Relative reactivity of alkenyl alcohols in the palladium-catalyzed redox-relay Heck reaction

Article abstract of DOI:10.1016/j.tet.2015.05.020

Abstract The relative rates of alkenyl alcohols in the Pd-catalyzed redox-relay Heck reaction were measured in order to examine the effect of their steric and electronic properties on the rate-determining step. Competition experiments between an allylic a

Full text of DOI:10.1016/j.tet.2015.05.020

Tetrahedron xxx (2015) 1e6
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Relative reactivity of alkenyl alcohols in the palladium-catalyzed
redox-relay Heck reaction
,
,
,e
Margaret J. Hilton a, Bin Cheng a b, Benjamin R. Buckley a c, Liping Xu d, Olaf Wiest d
,
,
Matthew S. Sigman a
*
a Department of Chemistry, University of Utah, 315 S. 1400 East, Salt Lake City, UT 84112, United States
b The State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China
c Department of Chemistry, Loughborough University, Loughborough, Leicestershire LE11 3TU, UK
d Lab of Computational Chemistry and Drug Design, Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen 518055,
China
e Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556-5670, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The relative rates of alkenyl alcohols in the Pd-catalyzed redox-relay Heck reaction were measured in
order to examine the effect of their steric and electronic properties on the rate-determining step.
Competition experiments between an allylic alkenyl alcohol and two substrates with differing chain
lengths revealed that the allylic alcohol reacts 3e4 times faster in either case. Competition between di-
and trisubstituted alkenyl alcohols provided an interesting scenario, in which the disubstituted alkene
was consumed first followed by reaction of the trisubstituted alkene. Consistent with this observation,
the transition structures for the migratory insertion of the aryl group into the di- and trisubstituted
alkenes were calculated with a lower barrier for the former. An internal competition between a substrate
containing two alcohols with differing chain lengths demonstrated the catalyst’s preference for mi-
grating toward the closest alcohol. Additionally, it was observed that increasing the electron-density in
Received 19 March 2015
Received in revised form 5 May 2015
Accepted 6 May 2015
Available online xxx
Keywords:
Redox-relay
Heck reaction
Relative rates of alkenes
Competition experiments
the arene boronic acid promotes a faster reaction, which correlates with Hammett sp values to give a
ꢀ0.87.
r of
Ó 2015 Elsevier Ltd. All rights reserved.
1. Introduction
In recent years, we have reported1e3 a redox-relay strategy4e7 in
the context of a Heck reaction8 with alkenyl alcohols, wherein an
enantioselective arylation occurs and the alkene unsaturation is
relayed to the chain-terminating alcohol (Fig. 1).9,10 Both tertiary1,2
and quaternary centers3 may be established in high enantiose-
lectivity while a new functional group, a ketone or aldehyde, is
concomitantly formed during the process at various distances from
the original alkene.
Due to this reaction’s robust ability to impart high enantiose-
lectivity with a diverse set of alkenes and its interesting trends in
site selectivity, it has been the focus of a number of mechanistic
studies,11e13 which support a rate-determining arylation step fol-
lowed by successive b-hydride elimination and migratory insertion
steps until the carbonyl product is released (Fig. 1). Computational
analysis12,13 of the reaction coordinate reveals a relatively flat
* Corresponding author. E-mail address: sigman@chem.utah.edu (M.S. Sigman).
Fig. 1. Enantioselective redox-relay Heck arylation.
http://dx.doi.org/10.1016/j.tet.2015.05.020
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.
