Regioselective and Stereoselective Heck-Matsuda Arylations of Trisubstituted Allylic Alkenols and Their Silyl and Methyl Ether Derivatives to Access Two Contiguous Stereogenic Centers: Expanding the Redox-Relay Process and Application in the Total Synthesis of meso-Hexestrol

Article abstract of DOI:10.1021/acs.joc.7b03098

Novel palladium-catalyzed redox-relay Heck arylation reactions of trisubstituted allylic alkenols were developed employing silyl and methyl ethers. The reactions proceeded under mild conditions in moderate to high yields in an excellent anti diastereoselectivity to form α,β-disubstituted methyl ketones containing two contiguous stereocenters. The new redox-relay arylations using silyl and methyl ethers of the starting alkenols demonstrate that the presence of a free hydroxyl group is not a sine qua non condition for an effective redox-relay process as previously thought. Deuterium-labeled alkenols 2-d-10a, 2-d-10b, and 2-d-10c permitted tracking the palladium-hydride reinsertion steps in the conversion of the starting free alcohols, silyl, and methyl ethers into the corresponding methyl ketone 3-d-11a, with >98% deuterium retention. Moreover, the synthetic potential of the method was demonstrated with a straightforward synthesis of the meso-hexestrol in 4 steps, in 41% overall yield from alkenol 10a.

Full text of DOI:10.1021/acs.joc.7b03098

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Article
Regio and Stereoselective Heck-Matsuda Arylations of Trisubstituted
Allylic Alkenols and their Silyl and Methyl Ether Derivatives to Access
Two Contiguous Stereogenic Centers: Expanding the Redox-Relay
Process and Application in the Total Synthesis of meso-Hexestrol
Carlise Frota, Ellen C. Polo, Henrique Esteves, and Carlos Roque Duarte Correia
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b03098 • Publication Date (Web): 24 Jan 2018
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Regio and Stereoselective HeckꢀMatsuda Arylations of Trisubstituted Allylic Alkenols
and their Silyl and Methyl Ether Derivatives to Access Two Contiguous Stereogenic
Centers: Expanding the RedoxꢀRelay Process and Application in the Total Synthesis
of mesoꢀHexestrol
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Carlise Frota, Ellen Christine Polo, Henrique Esteves, and Carlos Roque Duarte Correia*
Institute of Chemistry, University of Campinas, 13083ꢀ970, Campinas, SP, Brazil
*Eꢀmail: roque@iqm.unicamp.br
ABSTRACT GRAPHIC
ABSTRACT
Novel palladiumꢀcatalyzed redoxꢀrelay Heck arylation reactions of trisubstituted allylic
alkenols were developed employing silyl and methyl ethers. The reactions proceeded under
mild conditions in moderate to high yields in excellent anti diastereoselectivity to form α,βꢀ
disubstituted methyl ketones containing two contiguous stereocenters. The new redoxꢀrelay
arylations using silyl and methyl ethers of the starting alkenols demonstrates that the
presence of a free hydroxyl group is not a sine qua non condition for an effective redoxꢀ
relay process as previously thought. Deuterium labeled alkenols 2ꢀdꢀ10a, 2ꢀdꢀ10b, and 2ꢀdꢀ
10c permitted to track the palladiumꢀhydride reinsertion steps in the conversion of the
starting free alcohols, silyl, and methyl ethers into the corresponding methyl ketone 3ꢀdꢀ
11a, with 100% deuterium retention. Moreover, the synthetic potential of the method was
demonstrated with a straightforward synthesis of the mesoꢀhexestrol in 4 steps, in 41%
overall yield from alkenol 10a.
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1. INTRODUCTION
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The construction of contiguous stereogenic centers in a controlled manner is a key
issue in organic synthesis. Methods involving aldol reactions,1 Michael additions,2 and
pericyclic3 reactions as single transformations or in tandem have been instrumental in
addressing this challenge. On the other hand, the application of Heck reactions to assemble
these structural frameworks are relatively rare, with the notable exception of a recently
reported Heck alkenylation of alkenols reported by Sigman using vinyl triflates (Scheme
1a).4 Therefore, construction of contiguous stereogenic centers by Heck reactions, in
particular Heck arylations, constitutes a considerable task as it involves the functionalization
of rather congested tertiary substituted double bonds. Application of palladiumꢀcatalyzed
coupling of arenediazonium salts to olefins (HeckꢀMatsuda reaction) has emerged as a
powerful tool in recent years due to its ability to add structural complexity under
operationally simple conditions. Our research group5 and others6 have made significant
contributions to extend the application of the HeckꢀMatsuda reactions to more complex
olefinic systems and to the enantiocontrolled construction of stereogenic centers. In this
context, we recently described the arylation of trisubstituted olefin using aryldiazonium salts
as electrophiles to yield quaternary stereocenters with excellent levels of enantioꢀ and
regioselectivity5b (Scheme 1b). The preference for the arylation at the most substituted
carbon might be explained by the electronic bias of the double bond due to the distal
polarization promoted by the hydroxyl group, resulting in the delivery of the aryl group to the
more electron rich sp2 carbon. βꢀElimination and palladiumꢀhydride reinsertion yield the
corresponding aldehyde, which cyclizes in the methanolic medium to furnish the
corresponding methyl lactol.
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Herein, we report the arylation of trisubstituted allylic alcohols and their silyl and
methyl ether derivatives for the direct construction of methyl ketones decorated with two
continuous stereogenic centers in a straightforward way (Scheme 1c). The Heck arylations
using silyl and methyl ethers instead of free alkenols constitute the first examples extending
the soꢀcalled redoxꢀrelay process in Heck reactions. The synthetic potential of these Heck
reactions is demonstrated by a new strategy to the total synthesis of mesoꢀhexestrol
(Scheme 1d).7 Hexestrol and its derivatives exhibited a variety of biological activities8 and
they are considered effective inhibitors of microtubule assembly.9
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Scheme 1. Heck reaction of trisubstituted alkenols.
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2. RESULTS AND DISCUSSION
Our studies began with the HeckꢀMatsuda reaction between (E)ꢀ3ꢀmethylhexꢀ3ꢀenꢀ2ꢀ
ol (1a) and 4-chlorobenzenediazonium tetrafluoroborate (2c) as model coupling partners.
Initially, we used our previously developed catalytic system,10 Pd(TFA)2 (10 mol%), 0.5
o
equiv. of ZnCO3 as base, in MeOH at 40 C, without ligands (Table 1, entry 1) which
provided the methyl ketone 3c in moderate yield (65%) as a single diastereoisomer with
1,2ꢀanti relationship. The reaction was also performed at 60 °C without any significant
improvement (entry 2).
To evaluate the importance of the free alcohol functionality in the formation of redoxꢀ
relay product, we also carried out the HeckꢀMatsuda reaction with the corresponding silyl
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ethers 1b and 1c. Previous results from our laboratory have shown the compatibility of silyl
ethers with the redoxꢀrelay process.5a Gratifyingly, the reaction of the TBS ether 1b and
TIPS ether 1c with the arenediazonium salt 2c provided ketone 3c as single stereoisomer
in excellent yields of 98% after only 15 minutes (entries 3 and 4). These results prompted
further investigations regarding the palladium source, the solvent and the base of the
reaction (entries 5ꢀ14).
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Replacement of Pd(TFA)2 by other palladium sources, such as Pd2(dba)3 or
Pd(acac)2 (entries 5 and 6) resulted in lower reaction yields of 70% and 64%, respectively.
Except by using MeOH, DMC, and EtOH (entries 3, 8 and 12), all the other solvents
furnished the Heck product 3c in lower yields. Exchange of the ZnCO3 base by DTBMP and
Rochelle’s salt, provided the Heck product 3c in excellent yields of 92% and 88% (entries
13 and 14), thus allowing some flexibility regarding the choice of the base. Maintaining the
conditions display in entry 3, but changing the temperature to 40 oC led to slightly extend in
the reaction (30 min), but with an almost quantitative yield for the reaction (entry 15). The
HeckꢀMatsuda reaction maintained excellent performance at a lower catalyst loading of 5
mol% and 2 mol% (95% and 89% yields, entries 16 and 17), whereas a significant
decrease in chemical yield to 73% and longer reaction times were observed with 1 mol% of
catalyst (entry 18).
Table 1. Evaluation of the reaction under “ligandless” conditions
entry
R1
H
[Pd] (mol%)
Pd(TFA)2 (10)
Pd(TFA)2 (10)
solvent
MeOH
MeOH
MeOH
MeOH
base (equiv)
ZnCO3 (0.5)
ZnCO3 (0.5)
ZnCO3 (0.5)
ZnCO3 (0.5)
ZnCO3 (0.5)
ZnCO3 (0.5)
ZnCO3 (0.5)
ZnCO3 (0.5)
temp. (oC) t (min) yield (%)a
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60
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65
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98
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H
TBS Pd(TFA)2 (10)
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TIPS Pd(TFA)2 (10)
15
TBS Pd2(dba)3 (10)b MeOH
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TBS Pd(acac)2 (10)
MeOH
PhMe
DMC
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TBS
TBS
Pd(TFA)2 (10)
Pd(TFA)2 (10)
o.n.c
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TBS
TBS
TBS
TBS
TBS
TBS
TBS
TBS
TBS
TBS
Pd(TFA)2 (10)
Pd(TFA)2 (10)
Pd(TFA)2 (10)
Pd(TFA)2 (10)
Pd(TFA)2 (10)
Pd(TFA)2 (10)
Pd(TFA)2 (10)
Pd(TFA)2 (5)
Pd(TFA)2 (2)
Pd(TFA)2 (1)
THF
DMF
ZnCO3 (0.5)
ZnCO3 (0.5)
ZnCO3 (0.5)
ZnCO3 (0.5)
DTBMPd (1.0)
60
60
60
60
60
60
40
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40
40
o.n.
o.n.
o.n.
360
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73
MeCN
EtOH
MeOH
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MeOH Rochelle’s salt (1.0)
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MeOH
MeOH
MeOH
MeOH
ZnCO3 (0.5)
ZnCO3 (0.5)
ZnCO3 (0.5)
ZnCO3 (0.5)
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75
90
360
a) Determined by 1H NMR using internal standard. b) dba = dibenzylideneacetone. c) o.n. = overnight. d) DTBMP =
2,6ꢀdiꢀtertꢀbutylꢀ4ꢀmethylpyridine.
With the optimized conditions in hand, the reaction scope was explored with several
arenediazonium salts (Table 2). The reactions of olefin 1b with electronꢀrich and electronꢀ
deficient arenediazonium salts furnished the corresponding arylated products 3aꢀr as a
single diastereomer in moderate to excellent yields (up to 95%). Lower chemical yields
were observed for the benzenediazonium salt and for the orthoꢀsubstituted arenediazonium
salts (compounds 3g, 3h and 3i).
The efficiency of the newly developed method was also evaluated with respect to the
substituent R2 of the olefin by replacing the methyl group by an aryl group (Table 2). Thus,
olefins 4a (free OH group) and 4b (TBS protected alcohol) were synthesized and submitted
to the optimized HeckꢀMatsuda condition to provide the corresponding arylated products
3mꢀr as a single diastereomer in all cases in variable yields depending on the
aryldiazonium salt employed.
The relative anti stereochemistry of the Heck product was determined from single
crystal Xꢀray analysis of compound 3m and was extended to the other Heck products (see
the Supporting Information for details).11
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Table 2. Scope of the HeckꢀMatsuda arylation
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a) Conditions: 1aꢀb, 4aꢀb (0.2 mmol), 2aꢀl (0.4 mmol), Pd(TFA)2 (2 mol%), ZnCO3 (0.1 mmol), MeOH (1 mL). b) Isolated
yields.
