Investigating the nature of palladium chain-walking in the enantioselective redox-relay heck reaction of alkenyl alcohols

Article abstract of DOI:10.1021/jo501813d

The mechanism of the redox-relay Heck reaction was investigated using deuterium-labeled substrates. Results support a pathway through a low energy palladium-alkyl intermediate that immediately precedes product formation, ruling out a tautomerization mechanism. DFT calculations of the relevant transition structures at the M06/LAN2DZ+f/6-31+G level of theory show that the former pathway is favored by 5.8 kcal/mol. Palladium chain-walking toward the alcohol, following successive β-hydride eliminations and migratory insertions, is also supported in this study. The stereochemistry of deuterium labels is determined, lending support that the catalyst remains bound to the substrate during the relay process and that both cis- and trans-alkenes form from β-hydride elimination. (Chemical equation presented).

Full text of DOI:10.1021/jo501813d

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Open Access on 09/04/2015
Investigating the Nature of Palladium Chain-Walking in the
Enantioselective Redox-Relay Heck Reaction of Alkenyl Alcohols
Margaret J. Hilton,† Li-Ping Xu,‡ Per-Ola Norrby,§ Yun-Dong Wu,‡ Olaf Wiest,‡,∥
and Matthew S. Sigman*,†
†Department of Chemistry, University of Utah, 315 South 1400 East, Salt Lake City, Utah 84112, United States
‡Laboratory of Computational Chemistry and Drug Design, Laboratory of Chemical Genomics, Peking University Shenzhen
Graduate School, Shenzhen 518055, China
§Pharmaceutical Development, Global Medicines Development, AstraZeneca, Pepparedsleden 1, SE-431 83 Molndal, Sweden
̈
∥Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States
S
* Supporting Information
ABSTRACT: The mechanism of the redox-relay Heck
reaction was investigated using deuterium-labeled substrates.
Results support a pathway through a low energy palladium−
alkyl intermediate that immediately precedes product for-
mation, ruling out a tautomerization mechanism. DFT
calculations of the relevant transition structures at the M06/
LAN2DZ+f/6-31+G* level of theory show that the former
pathway is favored by 5.8 kcal/mol. Palladium chain-walking
toward the alcohol, following successive β-hydride eliminations
and migratory insertions, is also supported in this study. The
stereochemistry of deuterium labels is determined, lending
support that the catalyst remains bound to the substrate during
the relay process and that both cis- and trans-alkenes form from β-hydride elimination.
preferentially binds to one face of the alkene to form the
alkyl−aryl bond at the distal sp2 carbon to the alcohol, leading
to the major product (the γ-product for homoallylic alcohols).
When the alkene binds to the metal on the opposite face,
migratory insertion of the aryl group at the proximal sp2 carbon
results in the enantiomeric β-product. Additionally, (E)- and
(Z)-alkenyl alcohol substrates generate enantiomers.1,2
The site selectivity of the reaction is controlled by subtle
polarity differences of the alkene carbons in the transition state.
The trends in site selectivity are correlative to the polarity
differences in alkenes as determined by 13C NMR shifts,2 IR
CC stretches,4 and NBO charges.7 Furthermore, the site
selectivity is also related to the electron density in the aryl
coupling partner, as previously demonstrated in a Hammett
relationship2 as well as IR frequencies and intensities.4
Increased site selectivity is observed with electron-poor aryl
groups, bulkier substituents at R′, and shorter alkyl chain
lengths (Figure 1).
INTRODUCTION
■
The enantioselective redox-relay Heck reaction yields an aryl−
alkyl bond and repositions unsaturation from an alkene to an
alcohol (Figure 1).1−3 These reactions proceed in excellent
enantioselectivity with a wide range of aryl-coupling partners as
well as differing chain lengths between the alkene and the
alcohol in the substrate. The site selectivity in terms of where
the aryl group is introduced onto the alkene is sensitive to the
nature of both coupling partners.2,4 The reaction has been
optimized using both diazonium salts1 and boronic acids2 as the
aryl source and is also effective in producing quaternary centers
with high enantiomeric ratios starting from trisubstituted
alkenol substrates.5
Computational studies of the mechanism of the reaction
revealed the influences on enantioselectivity and site
selectivity.6,7 A rate-limiting migratory insertion of the arene
leads to a relatively shallow region of the potential energy
surface for the relay process, which involves the Pd-catalyst
migrating or walking toward the alcohol via successive β-
hydride eliminations and migratory insertions (Figure 2).
Enantioselectivity is attributed in both studies to the steric
While the two computational studies agree on the major
features of the pathway, there are distinct differences proposed
for the formation of the carbonyl product from the palladium−
enol species (right part of Figure 2). Wang et al. propose the
t
repulsion of the substrate with the Bu group on the oxazoline
portion of the ligand. These interactions lead to high
enantiomeric ratios of the products in all cases, indicating
that the identity of either coupling partner has little influence
over the enantioselectivity-determining step. The catalyst
Special Issue: Mechanisms in Metal-Based Organic Chemistry
Received: August 5, 2014
© XXXX American Chemical Society
A
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walking and the question of stereochemistry of the palladium−
alkyl and −alkenyl intermediates as the catalyst proceeds
toward the alcohol. The energy barriers calculated for the relay
sequence are relatively modest, suggesting that any β-hydride
elimination or migratory insertion step during this process may
be readily reversible.8−10 This poses a number of questions that
are important for the selectivity of these steps: (i) which
hydrogens are eliminated, (ii) where do the migratory
insertions take place, and (iii) does the palladium chain-
walking process occur by a reversible, bidirectional mechanism?
Poor selectivity during the β-hydride elimination steps could
result in mixtures of (E)- and (Z)-alkenes, although only (E)-
isomers were considered in the calculations shown in Figure 2.
Additionally, reversible binding of these alkenes could cause
erosion in the observed enantioselectivity if the face by which
the alkene is bound to the metal switches via dissociative/
associative processes. Migratory insertion of the palladium
hydride could then occur to the opposite prochiral face of the
alkene. Thus, the stereochemical integrity of these steps is of
significant interest. Finally, we will study the formation of the
carbonyl product. In addition to the differences found in the
two computational studies, it is noteworthy that substrates with
a greater distance (three to five carbons) between the alkene
and alcohol form aldehydes and ketones. In case of the minor
products resulting from a migratory insertion of the aryl group
at the proximal sp2 carbon to the alcohol, the catalyst is
required to migrate through an already established aryl−alkyl
bond to yield the carbonyl product. Irrespective of a reversible
relay sequence, it must be favorable for the catalyst to form
aldehydes and ketones under standard reaction conditions. It is
unclear if the driving force for this depends on the electronic
effect of the alcohol or an interaction between the alcohol and
the catalyst. In the present study, we will probe the steps of the
reaction relevant to these questions through isotopic labeling
studies and computational methods.
Figure 1. Oxidative enantioselective redox-relay Heck reaction details
and proposed mechanism.
direct deprotonation of the hydride by DMF,6 while our studies
indicate a reinsertion of the palladium hydride followed by
oxidative deprotonation.7 As the formation of the final product
is essential for a complete understanding of the mechanism of
the redox-relay Heck reaction, studies to distinguish these two
possibilities are desirable.
RESULTS AND DISCUSSION
■
Investigating the Reversibility of the Relay Process.
After the initial migratory insertion of the alkene into the Pd−
aryl species to form intermediate A (Figure 2), the barriers
between the iterative β-hydride eliminations and migratory
insertions are relatively low, suggesting that the catalyst could
Herein, we report an investigation regarding the nature of the
relay process, including the possibility of reversible chain-
Figure 2. Truncated reaction profile from calculated intermediates for major product formation in the redox-relay Heck reaction.