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2
M.J. Hilton et al. / Tetrahedron xxx (2015) 1e6
energy surface after the initial migratory insertion of the aryl group,
which is the site and enantioselectivity-determining step. Enan-
tioselectivity is controlled by repulsion between the alkenol and
selectivity ratios were related to Hammett sp values with a r of
1.42,2 suggesting a greater electronic influence on site selection
than the rate of the reaction.
the t-Bu group on the oxazoline of Ligand and by a stabilizing CeH
p
An interesting feature of this reaction is that similar enantio-
selectivity but different site selectivity is observed as a function of
the distance between the alkene and the alcohol. This raises the
question of the relative reactivity of different alkenes. Un-
derstanding these differences may allow for strategic reaction de-
signs, wherein two unique alkenes undergo selective
functionalizations. Therefore, the effect of chain length on the re-
action rate was examined through competition experiments. As
allylic and homoallylic alcohols have been the main focus of pre-
vious reports including scope and computational analysis, we ini-
tially evaluated the relative rates of 1 and 2 (Fig. 3a). In this
experiment, the allylic alcohol reacts 4.4 times faster than the
homoallylic alcohol. Independent rate measurements of 1 show
that the overall rate is retarded by w5 times in the presence of 2
(Fig. S2). These results suggest that reversible binding of the alkene
interaction between the aryl group and the pyridyl ring. The elec-
tronic and steric nature of the arene and the alkene do not have
a notable effect on enantioselectivity, yet significantly affect the site
selection, as was described using Hammett
s
values,2 IR vibra-
tions,14 and NBO charges.12 We hypothesize that polarization dur-
ing the migratory insertion transition state, leading to subtle
electronic differences in the alkene carbons, controls the site se-
lectivity. Consequently, site selectivity increases with decreasing
electron-density in the arene, increasing steric bulk on the alkene,
and decreasing chain length in the alkenol. Examination of these
factors on the rate of the reaction would provide further insight for
future catalyst design and substrate compatibility, improving re-
action rates, carrying out cascade reactions, and selectively func-
tionalizing complex starting materials. Specifically, investigating
whether the rate of reaction is more dependent on steric or elec-
tronic effects will allow for reaction designs, which account for
these influences.15
occurs and that the allylic alcohol reacts faster in
a Cur-
tineHammett controlled reaction.
2. Results and discussion
Herein, we report kinetic data to delineate the effect of sub-
stituents on the boronic acid and of the chain length between the
alcohol and alkene on the reaction rate. Rates were measured by
observing the formation of products by gas chromatography. In
general, we observed overall zero order kinetics through multiple
half lives. This suggests that transmetallation of the boronic acid is
fast prior to rapid alkene binding, leading to a saturated catalyst,
which then undergoes a rate limiting migratory insertion (Fig. 2a.
The saturated complex depicted is based on previous computa-
tions.12). To further probe this hypothesis, several electronically
differentiated boronic acid derivatives were evaluated under the
same reaction conditions (Fig. 2a,b). The rate of product formation
is dependent on the nature of the boronic acid, which is consistent
with rate limiting migratory insertion.16 More nucleophilic arenes
react faster than their electron-poor counterparts, which
correlate with Hammett sp values with a
r
of ꢀ0.87 (Fig. 2c). In
comparison, electron-rich boronic acids result in poor site selec-
tivity with the same substrate 1. For example, 4-OMePh boronic
acid favors the major insertion product in a ratio of about 2:1 while
4-CO2MePh boronic acid provides a ratio of 19:1.2 Additionally, site
Fig. 3. Effect of chain length on rate. Competition experiments with 4-CO2MePh bo-
ronic acid between (a) homoallylic 1 and allylic 2, (b) trishomoallylic 3 and allylic 2,
and (c) homoallylic 1 and trishomoallylic 3 alkenols.
To further explore this, the competitive rates between 2 and 3,
a trishomoallylic alcohol, were measured (Fig. 3b). Again, the allylic
alkenol reacted faster (3.6 times) than the substrate with a longer
chain. Similar competitive rates were observed for 1 and 3, which
suggests that the homoallylic and trishomoallylic alcohols react
similarly under these conditions. To test this, a competitive reaction
of the two (1 and 3) was performed. As anticipated, these alkenes
have nearly identical relative rates (Fig. 3c).
