Alkenes as chelating groups in diastereoselective additions of organometallics to ketones

Article abstract of DOI:10.1021/om5007006

Alkenes have been discovered to be chelating groups to Zn(II), enforcing highly stereoselective additions of organozincs to β,γ-unsaturated ketones. ¹H NMR studies and DFT calculations provide support for this surprising chelation mode. The results expand the range of coordinating groups for chelation-controlled carbonyl additions from heteroatom Lewis bases to simple C-C double bonds, broadening the 60 year old paradigm.

Full text of DOI:10.1021/om5007006

Article
pubs.acs.org/Organometallics
Alkenes as Chelating Groups in Diastereoselective Additions of
Organometallics to Ketones
Ludovic Raffier, Osvaldo Gutierrez, Gretchen R. Stanton, Marisa C. Kozlowski,* and Patrick J. Walsh*
P. Roy and Diana T. Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia,
Pennsylvania 19104-6323, United States
S
* Supporting Information
ABSTRACT: Alkenes have been discovered to be chelating groups to
Zn(II), enforcing highly stereoselective additions of organozincs to β,γ-
1
unsaturated ketones. H NMR studies and DFT calculations provide
support for this surprising chelation mode. The results expand the range
of coordinating groups for chelation-controlled carbonyl additions from
heteroatom Lewis bases to simple C−C double bonds, broadening the
60 year old paradigm.
halide or OSO2R), promotes the addition of a wide range of
alkyl and vinyl organozinc reagents to α- and β-silyloxy
aldehydes and ketones via chelation control with very high
diastereomeric ratios (Scheme 1B).7
On the basis of these results, we hypothesized that less Lewis
basic substituents, such as halides of C−X bonds, might also
coordinate to RZnX, leading to chelation control. As shown in
Scheme 2 we developed a highly diastereoselective method for
chelation-controlled additions to α-chloro N-sulfonyl aldimines
with dr’s as high as 20:1.8
1. INTRODUCTION
Diastereoselective additions of organometallic nucleophiles to
α-chiral carbonyl compounds has been a topic of significant
interest for over 60 years.1 During this time, several models
have been advanced to predict the stereochemical outcome of
such additions to α- and β-chiral aldehydes, ketones, and
imines.2 Among these models the Felkin−Ahn,3 Cornforth−
Evans,4 and Cram-chelation models5 are the most generally
accepted (Scheme 1).
It is well known that α- and β-silyloxy aldehydes and ketones
react with nucleophiles via the Felkin−Anh pathway with few
exceptions (Scheme 1A).2,6 We recently demonstrated,
however, that a remarkable class of Lewis acids, RZnX (X =
Scheme 2. Chelation-Controlled Addition of Organozinc
Reagents to α-Chloro Imines
Scheme 1. Models for Additions to Carbonyl Groups: (A)
Felkin−Ahn and Cornforth−Evans and (B) Cram-Chelation
In spite of these advances, the boundary conditions defining
effective chelating groups remain to be fully described.
Typically, heteroatoms containing basic, unhindered lone
pairs are utilized in chelation-directed processes, but the
above work has shown that even hindered and weakly basic
heteroatoms can participate. We contemplated whether it
would be possible to expand beyond heteroatoms by using
simple alkenes as chelating groups to effect facial control in
additions to carbonyls.