On the synthetic point of view, the high regioꢀ and diastereoselectivities of the
method allowed its application as key step in the total synthesis of mesoꢀhexestrol (14). We
commenced the synthesis with a reliable way to prepare the critical alkenol 10a bearing a
4ꢀOMeꢀphenyl group from the commercially available carboxylic acid 5 in a multigram scale
(Scheme 2). Esterification of carboxylic acid 5 with EtOH and TsOH (99% yield),12 followed
by bromination of the corresponding ester with NBS and AIBN13, and nucleophilic
substitution with PPh3, provided the phosphonium salt 6 in 84% of yield over two steps.14
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Treatment of phosphonium salt 6 with NaOH provided phosphorane 7 in 96% yield.14 Next,
the Wittig coupling between phosphorane 7 and propionaldehyde gave the unsaturated
ester 8 in 71% yield (E:Z 10:1).15 The reduction of ester 8 with DIBALꢀH16 followed by
oxidation under Swern conditions,16 and treatment with MeLi provided the olefin 10a in 77%
of yield over three steps. The configuration of double bond of product 10a as E was
confirmed by NOESY analysis.
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Scheme 2. Preparation of Eꢀolefin 10a.
In the sequence, gramꢀscale HeckꢀMatsuda arylation of Eꢀolefin 10a with 4ꢀ
methoxybenzenediazonium salt provided methyl ketone 11a as a single diastereoisomer in
78% isolated yield (Scheme 3). HeckꢀMatsuda arylation of TBS ether 10b improved the
yield of 11a to 85%, as expected from previous experiments. Treatment of methyl ketone
11a with 1,2ꢀethanedithiol and BF3.OEt2 furnished dithiane 12 in quantitative yield, which
underwent desulfurization with Raney Nickel17 to afford the diarylated hexane 13 in 77%
yield. Finally, demethylation of the compound 13 with BBr3 gave mesoꢀhexestrol (14) in
82% yield.18 The stereoselective synthesis of mesoꢀhexestrol (14) was accomplished in 4
steps from olefin 10a in 41% overall yield.
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Scheme 3. Diastereoselective total synthesis of mesoꢀhexestrol.
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The intriguing and to a certain extent unexpected19 results obtained with the alkenol
silyl ethers displayed in Table 2, in many instances affording results superior to the free
allylic alcohol, prompted us to reinvestigate this transformation in more details to obtain
some mechanistic insights. One obvious question was the purposely formation of a silyl
enol ether intermediate, which could, in principle, furnish the methyl ketone 3c upon workup
or in the reaction medium. Alternatively, we speculated that a variant of the regular redoxꢀ
relay process could be operative in this case. To investigate the former hypothesis ꢀ the
existence of a silyl enol ether intermediate ꢀ we submitted the more stable TBDPS silyl
ether 1d to the same reaction conditions (Table 3, entry 1) hoping to isolate or detect the
putative silyl enol ether intermediate, but only the Heck product 3c was isolated in 72%
yield.
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Table 3. The redoxꢀrelay process on trisubstituted silyl and methyl alkenols
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entry
R1
R2
base (equiv)
ZnCO3 (0.5)
t (min) yield (%)a
−
−
−
−
1
2
TBDPSb BF4
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60
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Me
Me
Me
Me
BF4
BF4
BF4
ZnCO3 (0.5)
3
protonꢀsponge (1.0)
ZnCO3 (0.5) + DTBMP (1.0)
ZnCO3 (0.5)
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TsO−
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TBDPS TsO−
ZnCO3 (0.5)
90
7c
TBDPS TsO−
ZnCO3 (0.5)
300
−
d
a)
b)
d)
Isolated yields. TBDPS = tertꢀbutyldiphenylsilyl. c) Toluene was used as solvent.
Compound 3c not observed.
At this point we considered that either the residual acidity of the reaction medium or
−
the presence of fluoride ions from the BF4 arenediazonium salt counterion could be
responsible for the conversion of the silyl enol ether into the corresponding ketone. To
circumvent this potential pathway, we also synthesized the methyl ether 1e, which we
expected to be more stable under the reaction conditions. Surprisingly, the HeckꢀMatsuda
reaction of methyl ether 1e led to ketone 3c cleanly in a good 74% yield (Table 3, entry 2).
To ensure that ketone 3c was not being generated by methanolysis of a putative methyl
enol ether under some local mild acidic conditions, either protonꢀsponge or an additional
equivalent of DTBMP was used as base. As shown in entries 3 and 4 (Table 3), ketone 3c
was obtained in 59% and 62% yield, respectively, suggesting that H+ formation during the
Heck reaction is apparently not responsible for converting the supposed methyl enol ether
into the ketone. HeckꢀMatsuda arylation of ether 1e using 4ꢀchlorobenzenediazonium
tosylate also led to ketone 3c in 66% indicating no need of a fluoride source in the redox
process (Entry 5). However, a lower yield was obtained in the case of TBDPS ether and 4ꢀ
chloro benzenediazonium tosylate (Entry 6). When the reaction was carried out in toluene
and in the absence of a fluoride source (use of arenediazonium tosylate salt 2m, entry 7)
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formation of compound 3c was not observed, even after 5 hours. We took this result as an
additional evidence for the role of methanol and/or fluoride ion in the redoxꢀrelay step.
Taken together, these data suggest that a weakly acidic medium is not responsible
to convert the enol ethers intermediates into the methyl ketones 3. Therefore, the silyl and
methyl groups are probably removed in a latter step after palladiumꢀhydride reinsertion into
the enol ether intermediate, implying that redoxꢀrelay processes might occur with functional
groups other than a free alcohol.
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To unequivocally validate the hypothesis that a redoxꢀrelay process can be operative
with other functional groups apart from the conventional conversion of a hydroxyl group into
a carbonyl group,20 we synthesized compounds 2ꢀdꢀ10a−2ꢀdꢀ10c bearing a deuterated
carbinol center and submitted them to the standard conditions shown in Table 2. All
deuteriumꢀlabeled derivatives led to the HeckꢀMatsuda methyl ketone 3ꢀdꢀ11a in good
yields with full incorporation of the deuterium at the internal α−carbonyl position. The
location of the deuterium was clearly confirmed by 1H NMR of methyl ketone 3ꢀdꢀ11a by the
absence of a doublet centered at 3.89 ppm which was indicative of the methine in nonꢀ
1
deuterated methyl ketone 11a used as standard. H NMR spectrum has also permitted to
measure >98% deuterium incorporation at the αꢀcarbonyl position (Scheme 4) (see the
Supporting Information for details). These results constitute unequivocal indication that
redoxꢀrelay processes can indeed occur with silyl and methyl ethers.
Scheme 4. Evaluation of deuterium migration in the redoxꢀrelay step.
A rationalization for the formation of HeckꢀMatsuda product is shown in Scheme 5.
The catalytic cycle starts with the oxidative addition of the palladium complex to the
aryldiazonium salt furnishing the cationic aryl palladium A. After complexation of the olefin
to complex A, synꢀcarbopalladation occurs, generating intermediate B. The more acidic
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carbinol hydrogen then becomes available for βꢀsynꢀelimination furnishing palladium enol
ether (silyl or methyl) as intermediate C. Palladium hydride reinsertion provides the isomeric
intermediate D, which in the case of silyl and methyl ethers, undergoes either a
nucleophilicꢀassisted redoxꢀrelay process (path a), or an anchimericꢀassisted palladium
reductive elimination (path b) followed by solvolysis and/or fluorination of the silyl/methyl
group bound to an oxonium intermediate. Both pathways would lead to the formation of the
ketone product and regeneration of palladium(0).
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The high anti diastereoselectivity observed can be explained by the nature of
palladium hydride chain walking. Since the βꢀelimination (B to C, Scheme 5) occurs at the
same face of migratory insertion step (A to B), the reꢀinsertion step onto the enol ether
intermediate (C to D) leads the βꢀgroup in an anti position with respect to the aryl group
coming from the corresponding diazonium salt. The high anti diastereoselectivity strongly
suggests that the reꢀinsertion step occurs intramolecularly.
Scheme 5. Proposed mechanism. R = H, Me, TBS, TIPS, TBDPS. Nu = MeOH or [F−].
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3. CONCLUSION
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We have developed efficient palladiumꢀcatalyzed redox Heck arylation reactions of
trisubstituted allylic alkenols and its corresponding silyl and methyl ethers. The reaction
proceeded under mild conditions in moderate to high yields in excellent anti
diastereoselectivity to form α,βꢀdisubstituted methyl ketones containing two contiguous
stereocenters. The successfully redoxꢀrelay processes achieved with silyl and methyl
ethers as starting alkenols 1bꢀ1e, 4b and 10b show that the presence of a free hydroxyl
group is not a sine qua non condition for an effective redoxꢀrelay process. Deuterium
labeled alkenols 2ꢀdꢀ10a, 2ꢀdꢀ10b, and 2ꢀdꢀ10c allowed to track the palladiumꢀhydride
reinsertion steps in the conversion of the starting silyl/methyl ethers into the corresponding
methyl ketone 3ꢀdꢀ11a, thus confirming that silyl and methyl ethers can indeed undergo late
oxidation in HeckꢀMatsuda reactions. Due to its increase in structural complexity, the
method was successfully applied in a straightforward synthesis of the mesoꢀhexestrol (4
steps) in 41% overall yield from alkenol 10a. Further studies regarding the redoxꢀrelay
process involving other functional groups are ongoing and should be reported in due
course.21
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4. EXPERIMENTAL SECTION
General Experimental Methods. All the HeckꢀMatsuda reactions were carried out in 4 mL
vessel under air atmosphere (openꢀvessel), unless stated otherwise. Reaction
temperatures are reported as the temperature of the heat transfer medium surrounding the
vessel. The other reactions were carried out under an atmosphere of nitrogen with dry
solvents under anhydrous conditions unless otherwise stated. Tetrahydrofuran (THF) was
distilled from sodium/benzophenone prior to use. Triethylamine (Et3N), dichloromethane
(DCM), hexane, and toluene (PhMe) were distilled from CaH2 prior to use. Nꢀ
bromosuccinimide (NBS) was recrystallized from water. Triphenylphosphine (PPh3) was
recrystallized from hexane. Carbon tetrachloride (CCl4) was distilled prior to use.
Propionaldehyde was distilled from hydroquinone prior to use. Oxalyl chloride was distilled
prior to use. Benzene anhydrous 99.8% was purchased and used as received. The other
reagents were used without further purification, unless otherwise stated. The purification of
reaction products was performed by flash chromatography using silica gel (220ꢀ440 mesh)
and EtOAc/hexane as the eluent. Solvents used for chromatography were technical grade
and were distilled before use. Analytical thin layer chromatography (TLC) was performed
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employing silica gel 60 F254 plates. Visualization was accomplished with UV light and
vanillin staining solutions followed by heating. NMR analyses were acquired at 250 MHz for
1H NMR and 62.5 MHz for 13C NMR, at 400 MHz for 1H NMR and 100 MHz for 13C NMR, at
500 MHz for 1H NMR and 125 MHz for 13C NMR, or at 600 MHz for 1H NMR and 150 MHz
for 13C NMR. Chemical shifts (δ) are reported in ppm using residual nonꢀdeuterated solvent
as an internal standard (CHCl3 at 7.26 ppm, DMSO at 2.50 ppm, MeOH at 3.31 ppm, and
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TMS at 0.00 ppm for H NMR spectra and CDCl3 at 77.16 ppm, DMSOꢀd6 at 39.52 ppm,
and MeOHꢀd4 at 49.0 ppm for 13C NMR spectra). Data are reported as follows: chemical
shift (δ), multiplicity, coupling constant (J) in Hertz, and integrated intensity. The
multiplicities of the signals are denoted by s (singlet), d (doublet), t (triplet), q (quartet), quint
(quintet), bs (broad singlet), dd (double doublet), dt (doublet of triplet), dq (doublet of
quartet), td (triplet of doublet), dqd (doublet of quartet of doublet), and m (multiplet). 1,3ꢀ
bis(trifluoromethyl)ꢀ5ꢀbromobenzene was used as internal standard for the determination of
1
chemical yields by H NMR. Highꢀresolution mass spectrometry (HRMS) were measured
using electrospray ionization (ESI) (QꢀTOF) or electron impact (EI) (QꢀTOF). Melting points
were measured in melting apparatus and the values are uncorrected. When applicable,
diastereomeric ratios (dr) were calculated through 1H NMR of the crude reaction.