An interesting consequence of these studies is that the allylic
alcohol substrate reacts faster than other alkenols. The origin of this
modest difference is unclear with the calculated energy difference
for the migratory insertion for an allylic alcohol being w0.5 kcal/
mol higher than for a homoallylic alkenol.13 This is clearly within
the error limits of the computations. Yet, a possible explanation is
a lower contribution to entropy-driven preorganization of the al-
lylic substrate, and as a result, the catalyst promotes a faster re-
action, compared to substrates with longer chains.17
Fig. 2. Effect of arene electronic nature on reaction rate. (a) Reaction scheme. (b)
Product formation over time (see Fig. S1 for linear fits). (c) Hammett correlation of
log(rate) to sp values.
As the reaction operates on both di- and trisubstituted alkenols,
we were also interested in determining their relative rates.
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M.J. Hilton et al. / Tetrahedron xxx (2015) 1e6
3
Empirically, trisubstituted alkenols were found to require more
time to react. However, trisubstituted alkenes are more electron-
rich and, thus, determining the relative rates would delineate
whether the empirical observations are governed by a steric effect
of alkene substitutions. Consistent with our previous observations,
the homoallylic disubstituted alkene 1 reacts significantly faster
than the homoallylic trisubstituted alkene 4 (Fig. 4). An interesting
aspect of this competitive scenario is that 1 is consumed before any
reaction of the trisubstituted alkene. In other words, there was no
simultaneous reaction of 1 and 4. However, the rate of consumption
of the disubstituted homoallylic alcohol is slightly inhibited (1.3
times), again suggesting the reaction is under CurtineHammett
control (Fig. S2).
hydrogens in the computed transition structure are relatively long
(2.30 and 2.24 A), and the dihedral angle during the insertion step is
ꢀ
ꢁ
ꢀ
8.9 . In comparison, the distances are shorter (2.13 and 2.20 A) for
the trisubstituted alkene (TS2), inducing more steric repulsion and
greater distortion during the transition (dihedral angle: 16.2ꢁ). This
suggests the main determinant of this chemoselectivity is steric in
nature.
Finally, we interrogated selectivity during the relay process to
uncover how the catalyst selects the hydrogen undergoing b-hy-
dride elimination. As this process is post rate limiting, we designed
two substrates, which contain a branching point with two different
distances to the chain-terminating alcohols (Fig. 6). After initial
migratory insertion, this internal competition presumably proceeds
through relay to the branch point, where the catalyst must select to
chain-walk toward either alcohol as highlighted in intermediate A.
Although migration toward the farther alcohol would result in Pd
bound to a trisubstituted alkene, we have previously shown that
the catalyst is able to relay through other branch points.3 Addi-
tionally, our recent isotopic labeling studies suggest that chain-
walking is likely to be unidirectional toward the alcohol and that
the catalyst relays to the carbinol position before releasing the
carbonyl product.11 In the event, the product distribution of the
resulting aldehydes from 5 (6.8:1) and 6 (6.9:1) reveals that the
catalyst prefers to relay to the closer alcohol for each case. This is
consistent with our previous isotopic labeling experiments and
computational analysis, which reveals lower energetic Pd-
intermediates as the catalyst migrates toward the alcohol. Thus, it
is energetically favorable for the catalyst to prefer the shorter dis-
tance between the branching point and the alcohol in substrates 5
and 6. These results should facilitate the design of more sophisti-
cated applications of the enantioselective relay Heck reactions.
Fig. 4. Competition between di- and trisubstituted alkenes.
To further investigate the origin of this chemoselectivity, we
calculated the relevant transition structures. We reported pre-
viously11,12 that the selectivity determining step is migratory in-
sertion through TS1 for the disubstituted homoallylic alcohol
(Fig. 5a). We have now computed the analogous transition struc-
ture TS2 for the corresponding trisubstituted olefin (Fig. 5b). The
DDGs is 4.9 kcal/mol in preference for the disubstituted alkene,
which is in agreement with the experimentally measured relative
rates. For the disubstituted alkene, the closest distances between
Fig. 6. Internal competition between alcohols of differing chain lengths.