Received: July 4, 2014
Published: September 9, 2014
© 2014 American Chemical Society
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The strength of a metal−π interaction depends on both the
nature of the alkene and the metal center, as described by the
Dewar−Chatt−Duncanson model.9 This model involves a
synergistic interaction with donation of the alkene π-orbital to
the metal and π-back-bonding from a filled d-orbital of the
metal to the π*-orbital of the alkene. The Dewar−Chatt−
Duncanson model explains well why stable olefin complexes of
d10 metals such as Ni(0), Pd(0), or Pt(0) are abundant.10 In
contrast, other d10 metals, such as Zn(II), Cd(II), or Hg(II), do
not usually form olefin complexes. The ability of a metal to
back-bond to an olefin is related to its promotion energy;11 the
higher the promotion energy, the lower the propensity for
back-bonding. Hg(II) has a promotion energy of 12.8 eV, and
some examples of binding with arene derivatives are known.12
For Zn(II) and Cd(II), the promotion energies are higher (17.1
and 16.6 eV, respectively). Coordination of π-systems to these
metals arises predominantly from σ-donation, which explains
the lability and, therefore, the scarcity of such systems.13 Olefin
complexes with Zn(II) are intramolecular and/or exist only in
the solid state.14 To the best of our knowledge, no
intermolecular π-interactions of this kind have been observed
in solution.
Scheme 4. Selectivity of the Ethyl Addition to Ketone 1a
Experimental Section for details). Ketone 1a was treated with
ZnEt2 and EtZnCl under a wide variety of conditions, giving
mixtures of addition product and aldol byproducts, with the
aldol products predominating in all cases. Nonetheless, when
racemic 1a was exposed to ZnEt2 (3 equiv) and EtZnCl (2
equiv) in toluene and heated to 55 °C, the chelation-controlled
2a and Felkin 2a′ addition products formed with a surprising
diastereomeric ratio of 50:1 (determined by GC). In contrast,
treatment of 1a with EtMgBr at 0 °C in diethyl ether generated
2a and 2a′ with only 1.2:1 dr. The high selectivity with
organozinc reagents provides proof of concept that the addition
proceeds via a chelation-controlled pathway. As mentioned, all
attempts to shift the balance between aldol processes and the
addition reaction by changing solvents, concentrations, reagent
ratios, zinc Lewis acids, temperatures, organozinc reagents, and
addition rates led to similar or lower yields of the addition
products. It should also be emphasized that no stereoselectivity
was obtained in coordinating solvents due to binding to the
zinc Lewis acid.
Not surprisingly, very few examples of Zn−π interactions
acting as stereocontrol elements have been proposed. In
seminal work, Marek, Beruben, and Normant demonstrated
that the presence of a terminal double bond in the allylzincation
resulted in a high degree of acylic stereocontrol (Scheme 3).14a
Scheme 3. Diastereoselective Olefin-Directed Allylzincation
1
2.2. Exploration of Chelation by NMR. H NMR has
been widely used to study alkene−metal coordination in
solution.17,18 We therefore decided to probe the binding of
racemic β,γ-enones to EtZnCl by treatment of 1a with 4 equiv
of EtZnCl in CD2Cl2.19 The chemical shift variations (Δδ) with
respect to the free substrate are reported in Table 1 (entry 1).
Notably, both vinyl protons shift downfield upon addition of
EtZnCl. Such downfield shifts are generally observed on
binding of olefins to d0 metals,8 which is consistent with σ-
donation of the alkene to the metal and little or no back-
bonding. In contrast, upfield shifts have been reported with d10
metals, such as Pd(0) and Pt(0).18 The different magnitudes of
the shifts for the β and γ protons in Table 1 (entry 1) are
consistent with unsymmetrical binding of the olefin to the
metal, a characteristic also observed with d0 metal−olefin
complexes,20 and expected for geometrically constrained
chelate formation.
To further probe interactions between enones and EtZnCl, a
series of γ-aryl substituted β,γ-unsaturated ketones (1b−d)
were examined. 1H NMR experiments analogous to those
executed with 1a were performed (Table 1, entries 2−4). When
the phenyl group is substituted with an electron-donating
group, the observed Δδ increases (entry 2 vs 3). In contrast,
with an electron-withdrawing aryl group, the Δδ decreases
(entry 2 vs 4). These results indicate that stronger interactions
with the zinc center occur when there is more electron density
on the π-system. The greater Δδ values observed for the γ
protons are consistent with the larger δ+ character of the double
Interaction of zinc with an aryl ring has also been proposed to
explain the reversal of diastereoselectivity in Simmons−Smith
halocyclopropanation reactions.15 Elegant studies by Yamamo-
to and co-workers have demonstrated that coordination of
double and triple bonds to aluminum(III) can change reaction
chemoselectivity.16
With this backdrop, we asked whether racemic β,γ-enones
could undergo chelation-controlled additions by means of
coordination of the carbonyl and alkene moieties to zinc.