4.1. Synthesis of substrates
4.1.1. Arenediazonium salts
The tetrafluoroborate arenediazonium salts 2aꢀ2l were prepared according to the literature
procedure.22
4ꢀchloroarenediazonium tosylate (2m). The title salt was obtained as previously
reported.22a IRꢀATR (cm−1): 2296 (N≡N). 1H NMR (400 MHz, CD3OD) δ 8.61 (d, J = 9.0 Hz,
2H), 7.97 (d, J = 9.0 Hz, 2H), 7.65 (d, J = 8.2 Hz, 2H), 7.21 (d, J = 7.7 Hz, 2H), 2.37 (s,
3H).; 13C NMR (100 MHz, CD3OD) δ 149.9, 143.6, 141.7, 135.2, 133.2, 129.8, 126.9, 115.0,
21.3.
4.1.2. Preparation of olefins 1a, 1b, 1c, 1d, 1e, 4a, 4b, 10a, 10b, 2ꢀdꢀ10a, 2ꢀdꢀ10b, 2ꢀdꢀ
10c.
(E)ꢀ3ꢀmethylhexꢀ3ꢀenꢀ2ꢀol (1a). To a solution of (E)ꢀ2ꢀmethylꢀ2ꢀpentenal (3.5 mL, 30.5
mmol, 1 equiv) in THF (300 mL) at 0 °C, it was added MeLi (1.6 M in ether, 21.0 mL 33.6
o
mmol, 1.1 equiv), dropwise. The reaction mixture was stirred at 0 C for 5 h and then the
reaction was quenched with aqueous saturated solution of NH4Cl (50 mL) and H2O (50 mL).
Then, the mixture was allowed to warm to room temperature, the layers were separated,
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and the aqueous layer was extracted with Et2O (2 × 150 mL). The organic layers were
combined, washed with brine (150 mL), dried over Na2SO4, filtered and concentrated under
reduced pressure. The residue was purified by flash column chromatography on silica gel
using hexane/EtOAc (95:5) as eluent to provide the (E)ꢀ3ꢀmethylhexꢀ3ꢀenꢀ2ꢀol (1a) (55%,
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1.9 g, 17 mmol). Note: volatile product. Physical state: light yellow oil; H NMR (400 MHz,
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CDCl3) δ 5.38 (t, J = 7.0 Hz, 1H), 4.19 (q, J = 6.4 Hz, 1H), 2.10–1.94 (m, 2H), 1.61 (s, 3H),
1.46 (s, 1H), 1.24 (d, J = 6.4 Hz, 3H), 0.95 (t, J = 7.6 Hz, 3H).; 13C NMR (100 MHz, CDCl3)
δ 138.0, 127.1, 73.5, 21.7, 20.9, 14.2, 11.4.; HRMS (ESI/QꢀTOF) m/z: [M+Na]+ Calcd for
C7H14ONa 137.0937; Found 137.0953.
(E)ꢀtertꢀbutyldimethyl((3ꢀmethylhexꢀ3ꢀenꢀ2ꢀyl)oxy)silane (1b).23 To a solution of 1a (0.5
g, 4.4 mmol, 1 equiv) in DCM (50 mL), were added imidazole (0.45 g, 6.6 mmol, 1.5 equiv)
and tertꢀbutyldimethylsilyl chloride (0.80 g, 5.3 mmol, 1.2 equiv). The mixture was stirred
overnight at room temperature. Water was then added, and the layers were separated. The
aqueous layer was extracted with DCM (3 × 150 mL). The organic layers were combined,
washed with brine (150 mL), dried over MgSO4, filtered and concentrated under reduced
pressure. The residue was purified by flash column chromatography on silica gel using
hexanes as eluent to provide the compound 1b (quantitative, 1.0 g, 4.4 mmol). Physical
state: colorless oil; 1H NMR (400 MHz, CDCl3) δ 5.30 (t, J = 7.1 Hz, 1H), 4.14 (q, J = 6.3 Hz,
1H), 2.11−1.87 (m, 2H), 1.56 (s, 3H), 1.18 (d, J = 6.3 Hz, 3H), 0.93 (t, J = 7.5 Hz, 3H), 0.88
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(s, 9H), 0.03 (s, 3H), 0.01 (s, 3H).; C NMR (101 MHz, CDCl3) δ 138.2, 125.8, 74.2, 26.0,
23.4, 20.8, 18.4, 14.2, 11.3, −4.6, −4.8.; HRMS (ESI/QꢀTOF) m/z: [M+Na]+ Calcd for
C13H28OSiNa 251.1801; Found 251.1809.
(E)ꢀtriisopropyl((3ꢀmethylhexꢀ3ꢀenꢀ2ꢀyl)oxy)silane (1c). To a solution of 1a (0.5 g, 4.4
mmol, 1 equiv) in DCM (50 mL), were added imidazole (0.45 g, 6.6 mmol, 1.5 equiv) and
triisopropylsilyl chloride (1.02 g, 5.4 mmol, 1.2 equiv). The mixture was stirred overnight at
room temperature. Water was then added, and the layers were separated. The aqueous
layer was extracted with DCM (3 × 150 mL). The organic layers were combined, washed
with brine (150 mL), dried over MgSO4, filtered and concentrated under reduced pressure.
The residue was purified by flash column chromatography on silica gel using hexanes as
eluent to provide the compound 1c (quantitative, 1.2 g, 4.4 mmol). Physical state: colorless
oil; 1H NMR (250 MHz, CDCl3) δ 5.30 (t, J = 7.1 Hz, 1H), 4.25 (q, J = 6.3 Hz, 1H), 2.20–1.87
(m, 2H), 1.58 (s, 3H), 1.21 (d, J = 6.3 Hz, 3H), 1.02–1.06 (m, 21H), 0.94 (t, J = 7.5 Hz, 3H).;
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13C NMR (101 MHz, CDCl3) δ 138.6, 125.8, 74.3, 23.8, 20.9, 18.24, 18.22, 14.2, 12.5, 11.0.;
HRMS (ESI/QꢀTOF) m/z: [M+Na]+ Calcd for C16H34OSiNa 293.2271; Found 293.2281.
(E)ꢀtertꢀbutyl((3ꢀmethylhexꢀ3ꢀenꢀ2ꢀyl)oxy)diphenylsilane (1d). A 50ꢀmL roundꢀbottomed
flask was charged with alcohol 1a (0.348 g, 3 mmol, 1 equiv) and imidazole (0.449 mg, 6.6
mmol, 2.2 equiv). Next, DMF (30 mL) and tertꢀbutyldiphenylsilyl chloride (1.02 mL, 1.08 g,
3.93 mmol, 1.3 equiv) were added. The reaction was magnetically stirred for over 24 h,
followed by addition of 200 mL of water. The mixture was then extracted with ethyl ether (3
× 50 mL) and the combined organic layers was washed with water (3 × 75 mL), dried over
NaSO4, filtered and concentrated under reduced pressure. The residue was purified by
flash chromatography on silica gel using hexanes as eluent to provide the compound 1d
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(91%, 0.963 g, 2.73 mmol). Physical state: colorless oil; H NMR (400 MHz, CDCl3) δ
7.82−7.76 (m, 4H), 7.54−7.42 (m, 6H), 5.25 (t, J = 7.1 Hz, 1H), 4.31 (q, J = 6.2 Hz, 1H),
2.14−1.96 (m, 2H), 1.72 (s, 3H), 1.27 (d, J = 6.3 Hz, 3H), 1.18 (s, 9H), 0.99 (t, J = 7.5 Hz,
3H).; 13C NMR (100 MHz, CDCl3) δ 137.6, 136.1, 136.0, 135.0, 134.6, 129.6, 129.5, 128.9,
127.6, 127.5, 127.3, 126.6, 75.2, 27.2, 23.3, 20.8, 19.5, 14.1, 11.1.; HRMS (ESI/QꢀTOF)
m/z: [M+Na]+ Calcd for C23H32OSiNa 375.2114; Found 375.2108.
(E)ꢀ2ꢀmethoxyꢀ3ꢀmethylhexꢀ3ꢀene (1e). A 50ꢀmL roundꢀbottomed flask was charged with
NaH (60% wt. suspension in mineral oil, 4.19 g, 124 mmol, 9 equiv) and the solid was
washed with hexane (7 × 5 mL) and anhydrous Et2O (2 × 5 mL) using a syringe until no
mineral oil was detected in TLC analysis. Then, Et2O (15 mL) was added and the
suspension was cooled to 0 °C. A solution of 1a (1.59 g, 13.9 mmol, 1 equiv) in Et2O (10
mL) was added and the mixture was allowed to warm to room temperature. After 3 hours
(hydrogen evolution was finished at that time), the mixture was cooled to 0°C and MeI (3.7
mL, 11 g, 60 mmol, 4.3 equiv) was added. The reaction was then magnetically stirred at
room temperature overnight. The resulting suspension was filtered through a sintered glass
filter and the inorganic residue was washed with Et2O (5 × 5 mL). The solvent was removed
by careful distillation and the residue was purified by flash chromatography on silica gel
using pentane. The fractions containing the product were combined and carefully distilled to
provide the product 1e as an 80% wt. solution in pentane. (38%, 851 mg, 5.31 mmol).
Physical state: colorless oil; 1H NMR (400 MHz, CDCl3) δ 5.32 (t, J = 7.0 Hz, 1H), 3.59 (q, J
= 6.4 Hz, 1H), 3.14 (s, 3H), 2.19−1.88 (m, 2H), 1.52 (s, 3H), 1.18 (d, J = 6.5 Hz, 3H), 0.95
(t, J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 135.0, 129.6, 82.9, 55.6, 20.9, 20.1, 14.2,
10.1.; HRMS (ESI/QꢀTOF) m/z: [M+Na]+ Calcd for C8H16ONa 151.1093; Found 151.1087.
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(E)ꢀ3ꢀphenylhexꢀ3ꢀenꢀ2ꢀol (4a). To a solution of phenylmagnesium bromide (1.0 M in THF,
51.5 mL, 51.5 mmol, 5 equiv) at −72 °C in THF (60 mL) it was added CuI (30 mol%, 0.6 g,
3.09 mmol) followed by addition of a solution of 3ꢀhexynꢀ2ꢀol (1.02 g, 10.3 mmol, 1 equiv) in
THF (25 mL) dropwise. Then, the reaction mixture was stirred at room temperature for 1 h,
followed by reflux overnight (until complete conversion by TLC). The reaction was cooled to
0 ºC, quenched with saturated aqueous solution of NH4Cl (60 mL) and filtered through a
pad of Celite. Then, the mixture was allowed to warm to room temperature and the layers
were separated. The aqueous layer was next extracted with Et2O (3 × 50 mL). The organic
layers were combined and washed with brine (50 mL), dried over Na2SO4, filtered and
concentrated under reduced pressure. The residue was purified by flash column
chromatography on silica gel using hexane/EtOAc (90:10) as eluent to provide compound
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4a (57%, 1.0 g, 5.7 mmol). Physical state: colorless oil; H NMR (500 MHz, CDCl3) δ 7.39–
7.36 (m, 2H), 7.32−7.29 (m, 1H), 7.19–7.17 (m, 2H), 5.73 (t, J = 7.3 Hz, 1H), 4.53 (q, J =
5.4 Hz, 1H), 1.93 (quint, J = 7.4 Hz, 2H), 1.24 (d, J = 6.4 Hz, 3H), 0.96 (t, J = 7.5 Hz, 3H).;
13C NMR (126 MHz, CDCl3) δ 144.3, 138.6, 129.3, 129.1, 128.2, 127.0, 72.3, 22.4, 22.0,
14.5.; HRMS (ESI/QꢀTOF) m/z: [M+Na]+ Calcd for C12H16ONa 199.1093; Found 199.1080.