3. Conclusions
The relative reactivity of various alkenes in the redox-relay Heck
reaction has provided valuable insight into the subtle effects on the
migratory insertion step. The distance between the alkene and the
alcohol does not significantly affect the rate of reaction, except in
the case of allylic alcohols. In addition, di- and trisubstituted al-
kenes are not competitive in the rate-limiting step, though Cur-
tineHammett pre-equilibrium binding of both alkenes occurs. Of
Fig. 5. Computed transition states for migratory insertion of an aryl group into (a)
a disubstituted and (b) a trisubstituted alkene.
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4
M.J. Hilton et al. / Tetrahedron xxx (2015) 1e6
practical note, this result indicates that selective functionalization
of disubstituted alkenes in the presences of trisubstituted alkenes is
a viable option for late-stage introduction of an aryl group in
complex molecules containing both types of alkenes. Moreover,
selective carbonyl formation from the redox-relay process is also
possible, with preference for the alcohol that lies closer to the site
of alkene addition. These results provide a foundation for de-
veloping chemoselective variants of relay Heck reactions, which is
a goal of current interest.
4.4. Effect of boronic acid
The same general procedure as described for the competition
experiments was followed using cis-5-hexen-1-ol (1). Conditions
were maintained in each experiment, yet the substitution (R) at the
para-position of the boronic acid was changed, according to the
Hammett series below.
R
Hammett sp
Rate (mM/h)
4. Experimental section
4.1. General methods
OBn
Me
Cl
ꢀ0.27
ꢀ0.17
þ0.23
þ0.45
3.71
2.77
1.22
0.88
CO2Me
ꢀ
Dry dimethylformamide (DMF) was stored over activated 3 A
Note: plots of product formation over time can be found in Supplementary data
(Fig. S1).
molecular sieves. Pd(CH3CN)2(OTs)2 and Ligand were synthesized
according to literature procedures.1,18 All starting materials were
commercially available and were used without further purification.
All products except 10 and 4-(4-(benzyloxy)phenyl)hexanal have
been previously characterized.2,3 Spectra of the products from this
study were in agreement with the previously characterized mate-
rials.2,3 1H NMR spectra were obtained either at 300 or 500 MHz;
chemical shifts are reported in parts per million (ppm), and refer-
enced to the CHCl3 singlet at 7.26 ppm. 13C NMR spectra were ob-
tained at 125 MHz and referenced to the center peak of the CDCl3
signals at 77.0 ppm. The abbreviations s, d, t, q, and m stand for the
resonance multiplicities singlet, doublet, triplet, and multiplet, re-
spectively. Analysis by gas chromatography (GC) was performed
using a Hewlett Packard HP 6890 series GC system fitted with an
Agilent HP-5 column. Each kinetic experiment was carried out in
a 10 mL round bottom flask equipped with a side arm and was
repeated twice. Rates were determined by GC measurements of
products (both regioisomers) relative to an internal standard of 2-
methoxynapthalene.
4.5. 4-(p-Tolyl)hexanal (10)
cis-5-hexen-1-ol (20.0 mg, 0.2 mmol) was dissolved in DMF
(2 ml), and in
a separate vial. Ligand (4.9 mg, 9 mol %),
Pd(CH3CN)2(OTs)2 (6.4 mg, 6 mol %), and Cu(OTf)2 (2.1 mg, 3 mol %)
were dissolved in DMF (2 mL). Powdered molecular sieves (25 mg)
and 4-tolyl boronic acid (81.6 mg, 3 equiv) were added to a 10 mL
round bottom flask, which was subsequently purged with oxygen.
The solutions were mixed and added to the reaction flask. The re-
action mixture was allowed to stir for 18 h at room temperature and
was quenched by addition of brine and diluted with diethyl ether.
The aqueous layer was extracted with diethyl ether (2ꢂ10 mL), and
the combined organic layers were washed with brine (2ꢂ10 mL).
