Diarylmethane synthesis through Re2O7-catalyzed bimolecular dehydrative Friedel-Crafts reactions

Article abstract of DOI:10.1039/c8sc03570a

This manuscript describes the application of Re₂O₇ to the syntheses of diarylmethanes from benzylic alcohols through solvolysis followed by Friedel-Crafts alkylation. The reactions are characterized by broad substrate scope, low catalyst loadings, high chemical yields, and minimal waste generation. The intermediate perrhenate esters are superior leaving groups to chlorides and bromides in these reactions. The polarity and water sequestering capacity of hexafluoroisopropyl alcohol are critical to the success of these processes. Re₂O₇ is a precatalyst for HOReO₃, which serves as a less costly and easily handled promoter for these reactions. Oxorhenium catalysts selectively activate alcohols in the presence of similarly substituted acetates, indicating a unique chemoselectivity and mechanism in comparison to Br?nsted acid catalysis.

Full text of DOI:10.1039/c8sc03570a

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Diarylmethane Synthesis through Re2O7-Catalyzed Bimolecular
Dehydrative Friedel-Crafts Reactions
Qi Qin,b Youwei Xiea* and Paul E. Floreancigb*
Received 00th January 20xx,
Accepted 00th January 20xx
This manuscript describes the application of Re2O7 to the syntheses of diarylmethanes from benzylic alcohols through
solvolysis followed by Friedel-Crafts alkylation. The reactions are characterized by broad substrate scope, low catalyst
loadings, high chemical yields, and minimal waste generation. The intermediate perrhenate esters are superior leaving
groups to chlorides and bromides in these reactions. The polarity and water sequestering capacity of hexafluoroisopropyl
alcohol are critical to the success of these processes. Re2O7 is a precatalyst for HOReO3, which serves as a less costly and
easily handled promoter for these reactions. Oxorhenium catalysts selectively activate alcohols in the presence of similarly
substituted acetates, indicating a unique chemoselectivity and mechanism in comparison to Brønsted acid catalysis.
DOI: 10.1039/x0xx00000x
www.rsc.org/
cyclization protocol in which allylic cations react with pendent
hydroxy groups.7,8 Re2O7 proved to be superior to Brønsted
acids for promoting these processes, leading us to speculate
Introduction
A report in 2007 from the American Chemical Society Green
Chemistry Institute Pharmaceutical Roundtable Research
Grant Program identified "OH activation for nucleophilic
substitution" as a process for which reactions are currently
used but better reagents are preferred.1 This can be achieved
by transiently enhancing the hydroxy group's nucleofugacity
through association with an electrophilic catalyst. The benefit
of this approach to substitution chemistry lies in the avoidance
of a distinct step to generate a leaving group and through the
generation of water as an environmentally benign by-product.
A number of recent reviews have highlighted the benefits of
dehydrative coupling reactions in complex molecule
synthesis.2 However, alcohol activation to generate minimally-
stabilized carbocations remains rare. The Hall group made a
notable advance in this area by showing3 that benzylic alcohols
bearing electron-withdrawing groups such as –CF3 or –CO2Me
ionize efficiently in the presence of a ferrocenyl boronic acid
catalyst in (CF3)2CHOH (HFIP) and CH3NO2 to form benzylic
cations that react with arenes in Friedel-Crafts reactions. The
Moran group subsequently showed4 that previously
inaccessible benzylic cations can be formed through TfOH-
mediated benzylic alcohol ionization in HFIP at elevated
temperatures.
that it could be an effective catalyst for enabling bimolecular
dehydrative coupling reactions. This manuscript describes the
realization of this objective by demonstrating that Re2O7 acts
as an exceptional catalyst for converting benzylic alcohols to
carbocations. This serves as an entry to efficient, green Friedel-
Crafts reactions with broad substrate scope at low catalyst
loadings, which is another transformation in the "reactions are
currently used but better reagents are preferred" list.
Experiments highlight the role of HFIP in promoting efficient
reactivity and define the reactivity of perrhenate as a leaving
group in ionization processes.