(E)ꢀtertꢀbutyldimethyl((3ꢀphenylhexꢀ3ꢀenꢀ2ꢀyl)oxy)silane (4b). To a solution of 4a (0.18
g, 1.0 mmol, 1 equiv) in DCM (15 mL) were added imidazole (0.136 g, 2.0 mmol, 2 equiv)
and tertꢀbutyldimethylsilyl chloride (0.301 g, 2.0 mmol, 2 equiv), and the mixture stirred
overnight at room temperature. Water was then added, and the layers were separated. The
aqueous layer was extracted with DCM (3 × 150 mL). The combined organic layers were
washed with brine (10 mL), dried over MgSO4, filtered and concentrated under reduced
pressure. The residue was purified by flash column chromatography on silica gel using
hexane/EtOAc (90:10) as eluent to provide the compound 4b (quantitative, 2.9 g, 1.0
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mmol). Physical state: colorless oil; H NMR (500 MHz, CDCl3) δ 7.34 (t, J = 7.4 Hz, 2H),
7.29–7.26 (m, 1H), 7.16–7.15 (m, 2H), 5.73 (t, J = 7.1 Hz, 1H), 4.48 (q, J = 6.1 Hz, 1H),
1.92 (quint, J = 7.5 Hz, 2H), 1.14 (d, J = 6.3 Hz, 3H), 0.96 (s, 9H), 0.94 (t, J = 7.5 Hz, 3H),
0.13 (s, 3H), 0.11 (s, 3H).; 13C NMR (126 MHz, CDCl3) δ 144.3, 139.6, 129.4, 128.1, 128.0,
126.7, 72.8, 26.1, 23.7, 21.9, 18.5, 14.6, −4.6, −4.8.; HRMS (ESI/QꢀTOF) m/z: [M+Na]+
Calcd for C18H30OSiNa 313.1958; Found 313.1943.
Ethylꢀ2ꢀ(4ꢀmethoxyphenyl)acetate (S1). The compound S1 was prepared from 4ꢀ
methoxyphenylacetic acid (5) according to the literature procedure.12 Physical state:
colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.20 (d, J = 8.6 Hz, 2H), 6.86 (d, J = 8.6 Hz, 2H),
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4.14 (q, J = 7.1 Hz, 2H), 3.79 (s, 3H), 3.55 (s, 2H), 1.25 (t, J = 7.1 Hz, 3H).; 13C NMR (100
MHz, CDCl3) δ 172.1, 158.8, 130.4, 126.4, 114.1, 60.9, 55.4, 40.7, 14.3.
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(2ꢀethoxyꢀ1ꢀ(4ꢀmethoxyphenyl)ꢀ2ꢀoxoethyl)triphenylphosphonium bromide (6). To a
solution of ethylꢀ2ꢀ(4ꢀmethoxyphenyl)acetate (S1) (5.77 g, 29.7 mmol) in CCl4 (66 mL) it
was added AIBN (0.243 g, 1.48 mmol, 0.05 equiv) and NBS (5.82 g, 32.7 mmol, 1.1 equiv).
The mixture was refluxed for 5 h. After this period, the reaction mixture was cooled to room
temperature and 150 mL of hexane was added. The mixture was filtered through a pad of
Celite and the cake was washed with hexane. The 2ꢀbromo ester product was then
concentrated under reduced pressure and used in the next step without further purification.
To a solution of PPh3 (8.58 g, 32.7 mmol, 1.1 equiv) in PhMe (51 mL) it was added the
bromo ester intermediate prepared above and the reaction mixture was stirred for 12 h at
70 °C (oil bath temperature). After this period, the mixture was cooled to room temperature
and filtered. The cake was then washed with PhMe (20 mL) and Et2O (2 × 15 mL). The
resulting phosphonium salt 6 was dried in vacuo (84% over 2 steps, 13.4 g, 25.1 mmol).
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Physical state: pale yellow solid. H NMR (500 MHz, CDCl3) δ 8.16 (d, J = 14.0 Hz, 1H),
7.92–7.88 (m, 6H), 7.77–7.74 (m, 3H), 7.64–7.60 (m, 6H), 7.30–7.28 (m, 2H), 6.71 (d, J =
8.6 Hz, 2H), 4.18–4.09 (m, 2H), 3.75 (s, 3H), 1.09 (t, J = 7.1 Hz, 3H).; 13C NMR (125 MHz,
CDCl3) δ 168.2, 160.5 (d, J = 2.8 Hz), 135.1 (d, J = 9.8 Hz), 134.9 (d, J = 2.8 Hz), 133.1 (d,
J = 5.3 Hz), 129.9 (d, J = 12.6 Hz), 119.0 (d, J = 6.0 Hz), 118.3, 117.6, 114.2 (d, J = 2.0
Hz), 63.2, 55.4, 48.1 (d, J = 52.4 Hz), 13.8.; HRMS (ESI/QꢀTOF) m/z: [M−Br−]+ Calcd for
C29H28O3P 455.1771; Found 455.1772.
(E)ꢀethyl 2ꢀ(4ꢀmethoxyphenyl)pentꢀ2ꢀenoate (Eꢀ8). To a solution of phosphonium salt 6
(13.4 g, 25.1 mmol) in MeOH (110 mL) it was added an aqueous solution of NaOH (30%
w/v) until pH 10, followed by addition of 170 mL of water. The MeOH was then removed
under reduced pressure (rotavapor water bath about 25 °C), and EtOAc (100 mL) was
added to the flask. The phases were separated, and the aqueous phase was extracted with
EtOAc (3 × 100 mL). The combined organic phases were dried over Na2SO4, filtered and
concentrated under reduced pressure to provide the phosphorane 7 (96% yield, 10.9 g,
24.0 mmol), which was used immediately.
To a solution of phosphorane 7 (8.63 g, 19.0 mmol) in anhydrous benzene (80 mL) it was
added propionaldehyde (4.2 mL, 57 mmol, 3.0 equiv). The reaction mixture was stirred for 5
days at 90 °C (oil bath temperature). After this period, the reaction was concentrated under
reduced pressure, and the residue was purified by flash column chromatography using a
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→ hexane/EtOAc (90:10) as eluent to provide ester Eꢀ8
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(71% yield, 3.17 g, 13.5 mmol, E:Z= 10:1). (E)ꢀethyl 2ꢀ(4ꢀmethoxyphenyl)pentꢀ2ꢀenoate
(Eꢀ8): Physical state: colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.15–7.06 (m, 2H), 7.00 (t,
J = 7.7 Hz, 1H), 6.94–6.85 (m, 2H), 4.20 (q, J = 7.1 Hz, 2H), 3.82 (s, 3H), 2.11 (quint, J =
7.6 Hz, 2H), 1.27 (t, J = 7.1 Hz, 3H), 1.02 (t, J = 7.5 Hz, 3H).; 13C NMR (100 MHz, CDCl3) δ
167.8, 158.9, 146.1, 133.1, 131.0, 127.8, 113.5, 60.9, 55.4, 23.1 14.4, 13.5.; HRMS (ESI/Qꢀ
TOF) m/z: [M+Na]+ Calcd for C14H18O3Na 257.1148; Found 257.1151. (Z)ꢀethyl 2ꢀ(4ꢀ
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methoxyphenyl)pentꢀ2ꢀenoate (Zꢀ8): Physical state: colorless oil; H NMR (400 MHz,
CDCl3) δ 7.27–7.24 (m, 2H), 6.87–6.84 (m, 2H), 6.07 (t, J = 7.6 Hz, 1H), 4.29 (q, J = 7.1 Hz,
2H), 3.81 (s, 3H), 2.40 (quint, J = 7.5 Hz, 2H), 1.32 (t, J = 7.1 Hz, 3H), 1.10 (t, J = 7.5 Hz,
3H).; 13C NMR (100 MHz, CDCl3) δ 168.7, 159.2, 139.4, 133.8, 130.5, 128.3, 113.8, 60.8,
55.4, 23.6, 14.4, 14.1.; HRMS (ESI/QꢀTOF) m/z: [M+Na]+ Calcd for C14H18O3Na 257.1148;
Found 257.1161.
(E)ꢀ3ꢀ(4ꢀmethoxyphenyl)hexꢀ3ꢀenꢀ2ꢀol (10a). To a solution of ester Eꢀ8 (1.24 g, 5.29
mmol) in DCM (30 mL) at −78 °C, it was added a solution of DIBALꢀH (1.0 M in toluene,
13.2 mL, 13.2 mmol, 2.5 equiv) dropwise over 1 h via syringe pump. The mixture was
stirred at −78 °C for 1 h. After this period, the reaction was warmed to 0 °C, quenched by
the addition of aqueous saturated solution of Rochelle’s salt (50 mL), and stirred overnight.
The phases were separated, and the aqueous phase was extracted with Et2O (3 × 50 mL).
The combined organic phases were dried over Na2SO4, filtered, and concentrated under
reduced pressure to provide the alcohol 9, which was used in the next step without further
purification.
To a solution of oxalyl chloride (0.54 mL, 6.35 mmol, 1.2 equiv) in DCM (30 mL), at −78 °C,
it was added DMSO (0.90 mL, 12.7 mmol, 2.4 equiv) dropwise. The mixture was stirred for
30 min, followed by the dropwise addition of a solution of alcohol 9 in DCM (15 mL). After
30 min, Et3N (3.7 mL, 26.4 mmol, 5 equiv) was added dropwise, and the resulting slurry
was warmed to 0 °C and stirred for 1 h. The mixture was diluted with Et2O (35 mL) and
saturated aqueous solution of NH4Cl (10 mL). The phases were separated, and the
aqueous phase was extracted with Et2O (3 × 100 mL). The combined organic phase was
washed with H2O (3 × 50 mL), brine (50 mL), dried over Na2SO4, filtered, and concentrated
under reduced pressure to provide the aldehyde, which was used in the next step without
further purification.
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To a solution of aldehyde prepared as described above in anhydrous THF (30 mL), under
nitrogen and at 0 °C, it was added a solution of MeLi (1.6 M in Et2O, 3.6 mL, 5.82 mmol, 1.1
equiv) dropwise. The mixture was stirred for 30 min in this temperature. Then, aqueous
saturated solution of NH4Cl (20 mL) and water (10 mL) were added. The phases were
separated, and the aqueous phase was extracted with Et2O (3×80 mL). The combined
organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure.