B
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migrate both away from and toward the alcohol before releasing
the product. To test this possibility, we synthesized several
deuterium-labeled substrates and submitted them to our
standard conditions for the oxidative redox-relay Heck reaction
(see the conditions in Figure 1). Both (Z)- and (E)-labeled
alkenes were evaluated using electron-rich and electron-poor
arenes so that both the β- and γ-products could be readily
analyzed (Scheme 1 and Scheme S1, Supporting Information,
possibility by calculating the KIE for the elimination of the β-
hydrogen using the free energies for the two isotopomers of the
previously described transition structure7 for this step as
described in the Supporting Information. The calculated
isotope effect of kH/kD = 2.66 is too small to account for the
high retention of deuterium incorporation in the formation of
(Z)-7, confirming the preferential directionality of β-hydride
elimination. Insertion of the aryl group at the β-position leads
to intermediate 1-G with the palladium−alkyl bond at the γ-
position (Scheme 1). Again, the catalyst may eliminate a
hydrogen or deuterium either away from or toward the alcohol,
respectively. In both cases, the catalyst must migrate through
the chiral center to yield the aldehyde product. Thus, the
deuterium at the benzylic position will be eliminated and
subsequently reinserted at the γ-position. If the catalyst first
shifts away from the alcohol in intermediate 1-G, then some
migration of deuterium from the γ-position to the δ-position
would be expected. Product 8 is observed with no detectable
hydrogens at the β- or δ-position, strongly suggesting that β-
hydride elimination occurs toward the benzylic position. This is
in line with the previously described polarization in the
transition state based on the dipole moment of the C−O
directing the relay process toward the alcohol.7 Nearly identical
results were observed for the (E)-deuterium labeled alkene
(Scheme S1, Supporting Information).
Scheme 1. Evaluation of Deuterium Labels and Site
Selectivity Resulting from (Z)-Labeled Alkene
To further probe the directionality of palladium chain-
walking, substrate 2 was submitted to the same reaction
conditions using an electron-poor and electron-rich coupling
partner (Scheme 2). With deuterium labels at the terminal
respectively). Electron-poor aryl substrates, such as the p-
MeO2CPhB(OH)2 used in most studies reported here, yield a
higher ratio of the major product with the migratory insertion
of the aryl group occurring at the γ-carbon as shown in Figure
2. Conversely, electron-rich arenes, such as the p-MeOPhB-
(OH)2, lead to poorer site selectivity, thus allowing analysis of
the minor β-product. As shown in Figure 2, insertion of the aryl
group at the γ-position leads to the major product in
homoallylic alcohol substrates via intermediate A with a
palladium−alkyl bond at the β-position. From this intermedi-
ate, β-hydride elimination can occur either toward the alcohol
to begin the relay process or toward the aryl group. The barrier
to eliminate the benzylic hydrogen is higher in energy by 0.9
kcal/mol, and the complex resulting from this step is 4.8 kcal/
mol higher in energy than complex B.7 Yet, these calculations
do not conclusively eliminate the possibility of this step
occurring.
Scheme 2. Assessment of Chain-Walking Away from the
Alcohol
The first substrate examined is (Z)-1 (Scheme 1).
Preferential insertion at the γ-position relative to the resultant
aldehyde product leads to intermediate 1-A, which can undergo
β-deuteride elimination at the benzylic γ-position or β-hydride
elimination at the α-position to begin the relay process. If the
catalyst migrates away from the alcohol beyond the aryl group,
loss of deuterium incorporation at the γ- and β-positions would
be expected in the products. Additionally, any incorporation of
deuterium at the α-position would indicate that chain-walking is
reversible from 1-A. Experimentally, retention of the deuterium
labels at the γ- and β-positions was observed for the major
product (Z)-7. This suggests that after formation of 1-A, the
catalyst preferentially walks toward the alcohol, in agreement
with the computationally derived kinetic barrier differences.
An alternative explanation for the preferential formation of
(Z)-7 is a kinetic isotope effect (KIE) rather than the
directionality of the hydrogen elimination. We tested this
allylic position, any incorporation of hydrogens at this site in
either the major or minor product will indicate that an
intermediate undergoes β-hydride eliminations away from the
alcohol. When the aryl group is inserted at the γ-carbon of 2 to
give intermediate 2-A, only β-hydride elimination toward the
alcohol results, thus preserving the deuterium labels at the
methyl group and yielding product 9.
After the insertion of the aryl group at the β-carbon,
producing intermediate 2-G, deuterium scrambling in a ∼1.5:1
ratio is observed (compare products 10 and 11). Starting from
2-G, elimination of either a hydrogen from the benzylic
position or a deuterium from the methyl group can occur. The
relay process yields product 10 after elimination of the benzylic
C
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hydrogen. When a β-deuteride elimination at the methyl group
occurs to form putative intermediate 2-H, a migratory insertion
of the deuterium follows to give a palladium−alkyl species at
the terminal carbon. The relay sequence from this complex
ultimately leads to product 11. It should be noted that all of the
deuterium atoms can be accounted for in the product ruling out
any H−D exchange processes. In comparing this to the
formation of 8, in which no deuterium incorporation was
detected at the δ-position, this example shows a significant
amount of Pd-walking away from the alcohol. Thus, migration
through the benzylic position provides enough hindrance to
allow reversible chain-walking away from the alcohol, resulting
in deuterium scrambling. Nonetheless, a driving force remains
to direct chain-walking toward the alcohol as aldehyde product
11 is still formed.
Lastly, we evaluated the reaction of substrate 3 with
deuterium labels remote to both the alkene and the alcohol
under the same reaction conditions (Scheme 3). If deuterium is
Scheme 3. Probing the Reversibility of the Relay Process
incorporated elsewhere in the alkyl chain (i.e., in the γ-, δ-, or ε-
positions), then the only explanation would be that the catalyst
walks reversibly along the chain until product is released. In
contrast, if the same bias as discussed above is observed for
chain-walking toward the alcohol, then deuterium should only
be detected at the α- and β-positions. Once intermediate 3-A is
formed by the initial migratory insertion and relay sequence, a
β-deuteride elimination occurs, yielding intermediate 3-B,
followed by a migratory insertion of the deuterium to give
complex 3-C. The product of this sequence, 12, which retains
one deuterium at the α-position and incorporates one
deuterium at the β-position, is the only product observed in
the reaction resulting from insertion of the aryl group at the ε-
position. No deuterium incorporation was detected beyond the
β-position. Accordingly, the catalyst performs an irreversible
sequence of β-deuteride elimination and migratory insertion
steps from 3-A to 3-C to eventually yield 12, although the
microscopic reversibility of individual steps (i.e., 3-B to 3-A)
cannot be ruled out. The lack of detectable deuterium
scrambling observed in these studies supports a unidirectional
palladium chain-walking leading to the energetically favorable
formation of the carbonyl product.