Results and discussion
p-Fluorobenzyl alcohol (1) served as the initial substrate for
this study (Scheme 1) since a fluoro group (σp = +0.06)9 will
provide modest destabilization for the intermediate benzylic
5c
1 to 10% (w/w) Re2O7•SiO2 (1 mol%) and p-
cation. Exposing
xylene (3 equiv) in HFIP (0.5 M) provided diarylmethane
3 in
85% yield within 6 h at rt. Re2O7•SiO2 was used as the catalyst
rather than crystalline Re2O7 because it can be measured more
easily for reactions in which low quantities of catalyst are
required. Conducting the reaction at 80 °C resulted in the
Our studies in the applications of Re2O7 to allylic alcohol
transposition reactions5,6 resulted in
reaction being complete within 2 h while delivering
yield. A reasonable pathway for this process involves the
conversion of to perrhenate ester by reaction with Re2O7
or HOReO3. The ionization of to form cation
the addition of yields diarylmethane
3 in 89%
a new dehydrative
1
4
4
5
followed by
2
3. The weak
nucleophilicity arenes and the substituent effects shown below
strongly implicate an ionization-based mechanism.
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carbomethoxy group (σp = +0.45), do not suppress ionization.
p-Cyanobenzyl alcohol is not a suitable substrate for this
process under the standard conditions (σp = +0.66 for the
cyano group), but can be employed if crystalline Re2O7 is
employed rather than Re2O7•SiO2. We postulate that the SiO2,
while facilitating reagent handling, provides a buffering effect
that diminishes reactivity. Crystalline Re2O7 can also be used to
effect ionization of 3,5-bis-trifluoromethylbenzyl alcohol (σ =
+0.43 for the CF3 group), though this reaction requires heating
for 2 d to achieve a moderate product yield. p-Nitrobenzyl
Scheme 1. Re2O7-mediated dehydrative Friedel-Crafts alkylation.
alcohol (σp = +0.78 for the nitro group) reacts very slowly (39%
A partial scope of the process is shown in Figure 1. These
transformations use p-xylene as the nucleophile (3 equiv), HFIP
as the solvent (used as supplied from the source), and
Re2O7•SiO2 as the catalyst (1 mol%) with the alcohol
concentration being 0.5 M. The reactions were conducted in a
sealed vial at 80 °C unless otherwise noted (oil bath
temperature) and were stopped after 2 h without monitoring
progress.
after 2 d at 100 °C, not shown), though p-nitrophenethyl
alcohol reacts smoothly under the standard reaction
conditions due to the cation stabilizing effect of the additional
methyl group. Small amounts of dialkylated products are also
formed in these reactions though generally in less than 10%
yield.
A study of initial reaction rates showed that Re2O7•SiO2 is
slightly less reactive than Re2O7 in promoting reactions with
most substrates. Our prior studies on the use of Re2O7•SiO2,5c
which is simply prepared from stirring Re2O7 with SiO2 in Et2O
followed by solvent evaporation, showed that the reclaimed
catalyst was less potent in subsequent transformations. This
indicates that catalytic activity arises from Re2O7 leeching from
the SiO2 surface. This was tested (Scheme 2) by stirring
Re2O7•SiO2 in HFIP at 80 °C for 30 min and removing the silica
gel by filtration (PTFE filter). Compounds
1 and 2 were then
added to the filtrate to generate 3 in 82% yield, indicating that
Re2O7 is released from SiO2 into solution to a sufficient degree
to promote the reaction of a moderately reactive substrate.
This behavior is distinct from agents in which Re2O7 is grafted
onto oxygenated surfaces at high temperature.10 We therefore
postulate that the difference in reactivity between crystalline
Re2O7 and Re2O7•SiO2 arises from the lower concentrations of
the relevant catalyst in solution due to incomplete release
from or readsorption onto the SiO2 surface.