The residue was purified by flash column chromatography using hexane/EtOAc (80:20) as
eluent to provide the alcohol 10a (77% over 3 steps, 0.836 g, 4.05 mmol). Physical state:
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yellow oil; H NMR (400 MHz, CDCl3) δ 7.13–7.04 (m, 2H), 6.94–6.84 (m, 2H), 5.67 (t, J =
7.3 Hz, 1H), 4.57–4.38 (m, 1H), 3.82 (s, 3H), 1.91 (quint, J = 7.4 Hz, 2H), 1.52 (d, J = 4.5
Hz, 1H), 1.21 (d, J = 6.4 Hz, 3H), 0.92 (t, J = 7.5 Hz, 3H).; 13C NMR (101 MHz, CDCl3) δ
158.7, 143.9, 130.7, 130.4, 129.2, 113.7, 72.5, 55.4, 22.4, 22.0, 14.5.; HRMS (ESI/QꢀTOF)
m/z: [M−H2O]+ Calcd for C13H16O 188.1274; Found 188.1262.
(E)ꢀtertꢀbutyl((3ꢀ(4ꢀmethoxyphenyl)hexꢀ3ꢀenꢀ2ꢀyl)oxy)dimethylsilane (10b). To
a
solution of 10a (0.206 g, 0.1 mmol, 1 equiv) in DCM (20 mL), were added imidazole (0.10 g,
0.15 mmol, 1.5 equiv) and tertꢀbutyldimethylsilyl chloride (0.18 g, 0.12 mmol, 1.2 equiv).
The mixture was stirred overnight at room temperature. Water was then added, and the
layers were separated. The aqueous layer was extracted with DCM (3 × 25 mL). The
organic layers were combined, washed with brine (30 mL), dried over MgSO4, filtered and
concentrated under reduced pressure. The residue was purified by flash column
chromatography on silica gel using hexane/EtOAc (90:10) as eluent to provide compound
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10b (60%, 0.192 g, 0.6 mmol). Physical state: colorless oil; H NMR (500 MHz, CDCl3) δ
7.07–7.04 (m, 2H), 6.88–6.85 (m, 2H), 5.68 (td, J = 7.4, 0.8 Hz, 1H), 4.43 (q, J = 6.2 Hz,
1H), 3.81 (s, 3H), 1.95–1.86 (m, 2H), 1.10 (d, J = 6.3 Hz, 3H), 0.93 (s, 9H), 0.91 (t, J = 7.5
Hz, 3H), 0.10 (s, 3H), 0.09 (s, 3H).; 13C NMR (126 MHz, CDCl3) δ 158.4, 143.7, 131.8,
130.4, 128.1, 113.4, 72.9, 55.3, 26.1, 23.7, 21.9, 18.5, 14.6, −4.5, −4.8.; HRMS (ESI/Qꢀ
TOF) m/z: [M+Na]+ Calcd for C19H32O2SiNa 343.2064; Found 343.2050.
2ꢀdꢀ(E)ꢀ3ꢀ(4ꢀmethoxyphenyl)hexꢀ3ꢀenꢀ2ꢀol (2ꢀdꢀ10a). To a solution of oxalyl chloride (0.2
mL, 2.3 mmol, 1.2 equiv) in CH2Cl2 (2.5 mL) at −78 °C it was added DMSO (0.4 mL, 5.6
mmol, 2.4 equiv) dropwise. The mixture was stirred for 30 min, followed by the dropwise
addition of a solution of alcohol 10a (0.109 g, 0.53 mmol, 1 equiv) in CH2Cl2 (2.5 mL). After
30 min, Et3N (0.70 mL, 5.0 mmol, 5 equiv) was added dropwise, and the resulting slurry
was left to warm up to 0 ºC (ice bath) for over 2 hours. The resulting mixture was extracted
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with EtOAc (3 × 25 mL). The combined organic layers were dried over Na2SO4, filtered, and
concentrated under reduced pressure to provide the corresponding ketone S2 (25%, 28
mg, 0.137 mmol). Next, to a 10ꢀml roundꢀbottomed flask charged with a solution of ketone
S2 (28 mg, 0.137 mmol, 1 equiv) in CD3OD (1.0 mL) at –48 ºC it was added sodium
borodeuteride (12 mg, 0.28 mmol, 1.02 equiv). The reaction was stirred until complete
consumption of the starting material (ca. 1.0 h) and quenched with H2O (0.5 mL), at –48 ºC,
for over 15 minutes. Then, water (5 mL) was added and the mixture was extracted with
EtOAc (3 × 2 mL). The organic layers were combined, dried over Na2SO4, filtered, and
concentrated under reduced pressure. The residue was purified by flash column
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chromatography on silica gel using a gradient of hexane/EtOAc (95:5)
→ hexane/EtOAc
(80:20) as eluent to provide compound 2ꢀdꢀ10a (84%, 24 mg, 0.116 mmol, >98% 2ꢀd). (E)ꢀ
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3ꢀ(4ꢀmethoxyphenyl)hexꢀ3ꢀenꢀ2ꢀone (S2): Physical state: colorless oil; H NMR (400
MHz, CDCl3) δ 7.03−7.00 (m, 2H); 6.93−6.89 (m, 2H), 6.83 (t, J = 7.5 Hz, 1H), 3.82 (s, 3H),
2.28 (s, 3H), 2.10 (quint, J = 7.5 Hz, 2H), 1.02 (t, J = 7.5 Hz, 3H).;13C NMR (100 MHz,
CDCl3) δ 199.4, 159.0, 145.7, 142.2, 130.8, 128.3, 113.8, 55.3, 27.4, 23.3, 13.5.; HRMS
(ESI/QꢀTOF) m/z: [M+Na]+ Calcd for C13H16O2Na 227.1042; Found 227.1047. 2ꢀdꢀ(E)ꢀ3ꢀ(4ꢀ
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methoxyphenyl)hexꢀ3ꢀenꢀ2ꢀol (2ꢀdꢀ10a): Physical state: colorless oil; H NMR (400 MHz,
CDCl3) δ 7.10−7.06 (m, 2H), 6.91−6.87 (m, 2H), 5.67 (t, J = 7.3 Hz, 1H), 3.82 (s, 3H), 1.91
(quint, J = 7.5 Hz, 2H), 1.54 (s, 1H), 1.20 (s, 3H), 0.92 (t, J = 7.5 Hz, 3H).; 13C NMR (100
MHz, CDCl3) δ 158.7, 143.8, 130.7, 130.4, 129.2, 113.7, 72.1 (three lines, J = 22 Hz), 55.3,
22.3, 22.0, 14.5.; HRMS (ESI/QꢀTOF) m/z: [M+Na]+ Calcd for C13H17DO2Na 230.1262;
Found 230.1262.
2ꢀdꢀ(E)ꢀtertꢀbutyl((3ꢀ(4ꢀmethoxyphenyl)hexꢀ3ꢀenꢀ2ꢀyl)oxy)dimethylsilane (2ꢀdꢀ10b). To
a 5ꢀmL roundꢀbottomed flask charged with 2ꢀdꢀ10a (35 mg, 0.17 mmol) and imidazole (25
mg, 0.37 mmol, 2.2 equiv) at 0 °C was added DCM (2 mL). Then, tertꢀbutyldimethylsilyl
chloride (28 mg, 0.19 mmol, 1.1 equiv) was added and the reaction was allowed to warm up
to room temperature. The starting material was monitored by TLC until its complete
consumption. The resulting mixture was filtered throw a pad of silica, and the cake was
washed with DCM and the resulting solution was concentrated under reduced pressure.
The residue was purified by flash column chromatography on silica gel using hexanes as
eluent to provide the silyl ether 2ꢀdꢀ10b (95%, 52 mg, 0.16 mmol, >98% 2ꢀd). Physical
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state: colorless oil; H NMR (400 MHz, CDCl3) δ 7.07−7.04 (m, 2H), 6.88−6.85 (m, 2H),
5.67 (t, J = 7.4 Hz, 1H), 3.81 (s, 3H), 1.90 (quint, J = 7.4 Hz, 2H), 1.09 (s, 3H), 0.93 (s, 9H),
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0.91 (t, J = 7.4 Hz, 3H), 0.09 (s, 3H), 0.08 (s, 3H).; 13C NMR (100 MHz, CDCl3) δ 158.4,
143.7, 131.7, 130.4, 128.2, 113.4, 72.6 (three lines, J = 21.0 Hz), 55.3, 26.1, 23.6, 21.9,
18.5, 14.6, −4.5, −4.8.; HRMS (ESI/QꢀTOF) m/z: [M+Na]+ Calcd for C19H31DO2SiNa
344.2126; Found 344.2125.
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2ꢀdꢀ(E)ꢀ1ꢀmethoxyꢀ4ꢀ(2ꢀmethoxyhexꢀ3ꢀenꢀ3ꢀyl)benzene (2ꢀdꢀ10c). To a 5ꢀmL roundꢀ
bottomed flask charged with NaH (60% in mineral oil, 16 mg, 0.34 mmol, 1.8 equiv) at 0 °C,
a solution of 2ꢀdꢀ10a (39 mg, 0.19 mmol) in THF (2 mL) was quickly added. The
suspension was stirred at this temperature for over 1 h and MeI (32 ꢁL, 72 mg, 0.51 mmol)
was then added. The reaction was allowed to warm up to room temperature. The starting
material was monitored by TLC until its complete consumption. The resulting mixture was
filtered throw a silica pad, and the cake was washed with THF, and the resulting solution
was concentrated under reduced pressure. The crude product was purified by flash column
chromatography on silica gel using hexane/EtOAc (95:5) as eluent to provide the methyl
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ether 2ꢀdꢀ10c (74%, 31 mg, 0.14 mmol, >98% 2ꢀd). Physical state: colorless oil; H NMR
(400 MHz, CDCl3) δ 7.07−7.04 (m, 2H), 6.89−6.85 (m, 2H), 5.61 (t, J = 7.3 Hz, 1H), 3.81 (s,
3H), 3.37 (s, 3H), 1.96 (quint, J = 7.4 Hz, 2H), 1.12 (s, 3H), 0.94 (t, J = 7.5 Hz, 3H).; 13C
NMR (100 MHz, CDCl3) δ 158.5, 139.7,132.0, 130.8, 130.3, 113.5, 82.1 (three lines, J =
21.6 Hz), 55.9, 55.3, 22.0, 20.6,14.7.; HRMS (ESI/QꢀTOF) m/z: [M+Na]+ Calcd for
C14H19DO2Na 244.1418; Found 244.1419.
4.2. General procedure for the synthesis of aryl methyl ketones 3aꢀ3r
A 4 mL vial equipped with a magnetic stir bar was charged with Pd(TFA)2 (2.0 mol%, 0.004
mmol, 1.33 mg), olefin 1aꢀ1b or 4aꢀ4b (1 equiv, 0.2 mmol), ZnCO3 (0.5 equiv, 0.1 mmol,
12.5 mg), the appropriate arenediazonium salt 2 (2.0 equiv, 0.4 mmol) and MeOH (0.2 M,
1.0 mL). The vial was then closed and allowed to stir at 40 °C for 1aꢀ1b or 60 °C for 4aꢀ4b
until total consumption of the olefin (TLC). After completion, the solvent was removed under
reduced pressure. The crude material was dissolved in EtOAc (3 mL), filtered through a
short pad of silica gel and the cake was washed with EtOAc (3 × 5 mL). The crude material
was concentrated under reduced pressure and purified by flash column chromatography on
silica gel using hexane/EtOAc (90:10) as eluent to afford the corresponding HeckꢀMatsuda
products 3aꢀ3r.