The organic layer was dried over magnesium sulfate, and the sol-
vent was evaporated in vacuo. The crude product was purified by
flash chromatography (1e5% EtOAc/hexanes) to afford aldehyde 10
(17.0 mg, 45%, colorless oil) as mixture of regioisomers (3.7:1). Rf
(20% EtOAc/hexanes) 0.74; FTIR (neat) 2923.8, 1722.1, 1513.9,
4.2. Computational methods
All calculations were performed using M0619 functional imple-
mented in Gaussian09.20 The Lanl2DZ and 6-31þG(d) basis sets
were used for Pd and all other atoms, respectively. Single point
calculations using the SDD basis set for Pd and the 6-311þþG(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. Fre-
quency calculations at the same level of theory at the optimized
geometries were carried out to conform the stationary points as
minima (no imaginary frequency) or transition state (one imagi-
nary frequency) and provided the thermal corrections to the single
point energies.
1456.6, 815.9, 668.2, 548.7 cmꢀ1 1H NMR (500 MHz, CDCl3) 9.65
;
(1H, t, J 1.5 Hz), 7.11 (2H, d, J 8.0 Hz), 7.00 (2H, d, J 8.0 Hz), 2.41e2.35
(1H, m), 2.32 (3H, s), 2.30e2.24 (2H, m), 2.04e1.98 (1H, m),
1.83e1.76 (1H, m), 1.72e1.64 (1H, m), 1.62e1.56 (1H, m), 0.78 (3H, t,
J 7.5 Hz) ppm; 13C{1H} NMR (125 MHz, CDCl3) 202.8, 141.4, 136.0,
129.4, 127.8, 47.0, 39.1, 30.0, 28.8, 20.7, 12.4 ppm; HRMS (TOF ESþ):
MNaþ, found 213.1249. C13H18ONa requires 213.1255.
4.3. Competition experiments
Standard solutions of Pd(CH3CN)2(OTs)2, Cu(OTf)2, Ligand, and
alkene were prepared in DMF for each set of experiments. The
appropriate amounts were added to individual reactions to give
0.05 M concentration with equimolar amounts of competing alkene
(totaling 0.3 mmol), palladium catalyst (6 mol %), copper co-
catalyst (3 mol %), and Ligand (9 mol %). The solutions containing
palladium, copper, and ligand were mixed, and then the alkene was
added. Boronic acid (3 equiv) and powdered molecular sieves
(45 mg, 150 mg/mmol) were added to the reaction flask, which was
subsequently purged with O2. Once the reaction mixture was added
4.6. 4-(4-(Benzyloxy)phenyl)hexanal
to the reaction flask, aliquots (w100 mL) were removed periodically
and passed through a silica plug eluting with ethyl acetate for GC
analysis.
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M.J. Hilton et al. / Tetrahedron xxx (2015) 1e6
5
Prepared in an identical manner to 10 described above,
4.8. General procedure B: oxidative Heck reaction of 5 and 6
employing 4-benzyloxyphenyl boronic acid (136.8 mg, 0.6 mmol),
afforded the aldehyde (32.1 mg, 57%, white semi-solid) as a mix-
ture of regioisomers (3.2:1). Rf (20% EtOAc/hexanes) 0.58; FTIR
(neat) 2930.7, 2022.7, 1723.3, 1652.9, 1558.7, 1455.8, 836.5, 750.0,
667.9 cmꢀ1 1H NMR (500 MHz, CDCl3) 9.66 (1H, t, J 1.5 Hz), 7.44
;
(2H, d, J 7.5 Hz), 7.39 (2H, t, J 7.5 Hz), 7.33 (1H, t, J 8.0 Hz), 7.04 (2H,
d, J 9.0 Hz), 6.93 (2H, d, J 9.0 Hz), 5.04 (2H, s), 2.41e2.35 (1H, m),
2.33e2.22 (2H, m), 2.04e1.98 (1H, m), 1.82e1.75 (1H, m),
1.72e1.64 (1H, m), 1.62e1.52 (1H, m), 0.79 (3H, t, J 7.5 Hz) ppm;
13C{1H} NMR (125 MHz, CDCl3) 202.8, 157.6, 137.4, 136.8, 128.8,
128.6, 128.2, 127.8, 115.1, 70.3, 46.6, 42.5, 30.0, 29.0, 12.4 ppm;
HRMS (TOF ESþ): MNaþ, found 305.1522. C19H22O2Na requires
305.1517.