Figure 3. Comparison of the proposed product releasing steps.
allows a palladium-assisted tautomerization to occur via W1
and W2, affording the carbonyl product. Alternatively, we
proposed a migratory insertion of the hydride in complex D to
yield the palladium−alkyl intermediate E, which then under-
goes an oxidative deprotonation by DMF to close the catalytic
cycle and release product.7
To compare these two possibilities, we calculated both
pathways at the M06/LAN2DZ+f/6-31+G* level of theory
used previously.7 The results, summarized in Figure 3, show
that the deprotonation of D by DMF has an activation barrier
of 15.7 kcal/mol, which is significantly less favorable than the
reinsertion and oxidative deprotonation pathway (12 kcal/mol
lower in energy). This is consistent with the hydridic character
of the hydrogen in D causing the coordination of DMF to be
endergonic by 9.8 kcal/mol. As a result, deprotonation by the
weak base DMF (pKa of DMF−H+ = −0.01)11 is overall
endergonic by 9.9 kcal/mol. In comparison, the activation free
energy of the reinsertion is 3.7 kcal/mol, which is consistent
with the barriers calculated for the chain walking process,
leading to intermediate E. Calculations of the protonation of
DMF by E show a monotonous increase in energy. This is
indicative of a diffusion-controlled situation where the free
Examining the Product-Releasing Step(s). The results
discussed above indicate that unidirectional migration ulti-
mately leads to the formation of the carbonyl products. Two
different proposals for eventual formation of the carbonyl were
reported and are compared in Figure 3. Wang and co-workers
suggested6 that once the palladium−enol intermediate D is
reached, a DMF molecule deprotonates the hydride, which
D
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energy barrier to the backward reaction is ca. 4.5 kcal/mol
higher than the separated F + DMF-H+, that is, a transition
state with a free energy of ∼4.8 kcal/mol.12 Identical behavior is
seen in model calculations of DMF-H+ combined with, for
example, a fluoride anion.
The transition structures for the two pathways are shown at
the bottom of Figure 3. Consistent with the endergonic nature
of the reaction, TS(1−2) is a late transition structure with a long
Pd−H and a short O−H bond. The dihedral angle C1−C2−
Pd−N1 is −68.7° in TS(1−2), positioning the planes of the
ligand and the substrate almost perpendicular to each other to
allow the approach of the DMF base. In contrast, TS(D‑E) is an
early transition structure with an extensively elongated C−H
bond of 1.85 Å and a nearly square planar environment with a
dihedral angle of 168.7°, which contributes to the lower energy
of this transition state.
Stereochemistry of the Relay Process. As the final set of
analyses, we explored the stereochemical integrity of the relay
process. Determining whether the catalyst remains on the same
side of the alkyl chain throughout the relay process would lend
insight into the stereochemistry of the palladium−alkyl
intermediates following migratory insertion. By establishing
which hydrogens are eliminated during β-hydride elimina-
tion(s), the alkene isomers formed during chain-walking can be
determined. As reported in previous studies, (E)- and (Z)-
alkenes return enantiomeric products.1,2 The stereochemistry at
both alkene carbons is set by the catalyst during the migratory
insertion of the aryl group, as shown in intermediates 1-A
(Figure 4). Thus, we would expect the deuterium labels at the
Considering that the energy of the transition structure
connecting E and F could not be conclusively established,
homoallylic alcohol 4 and tris-homoallylic alcohol 5 were
submitted to standard conditions (Scheme 4) to differentiate
Scheme 4. Interrogation of the Product-Forming Step(s)
Figure 4. Comparison of the formation of cis- and trans-alkenes during
the relay process.
β-centers to exhibit high diastereomeric ratios (dr) if the first
migratory insertion was the only observed step in the reaction.
However, the stereochemistry of the relay sequence could affect
the observed dr. If the catalyst remains bound to the alkene in
complex 1-B, then the hydride will be inserted on the same face
of the alkene and the relay process will continue as outlined in
Figure 4, yielding product (Z)-7 with the designated stereo-
chemistry, regardless of the types of alkenes formed during the
process. In other words, the stereochemistry set by the initial
migratory insertion should be retained at the β-position, if a
Pd−H species does not dissociate, bind the alkene on the
opposite face, and insert the hydrogen from this face. Since we
previously did not detect a loss of deuterium incorporation
during the formation of Pd−D species, a dissociation/
association process by the catalyst is unlikely. Indeed, when
comparing the 1H NMR spectra of the products resulting from
the reaction of substrates (Z)-1 and (E)-1, it was noted that
distinct peaks are present for the protons at the β-position,
which supports the retention of alkene face selection by the
catalyst in intermediates 1-B. In order to confirm this
hypothesis, we set out to determine the relative stereochemistry
of the protons at the β-position.
the two possible pathways experimentally. In both cases,
incorporation of one deuterium at the α-position and retention
of one deuterium at the aldehyde are observed. The mechanism
that is most consistent with these data is a β-deuteride
elimination from the palladium alkyl intermediate C yielding
the palladium−deuteride complex D. Subsequent migratory
insertion of the deuteride and oxidative deprotonation from
complex E would give the observed products 13 and 14. If a
tautomerization mechanism occurred, incorporation of deute-
rium at the α-position would not be detected. Thus, the results
illustrate that the reaction proceeds through a palladium alkyl
intermediate analogous to complex E in order to lead to a
carbonyl product.
The computational results indicate that E is approximately 5
kcal/mol lower in energy than the preceding complex D.7 It is
also the lowest energy intermediate calculated along the
reaction coordinate. With no detectable deuterium incorpo-
ration beyond the α-carbon in products 13 and 14, palladium
chain-walking is likely irreversible as soon as this species is
reached. As previously mentioned, the relay process occurs in
one direction, toward the alcohol leading to the formation of
this low energy intermediate. Thus, reaching complex E can be
considered as a thermodynamic driver of this process.
The product of the redox relay Heck reaction was converted
to the tetralone derivative 15 through oxidation and Friedel−
Crafts acylation (Figure 5). The relative stereochemistry of
each distinct hydrogen in the six-membered ring of 15 can be
1
related to their respective peaks in the H NMR spectrum. To
confirm our assignment, a designated protocol, which included
a conformational analysis, geometry optimization of each
conformer, NMR shielding tensors calculations, and Boltzmann
weighting of these tensors, was followed to determine NMR
E
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diastereomers. If the catalyst eliminates Da from intermediate 6-
A, this leads to a trans-alkene and anti-orientation of the
deuterium labels (Figure 6). To eliminate Db, a bond rotation
must first take place, as previously discussed (Figure 4). A cis-
alkene forms, and palladium chain-walking yields a syn-
orientation of the deuterium labels. The steric repulsion
between the alcohol and the opposite end of the alkyl chain
is not sufficient to limit the bond rotation, as the observed
diastereomeric ratio is low. Consequently, cis- and trans-alkenes
form in nearly equal amounts from the initial β-hydride
elimination during the relay process in homoallylic alcohols. It
is possible that with a bulkier alkyl chain, the barrier to bond
rotation would become too large, limiting the formation of the
cis-alkene. Nevertheless, the catalyst remains on the same side
of the substrate throughout the relay process, as demonstrated
by the uniform stereochemistry at the β-position in products 20
and 21.
In summary, we have provided experimental and computa-
tional evidence elucidating the chain-walking and product-
forming steps of the redox-relay Heck reaction. The trans-
formation proceeds through iterative β-hydride elimination and
migratory insertion steps until arriving at a low energy
palladium−alkyl intermediate, as demonstrated by the series
of deuterium-labeling studies presented. Reaching this low
energy complex is proposed to be a driving force for directing
the catalyst toward the alcohol and toward the formation of
carbonyl products. During the relay sequence, the face selection
of the alkene by the catalyst remains consistent, indicating that
it remains bound to the substrate. Additionally, both (E)- and
(Z)-alkene isomers form during the relay process. Finally, the
product-forming step was shown to proceed from the migratory
insertion cascade by deprotonation of the low energy
intermediate rather than a deprotonation of the palladium
hydride species by DMF. Future studies look to take advantage
of these insights in the continued development of relay Heck
processes.
