species 11. The reductive
elimination (dehydrogenation) and the coordination of another
olefin substrate would lead to the formation of the cationic
ruthenium-alkenyl species 12. Alternatively, one can envision a
σ-bond metathesis mechanism in forming the alkenyl complex
12, the possibility which cannot be rigorously excluded at this
time.32 All of the kinetic data, including the observation of a
normal isotope effect of kH/kD = 1.7 0.1 from the coupling
reaction of styrene and styrene-d8 as well as a negligible
deuterium isotope effect from (E)-C6H5CHC(CH3)-
CONHCH3 and (E)-C6H5CDC(CH3)CONHCH3, are
consistent with the styrenyl C−H bond activation rate-limiting
step. Both the carbon isotope effect and the deuterium labeling
studies also provide supporting evidence for the rate-limiting
styrenyl C−H bond activation step. It is imperative to mention
that the C−C bond formation step has been generally found to
be the turnover-limiting step in Murai-type chelate-assisted C−
H insertion reactions catalyzed by neutral Ru catalysts.22,33 In
our case, the electrophilic nature of the Ru catalyst appears to
promote the vinyl C−H bond activation of electron-deficient
alkenes in forming the oxidative coupling product 4, where the
formation of ethylbenzene from dehydrogenation should also
serve as the driving force for the vinyl C−H activation.
Hammett study of para-substituted styrene derivatives revealed
a fine electronic balance on dictating the olefin insertion vs
oxidative coupling pathways, and the vinyl C−H activation is
favored over the alkene insertion for electron-deficient alkenes.
Table 4 compares the major kinetic data between the
insertion and oxidative coupling pathways. The coupling
reaction of cinnamic acid derivatives with simple alkenes
normally favors the insertion pathway in forming the coupling
product 3. As inferred from the kinetic isotope effect data, we
found that the alkene insertion step (C−C bond formation) is
the most likely turnover-limiting step for this pathway. By
employing α-substituted cinnamides and electron-poor alkene
substrates, we have been able to alter the reaction path toward
the oxidative coupling product 4, for which case the kinetic data
are consistent with the vinyl C−H activation rate-limiting step.
Both the conformation of the cinnamide substrate and the
electronic nature of the olefin substrate have been found to be
important in promoting the C−H oxidative coupling product 4.
A simple conformational analysis indicates that a normally facile
hydride migration to the α,β-unsaturated carbonyl substrate
would be less favored for the α-substituted cinnamide substrate,
due to the steric interaction between phenyl and the α-
CONCLUSIONS
■
The scope and mechanistic aspects of the ruthenium-catalyzed
coupling reaction of α,β-unsaturated carbonyl compounds and
alkenes have been delineated. The coupling reaction of α,β-
unsaturated carbonyl compounds with simple electron-rich
alkenes exclusively gave (Z)-selective conjugate addition
products 3, while the analogous reaction of cinnamides with
electron-poor alkenes predominantly yielded the C−H
oxidative coupling products 4. The intramolecular version of
the coupling reaction has led to an efficient synthesis for indene
and fulvene derivatives 5 and 6. Detailed kinetic studies
revealed that the olefin insertion into an α,β-unsaturated
carbonyl substrate is the most likely rate-limiting step in
forming the insertion products 3. In contrast, the kinetic data
are consistent with the vinyl C−H activation rate-limiting step
for the oxidative coupling products 4. Further, both kinetic and
mechanistic studies illuminated that the conformation of the
α,β-unsaturated carbonyl substrate as well as the alkene
electronic environments are important factors in modulating
between the insertion vs oxidative coupling pathways. We
anticipate that the catalytic coupling method would provide an
efficient synthetic methodology to highly substituted olefins as
well as indene and fulvene derivatives from readily available
cinnamic acid derivatives and simple alkenes.