Herein, we substantiate this hypothesis with the counter-
intuitive discovery that chiral β,γ-enones undergo highly
diastereoselective additions, albeit in low yield due to
competing aldol processes. NMR and computational studies
provide support for chelation of the β,γ-enones to Zn(II). This
study hints that even weak metal π-interactions can be used to
control diastereoselectivity and expands the boundaries of
groups that undergo stereoselective chelation-controlled
carbonyl additions.
2. RESULTS AND DISCUSSION
2.1. Proof of Concept. To determine whether or not
racemic β,γ-enones would undergo chelation-controlled
addition reactions, we prepared ketone 1a (Scheme 4; see
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1
Table 1. H NMR Binding Study of EtZnCl with β,γ-
Scheme 5. Addition of Et2Zn to Ketones 1b and 1e in the
Presence of EtZnCl
Unsaturated Ketones 1a−g
1
giving rise to the observed diastereoselectivities and H NMR
chemical shift changes in Scheme 5 and Table 1, respectively,
DFT calculations were undertaken.21 First, the ground-state
geometries were calculated for the adduct between the β,γ-
unsaturated ketone and MeZnCl. Coordination of the alkene to
the Zn(II) center was readily found even when a solvation
model (toluene, CPCM) was exmployed. Table 2 shows how
alkene binding is modulated by the electronic properties of the
γ-aryl substituent. In agreement with 1H NMR binding studies,
a substrate with an electron donor group (R = OMe)
coordinates more strongly than a substrate with an electron-
withdrawing group (R = CF3), as evidenced by the Zn−alkene
distances. Comparison of the Zn−Cβ and Zn−Cγ bond lengths
also suggests a stronger coordination between the metal center
1
and the β carbon, which is consistent with the H NMR
observations described above.
a
Chemical shift variations with respect to the free β,γ-unsaturated
ketones 1a−g.
Table 2. Selected Distances and Relative Enthalpies
Calculated at the B3LYP/LANL2DZ Level in Toluene
(CPCM) after Coordination of 1b−d with MeZnCl
bond at benzylic position. It also suggests that coordination
preferentially occurs at the β position.
Similar 1H NMR studies were then conducted on the methyl
ketones 1e−g (Table 1, entries 5−7). To our surprise, the
results obtained were drastically different from those in entries
1−4. Irrespective of the electron density of the double bond,
the Δδ values were almost unchanged compared to the
reference compound 1e (entries 5 vs 6 and 7). Moreover, the
chemical shift variations are systematically greater for the α′
protons relative to the α proton, which is opposite that
expected for chelation.6e Together, these results suggest that
substrates 1e−g do not undergo alkene chelation.
a
entry
R
ΔH (kcal/mol)
Zn−Cβ (Å) Zn−Cγ (Å) CC (Å)
1
2
3
H
−1.7
−2.1
−1.8
3.421
3.420
3.427
3.845
3.840
3.855
1.354
1.355
1.354
OMe
CF3
a
Enthalpy difference calculated between the mono- and tricoordinated
2.3. Reactivity Studies with α-Phenyl and α-Methyl
Ketones. On the basis of the contrasting results from the
NMR studies above, we examined additions to phenyl ketone
1b and methyl ketone 1e (Scheme 5) under the conditions
employed in Scheme 4. The phenyl ketone 1b underwent
addition in the presence of EtZnCl to give the chelation-
controlled adduct 2b with a very high selectivity (dr >20:1)
consistent with the chelation observed in the 1H NMR spectra.