Figure 5. Determination of stereochemistry of deuterium labels.
shifts computationally (see the Supporting Information).13
Calculated NMR shifts and coupling constants agreed well with
experimental values. Products (Z)-7 and (E)-7 were also
transformed into tetralone derivatives 16 and 17 to allow the
analysis of their 1H NMR spectra and thus the determination of
the stereochemistry of the deuterium labels. The character-
ization of 16 and 17 demonstrates unequivocally that the
stereochemistry is conserved during the chain walking process
as outlined in Figures 4 and 5. This agrees with a deuterium
labeling study performed in a previous report,5 where the
stereochemical integrity of a substrate containing a preinstalled
chiral center was maintained during the relay process.
Additionally, this explains why the observed enantioselectivity
of the minor β-products are high and do not erode during the
relay sequence.
These findings confirm our hypothesis that the catalyst does
not dissociate and associate from the substrate during the relay
sequence. Interestingly, as palladium remains bound to one face
of the alkene, the stereochemistry of the β-center is not affected
by the type of alkenes formed after the first β-hydride
elimination in intermediates 1-B (Figure 4), yet the alkene
isomers formed during the relay process should affect the
diastereomeric ratio of the α-position.
EXPERIMENTAL SECTION
■
To interrogate the stereochemistry of the alkene isomer(s)
formed from the initial β-hydride elimination, substrate 6 was
subjected to the same reaction conditions and ultimately
converted into 20 and 21 (Figure 6). While the stereocenter at
the β-position is formed in high fidelity as predicted, the
stereocenter at the α-position is formed as a 1.3:1 mixture of
General Methods. Dry dimethylformamide (DMF) was stored
over activated 3 Å molecular sieves (3 Å MS). Powdered 3 Å MS were
activated by flowing N2 through a glass tube filled with sieves
maintained at 200 °C. Pd(CH3CN)2(OTs)2 and the pyrox ligand were
synthesized according to literature procedures.1,14 Spectra of the
deuterium-labeled substrates were compared to previously charac-
terized or commercially available substrates without deuterium labels.
Spectra of the resulting products were compared to previously
characterized products.1,2 1H NMR spectra were obtained at 300, 500,
or 800 MHz; chemical shifts are reported in ppm and referenced to the
CHCl3 singlet at 7.26 ppm. 13C NMR spectra were obtained at 125
MHz and referenced to the center peak of the CDCl3 triplet at 77.00
ppm. The abbreviations s, d, t, q, quin, sext, dd, dt, and m stand for the
resonance multiplicities singlet, doublet, triplet, quartet, quintet, sextet,
doublet of doublets, doublet of triplets, and multiplet, respectively.
Synthesis of Deuterium-Labeled Substrates. (Z)-Hex-3-en-
3,4-d2-1-ol ((Z)-1). To reduce 3-hexyn-1-ol (0.42 g, 4.3 mmol), a
previously reported procedure was employed using Ni(OAc)2, NaBD4,
D2 (balloon), D2O, and MeOD-d4.1 A clear oil was isolated after flash
1
chromatography in 48% yield (0.22 g): H NMR (CDCl3, 500 MHz)
δ = 3.63 (t, J = 6.5 Hz, 2 H), 2.32 (t, J = 6.5 Hz, 2 H), 2.03 (q, J = 7.5
Hz, 2 H), 1.51 (bs, 1 H), 0.97 (t, J = 7.5, 3 H) ppm.
(E)-Hex-3-en-3,4-d2-1-ol ((E)-1). To a dry 100 mL round-bottom
flask was added lithium aluminum deuteride (LAD) (0.54 g, 13.2
mmol, 2 equiv). The flask was fitted with a reflux condenser, and the
apparatus was purged with nitrogen. Dry THF (40 mL) was added,
and the flask was cooled in an ice bath. To this was added 3-hexyn-1-ol
(0.65 g, 6.6 mmol) dissolved in THF (10 mL). The reaction mixture
Figure 6. Stereochemical outcome resulting from the relay process and
mechanistic analysis.
F
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was allowed to reflux until full consumption of the alkyne, determined
by 1H NMR. The reaction was cooled in an ice bath and was quenched
with D2O (15 mL). The layers were separated, and the aqueous layer
was extracted with diethyl ether (2 × 15 mL). The combined organic
layers were washed with brine (3 × 15 mL), dried over magnesium
sulfate, and concentrated under reduced pressure. The deuterated
trans-alkene was isolated as a clear oil in 74% yield (0.50 g): 1H NMR
(CDCl3, 500 MHz) δ = 3.62 (t, J = 7.5, 2 H), 2.26 (t, J = 6.5 Hz, 2 H),
2.03 (q, J = 7.5 Hz, 2 H), 1.41 (bs, 1 H), 0.98 (t, J = 7.5, 3 H) ppm.
tert-Butyldimethyl(pent-3-yn-5-d3-1-yloxy)silane. To a dry 250
mL round-bottom flask were added (but-3-yn-1-yloxy)(tert-butyl)-
dimethylsilane (6.36 g, 35.0 mmol) and THF (100 mL). The solution
was cooled in a dry ice bath to −78 °C. To this was added n-BuLi
(16.6 mL, 38.0 mmol, 1.2 equiv), and the reaction was allowed to stir
for 2 h. Iodomethane-d3 (5.00 g, 34.5 mmol) in THF (10 mL) was
added to the mixture, which was stirred overnight with warming to
room temperature. The reaction was quenched with water (10 mL).
The layers were separated, and the aqueous layer was extracted with
diethyl ether (3 × 10 mL). The combined organic layers were washed
with brine (3 × 10 mL), dried over magnesium sulfate, and
concentrated under reduced pressure. The product was purified
using flash chromatography and recovered in a 79% yield (5.54 g) as a
was quenched with D2O (1 mL). Then aqueous ammonium chloride
(15 mL) and diethyl ether (15 mL) were added. The layers were
separated, and the aqueous layer was extracted with ether (2 × 15
mL). The combined organic layers were washed with aqueous
ammonium chloride (3 × 10 mL), dried over magnesium sulfate, and
concentrated under reduced pressure. To reduce the deuterated ester
(0.21 g, 1.4 mmol) to the alcohol, LiAlH4 (0.10 g, 2.7 mmol, 2 equiv)
was added to a dry 50 mL round-bottom flask, which was subsequently
purged with nitrogen. To this, placed in an ice bath, was added THF
(10 mL). The deuterated ester was dissolved in THF (5 mL) and
added to the flask. The reaction mixture was allowed to stir overnight
with warming to room temperature. The reaction was cooled in an ice
bath and quenched slowly with water (2 mL) and then 20 wt %
aqueous KOH (20 mL). This was allowed to stir for 1 h. The layers
were separated in a separatory funnel, and the aqueous layer was
extracted with ether (3 × 10 mL). The combined organic layers were
washed with brine (3 × 10 mL), dried over magnesium sulfate, and
concentrated under reduced pressure. A colorless oil was isolated after
purification using flash chromatography, eluting with a 10% ethyl
acetate in hexanes: yield over two steps 24% (0.10 g); 1H NMR
(CDCl3, 500 MHz) δ = 5.40−5.29 (m, 2H), 3.64 (s, 2H), 2.08−2.00
(m, 4H), 1.40 (t, J = 7.5 Hz, 2H), 0.95 (t, J = 7.5 Hz, 3H) ppm.