EXPERIMENTAL SECTION
■
Representative Procedure of the Catalytic Reaction. In a
glovebox, complex 1 (10 mg, 17 μmol), a carbonyl compound (0.60
mmol), and an alkene (3.0 mmol) were dissolved in CH2Cl2 (3 mL) in
a 25 mL Schlenk tube equipped with a Teflon stopcock and a magnetic
stirring bar. The tube was brought out of the box and was stirred for
12−14 h in an oil bath that was preset at 70 °C, after which it was
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Organometallics
Article
chilled in a dry ice/acetone bath. After the tube was open to air, the
solution was filtered through a small pad of silica gel (hexanes/EtOAc,
2:1), and the resulting solution was analyzed by GC. Analytically pure
product was isolated after a simple column chromatography on silica
gel (hexanes/EtOAc, 20:1 to 4:1). All substrates for the intramolecular
coupling reaction listed in Table 3 were prepared by following the
literature methods.24 See the Supporting Information for a detailed
experimental procedure for the preparation of these substrates.
General Procedure for the Rate Measurements. In a
glovebox, complex 1 (1.5−12 mol %) and (E)-C6H5CHCHCO2Et
(0.03−0.38 mmol) were dissolved in CD2Cl2 (0.4 mL) in a thick-
walled J-Young NMR tube with a Teflon screw cap. The tube was
cooled in a liquid nitrogen bath, and excess propene (0.3−0.9 mmol)
was condensed via a vacuum line transfer. The tube was gradually
warmed to room temperature. The sample was inserted into the NMR
probe, which was preset at 20 °C. The initial rate at each concentration
of 1 was determined by measuring the appearance of the product
signals in 5 min intervals, and these were normalized against an
internal standard (solvent resonance). The kobs was estimated from a
first-order plot of −ln{[(E)-C6H5CHCHCO2Et]t/[(E)-C6H5CH
CHCO2Et]o} vs time.
Deuterium Kinetic Isotope Effect Study: Reaction in
CD2Cl2. In a glovebox, complex 1 (2 mg, 3.5 μmol) and (E)-
C6H5CHCHCO2Et (20 mg, 0.12 mmol) were dissolved in CD2Cl2
(0.4 mL) in a thick-walled J-Young NMR tube with a Teflon screw
cap. The tube was cooled in a liquid nitrogen bath, and excess ethylene
or ethylene-d4 (0.6 mmol) was condensed via a vacuum line transfer.
The tube was gradually warmed to room temperature, and the sample
tube was inserted into the NMR probe, which was preset at 20 °C.
The rate was measured by monitoring the 1H integration of the
product signals in 5 min intervals, and these were normalized against
an internal standard (solvent resonance). The kobs was estimated from
a first-order plot of −ln([C6H5CHCHCO2Et]t/[C6H5CH
CHCO2Et]o) vs time.
Reaction in CH2Cl2. In a glovebox, complex 1 (20 mg, 35 μmol),
(E)-C6H5CHC(CH3)CONHCH3 (122 mg, 0.7 mmol), or
C6H5CDC(CH3)CONHCH3 (122 mg, 0.7 mmol) and styrene or
styrene-d8 (0.36 g, 35 mmol) were dissolved in CH2Cl2 (6.0 mL) in a
25 mL Schlenk tube equipped with a Teflon screw cap stopcock and a
magnetic stirring bar. After the solution was stirred at room
temperature for 10 min, an equal amount of the solution (1.0 mL)
was placed in five different Schlenk tubes. The tubes were brought out
of the box, and they were stirred in an oil bath set at 50 °C. Each
reaction tube was taken out from the oil bath in 30 min intervals and
was immediately cooled in a dry ice/acetone bath. After filtering
through a small silica gel column (hexanes/EtOAc, 2:1), the solution
was analyzed by GC. The kobs was determined from a first-order plot
of −ln([cinnamide]t/[cinnamide]o) vs time.
with a Teflon screw cap. The tube was cooled in a liquid nitrogen bath,
and excess propene (0.60 mmol) was condensed via a vacuum line
transfer. The tube was gradually warmed to room temperature, and the
sample was inserted into the NMR probe, which was preset at 20 °C.