On the other hand, the methyl ketone 1e afforded a 1:1 mixture
of diastereomers 2c and 2c′, in agreement with the absence of
chelation features in the 1H NMR spectra of 1e and its
analogues. Although the tertiary alcohols are the minor
products in these reactions, the observed stereoselectivities
clearly point to distinct reaction manifolds. These unanticipated
reaction outcomes are explored computationally in the next
section.
complexes.
Next, the transition states for the additions of ZnMe2 were
calculated using MeZnCl as Lewis acid. The lowest energy
transition states leading to the anti-Felkin adduct (TS-1) and
the Felkin adduct (TS-2) incorporate two zinc atoms each
(Figure 1). This general model for dialkylzinc addition to
carbonyls has been extensively studied both experimentally and
computationally.22−24 The more Lewis acidic MeZnCl serves to
activate the carbonyl. The zinc atom of the ZnMe2 complexes
to both the choride and the carbonyl of this initial adduct,
causing nucleophilic activation of the ZnMe2. In the lowest
energy transition state, chelation occurs between the alkene and
the zinc of the MeZnCl. The Zn−alkene distances are
comparable to those previously observed in the solid state for
Zn(II)−π coordination.14c The Zn−π coordination forces the
alkene moiety to orient syn to the CO bond (OCCβCγ
2.4. Exploration of the Reaction Pathways Using
Computational Methods. To gain insight into the factors
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Figure 2. Relative free energies and enthalpies (in parentheses),
displayed in kcal/mol, calculated for the methyl addition to ketone 4,
calculated at the B3LYP/LANL2DZ level in toluene (CPCM).
Selected bond distances are in angstroms.
Figure 1. Relative free energies and enthalpies (in parentheses), in
kcal/mol, calculated for the methyl addition to ketone 3, calculated at
the B3LYP/LANL2DZ level in toluene (CPCM). Selected bond
distances are in angstroms.
similarly. Experimentally, this hypothesis was validated with β,γ-
enones undergoing chelation-controlled additions of alkylzinc
reagents in the presence of Lewis acid EtZnCl with
diastereoselectivities as high as 50:1. The proposed chelation
dihedral = −46°). This orientation minimizes the steric
interactions between the α-methyl and the phenyl ring in the
anti-Felkin approach (see left Newman projection in Figure 1).
Other conformations were >5 kcal/mol higher in energy (see
Supporting Information for structures).
In contrast, the lowest energy transition state leading to the
Felkin adduct (TS-2) does not involve alkene chelation to the
Zn and is significantly higher in energy (2−3 kcal/mol).25 It
was possible to locate transition-state structures for the Felkin
approach with Zn−π chelation, but severe steric interactions
between the α-methyl and the phenyl ring cause them to be an
additional ∼3 kcal/mol higher in energy than TS-2 (see
Supporting Information). Notably, the relative energies
between the two diastereomeric transition states are in excellent
agreement with the experimentally determined diastereoselec-
tivities, which favor the chelation-controlled product by >20:1
dr.26
In contrast to the phenyl ketone, computations show a
negligible energy difference between the two lowest energy
diastereomeric transition-state structures for the methyl ketone
(Figure 2, TS-1a and TS-2a). Again, the lowest energy
transition-state structure leading to the anti-Felkin product
shows chelation between the π-system and the Zn, whereas that
leading to the Felkin product is not chelated. However, TS-2a,
which leads to the Felkin product, is now nearly isoenergetic
with TS-1a, predicting low diastereoselectivty, in accord with
that observed (Scheme 5). The unfavorable steric interactions
present between the phenyl ketone and the α-alkenyl
substituent that destabilize TS-2 (see right Newman projection
in Figure 1) are diminished in TS-2a (see right Newman
projection in Figure 2) due to the smaller methyl ketone group
(see Supporting Information).