Methyl (Z)-Hex-3-enoate. The carboxylic acid, (Z)-3-hexenoic acid,
was prepared according to a previously reported procedure from (Z)-
1
clear oil: H NMR (CDCl3, 300 MHz) δ = 3.70 (t, J = 7.5 Hz, 2H),
2.35 (t, J = 7.5 Hz, 2H), 0.91 (s, 9 H), 0.08 (s, 6 H) ppm.
1
(Z)-Pent-3-en-5-d3-1-ol (2). The protected alcohol, tert-
butyldimethyl(pent-3-yn-5-d3-1-yloxy)silane (5.54 g, 27.4 mmol),
was deprotected using 1 M tetra-n-butylammonium fluoride (TBAF)
(14.3 mL, 54.8 mmol, 2 equiv) in THF (50 mL). The reaction was
allowed to stir overnight and was quenched with water (15 mL). The
layers were separated, and the aqueous layer was extracted with diethyl
ether (3 × 10 mL). The combined organic layers were washed with
brine (3 × 10 mL), dried over magnesium sulfate, and concentrated
under reduced pressure. The alcohol was carried on without
purification. To reduce the alkyne (2.0 g, 23 mmol) to the alkene, a
hex-3-en-1-ol (3.0 g, 30 mmol), and its purity was confirmed by H
NMR.16 The ester was prepared in the same manner as described for
methyl (Z)-oct-5-enoate and was purified using flash chromatography
eluting with a gradient of 5−20% ethyl acetate to hexanes to give a
clear oil in a 37% yield over two steps (1.1 g): Rf = 0.72 (80:20
1
hexanes/ethyl acetate); H NMR (CDCl3, 300 MHz) 5.62−5.46 (m,
2H), 3.68 (s, 3H), 3.09 (d, J = 6.3 Hz, 2H), 2.05 (p, J = 7.5 Hz, 2H),
0.97 (t, J = 7.5 Hz, 3H) ppm; 13C{1H} NMR (CDCl3, 125 MHz) δ =
172.6, 135.3, 120.3, 52.0, 32.9, 20.9, 14.1 ppm; IR (neat) 3025, 2964,
2876, 1738, 1436, 1402, 1330, 1305, 1255, 1162, 1114, 1070, 1018,
982, 933, 893, 870, 844, 692 cm−1; HRMS (ESI-TOF) m/z [M + Na]+
calcd for C9H13O2Na 129.0916, found 129.0925.
·
previously reported procedure was used, employing Ni(OAc)2 4H2O
(1.4 g, 5.7 mmol, 25 mol %), NaBH4 (0.22 g, 5.7 mmol, 25 mol %),
and H2 (balloon).1 A clear oil was isolated after purification using flash
chromatography, eluting with a gradient of 10−30% ethyl acetate in
(Z)-Hex-3-en-1,1-d2-1-ol (4). To an oven-dried 50 mL round-
bottom flask was added LAD (0.27 g, 6.4 mmol, 2 equiv), which was
subsequently purged with nitrogen. The flask was placed in an ice bath,
and THF (10 mL) was added. Methyl (Z)-hex-3-enoate (0.50 g, 3.2
mmol) was dissolved in THF (10 mL) and added to the reaction flask.
The mixture was stirred for 18 h. The reaction was cooled in an ice
bath and quenched slowly with water (2 mL) and then 20 wt %
aqueous KOH (20 mL). This was allowed to stir for 1 h. The layers
were separated in a separatory funnel, and the aqueous layer was
extracted with ether (3 × 10 mL). The combined organic layers were
washed with brine (3 × 10 mL), dried over magnesium sulfate, and
concentrated under reduced pressure. The crude mixture was purified
using flash chromatography eluting with a gradient of 5−20% ethyl
acetate in hexanes to give a clear oil in a 39% yield (0.16 g): 1H NMR
(CDCl3, 300 MHz) δ = 5.58−5.52 (m, 1H), 5.35−5.30 (m, 1H), 2.31
(d, J = 7.5 Hz, 2H), 2.08 (quin, J = 7.5 Hz, 2H), 1.52 (s, 1H), 0.97 (t, J
= 7.5 Hz, 3H) ppm.
1
hexanes: yield over two steps 21% (0.52 g); H NMR (CDCl3, 300
MHz) δ = 5.65 (d, J = 6.3 Hz, 1 H), 5.42−5.37 (m, 1 H), 3.67 (t, J =
6.0 Hz, 2H), 2.33 (q, J = 6.5 Hz, 2H) ppm.
Methyl (Z)-Oct-5-enoate. (Z)-5-Octenoic acid was prepared
according to a previously reported procedure from (Z)-oct-5-en-1-ol
(5.0 g, 39 mmol), and its purity was confirmed by 1H NMR.15,16 In an
ice bath, nitrosomethylurea (3.2 g, 30 mmol, 3 equiv) was dissolved in
ether (10 mL) and aqueous 20 wt % KOH (10 mL). The organic
phase turned bright yellow upon formation of diazomethane. To a
different flask were added (Z)-5-octenoic acid (1.9 g, 13 mmol) and
ether (10 mL). The organic phase containing diazomethane was
transferred dropwise by pipet to the carboxylic acid solution, and the
evolution of nitrogen gas was observed. The diazomethane solution
was added until the solution remained bright yellow. Excess
diazomethane in both solutions was quenched slowly with glacial
acetic acid (<1 mL each). The reaction mixture was dried over
magnesium sulfate, concentrated under reduced pressure, and purified
using flash chromatography. A clear oil was isolated in 38% yield over
(Z)-Oct-5-en-1,1-d2-1-ol (5). The alcohol was prepared in the same
manner as described for (Z)-hex-3-en-1,1-d2-1-ol from the correspond-
ing ester, methyl (Z)-oct-5-enoate (0.5 g, 3.2 mmol). A clear oil was
isolated in 62% yield (0.26 g) after purification using flash
1
two steps (2.0 g): Rf = 0.69 (80:20 hexanes/ethyl acetate); H NMR
1
(CDCl3, 300 MHz) δ = 5.45−5.24 (m, 2H), 3.66 (s, 3H), 2.31 (t, J =
7.5 Hz, 2H), 2.08−1.98 (m, 4H), 1.71−1.65 (m, 2H), 0.94 (t, J = 7.7
Hz, 3H) ppm; 13C{1H} NMR (CDCl3, 125 MHz) δ = 174.3, 132.9,
128.0, 51.6, 33.6, 26.6, 25.1, 20.7, 14.5 ppm; IR (neat) 3005, 2961,
2874, 1737, 1436, 1365, 1206, 1161, 1115, 1050, 953, 885, 864, 797,
702 cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C9H17O2Na
157.1229, found 157.1232.
(Z)-Oct-5-en-2,2-d2-1-ol (3). To an oven-dried 50 mL round-
bottom flask equipped with a stir bar was added methyl (Z)-oct-5-
enoate (0.50 g, 3.2 mmol). To this was added a 1 M solution of
NaOMe in MeOH-d4 (6.4 mL, 6.4 mmol, 2 equiv), which was
prepared from sodium and MeOH-d4. The reaction was allowed to stir
at room temperature under nitrogen for 18 h. The reaction mixture
chromatography: H NMR (CDCl3, 500 MHz) δ = 5.40−5.29 (m,
2H), 2.08−2.00 (m, 4H), 1.58−1.55 (m, 2H), 1.44−1.38 (m, 2H),
1.33 (br s, 1H), 0.95 (t, J = 7.7 Hz, 3H) ppm.