A mixture of Pd(CH3CN)2(OTs)2 (14.5 mg, 27.3 mmol, 10 mol %),
Cu(OTf)2 (4.4 mg, 12 mmol, 4.5 mol %), ligand (10.7 mg, 39.3 mmol,
ꢀ
14.5 mol %), 3 A MS (42 mg) in DMF (2 mL) was stirred for 10 min.
After the mixture was purged three times with O2, a solution of 5
(50 mg, 0.27 mol) and boronic acid (183 mg, 0.80 mmol, 300 mol %)
in DMF (1 mL) was added. The resulting mixture was stirred for
24 h at room temperature. The mixture was quenched with water,
diluted with EtOAc and extracted with EtOAc. The combined or-
ganic layers were dried (Na2SO4), filtered, and concentrated to give
a residue, which was purified by flash chromatography on silica gel
(petroleum ether/EtOAc, 4:1) to afford a mixture of P1 and P2
(73 mg, 74%) as a colorless oil. The ratio of P1/P2 is about 6.8:1
according to the crude 1H NMR. Rf (petroleum ether/EtOAc, 3:1)¼
0.6. P1 1H NMR (500 MHz, CDCl3) 9.47e9.46 (m, 1H), 7.47e7.31 (m,
5H), 7.28e7.22 (m, 2H), 6.95e6.92 (m, 2H), 5.31 (s, 2H), 3.61 (t,
J¼6.0 Hz, 2H), 2.20e2.10 (m, 1H), 1.66e1.21 (m, 10H), 1.29 (s,
6H) ppm. 13C{1H} NMR (75 MHz, CDCl3) 250.4, 156.6, 141.0, 137.1,
128.5, 127.9, 127.5, 126.7, 114.3, 70.0, 62.5, 52.2, 41.6, 37.0, 32.6, 29.0,
4.7. General procedure A: preparation of the diol substrates 5
and 6
28.3, 23.9, 23.2 ppm. IR (neat): 2934, 2864, 1734, 1508, 1497 cmꢀ1
.
To a solution of lithium diisopropyl amine (LDA), which was
prepared from n-BuLi (2.5 M, 10.5 mL, 26.3 mmol) and i-Pr2NH
(4.2 mL, 30 mmol) in dry THF (60 mL) at ꢀ78 ꢁC for 15 min, was
HRMS (TOF ESþ): MNaþ, found 391.2254. C24H32O3Na requires
391.2249.
A mixture of P3 and P4 was prepared from 6 according to the
general procedure B as a colorless oil in 78% yield. The ratio of P3/P4
is about 6.9:1 according to the crude 1H NMR. Rf (petroleum ether/
EtOAc, 3:1)¼0.6. P3 1H NMR (500 MHz, CDCl3) 9.44e9.43 (m, 1H),
7.45e7.31 (m, 5H), 7.22e7.21 (m, 2H), 6.93e6.91 (m, 2H), 5.04 (s,
2H), 3.62 (t, J¼5.0 Hz, 2H), 2.16e2.06 (m, 1H), 1.66e1.50 (m, 6H),
1.40e1.13 (m, 14H), 1.27 (s, 6H) ppm. 13C{1H}-NMR (75 MHz, CDCl3)
205.6, 156.6, 141.0, 137.1, 128.5, 127.8, 127.4, 126.7, 114.2, 114.2, 69.9,
62.9, 52.2, 41.5, 37.0, 32.7, 29.5, 29.4, 29.3, 29.2, 29.0, 28.6, 26.9,
25.6, 23.9 ppm. IR (neat): 2925, 2854, 1718, 1511, 1242 cmꢀ1. HRMS
(TOF ESþ): MNaþ, found 461.3037. C29H42O3Na requires 461.3056.