1
control is also supported by DFT calculations and solution H
NMR binding studies with β,γ-unsaturated ketones. To our
surprise, we found that the nature of the substrate played a
dramatic role in the proclivity to form Zn−π interactions, which
showed excellent correlation with both solution binding studies
and computations. Importantly, these results show that metal−
alkene interactions, even with metal centers for which no
solution-phase η2-alkene adducts are known, can be sufficient to
control diastereoselectivity in carbonyl addition reactions.
These insights show that the range of effective coordinating
groups for chelation-controlled carbonyl additions and related
processes extends beyond highly basic heteroatoms, augment-
ing the long-standing paradigm. In a broader synthetic context,
such interactions may enable control of stereo- and chemo-
selectivities of related chemical processes.
4. EXPERIMENTAL SECTION
4.1. General Methods. All water- and air-sensitive reactions were
performed under an N2 atmosphere using flame-dried glassware and
standard Schlenk and vacuum line techniques. The progress of
reactions was monitored by thin-layer chromatography (TLC) and
visualized by UV or by staining with ceric ammonium molybdate or
potassium permanganate. Silica gel (230−400 mesh) was used for flash
chromatography. The 1H NMR and 13C{1H} NMR spectra were
obtained using a 500 and 125 MHz Fourier transform NMR
spectrometer, respectively. 1H NMR were referenced to tetramethylsi-
lane in CDCl3 (δ = 0 ppm), and 13C{1H} NMR spectra were
referenced to residual solvent (CDCl3, δ = 77.16 ppm). Coupling
constants are reported in hertz. Toluene, acetonitrile, and dichloro-
methane were dried through alumina columns and degassed before
use. Ethyl zinc chloride was synthesized according to a method
reported in the literature.27 Other reagents were obtained from
commercial sources and used without further purification. CAUTION:
Care must be taken when handling pyrophoric dialkylzinc reagents.
4.2. Quantum Mechanical Methods. All geometries were
optimized using DFT at the B3LYP/LANL2DZ28 level of theory in
toluene (unless otherwise noted) with the CPCM29 solvation model as
implemented in GAUSSIAN09.30 All stationary points were
3. CONCLUSIONS
In summary, on the basis of the ability of Lewis acidic alkyl zinc
halides and pseudohalides to promote chelation-controlled
additions with carbonyl compounds possessing α- or β-silyloxy
and α-halo groups, which are typically regarded as ineffective
chelating groups, we hypothesized that alkenes might act
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characterized as transition states (one and only one imaginary
frequency) or minima (zero imaginary frequencies). Various methods
were assessed to compare with the solid-state geometry of the zinc−
alkene coordination (see Supporting Information, Figure C1).
4.3. Synthesis of the β,γ-Unsaturated Ketones 1a−d. β,γ-
Unsaturated benzyl ketones 1a−d were synthesized from benzalde-
hyde in a three-step sequence, involving a Barbier crotylation, an olefin
cross-metathesis, and a Dess−Martin periodinane oxidation.
4.4. Synthesis of the β,γ-Unsaturated Ketones 1e−g. β,γ-
Unsaturated ketones 1e−g were synthesized from acetaldehyde in a
three-step sequence, involving a Barbier crotylation, a Heck reaction,
and a Dess−Martin periodinane oxidation.