((2-Iodoethoxy-2,2-d2)methanetriyl)tribenzene. Methyl glycolate
(1.4 mL, 18 mmol) was protected with trityl chloride (5.2 g, 18 mmol)
using a previously reported procedure to yield the protected alcohol.17
The ester (4.0 g, 12 mmol) was reduced with LAD (0.75 g, 18 mmol)
in a procedure as described above for the reduction of methyl (Z)-hex-
3-enoate and methyl (Z)-oct-5-enoate. The free alcohol (3.4 g, 11
mmol) was converted to the corresponding alkyl iodide, according to a
previously reported procedure.18 A white solid was recovered: ield
over three steps 53% (4.0 g); mp 128−131 °C; Rf = 0.78 (90:10
hexanes/ethyl acetate); 1H NMR (CDCl3, 500 MHz) δ = 7.62 (d, J =
G
dx.doi.org/10.1021/jo501813d | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
13.0 Hz, 6 H), 7.45−7.32 (m, 9 H), 3.52 (s, 2H) ppm; 13C{1H} NMR
(CDCl3, 125 MHz) δ = 144.2, 129.0, 128.2, 127.5, 87.3, 64.5 ppm; IR
(neat) 2973, 2859, 1490, 1448, 1065, 1032, 1002, 983, 902, 759, 747,
699, 668, 646, 633, 605 cm−1; HRMS (ESI-TOF) m/z [M + Na]+
calcd for C21H17D2ONaI 439.0519, found 439.0519.
(Z)-7-OMe. A colorless oil was recovered after flash chromatog-
raphy: yield 72% (84 mg). 1H NMR (500 MHz, CDCl3) δ = 9.64 (t, J
= 1.5 Hz, 1 H), 7.03 (d, J = 8.5 Hz, 2H), 6.87 (d, J = 8.5 Hz, 2 H), 3.79
(s, 3 H), 2.31−2.21 (m, 2 H), 1.98 (t, J = 8.0 Hz, 1 H), 1.70−1.51 (m,
2 H), 0.77 (t, J = 7.5 Hz, 3 H) ppm; MS (low res) 208.2.
Hept-3-yn-2,2-d2-1-ol. Pent-1-yne (1.7 mL, 17 mmol, 3.0 equiv)
was dissolved in THF (50 mL) and cooled to 0 °C. To this was added
n-BuLi (8.5 mmol, 3.5 equiv), and the mixture was allowed to stir for 2
h. To this was added ((2-iodoethoxy-2,2-d2)methanetriyl)tribenzene
(2.3 g, 5.6 mmol) dissolved in THF (10 mL) and hexamethylphos-
phoramide (2.9 mL, 17 mmol, 3.0 equiv). The reaction mixture was
allowed to stir overnight and was quenched with water (10 mL). The
layers were separated, and the aqueous layer was extracted with diethyl
ether (3 × 10 mL). The combined organic layers were washed with
brine (3 × 15 mL), dried over magnesium sulfate, and concentrated
under reduced pressure. The resulting solid was dissolved in 2:1
DCM/MeOH (20 mL). To this was added p-toluenesulfonic acid (1
equiv), and the reaction was allowed to stir overnight. The mixture was
quenched with water (10 mL), the layers were separated, and the
aqueous layer was extracted with dichloromethane (3 × 10 mL). The
combined organic layers were washed with brine (3 × 15 mL), dried
over magnesium sulfate, and concentrated under reduced pressure.
The free alcohol was purified using flash chromatography to give a
colorless oil: yield over two steps 31% (0.20 g); 1H NMR (CDCl3, 500
MHz) 3.67 (s, 2H), 2.14 (t, J = 7.0 Hz, 2 H), 1.76 (bs, 1 H), 1.51
(sext, J = 7.5 Hz, 2 H), 0.97 (t, J = 7.0 Hz, 3 H) ppm.
(Z)-8-OMe. A colorless oil was recovered after flash chromatog-
raphy: 1H NMR (500 MHz, CDCl3) δ = 9.65 (t, J = 1.5 Hz, 1 H), 7.10
(d, J = 8.5 Hz, 2H), 6.87 (d, J = 8.5 Hz, 2 H), 3.78 (s, 3 H), 3.13 (q, J
= 7.0 Hz, 1H), 2.67 (dd, J = 2.0, 7.0 Hz, 2H), 1.22−1.12 (m, 2 H),
0.85 (t, J = 7.5 Hz, 3 H) ppm; MS (low res) 208.2.
(E)-7-OMe. A colorless oil was recovered after flash chromatog-
raphy: yield 87% (102 mg); 1H NMR (500 MHz, CDCl3) δ = 9.64 (t,
J = 1.5 Hz, 1 H), 7.03 (d, J = 8.5 Hz, 2 H), 6.84 (d, J = 8.5 Hz, 2 H),
3.77 (s, 3 H), 2.30−2.20 (m, 2 H), 1.73 (t, J = 7.0 Hz, 1 H), 1.69−1.51
(m, 2 H), 0.77 (t, J = 7.5 Hz, 3 H) ppm; MS (low res) 208.2.
(E)-8-OMe. A colorless oil was recovered after flash chromatog-
raphy: 1H NMR (500 MHz, CDCl3) δ = 9.64 (t, J = 1.5 Hz, 1 H), 7.09
(d, J = 8.5 Hz, 2 H), 6.84 (d, J = 8.5 Hz, 2 H), 3.78 (s, 3 H), 3.12 (t, J
= 7.5 Hz, 1H), 2.66 (dd, J = 2.0, 7.2 Hz, 2H), 1.21−1.13 (m, 2 H),
0.85 (t, J = 7.0 Hz, 3 H) ppm; MS (low res) 208.2.
9-CO2Me. A colorless oil was recovered after flash chromatography:
1
yield 62% (64 mg); H NMR (500 MHz, CDCl3) δ = 9.68 (t, J = 1.5
Hz, 1 H), 7.97 (d, J = 8.5 Hz, 2 H), 7.24 (d, J = 8.0 Hz, 2 H), 3.90 (s, 3
H), 2.80−2.74 (m, 1 H), 2.38−2.18 (m, 2 H), 1.99−1.84 (m, 2H)
ppm; MS (low res) 223.1.
9-OMe. A colorless oil was recovered after flash chromatography:
1
(Z)-Hept-3-en-2,2-d2-1-ol (6). Hept-3-yn-2,2-d2-1-ol (0.20 g, 1.7
mmol) was reduced according to a previously reported procedure
using Ni(OAc)2·4H2O, NaBH4, and H2 to yield a clear oil:1 yield 70%
(0.14 g); 1H NMR (CDCl3, 500 MHz) 5.59−5.54 (m, 1H), 5.37 (d, J
= 10.5 Hz, 1 H), 3.63 (s, 2 H), 2.05 (q, J = 7.5 Hz, 2 H), 1.38 (sext, J =
7.5 Hz, 2 H), 0.91 (t, J = 7.5 Hz, 3 H) ppm.
yield 72% (75 mg); H NMR (500 MHz, CDCl3) δ = 9.65 (t, J = 2.0
Hz, 1 H), 7.08 (d, J = 9.0 Hz, 2 H), 6.84 (d, J = 8.5 Hz, 2 H), 3.78 (s, 3
H), 2.67−2.64 (m, 1 H), 2.36−2.24 (m, 1H), 1.95−1.78 (m, 1 H)
ppm; MS (low res) 195.1.