added -caprolactone (2.0 g, 18 mmol) dropwise. After the reaction
3
mixture was stirred at ꢀ78 ꢁC for 30 min, 1-bromo-3-methyl-2-
butene (3.3 mL, 28 mmol) was added dropwise. The resultant
mixture was stirred for another 30 min, quenched with saturated
aqueous NH4Cl solution and extracted with EtOAc. The combined
organic layers were dried (Na2SO4), filtered, and concentrated to
give a residue, which was purified by flash chromatography on
silica gel (petroleum ether/EtOAc, 10:1) to afford S1 (1.82 g, 57%) as
a colorless oil.
To a solution of S1 (142 mg, 0.779 mol) in DCM (8 mL) at
ꢀ78 ꢁC, DIBAL-H (25 wt % in toluene, 2.34 mmol) was added
dropwise. The resultant mixture was stirred for 30 min at ꢀ78 ꢁC,
quenched with HCl (1 M), and extracted with DCM. The com-
bined organic layers were dried (Na2SO4), filtered, and concen-
Acknowledgements
trated to give
a
residue, which was purified by flash
The work was supported by the National Institutes of Health
(NIGMS R01GM063540). The scholarship from China Scholarship
Council (No. 201406185008) for B.C. as a visiting scholar is greatly
appreciated. B.R.B. would like to thank Loughborough University
for study leave funding. O.W. and L.X. gratefully acknowledge fi-
nancial support of this research by the National Science Foundation
(CHE1058075) and the Nanshan District (KC2014ZDZJ0026A).
chromatography on silica gel (petroleum ether/EtOAc, 3:1) to
afford diol 5 (117 mg, 81%) as a colorless oil. Rf (petroleum ether/
EtOAc, 1:1) 0.2; 1H NMR (500 MHz, CDCl3) 5.16e5.14 (m, 1H),
3.68e3.62 (m, 2H), 3.57e3.52 (m, 2H), 2.04e2.02 (m, 2H), 1.70 (s,
3H), 1.62 (s, 3H), 1.59e1.53 (m, 3H), 1.45e1.28 (m, 4H) ppm. 13C
{1H} NMR (75 MHz, CDCl3) 132.5, 122.5, 65.0, 62.2, 60.4, 41.1, 32.7,
30.2, 29.6, 25.7, 22.8, 17.7, 17.0 ppm. IR (neat): 3322, 2922, 2852,
1456, 1035 cmꢀ1
11H22O2Na requires 209.1517.
Compound 6 was prepared according to the general procedure A
.
HRMS (TOF ESþ): MNaþ, found 217.1521.
Supplementary data
C
Kinetic plots not presented herein, NMR spectra, and details of
the computational results. Supplementary data associated with this
article can be found in the online version, at http://dx.doi.org/
10.1016/j.tet.2015.05.020.
as a colorless oil, in 63% yield for the first step and 74% yield for the
second step. Rf (petroleum ether/EtOAc, 1:1)¼0.2. 1H NMR
(500 MHz, CDCl3) 5.12e5.10 (m, 1H), 3.58e3.55 (m, 2H), 3.47e3.45
(m, 2H), 2.33 (br s, 2H), 1.99e1.96 (m, 2H), 1.66 (s, 3H), 1.58 (s, 3H),
1.54e1.46 (m, 3H), 1.31e1.19 (m, 14H) ppm. 13C{1H} NMR (125 MHz,
CDCl3) 132.5, 122.6, 65.6, 62.7, 41.2, 32.6, 30.7, 29.9, 29.6, 29.5, 29.4,
29.3, 26.9, 25.7, 25.7, 17.7 ppm. IR (neat): 3322, 2925, 2860, 1457,
1040 cmꢀ1. HRMS (TOF ESþ): MNaþ, found 279.2301. C16H32O2Na
requires 279.2300.
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