General Procedure for the Synthesis of Compounds 1e−g. To a
solution of acetaldehyde (1.0 g, 22.70 mmol) in a THF/NH4Claq.sat
mixture (50:50 mL) were added crotyl chloride (3.32 mL, 34.05
mmol) and zinc powder (2.97 g, 45.40 mmol). The reaction mixture
was stirred at room temperature for 12 h. The reaction media was then
filtered, and most of the THF removed in vacuo. The resulting solution
was then extracted with DCM (3 × 25 mL). The combined organic
layers were washed with brine (25 mL), dried over Na2SO4, filtered,
and concentrated in vacuo to give 3-methylpent-4-en-2-ol (1.18 g,
11.80 mmol, 45:55 diastereomer mixture) as a light yellow oil in 52%
yield, without further purification. To a mixture of Pd(OAc)2 (4.5 mg,
20.0 μmol) and tris(o-tolyl)phosphine (12 mg, 40.0 μmol) under
nitrogen was added a dry degassed solution of the prepared
homoallylic alcohol (100 mg, 1.0 mmol) in MeCN (5 mL). Freshly
distilled triethylamine (0.14 mL, 1.0 mmol) and an aryl bromide
(bromobenzene, 4-bromoanisole, or 4-bromobenzotrifluoride for 1e−
g, respectively, 2.0 mmol) were then added. The mixture was heated
under reflux for 12 h. The reaction media was concentrated in vacuo,
taken up in DCM (10 mL), and washed with NH4Claq.sat (3 × 5 mL)
and brine (5 mL). The organic layer was filtered, dried, and
concentrated in vacuo to give a crude mixture, which was purified by
silica gel flash chromatography. The resulting pure crossed alcohol was
then taken up in dry DCM (0.2 M), and a 15% solution of Dess−
Martin periodinane in DCM (1.2 equiv) was added dropwise. The
reaction mixture was stirred at room temperature for 2 h. The white
solid that formed was filtered off and washed with cold diethyl ether (5
mL). The filtrate was concentrated in vacuo and purified by silica gel
flash chromatography to yield β,γ-unsaturated ketones 1e−g.
General Procedure for the Synthesis of Compounds 1a−d. To a
solution of benzaldehyde (1.0 g, 9.42 mmol) in a THF/NH4Claq.sat
mixture (25:25 mL) were added crotyl chloride (1.38 mL, 14.13
mmol) and zinc powder (1.23 g, 18.84 mmol). The reaction mixture
was stirred at room temperature for 12 h. The media was then filtered,
and most of the THF removed in vacuo. The media was then extracted
with DCM (3 × 15 mL). The combined organic layers were washed
with brine (15 mL), dried over Na2SO4, filtered, and concentrated in
vacuo to give 2-methyl-1-phenylbut-3-en-1-ol (1.0 g, 6.22 mmol, 45:55
diastereomer mixture) as a light yellow oil in 66% yield, without
further purification. Part of this homoallylic alcohol (100 mg, 0.62
mmol) was taken up in dry degassed DCM (3 mL). A terminal alkene
(1-hexene, styrene, 4-methoxy styrene, or 4-trifluoromethylstyrene for
1a−d, respectively, 1.86 mmol) and second-generation Grubbs catalyst
(26 mg, 31.0 μmol) were then added. The reaction mixture was heated
at reflux under N2 for 12 h. The reaction media was concentrated in
vacuo, and the crude mixture was purified by silica gel flash
chromatography. The resulting pure crossed alcohols were then
taken up in dry DCM (0.2 M), and a 15% solution of Dess−Martin
periodinane in DCM (1.2 equiv) was added dropwise. The reaction
mixture was stirred at room temperature for 2 h. The white solid that
formed was filtered off and washed with cold diethyl ether (5 mL).
The filtrate was concentrated in vacuo and purified by silica gel flash
chromatography to yield β,γ-unsaturated ketones 1a−d.
(E)-2-Methyl-1-phenyloct-3-en-1-one (1a). The general procedure
was applied with 1-hexene (0.23 mL, 1.86 mmol) as coupling partner.