10/11-OMe. A colorless oil was recovered after flash chromatog-
raphy: 1H NMR (500 MHz, CDCl3) δ = 9.67 (t, J = 2.0 Hz, 1 H), 7.09
(d, J = 8.5 Hz, 2 H), 6.84 (d, J = 8.5 Hz, 2 H), 3.78 (s, 3 H), 3.06−3.00
(m, 1 H), 2.67 (dd, J = 2.0, 7.5 Hz, 2 H), 1.68−1.64 (m, 1H), 1.59−
1.54 (m, 1 H) ppm; MS (low res) 195.1.
12. A colorless oil was recovered after flash chromatography: yield
54% (71 mg); 1H NMR (500 MHz, CDCl3) δ = 9.71 (t, J = 1.5 Hz, 1
H), 7.96 (d, J = 8.0 Hz, 2 H), 7.19 (d, J = 8.0 Hz, 2 H), 3.90 (s, 3 H),
2.50−2.44 (m, 1 H), 2.34 (d, J = 7.5 Hz, 2 H), 1.73−1.65 (m, 2 H),
1.61−1.49 (m, 3 H), 1.23−1.06 (m, 2 H), 0.75 (t, J = 7.5 Hz, 3 H)
ppm; MS (low res) 263.1.
General Procedure for Oxidative Heck Reactions. To a dry 10
mL round-bottom flask equipped with a stir bar was added
Pd(CH3CN)2(OTs)2 (15.9 mg, 0.0300 mmol, 6.00 mol %), Cu(OTf)2
(10.9 mg, 0.0300 mmol, 6.00 mol %), ligand (17.7 mg, 0.0650 mmol),
and DMF (3 mL). The resulting mixture was stirred for 10 min. To
this was added a DMF solution (2 mL) of the alkenyl alcohol (0.500
mmol). To a dry 10 mL round-bottom flask equipped with a stir bar
was added the corresponding boronic acid (1.50 mmol, 3 equiv) and 3
Å MS (75.0 mg, 150 mg/mmol), which was subsequently purged with
oxygen. The palladium and substrate mixture was added to the flask
containing the boronic acid and was stirred at room temperature for
18 h. The mixture was diluted with diethyl ether (20 mL) and water
(10 mL). The aqueous layer was extracted with diethyl ether (2 × 15
mL). The combined organic layers were washed with brine (3 × 15
mL), dried over magnesium sulfate, and concentrated under reduced
pressure. The crude mixture was purified using flash chromatography.
The isolated aldehydes were reduced to alcohols with NaBH4 (2
equiv) in MeOH for greater stability. Spectra of the aldehydes and
alcohols were compared to previously characterized products without
deuterium labels.2 Labeling experiments were repeated at least two
times. Isolated yields are reported with the major product as a mixture
of regioisomers.
(Z)-7-CO2Me. A colorless oil was recovered after flash chromatog-
raphy: yield 68% (79 mg); 1H NMR (300 MHz, CDCl3) δ = 9.66 (t, J
= 1.5 Hz, 1 H), 7.97 (d, J = 8.1 Hz, 2 H), 7.19 (d, J = 8.1 Hz, 2 H),
3.90 (s, 3 H), 2.34−2.14 (m, 2 H), 2.03 (t, J = 7.8 Hz, 1 H), 1.78−1.54
(m, 2 H), 0.77 (t, J = 7.5 Hz, 3 H) ppm; MS (low res) 236.1.
(E)-7-CO2Me. A colorless oil was recovered after flash chromatog-
raphy: yield 42% (49 mg); 1H NMR (500 MHz, CDCl3) δ = 9.66 (t, J
= 1.5 Hz, 1 H), 7.97 (d, J = 8.5 Hz, 2 H), 7.19 (d, J = 8.5 Hz, 2 H),
3.90 (s, 3 H), 2.31−2.20 (m, 2 H), 1.80 (t, J = 7.0 Hz, 1 H), 1.75−1.56
(m, 2 H), 0.77 (t, J = 7.5 Hz, 3 H) ppm; MS (low res) 236.2.
(E)-8-CO2Me. A colorless oil was recovered after flash chromatog-
raphy: 1H NMR (500 MHz, CDCl3) δ = 9.66 (t, J = 1.5 Hz, 1 H), 7.97
(d, J = 8.5 Hz, 2 H), 7.26 (d, J = 8.0 Hz, 2 H), 3.90 (s, 3 H), 3.24 (t, J
= 7.0, 1 H), 2.73 (dd, J = 2.0, 7.2 Hz, 2 H), 1.18−1.05 (m, 2H), 0.82
(t, J = 7.5 Hz, 3 H) ppm; MS (low res) 236.2.
13. A colorless oil was recovered after flash chromatography: yield
1
31% (32 mg); H NMR (500 MHz, CDCl3) δ = 7.95 (d, J = 8.0 Hz,
2H), 7.18 (d, J = 8.0 Hz, 2 H), 3.88 (s, 3 H), 2.52−2.46 (m, 1H),
2.30−2.18 (m, 1 H), 2.07−2.00 (m, 1 H), 1.85−1.77 (m, 1 H), 1.75−
1.66 (m, 1 H), 1.63−1.54 (m, 1 H), 0.75 (t, J = 7.5 Hz, 3 H) ppm; MS
(low res) 236.2.
13-OH. A colorless oil was recovered after flash chromatography:
yield 86% (28 mg); 1H NMR (500 MHz, CDCl3) δ = 7.94 (d, J = 8.0
Hz, 2H), 7.20 (d, J = 8.0 Hz, 2 H), 3.88 (s, 3 H), 3.52 (d, J = 6.5 Hz, 1
H), 2.51−2.45 (m, 1H), 1.77−1.66 (m, 2 H), 1.62−1.53 (m, 2 H),
1.42−1.37 (m, 1 H), 0.74 (t, J = 7.5 Hz, 3 H) ppm.
14. A colorless oil was recovered after flash chromatography: yield
26% (34 mg); 1H NMR (500 MHz, CDCl3) δ =9.67 (t, J = 1.5 Hz, 1
H), 7.95 (d, J = 8.5 Hz, 2H), 7.19 (d, J = 8.0 Hz, 2 H), 3.90 (s, 3 H),
3.55 (d, J = 6.0 Hz, 1H), 2.50−2.44 (m, 1 H), 1.73−1.63 (m, 2H),
1.61−1.50 (m, 2H), 1.47−1.43 (m, 1H), 1.36−1.05 (m, 4H), 0.75 (t, J
= 7.5 Hz, 3 H) ppm. MS (low res): 263.1.
14-OH. A colorless oil was recovered after flash chromatography:
yield 82% (28 mg); 1H NMR (500 MHz, CDCl3) δ = 7.96 (d, J = 8.5
Hz, 2H), 7.20 (d, J = 8.0 Hz, 2 H), 3.90 (s, 3 H), 3.55 (d, J = 6.0 Hz,
1H), 2.50−2.44 (m, 1 H), 1.73−1.63 (m, 2H), 1.61−1.50 (m, 2H),
1.47−1.43 (m, 1H), 1.36−1.05 (m, 4H), 0.75 (t, J = 7.5 Hz, 3 H) ppm.
18/19. A colorless oil was recovered after flash chromatography:
1
yield 42% (26 mg); H NMR (300 MHz, CDCl3) δ = 9.64 (t, J = 2.0
Hz, 1 H), 7.95 (d, J = 8.0 Hz, 2 H), 7.18 (d, J = 8.0 Hz, 2 H), 3.88 (s, 3
H), 2.63−2.54 (m, 1 H), 2.26−2.18 (m, 1 H), 1.81−1.76 (m, 1 H),
1.67−1.50 (m, 2 H), 1.21−1.03 (m, 2 H), 0.82 (t, J = 7.2 Hz, 3 H)
ppm; MS (low res) 250.2.