(3R*,4R*)ꢀ3ꢀmethylꢀ4ꢀ(4ꢀ(trifluoromethyl)phenyl)hexanꢀ2ꢀone (3a) was obtained in 80%
isolated yield (0.16 mmol; 40 mg) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.53 (d,
J = 8.1 Hz, 2H), 7.26 (d, J = 8.1 Hz, 2H), 2.88–2.78 (m, 2H), 1.87 (s, 3H), 1.90–1.80 (m,
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1H), 1.59–1.48 (m, 1H), 1.17 (d, J = 6.5 Hz, 3H), 0.70 (t, J = 7.4 Hz, 3H).; 13C NMR (100
MHz, CDCl3) δ 211.9, 147.6, 128.8 (q, J = 32.4 Hz), 128.7, 125.4 (q, J = 3.5 Hz), 124.4 (q, J
= 271.5 Hz), 52.9, 49.6, 29.5, 24.8, 14.7, 11.8.; HRMS (EI/QꢀTOF) m/z: [M]+˙ Calcd for
C14H17F3O 258.1231; Found 258.1236.
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(3R*,4R*)ꢀ4ꢀ(4ꢀbromophenyl)ꢀ3ꢀmethylhexanꢀ2ꢀone (3b) was obtained in 85% isolated
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yield (0.17 mmol, 45 mg) as a pale yellow oil. H NMR (400 MHz, CDCl3) δ 7.42−7.36 (m,
2H), 7.03−7.00 (d, J = 8.4 Hz, 2H), 2.78 (dq, J = 9.1, 6.8 Hz, 1H), 2.71–2.65 (m, 1H), 1.86
(s, 3H), 1.84–1.76 (m, 1H), 1.53–1.41 (m, 1H), 1.14 (d, J = 6.8 Hz, 3H), 0.69 (t, J = 7.4 Hz,
3H).;13C NMR (100 MHz, CDCl3) δ 212.2, 142.3, 131.6, 130.1, 120.2, 53.0, 49.3, 29.6, 24,8,
14.7, 11.8.; HRMS (EI/QꢀTOF) m/z: [M]+˙ Calcd for C13H17BrO 268.0463; Found 268.0475.
(3R*,4R*)ꢀ4ꢀ(4ꢀchlorophenyl)ꢀ3ꢀmethylhexanꢀ2ꢀone (3c) was obtained in 88% isolated
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yield (0.17 mmol, 39 mg) as a pale yellow oil. H NMR (400 MHz, CDCl3) δ 7.26−7.23 (m,
2H), 7.09−7.05 (m, 2H), 2.78 (dq, J = 9.1, 6.8 Hz, 1H), 2.72–2.66 (m, 1H), 1.86 (s, 3H),
1.86–1.77 (m, 1H), 1.54−1.42 (m, 1H), 1.15 (d, J = 6.8 Hz, 3H), 0.69 (t, J = 7.3 Hz, 3H).; 13C
NMR (100 MHz, CDCl3) δ 212.2, 141.8, 132.2, 129.7, 128.7, 53.1, 49.3, 29.6, 24.8, 14.7,
11.8.; HRMS (EI/QꢀTOF) m/z: [M]+˙ Calcd for C13H17ClO 224.0968; Found 224.0952.
(3R*,4R*)ꢀ3ꢀmethylꢀ4ꢀ(4ꢀnitrophenyl)hexanꢀ2ꢀone (3d) was obtained in 95% isolated yield
(0.19 mmol, 44.2 mg) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.16−8.12 (m, 2H),
7.33−7.29 (m, 2H), 2.91–2.81 (m, 2H), 1.89 (s, 3H), 1.93–1.83 (m, 1H), 1.60–1.48 (m, 1H),
1.19 (d, J = 6.5 Hz, 3H), 0.69 (t, J = 7.4 Hz, 3H).; 13C NMR (100 MHz, CDCl3) δ 211.4,
151.6, 146.8, 129.2, 123.8, 52.8, 49.5, 29.6, 24.8, 14.8, 11.8.; HRMS (ESI/QꢀTOF) m/z:
[M+H]+ Calcd for C13H18NO3 236.1281; Found 236.1289.
(3R*,4R*)ꢀ4ꢀ(4ꢀmethoxyphenyl)ꢀ3ꢀmethylhexanꢀ2ꢀone (3e) was obtained in 87% isolated
yield (0.17 mmol, 38 mg) as a pale yellow oil. 1H NMR (250 MHz, CDCl3) δ 7.05 (d, J = 8.7
Hz, 2H), 6.81 (d, J = 8.6 Hz, 2H), 3.78 (s, 3H), 2.77 (dq, J = 13.2, 6.7 Hz, 1H), 2.68–2.59
(m, 1H), 1.83 (s, 3H), 1.83–1.72 (m, 1H), 1.54–1.41 (m, 1H), 1.13 (d, J = 6.7 Hz, 3H), 0.70
(t, J = 7.3 Hz, 3H).; 13C NMR (100 MHz, CDCl3) δ 213.0, 158.2, 135.1, 129.2, 113.9, 55.3,
53.4, 49.3, 29.5, 25.0, 14.7, 11.9.; HRMS (EI/QꢀTOF) m/z: [M]+˙ Calcd for C14H20O2
220.1463; Found 220.1433.
methyl (4ꢀ((3R*,4R*)ꢀ4ꢀmethylꢀ5ꢀoxohexanꢀ3ꢀyl)phenyl)carbamate (3f) was obtained in
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60% isolated yield (0.12 mmol, 31 mg) as a pale yellow oil. H NMR (400 MHz, CDCl3) δ
7.29 (d, J = 8.2 Hz, 2H), 7.08–7.05 (m, 2H), 6.64 (s, 1H), 3.76 (s, 3H), 2.78 (dq, J = 9.0, 6.8
Hz, 1H), 2.69–2.63 (m, 1H), 1.84 (s, 3H), 1.84–1.75 (m, 1H), 1.54–1.42 (m, 1H), 1.13 (d, J =
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6.8 Hz, 3H), 0.69 (t, J = 7.3 Hz, 3H).; 13C NMR (100 MHz, CDCl3) δ 212.8, 154.2, 138.2,
136.3, 128.9, 118.8, 53.2, 52.4, 49.4, 29.5, 24.9, 14.6, 11.8.; HRMS (EI/QꢀTOF) m/z: [M]+˙
Calcd for C15H21NO3 263.1521; Found 263.1543.
(3R*,4R*)ꢀ3ꢀmethylꢀ4ꢀphenylhexanꢀ2ꢀone (3g) was obtained in 45% isolated yield (0.09
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mmol, 17 mg) as a pale yellow oil. H NMR (400 MHz, CDCl3) δ 7.29–7.26 (m, 2H), 7.20–
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7.16 (m, 1H), 7.15–7.13 (m, 2H), 2.82 (dq, J = 9.0, 6.8 Hz, 1H), 2.73–2.67 (m, 1H), 1.87–
1.77 (m, 1H), 1.83 (s, 3H), 1.59–1.48 (m, 1H), 1.15 (d, J = 6.8 Hz, 3H), 0.71 (t, J = 7.3 Hz,
3H).; 13C NMR (100 MHz, CDCl3) δ 212.8, 143.2, 128.5, 128.3, 126.5, 53.2, 50.1, 29.5,
24.8, 14.6, 11.9.; HRMS (EI/QꢀTOF) m/z: [M]+˙ Calcd for C13H18O 190.1358; Found
190.1329.
(3R*,4R*)ꢀ4ꢀ(2ꢀmethoxyphenyl)ꢀ3ꢀmethylhexanꢀ2ꢀone (3h) was obtained in 55% isolated
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yield (0.11 mmol, 24 mg) as a pale yellow oil. H NMR (400 MHz, CDCl3) δ 7.20–7.15 (m,
1H), 7.09 (dd, J = 7.6, 1.6 Hz, 1H), 6.91 (td, J = 7.5, 0.9 Hz, 1H), 6.86 (d, J = 8.2 Hz, 1H),
3.84 (s, 3H), 3.35–3.29 (m, 1H), 2.88 (quint, J = 7.0 Hz, 1H), 2.00 (s, 3H), 1.68–1.58 (m,
2H), 1.05 (d, J = 6.9 Hz, 3H), 0.72 (t, J = 7.4 Hz, 3H).; 13C NMR (100 MHz, CDCl3) δ 212.7,
157.5, 131.0, 128.4, 127.3, 120.6, 110.7, 55.5, 51.5, 41.8, 28.2, 22.7, 13.0, 11.9.; HRMS
(EI/QꢀTOF) m/z: [M]+˙ Calcd for C14H20O2 220.1463; Found 220.1433.
(3R*,4R*)ꢀ3ꢀmethylꢀ4ꢀ(2ꢀnitrophenyl)hexanꢀ2ꢀone (3i) was obtained in 45% isolated yield
(0.09 mmol, 21 mg) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.71 (dd, J = 8.1, 1.2
Hz, 1H), 7.55–7.51 (m, 1H), 7.38–7.30 (m, 2H), 3.53–3.47 (m, 1H), 2.90 (quint, J = 7.1 Hz,
1H), 2.01 (s, 3H), 1.86–1.76 (m, 1H), 1.68–1.57 (m, 1H), 1.14 (d, J = 7.0 Hz, 3H), 0.74 (t, J
= 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 211.0, 137.3, 133.5, 132.3, 128.9, 127.3,
124.4, 52.5, 42.2, 28.3, 24.1, 13.5, 11.5.; HRMS (ESI/QꢀTOF) m/z: [M+H]+ Calcd for
C13H18NO3 236.1281; Found 236.1287.
(3R*,4R*)ꢀ4ꢀ(3ꢀmethoxyphenyl)ꢀ3ꢀmethylhexanꢀ2ꢀone (3j) was obtained in 77% isolated
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yield (0.15 mmol, 32 mg) as a pale yellow oil. H NMR (400 MHz, CDCl3) δ 7.19 (t, J = 7.9
Hz, 1H), 6.75–6.68 (m, 3H), 3.79 (s, 3H), 2.81 (dq, J = 9.0, 6.9 Hz, 1H), 2.67 (ddd, J = 11.0,
9.3, 3.6 Hz, 1H), 1.86 (s, 3H), 1.86–1.75 (m, 1H), 1.58–1.44 (m, 1H), 1.14 (d, J = 6.9 Hz,
3H), 0.72 (t, J = 7.3 Hz, 3H).; 13C NMR (100 MHz, CDCl3) δ 212.7, 159.7, 144.9, 129.4,
120.8, 114.4, 111.5, 55.3, 53.1, 50.0, 29.5, 24.8, 14.6, 11.9.; HRMS (ESI/QꢀTOF) m/z:
[M+H]+ Calcd for C14H21O2 221.1536; Found 221.1536.
(3R*,4R*)ꢀ3ꢀmethylꢀ4ꢀ(3ꢀ(trifluoromethyl)phenyl)hexanꢀ2ꢀone (3k) was obtained in 80%
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isolated yield (0.16 mmol, 41 mg) as a pale yellow oil. H NMR (400 MHz, CDCl3) δ 7.46–
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7.32 (m, 4H), 2.88–2.78 (m, 2H), 1.87 (s, 3H), 1.80–1.80 (m, 1H), 1.58–1.48 (m, 1H), 1.16
(d, J = 6.5 Hz, 3H), 0.70 (t, J = 7.4 Hz, 3H).; 13C NMR (100 MHz, CDCl3) δ 211.9, 144.4,
132.0, 130.8 (q, J = 32.1 Hz), 129.0, 124.7 (q, J = 3.8 Hz), 124.3 (q, J = 272.3 Hz), 123.5
(q, J = 3.8 Hz), 52.9, 49.6, 29.6, 24.7, 14.6, 11.8.; HRMS (EI/QꢀTOF) m/z: [M]+˙ Calcd for
C14H17F3O 258.1231; Found 258.1257.