The title compound 1a (79 mg, 0.37 mmol) was obtained as a
colorless oil in 39% yield over the three steps. Spectral data obtained
were in accordance with the literature.31
(E)-2-Methyl-1,4-diphenylbut-3-en-1-one (1b). The general pro-
cedure was applied with styrene (0.21 mL, 1.86 mmol) as coupling
partner. The title compound 1b (76 mg, 0.32 mmol) was obtained as a
colorless oil in 34% yield over the three steps. Spectral data obtained
were in accordance with the literature.31
(E)-3-Methyl-5-phenylpent-4-en-2-one (1e). The general proce-
dure was applied with bromobenzene (0.21 mL, 2.0 mmol) as
coupling partner. The title compound 1e (49 mg, 0.28 mmol) was
obtained as a colorless oil in 15% yield over the three steps. Spectral
data obtained were in accordance with the literature.32
(E)-5-(4-Methoxyphenyl)-3-methylpent-4-en-2-one (1f). The gen-
eral procedure was applied with 4-bromoanisole (0.25 mL, 2.0 mmol)
as coupling partner. The title compound 1f (73 mg, 0.36 mmol) was
1
obtained as a white solid in 19% yield over the three steps. H NMR
(CDCl3, 500 MHz): δ 1.26 (d, J = 6.9 Hz, 3H), 2.18 (s, 3H), 3.32
(apparent quintet, J = 7.2 Hz, 1H), 3.80 (s, 3H), 6.01 (dd, J = 15.8, 8.5
Hz, 1H), 6.46 (d, J = 15.8 Hz, 1H), 6.83−6.87 (m, 2H), 7.27−7.32
(m, 2H). 13C{1H} NMR (CDCl3, 125 MHz): δ 16.3, 28.2, 51.5, 55.4,
114.2, 126.7, 127.6, 129.8, 131.7, 159.4, 209.7. IR (neat): 2963, 2933,
2837, 1710, 1606, 1512, 1452, 1356, 1252, 1168, 1032, 968, 813.
HRMS (ESI): m/z [C13H16O2 + H]+ calcd 205.1229, found 205.1230.
Tfus: 34−35 °C.
(E)-3-Methyl-5-(4-(trifluoromethyl)phenyl)pent-4-en-2-one (1g).
The general procedure was applied with 4-bromobenzotrifluoride
(0.28 mL, 2.0 mmol) as coupling partner. The title compound 1g (39
mg, 0.16 mmol) was obtained as a colorless oil in 8% yield over the
three steps. 1H NMR (CDCl3, 500 MHz): δ 1.30 (d, J = 6.9 Hz, 3H),
2.21 (s, 3H), 3.39 (apparent quintet, J = 7.4 Hz, 1H), 6.30 (dd, J =
15.9, 8.4 Hz, 1H), 6.54 (d, J = 15.9 Hz, 1H), 7.45 (br d, J = 8.2 Hz,
2H), 7.56 (br d, J = 8.2 Hz, 2H). 13C{1H} NMR (CDCl3, 125 MHz):
δ 16.3, 28.4, 51.3, 124.3 (q, J = 271.8 Hz), 125.7 (q, J = 3.7 Hz), 126.6,
129.6 (q, J = 32.4 Hz), 130.9, 131.7, 140.4, 208.9. IR (neat): 2978,
2935, 2876, 1717, 1616, 1416, 1357, 1325, 1165, 1123, 1067, 1016,
971, 820. HRMS (ESI): m/z [C13H13F3O − H]− calcd 241.0840,
found 241.0836.
(E)-4-(4-Methoxyphenyl)-2-methyl-1-phenylbut-3-en-1-one (1c).
The general procedure was applied with 4-methoxystyrene (0.25
mL, 1.86 mmol) as coupling partner. The title compound 1c (89 mg,
0.33 mmol) was obtained as a colorless oil in 36% yield over the three
1
steps. H NMR (CDCl3, 500 MHz): δ 1.41 (d, J = 6.8 Hz, 3H), 3.78
(s, 3H), 4.29 (apparent quintet, J = 6.9 Hz, 1H), 6.20 (dd, J = 15.9, 8.2
Hz, 1H), 6.46 (d, J = 15.9 Hz, 1H), 6.80−6.83 (m, 2H), 7.24−7.28
(m, 2H), 7.43−7.48 (m, 2H), 7.52−7.56 (m, 1H), 8.00−8.03 (m, 2H).