H
dx.doi.org/10.1021/jo501813d | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
(18/19-OH). A colorless oil was recovered after flash chromatog-
raphy: yield 30% (3.6 mg); 1H NMR (300 MHz, CDCl3) δ = 7.96 (d, J
= 8.0 Hz, 2 H), 7.21 (d, J = 8.0 Hz, 2 H), 3.90 (s, 3 H), 3.56 (d, J = 6.5
Hz, 2 H), 2.62−2.56 (m, 1 H), 1.67−1.48 (m, 2 H), 1.46−1.38 (m, 1
H), 1.35−1.28 (m, 1 H), 1.22−1.08 (m, 2 H), 0.84 (t, J = 7.2 Hz, 3 H)
ppm. 13C{1H} NMR (500 MHz, CDCl3) δ = 167.4, 151.7, 129.9,
127.9, 126.0, 63.1, 52.2, 45.9, 39.2, 32.5 (t, J = 76.5 Hz), 30.5 (t, J =
76.0 Hz), 29.9, 20.8, 14.3 ppm; IR (neat) 3421, 2955, 2925, 2872,
1721, 1653, 1610, 1559, 1507, 1457, 1436, 1418, 1378, 1180, 1112,
1049, 967, 857, 774, 709, 668 cm−1; HRMS (ESI-TOF) m/z [M +
Na]+ calcd for C15H2D2O3Na 275.1592, found 275.1598.
General Procedure for Cyclization of Isolated Heck
Products. Aldehyde product was oxidized to the corresponding
carboxylic acid by stirring with oxone (2 equiv) in DMF (3 mL) for 18
h. The reaction mixture was quenched with 1 M HCl (10 mL) and
ether (10 mL).The layers were separated, and the aqueous layer was
extracted with ether (3 × 10 mL). The combined organic layers were
washed with 1 M HCl (1 × 10 mL) and brine (2 × 10 mL), dried over
magnesium sulfate, and concentrated under reduced pressure. The
isolated acid was dissolved in dichloromethane (10 mL) and cooled in
an ice bath. Oxalyl chloride (2 equiv) was added, and the reaction was
stirred at 0 °C for 3 h. The reaction was diluted with dichloromethane
(40 mL), and aluminum chloride (2 equiv) was added. The reaction
mixture stirred overnight and was quenched with water (20 mL). The
layers were separated, and the aqueous layer was extracted with
dichloromethane (3 × 10 mL). The combined organic layers were
washed with brine (3 × 10 mL), dried over magnesium sulfate, and
concentrated under reduced pressure. The crude mixture was purified
using flash chromatography.
calculations using the SDD basis set for Pd and the 6-311++G(d, p)
basis set for all other atoms and the SMD solvent model with the
parameters for DMF were used to account for solvent effects. The final
free energies from the single-point calculations with solvent and
thermal corrections are reported in kcal/mol at standard conditions.
Kinetic isotope effects were estimated from the M06/LAN2DZ/6-
31+G(d) free energies and corrected for hydrogen tunneling using the
one-dimensional approximation proposed by Bell.22 Figures of the key
transition structures were prepared using CYLView.23
ASSOCIATED CONTENT
■
S
* Supporting Information
Supplementary figures, determination of relative stereochemis-
try, NMR spectra, and optimized Cartesian coordinates and
energies. This material is available free of charge via the
Internet at http://pubs.acs.org.p://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: sigman@chem.utah.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Institutes of Health
(NIGMS RO1 GM063540), the National Science Foundation
of China (21133002, 21232001), the MOST of China
(2013CB911501), the Shenzhen Peacock Program
(KQTD201103), and NSF CHE 1058075. L.-P.X. acknowl-
edges support from the Graduate School of Peking University
for international exchange.
15. A colorless oil was recovered after flash chromatography: yield
1
over two steps 46% (0.27 g); Rf (80:20 EtOAc/hexanes) = 0.53; H
NMR (500 MHz, CDCl3) δ = 8.65 (d, J = 2.0 Hz, 1 H), 8.14 (dd, J =
8.2, 2.0 Hz, 1 H), 7.37 (d, J = 8.0 Hz, 1 H), 3.91 (s, 3 H), 2.90−2.87
(m, 1 H), 2.79−2.75 (m, 1 H), 2.60 (dt, J = 17.5, 5.0 Hz, 1 H), 2.26−
2.22 (m, 1 H), 2.09 (dq, J = 13.8, 5.0 Hz, 1 H), 1.80−1.70 (m, 2 H),
1.02 (t, J = 7.5 Hz, 3 H) ppm; 13C{1H} NMR (125 MHz, CDCl3) δ =
197.7, 166.6, 153.1, 134.0, 132.2, 129.1, 128.9, 52.4, 40.0, 35.0, 27.5,
26.2, 12.3 ppm; IR (neat) 3853, 3838, 3744, 3735, 3711, 3689, 3676,
3649, 3629, 2955, 2875, 1720, 1687, 1653, 1636, 1609, 1559, 1540,
1521, 1489, 1457, 1436, 1418, 1303, 1243, 1190, 1111, 975, 918, 859,
763, 668, 651 cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C14H16O3Na 255.0997, found 255.1003.
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16. A colorless oil was recovered after flash chromatography: yield
over two steps 49% (0.11 g); H NMR (500 MHz, CDCl3) δ = 8.67
(d, J = 2.0 Hz, 1 H), 8.15 (dd, J = 8.0, 2.0 Hz, 1 H), 7.38 (d, J = 8.0
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1
17. A colorless oil was recovered after flash chromatography: yield
1
over two steps 32% (0.10 g); H NMR (500 MHz, CDCl3) δ = 8.65
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20/21. A colorless oil was recovered after flash chromatography:
yield over two steps 67% (0.14 g); Rf (80:20 hexanes/ethyl acetate) =
0.39; 1H NMR (500 MHz, CDCl3) δ = 8.67 (s, 1 H), 8.14 (d, J = 8.0,
1 H), 7.36 (d, J = 8.0 Hz, 1 H), 3.92 (s, 3 H), 3.00−2.96 (m, 1 H),
2.78 (dd, J = 4.5, 18 Hz, 0.55 H), 2.60 (dd, J = 5.5, 18 Hz, 0.72 H),
2.07−2.02 (m, 1H), 1.68 (q, J = 8.0 Hz, 2 H), 1.53−1.33 (m, 2 H),
0.97 (t, J = 7. Hz, 3 H) ppm; 13C{1H} NMR (125 MHz, CDCl3) δ =
197.8, 166.6, 153.5, 134.0, 132.1, 130.4, 129.1, 127.5, 52.5, 38.1, 36.9,
34.5 (q, J = 78.5 Hz), 26.1 (m), 20.9, 14.3 ppm; IR (neat) 2955, 2931,
2872, 1720, 1686, 1608, 1457, 1435, 1415, 1300, 1228, 1104, 962, 930,
852, 767, 668, 540 cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C15H16D2O3Na 271.1279, found 271.1281.
Computational Details. The M06 functional19 implemented in
Gaussian09.C0120 is used in unconstrained geometry optimization and
frequency calculation. The LANL2DZ+f21 and 6-31+G(d) basis sets
were used for Pd and all other atoms, respectively. Single-point
I
dx.doi.org/10.1021/jo501813d | J. Org. Chem. XXXX, XXX, XXX−XXX

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