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(3R*,4R*)ꢀ3ꢀmethylꢀ4ꢀ(3,4,5ꢀtrimethoxyphenyl)hexanꢀ2ꢀone (3l) was obtained in 75%
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isolated yield (0.15 mmol, 41.7 mg) as a pale yellow oil. H NMR (400 MHz, CDCl3) δ 6.33
(s, 2H), 3.82 (s, 6H), 3.80 (s, 3H), 2.79 (dq, J = 9.1, 6.9 Hz, 1H), 2.64–2.58 (m, 1H), 1.86 (s,
3H), 1.79 (dqd, J = 14.7, 7.4, 3.7 Hz, 1H), 1.47 (ddq, J = 14.4, 11.0, 7.2 Hz, 1H), 1.14 (d, J
= 6.9 Hz, 3H), 0.73 (t, J = 7.3 Hz, 3H).; 13C NMR (100 MHz, CDCl3) δ 212.7, 153.2, 139.0,
136.6, 105.3, 61.0, 56.2, 53.0, 50.4, 29.6, 25.0, 14.8, 11.9.; HRMS (ESI/QꢀTOF) m/z:
[M+H]+ Calcd for C16H25O4 281.1747; Found 281.1765.
(3S*,4R*)ꢀ4ꢀ(4ꢀmethoxyphenyl)ꢀ3ꢀphenylhexanꢀ2ꢀone (3m) was obtained in 70% isolated
yield (0.14 mmol, 39 mg) as a white solid. mp: 125ꢀ128 °C. 1H NMR (400 MHz, CDCl3) δ
7.38–7.27 (m, 5H), 7.19–7.15 (m, 2H), 6.87–6.83 (m, 2H), 3.96 (d, J = 11.2 Hz, 1H), 3.79
(s, 3H), 3.20 (td, J = 11.2, 3.6 Hz, 1H), 1.82 (s, 3H), 1.41–1.20 (m, 2H), 0.57 (t, J = 7.3 Hz,
3H).; 13C NMR (100 MHz, CDCl3) δ 208.1, 158.2, 137.5, 135.1, 129.3, 129.0, 127.6, 113.9,
66.3, 55.3, 48.8, 30.8, 26.4, 11.7.; HRMS (ESI/QꢀTOF) m/z: [M+H]+ Calcd for C19H23O2
283.1693; Found 283,1688.
(3S*,4R*)ꢀ4ꢀ(4ꢀbromophenyl)ꢀ3ꢀphenylhexanꢀ2ꢀone (3n) was obtained in 75% isolated
yield (0.15 mmol, 47 mg) as a pale yellow oil. 1H NMR (500 MHz, CDCl3) δ 7.43 (d, J = 8.3
Hz, 2H), 7.37–7.28 (m, 5H), 7.14 (d, J = 8.3 Hz, 2H), 3.94 (d, J = 11.2 Hz, 1H), 3.23 (td, J =
11.2, 3.4 Hz, 1H), 1.84 (s, 3H), 1.39–1.30 (m, 1H), 1.30–1.21 (m, 1H), 0.55 (t, J = 7.3 Hz,
3H).; 13C NMR (125 MHz, CDCl3) δ 207.4, 142.5, 137.0, 131.6, 130.2, 129.1, 129.0, 127.8,
120.2, 65.9, 48.9, 30.7, 26.2, 11.7.; HRMS (ESI/QꢀTOF) m/z: [M+H]+ Calcd for C18H20BrO
331.0692; Found 331.0677.
(3S*,4R*)ꢀ3ꢀphenylꢀ4ꢀ(4ꢀ(trifluoromethyl)phenyl)hexanꢀ2ꢀone (3o) was obtained in 77%
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isolated yield (0.154 mmol, 47 mg) as a pale yellow oil. H NMR (400 MHz, CDCl3) δ 7.49
(d, J = 8.0 Hz, 2H), 7.32–7.22 (m, 7H), 3.93 (d, J = 11.2 Hz, 1H), 3.26 (td, J = 11.1, 3.7 Hz,
1H), 1.77 (s, 3H), 1.36–1.13 (m, 2H), 0.48 (t, J = 7.3 Hz, 3H).; 13C NMR (100 MHz, CDCl3) δ
207.2, 147.8, 136.8, 129.2, 129.0, 128.8, 128.8 (q, J = 32.1 Hz), 127.9, 125.4 (q, J = 3.7
Hz), 124.4 (q, J = 272.0 Hz), 65.7, 49.2, 30.6, 26.3, 11.6.; HRMS (ESI/QꢀTOF) m/z: [M+H]+
Calcd for C19H20F3O 321.1461; Found 321.1458.
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isolated yield (0.12 mmol, 33 mg) as a pale yellow oil. H NMR (400 MHz, CDCl3) δ 7.43–
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7.22 (m, 9H), 3.93 (d, J = 11.1 Hz, 1H), 3.26 (td, J = 11.1, 3.7 Hz, 1H), 1.77 (s, 3H), 1.37–
1.16 (m, 2H), 0.48 (t, J = 7.4 Hz, 3H).; 13C NMR (101 MHz, CDCl3) δ 207.2, 144.6, 136.8,
132.4, 130.8 (q, J = 31.8 Hz), 129.2, 129.0, 128.9, 127.9, 124.6 (q, J = 3.6 Hz), 124.4 (q, J
= 272.3 Hz), 123.5 (q, J = 3.7 Hz), 65.7, 49.2, 30.6, 26.3, 11.6.; HRMS (ESI/QꢀTOF) m/z:
[M+H]+ Calcd for C19H20F3O 321.1461; Found 321.1437.
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(3S*,4R*)ꢀ4ꢀ(2ꢀmethoxyphenyl)ꢀ3ꢀphenylhexanꢀ2ꢀone (3q) was obtained in 50% isolated
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yield (0.10 mmol, 27 mg) as a pale yellow oil. H NMR (500 MHz, CDCl3) δ 7.40–7.25 (m,
5H), 7.19–7.15 (m, 2H), 6.91 (t, J = 7.5 Hz, 1H), 6.88 (d, J = 8.1 Hz, 1H), 4.23 (d, J = 11.1
Hz, 1H), 3.88 (s, 3H), 3.74 (dd, J = 12.9, 5.2 Hz, 1H), 1.86 (s, 3H), 1.41–1.35 (m, 2H), 0.57
(t, J = 7.4 Hz, 3H).; 13C NMR (125 MHz, CDCl3) δ 208.2, 157.9, 137.8, 131.1, 129.2, 128.8,
127.4, 120.7, 111.1, 64.3, 55.7, 29.7, 25.3, 11.5.; HRMS (ESI/QꢀTOF) m/z: [M+H]+ Calcd for
C19H23O2 283.1693; Found 283.1688.
(3S*,4R*)ꢀ3,4ꢀdiphenylhexanꢀ2ꢀone (3r) was obtained in 60% isolated yield (0.12 mmol,
28 mg) as a white solid. 1H NMR (500 MHz, CDCl3) δ 7.38–7.18 (m, 10H), 4.01 (d, J = 11.2
Hz, 1H), 3.25 (td, J = 11.1, 3.6 Hz, 1H), 1.82 (s, 3H), 1.41–1.26 (m, 2H), 0.57 (t, J = 7.3 Hz,
3H).; 13C NMR (125 MHz, CDCl3) δ 207.9, 143.2, 137.4, 129.0, 128.5, 128.4, 127.6, 126.5,
66.0, 49.6, 30.7, 26.4, 11.7.; HRMS (EI/QꢀTOF) m/z: [M]+˙ Calcd for C18H20O 252.1514;
Found 252.1532.
4.3. Total synthesis of mesoꢀhexestrol (14) from olefin 10a
(3S*,4R*)ꢀ3,4ꢀbis(4ꢀmethoxyphenyl)hexanꢀ2ꢀone (11a) – gram scale. A 50ꢀmL roundꢀ
bottomed flask equipped with a magnetic stir bar was charged with Pd(TFA)2 (2.0 mol%,
0.1 mmol, 32.2 mg), olefin 10a (1.0 g, 4.85 mmol, 1 equiv), ZnCO3 (304 mg, 2.42 mmol, 0.5
equiv), the appropriate arenediazonium salt 2e (9.70 mmol, 2.0 equiv) and MeOH (0.2 M,
25.5 mL). The flask was then closed and allowed to stir at 60 °C until total consumption of
olefin (TLC). After completion, the solvent was removed under reduced pressure. The crude
material was solubilized with EtOAc (30 mL), filtered through a short pad of silica gel and
the cake was washed with EtOAc (3 × 50 mL). The crude material was concentrated under
reduced pressure and purified by flash column chromatography on silica gel using
hexane/EtOAc (90:10) as eluent to afford the product 11a (65%, 0.98 g, 3.14 mmol).
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Physical state: white solid. mp: 125ꢀ128 °C. H NMR (500 MHz, CDCl3) δ 7.27 (d, J = 8.7
Hz, 2H), 7.15 (d, J = 8.6 Hz, 2H), 6.89 (d, J = 8.7 Hz, 2H), 6.84 (d, J = 8.6 Hz, 2H), 3.89 (d,
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J = 11.2 Hz, 1H), 3.81 (s, 3H), 3.79 (s, 3H), 3.15 (td, J = 11.2, 3.4 Hz, 1H), 1.81 (s, 3H),
1.42−1.34 (m, 1H), 1.30–1.21 (m, 1H), 0.57 (t, J = 7.3 Hz, 3H).; 13C NMR (126 MHz,
CDCl3) δ 208.4, 159.1, 158.1, 135.2, 130.0, 129.5, 129.3, 114.4, 113.9, 65.3, 55.4, 55.3,
48.8, 30.6, 26.4, 11.7.; HRMS (EI/QꢀTOF) m/z: [M]+˙ Calcd for C20H24O3 312.1725; Found
312.1752.
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(3S*,4R*)ꢀ3,4ꢀbis(4ꢀmethoxyphenyl)hexanꢀ2ꢀone (11a) – 0.2 mmol scale. A 4 mL vial
equipped with a magnetic stir bar was charged with Pd(TFA)2 (2.0 mol%, 0.004 mmol, 1.33
mg), olefin 10a or 10b (1 equiv, 0.2 mmol), ZnCO3 (0.5 equiv, 0.1 mmol, 12.5 mg), the
appropriate arenediazonium salt 2e (2.0 equiv, 0.4 mmol) and MeOH (0.2 M, 1.0 mL). The
vial was then closed and allowed to stir at 60 °C until total consumption of olefin (TLC).
After completion, the solvent was removed under reduced pressure. The crude material
was solubilized with EtOAc (3 mL), filtered through a short pad of silica gel and the cake
was washed with EtOAc (3 × 5 mL). The crude material was concentrated under reduced
pressure and purified by flash column chromatography on silica gel using hexane/EtOAc
(90:10) as eluent to afford the product 11a (78%, 46 mg, 0.15 mmol).
2ꢀ((1S*,2R*)ꢀ1,2ꢀbis(4ꢀmethoxyphenyl)butyl)ꢀ2ꢀmethylꢀ1,3ꢀdithiolane (12). To a stirred
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solution of ketone 11a (0.031 g, 0.1 mmol) in DCM (0.25 mL), at −5 C, was added 1,2ꢀ
ethanedithiol (0.017 mL, 0.2 mmol, 2.5 equiv) followed by BF3.OEt2 (0.09 mL, 0.07 mmol).
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The reaction mixture was maintained at −5 C for 2 h. After this time more BF3.OEt2 (0.09
mL, 0.07 mmol) was added. The mixture was allowed to warm room temperature and
maintained under magnetic stirring for 12 h. After completion, the reaction mixture was
filtered through a short pad of silica gel and the cake was washed with EtOAc (3 × 5 mL).