1
The reaction rate was measured by monitoring the H integration of
the product signals, which were normalized against an internal
standard (solvent resonance) in 5 min intervals. The kobs was
estimated from a first-order plot of −ln([cinnamate]t/[cinnamate]o)
vs time.
Reaction in CH2Cl2. In a glovebox, complex 1 (20 mg, 35 μmol),
(E)-C6H5CHC(CH3)CONHCH3 (122 mg, 0.7 mmol), and para-
substituted p-Y-C6H4CHCH2 (X = OCH3, CH3, H, F, Cl, CF3) (3.5
mmol) were dissolved in CH2Cl2 (6.0 mL) in a 25 mL Schlenk tube
equipped with a Teflon stopcock and a magnetic stirring bar. After the
solution was stirred at room temperature for 10 min, an equal amount
of the solution (1.0 mL) was divided and placed in five different
Schlenk tubes. The tubes were brought out of the box and were stirred
in an oil bath set at 50 °C. Each reaction tube was taken out from the
oil bath in 30 min intervals and was immediately cooled in a dry ice/
acetone bath. After filtering through a small silica gel column
(hexanes/EtOAc, 2:1), an internal standard (C6Me6) was added, and
the resulting solution was analyzed by GC. The kobs was determined
from a first-order plot of −ln([C6H5CHC(CH3)CONHCH3]t/
[C6H5CHC(CH3)CONHCH3]o) vs time.
General Procedure for the Erying Analysis. In a glovebox,
complex 1 (2 mg, 3.5 μmol) and (E)-C6H5CHCHCO2Et (20 mg,
0.12 mmol) were dissolved in CD2Cl2 (0.5 mL) in a thick-walled J-
Young NMR tube with a Teflon screw cap. The tube was brought out
of the box and cooled in a liquid nitrogen bath. Excess propene (0.60
mmol) was condensed via a vacuum line transfer. After the tube was
gradually warmed to room temperature, the sample tube was inserted
into the NMR probe, which was preset at 20−40 °C. The rate was
measured by monitoring the 1H integration of the product signals in 5
min intervals, and these were normalized against an internal standard
(solvent resonance). The kobs was estimated from a first-order plot of
−ln([C6H5CHCHCO2Et]t/[C6H5CHCHCO2Et]o) vs time.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and spectroscopic data of organic
products. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: chae.yi@marquette.edu.
■
Carbon Isotope Effect Study. In a glovebox, complex 1 (164
mg, 0.28 mmol), (E)-C6H5CHCH(CH3)CONEt2 (1.0 g, 5.7
mmol), and styrene (57 mmol) in CH2Cl2 (10 mL) were placed in
two separate 100 mL Schlenk tubes, each equipped with a Teflon
screw cap stopcock and a magnetic stirring bar. The tubes were
brought out of the box and stirred for 14 h in an oil bath, which was
preset at 100 °C. Unreacted (E)-C6H5CHCH(CH3)CONEt2 was
collected separately after filtering through a short silica gel column
(hexanes/EtOAc, 2:1), and the solution was analyzed by GC (68−82%
conversion). The NMR sample of the virgin and recovered (E)-
C6H5CHCH(CH3)CONEt2 was prepared identically by dissolving
an equal amount of (E)-C6H5CHCH(CH3)CONEt2 (100 mg) in
CDCl3 (0.5 mL) in a 5 mm high-precision NMR tube. The 13C{1H}
NMR spectra of both samples were recorded by following Singleton’s
NMR method.28 The 13C{1H} NMR spectra were recorded with H-
decoupling and 45-degree pulses, and a 60 s delay was imposed to
minimize T1 variations (d1 = 60 s, at = 5.0 s, np = 245 098, nt = 704)
between each aquisition.
ACKNOWLEDGMENTS
■
Financial support from the National Science Foundation
(CHE-1011891) and the National Institute of Health General
Medical Sciences (R15 GM55987) is gratefully acknowledged.
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