13C{1H} NMR (CDCl3, 125 MHz): δ 17.9, 45.0, 55.4, 114.1, 127.6,
127.7, 128.7, 128.8, 129.9, 131.2, 133.1, 136.6, 159.3, 201.4. IR (neat):
3060, 3032, 2966, 2930, 2872, 2836, 1679, 1606, 1510, 1447, 1247,
1174, 1031, 969, 819, 701. HRMS (CI): m/z [C18H18O2]+ calcd
266.1307, found 266.1312.
(E)-2-Methyl-1-phenyl-4-(4-(trifluoromethyl)phenyl)but-3-en-1-
one (1d). The general procedure was applied with 4-trifluoromethyl-
styrene (0.27 mL, 1.86 mmol) as coupling partner. The title
compound 1d (70 mg, 0.23 mmol) was obtained as a colorless oil
in 24% yield over the three steps. 1H NMR (CDCl3, 500 MHz): δ 1.44
(d, J = 6.8 Hz, 3H), 4.35 (apparent quintet, J = 6.9 Hz, 1H), 6.49 (dd,
J = 16.0, 7.3 Hz, 1H), 6.55 (d, J = 16.0 Hz, 1H), 7.43 (br d, J = 8.2 Hz,
2H), 7.48 (br t, J = 7.7 Hz, 2H), 7.53 (br d, J = 8.2 Hz, 2H), 7.55−7.59
(m, 1H), 7.99−8.03 (m, 2H). 13C{1H} NMR (CDCl3, 125 MHz): δ
17.9, 44.9, 124.3 (q, J = 271.9 Hz), 125.6 (q, J = 3.8 Hz), 126.6, 128.7,
128.9, 129.5 (q, J = 32.5 Hz), 130.4, 132.7, 133.4, 136.4, 140.6, 200.9.
IR (neat): 3060, 2975, 2933, 1683, 1615, 1448, 1414, 1325, 1165,
1122, 1067, 1016, 972, 822, 705. HRMS (ESI): m/z [C18H15F3O +
H]+ calcd 305.1153, found 305.1152.
4.5. General Procedure for the Additions to the β,γ-
Unsaturated Ketones. In a drybox, to a Schlenk flask containing
the β,γ-unsaturated ketone (0.3 mmol) were added successively dry
toluene (1.5 mL), EtZnCl (78 mg, 0.6 mmol), and Et2Zn (0.45 mL,
0.9 mmol, 2 M in toluene). The flask was taken out of the glovebox
and heated under nitrogen at 55 °C for 48 h. The reaction mixture was
then cooled to 0 °C and carefully quenched successively with water (1
mL) and 1 N HCl (1 mL). The layers were separated, and the aqueous
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Organometallics
Article
one was extracted with EtOAc (3 × 5 mL). The combined organic
extracts were washed with brine (5 mL), dried over Na2SO4, filtered,
and concentrated in vacuo. The crude mixture was purified by silica gel
flash chromatography (using 90:10 hexanes/EtOAc eluent).
(GM087605). L.R. thanks the “Reg
Explora’Pro fellowship.
́
ion Rho
̂
ne-Alpes” for its
REFERENCES
■
( )-(3R,4S,E)-4-Methyl-3-phenyldec-5-en-3-ol (2a). The general
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1
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ASSOCIATED CONTENT
■
S
* Supporting Information
A text file of all computed molecule Cartesian coordinates in a
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format for convenient visualization. H and 13C{1H} NMR
1
spectra. This material is available free of charge via the Internet
at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
*E-mail: marisa@sas.upenn.edu.
*E-mail: pwalsh@sas.upenn.edu.
Notes
■
Babiano, R.; Cintas, P.; Duran
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ACKNOWLEDGMENTS
P.J.W. acknowledges the NSF (CHE-1152488). M.C.K.
acknowledges XSEDE TG-CHE120052 and the NIH
■
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