The solvent was removed under reduced pressure and the crude product was purified by
flash column chromatography on silica gel using hexane/EtOAc (90:10) as eluent to provide
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the dithiane 12 (quantitative, 0.038 g, 0.1 mmol). Physical state: viscous colorless oil. H
NMR (400 MHz, CDCl3) δ 7.29–7.26 (m, 2H), 7.18–7.14 (m, 2H), 6.85 (d, J = 8.7 Hz, 4H),
3.82 (s, 3H), 3.81 (s, 3H), 3.42 (d, J = 8.8 Hz, 1H), 3.22–3.01 (m, 5H), 1.75 (s, 3H), 1.64–
1.53 (m, 1H), 1.27–1.15 (m, 1H), 0.51 (t, J = 7.3 Hz, 3H).; 13C NMR (100 MHz, CDCl3) δ
158.6, 158.5, 135.7, 134.5, 130.5, 113.5, 113.2, 72.0, 62.6, 55.31, 55.28, 49.6, 40.9, 37.3,
32.2, 28.0, 12.4.; HRMS (ESI/QꢀTOF) m/z: [M+H]+ Calcd for C22H28O2S2Na 411.1423;
Found 411.1445.
4,4'ꢀ((3RS,4SR)ꢀhexaneꢀ3,4ꢀdiyl)bis(methoxybenzene) (13).18 A solution of dithiane 12
(0.038 g, 0.1 mmol) in MeOH (5 mL) was stirred under hydrogen with activated Raney
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nickel (570 mg, 15 equiv. in mass). The reaction mixture was stirred at room temperature
for 24 h. After completion, the reaction mixture was carefully filtered through a short pad of
silica gel and the cake was washed with EtOAc (3 × 5 mL). The combined filtrate was taken
to dryness under vacuum and the residue was purified by flash chromatography on silica
gel using hexane/EtOAc (90:10) as eluent to provide the compound 13 (77%, 0.023 g,
0.077 mmol). Physical state: white solid. mp: 140ꢀ143 °C. 1H NMR (400 MHz, CDCl3) δ 7.08
(d, J = 8.5 Hz, 4H), 6.87 (d, J = 8.5 Hz, 4H), 3.82 (s, 6H), 2.52–2.45 (m, 2H), 1.45–1.19 (m,
4H), 0.54 (t, J = 7.3 Hz, 6H).; 13C NMR (101 MHz, CDCl3) δ 157.9, 136.8, 129.3, 113.7,
55.3, 53.7, 27.5, 12.4.; HRMS (ESI/QꢀTOF) m/z: [M+H]+ Calcd for C20H26O2Na 321.1825;
Found 321.1801.
4,4'ꢀ((3R*,4S*)ꢀhexaneꢀ3,4ꢀdiyl)diphenol (14).24 To a solution of compound 13 (0.029 g,
0.1 mmol) in DCM (20 mL) was added a solution of BBr3 (0.9 M in DCM, 0.54 mL, 0.5
mmol), at −72 oC. The solution was allowed to warm to room temperature and stirred for 3.5
h, poured onto 20 mL of iceꢀwater, and extracted with Et2O (3 × 15 mL). The combined
organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure.
The crude product was purified by flash column chromatography on silica gel using
hexane/EtOAc (50:50) as the eluent to provide the mesoꢀhexestrol (14) (82%, 0.022 g,
0.082 mmol). Physical state: white solid. mp: 184ꢀ186 °C. 1H NMR (500 MHz,
DMSO/CDCl3) δ 8.88 (bs, 2H), 6.88 (d, J = 8.1 Hz, 4H), 6.66 (d, J = 8.0 Hz, 4H), 2.34−2.32
(m, 2H), 1.32 – 1.10 (m, 4H), 0.43 (t, J = 7.2 Hz, 6H).; 13C NMR (126 MHz, DMSO/CDCl3) δ
155.0, 134.2, 128.5, 114.7, 52.7, 26.7, 11.8.
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4.4. Experimental procedure for mechanistic studies
General procedure for HeckꢀMatsuda arylations (Table 3 and Scheme 4). A 4ꢀmL vial
containing a stir bar was charged with the olefin 1d−e (1 equiv, 0.2 mmol) or 2ꢀdꢀ10a−c (1
equiv, 0.1 mmol), the arenediazonium salt (2 equiv) and base (0.5 equiv for ZnCO3, 1.0
equiv for protonꢀsponge, and 0.5 equiv for ZnCO3 + 1.0 equiv for DTBMP). A solution of
Pd(TFA)2 (5 mol%) in HPLCꢀgrade methanol or toluene (0.2 M) was prepared and
immediately added to the former mixture. The vial was sealed with a polypropylene screw
top hole cap and heated at 40 °C in a heating block. A needle was kept pierce into the vial
top to release N2 pressure. The reaction was monitored by TLC analysis until complete
consumption of the starting material (1ꢀ2 h). The crude reaction mixture was concentrated
under reduced pressure, dissolved in ethyl acetate (5 mL) and filtered through a silica gel
(2ꢀ3 g) pad with ethyl acetate (20 mL). The solution was concentrated under reduced
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pressure and the residue was purified by flash chromatography on silica gel using
hexane/EtOAc (95:5) as eluent to afford the HeckꢀMatsuda products 3c and 3ꢀdꢀ11a.
3ꢀdꢀ(3R*,4S*)ꢀ3,4ꢀbis(4ꢀmethoxyphenyl)hexanꢀ2ꢀone (3ꢀdꢀ11a) was obtained in 45%
isolated yield (0.045 mmol, >98% 3ꢀd) from 2ꢀdꢀ10a, 71% isolated yield (0.071 mmol, >98%
3ꢀd) from 2ꢀdꢀ10b, and 58% isolated yield (0.058 mmol, >98% 3ꢀd) from 2ꢀdꢀ10c as a white
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solid. H NMR (400 MHz, CDCl3) δ 7.29−7.25 (m, 2H), 7.17−7.14 (m, 2H), 6.91−6.87 (m,
2H), 6.86−6.82 (m, 2H), 3.81 (s, 3H), 3.79 (s, 3H), 3.14 (dd, J = 11.1 Hz, 3.2 Hz, 1H), 1.81
(s, 3H), 1.43−1.19 (m, 2H), 0.57 (t, J = 7.3 Hz, 3H).; 13C NMR (100 MHz, CDCl3) δ 208.4,
159.1, 158.1, 135.2, 129.9, 129.4, 129.3, 114.4, 113.9, 64.8 (three lines, J = 19.4 Hz), 55.4,
55.3, 48.7, 30.5, 26.4, 11.7.; HRMS (ESI/QꢀTOF) m/z: [M+Na]+ Calcd for C20H23DO3Na
336.1680; Found 336.1678.
ASSOCIATED CONTENT
SUPPORTING INFORMATION
The Supporting Information is available free of charge on the ACS Publications website.
Xꢀray crystallographic data of compound 3m (CIF).
1H and 13C NMR spectra of all compounds are provided (PDF).
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: roque@iqm.unicamp.br
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the São Paulo Research Foundation (FAPESP, grants: 2014/25770ꢀ6 and
2013/07600ꢀ3 [CRDC]; 2013/10639ꢀ9 [CF]; 2016/18061ꢀ4 [HE]); the Brazilian National
Research Council (CNPq, grants: 157522/2015ꢀ6 [ECP] and 457027/2014ꢀ 2 [CRDC]), and
the Coordination for the Improvement of Higher Education Personnel (PNPDꢀCAPES
[ECP]) for financial support and fellowships. We also thank Prof. Caio C. Oliveira
(UNICAMP) for valuable suggestions during the course of this study, and to Dr. D. Simoni
(UNICAMP) for the Xꢀray crystallographic analysis.
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3
REFERENCES
4
5
6
7
8
(1) a) Noda, H.; Amemiya, F.; Weidner, K.; Kumugai, N.; Shibasaki, M. Chem. Sci. 2017, 8,
3260–3269. b) Han, B.; Huang, W.; Ren, W.; He, G.; Wang, Jꢀ.H.; Peng, C. Adv. Synth.
Catal. 2015, 357, 561–568. c) Gati, W.; Yamamoto, H. Acc. Chem. Res. 2016, 49, 1757–
1768.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(2) a) Ozeki, M.; Hayama, N.; Fukutome, S.; Egawa, H.; Arimitsu, K.; Kajimoto, T.; Hosoi,
S.; Iwasaki, H.; Kojima, N.; Node, M.; Masayuki, M. ChemistrySelect. 2016, 1, 2565–2569.
b) Gurubrahamam, R. Cheng, Yꢀ.S.; Chen, K. Org. Lett. 2015, 17, 430−433.
(3) a) Kitamura, K.; Shimada, N.; Stewart, C.; Atesin, A. C.; Ateꢂin, T. A.; Tius, M. A.
Angew. Chem. Int. Ed. 2015, 54, 1–5. b) Li, J.; Lin, L.; Hu, B.; Zhou, P.; Huang, T.; Liu, X.;
Feng, X. Angew. Chem. Int. Ed. 2016, 55, 1–5.
(4) Zhang, C.; Tutkowski, B.; DeLuca, R. J.; Joyce, L. A.; Wiest, O.; Sigman, M. S. Chem.
Sci. 2017, 8, 2277–2282.
(5) For recent references see: a) Carmona, R. C.; Correia, C. R. D. Adv. Synth. Cat. 2015,
357, 2639–2643. b) Oliveira, C. C.; Pfaltz, A.; Correia, C. R. D. Angew. Chem. Int. Ed.
2015, 54, 14036–14039. c) Silva, J. O.; Angnes, R.A.; Silva, V. H. M.; Servilha, B. M.;
Adeel, M.; Braga, A. A. C.; Aponick, A.; Correia, C. R. D. J. Org. Chem. 2016, 81, 2010–
2018. d) de Azambuja, F.; Carmona, R. C.; Chorro, T.; Heerdt, G.; Correia, C. R. D. Chem.
Eur. J. 2016, 22, 11205–11209. e) Khan, I. U.; Kattela, S.; Hassan, A.; Correia, C. R. D.
Org. Biomol. Chem. 2016, 14, 9476–9480. f) Kattela, S.; Heerdt, G.; Correia, C. R. D. Adv.
Synth. Cat. 2017, 359, 260–267. g) Silva, A. R.; Polo, E. C.; Martins, N. C; Correia, C. R. D.
Adv. Synth. Cat. 2018, 360, 346–365.
(6) For latest references see: a) Zhang, C.; Santiago, C. B.; Kou, L.; Sigman, M. S. J. Am.
Chem. Soc. 2015, 137, 7290–7293. b) Hilton, M. J.; Cheng, B.; Buckley, B. R.; Xu, L.;
Wiest, O.; Sigman, M. S. Tetrahedron 2015, 71, 6513–6518. c) Eiji, Y.; Hilton, M. J.;
Orlandi, M.; Saini, V.; Toste, F.D.; Sigman, M. S. J. Am. Chem. Soc. 2016, 138, 15877–
15880. d) Chen, Z.ꢀM.; Hilton, M. J.; Sigman, M. S. J. Am. Chem. Soc. 2016, 138, 11461–
11464. e) Thornbury, R. T.; Saini, V.; Fernandes, T. d. A.; Santiago, C. B.; Talbot, E. P. A.;
Sigman, M. S.; McKenna, J. M.; Toste, F. D. Chem. Sci. 2017, 8, 2890–2897. f) Avila, C.
M.; Patel, J. S.; Reddi, Y.; Saito, M.; Nelson, H. M.; Shunatona, H. P.; Sigman, M. S.;
Sunoj, R. B.; Toste, F. D. Angew. Chem. Int. Ed. 2017, 56, 5806–5811.
(7) For synthesis of hexestrol see: a) Campbell, N. R.; Dodds, C.; Lawson, W. Proc. Roy.
Soc. 1940, 128, 253–268. b) Solmssen, U. V. Chem. Rev. 1945, 37, 481–598. c) Grundy, J.
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