Figure 1. Representative scope of the dehydrative diarylmethane synthesis. a Reaction
Scheme 2. Demonstration of catalyst release from SiO2.
was conducted at 100 °C for 24 h. The product was isolated in 95% yield when the
b
reaction was conducted at 80 °C for
5
h
with crystalline Re2O7. Reaction was
c
conducted with crystalline Re2O7 for 23 h. Reaction was conducted with crystalline
Re2O7 for 48 h.
We next studied the reactivity of various simple arene
nucleophiles in this reaction. This study utilized
pentafluorobenzyl alcohol (18) as a relatively unreactive
substrate. The results are shown in Table 1. Reaction rates
generally correlated with expected nucleophilicity trends. Thus
benzene reacts efficiently but significantly more slowly than p-
xylene. Increasing the number of methyl groups leads to faster
reactions. Reactions with nucleophiles that have more than
one reactive site lead to regioisomeric product mixtures.
Naphthalene also serves as a competent nucleophile, with
reaction rates that are comparable to methylated benzene
derivatives. Anisole reacts at a rate that is comparable to
toluene, despite the superior electron donating ability of the
methoxy group in comparison to a methyl group. We postulate
that the HFIP forms hydrogen bonds to the oxygen of the
The reaction is effective for regioisomeric fluorobenzylic
alcohols and polyfluorinated substrates. This is noteworthy
because of the strong inductive cation destabilization
displayed by m-fluoro groups (
σ = +0.34). Pentafluorobenzyl
alcohol reacts somewhat more sluggishly but it can be
converted to the diarylmethane efficiently at slightly higher
temperature and over
inductively electron-withdrawing moieties,
trifluoromethyl groups ( p = +0.54) do not suppress ionization.
Chloro and bromo groups ( p = +0.23) are also tolerated in the
a
longer reaction time. Other
such as
σ
σ
processes. Groups that moderately destabilize the
intermediate cation through conjugation, such as the
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Table 1. Reactivity comparison of simple arene nucleophiles.a
methoxy group, thereby inhibiting its capacity to act as an
electron donor. Regiocontrol was not high in these processes,
as expected for electrophilic aromatic substitution reactions
with extremely reactive electrophiles
The high electrophilicity of the intermediate carbocations
in these processes led us to explore haloarene nucleophiles
(Table 2). Haloarenes were predominantly used as the
nucleophiles in these reactions due to the capacity to convert
the products to other materials through cross-coupling
reactions and because of the established benefits of
incorporating fluorine into pharmaceutical agents.11 The
reactions with weaker nucleophiles were somewhat less
efficient, due to increased polyalkylation resulting from the
formation of products that are less sterically hindered than
those derived from p-xylene, Regioisomeric mixtures were
produced,12 as expected for Friedel-Crafts reactions on
halobenzenes, with fluorobenzene being more selective for
para-additions than the other halobenzenes. Despite these
issues the reactions delivered useful yields of the desired
products. Mayr proposed that arene nucleophilicity correlates
with σ+ Hammett values.13 The success of fluoro- (σ+ = –0.07,
entries 1, 4, and 5), chloro- (σ+ = +0.12), bromo- (σ+ = +0.15),
and iodo- (σ+ = +0.14) benzenes, coupled with our observation
of only trace amounts of the adduct with methyl benzoate (σ+
= +0.32) by LC-MS (not shown), suggest that the σ+ cut-off for
substituents to show useful reactivity is approximately +0.2.
Regiocontrol can be dictated by avoiding steric interactions, as
seen in the selective formation of 33 (entry 8).12 The capacity
to remove the tert-butyl group through retro Friedel-Crafts
chemistry14 make this a potentially powerful approach to
preparing ortho-disubstituted products.15
entry
1
product
yieldb
92%
temp, t
100 °C
72 h
99%
1.8:1.0:1.7
o:m:p
2
80 °C
24 h
97%
3:2
3
4
5
80 °C
5 h
1,2,4:1,2,3
99%
97%
80 °C
4 h
80 °C
4 h
Table 2. Expanding the nucleophile scope.a
6
94%
80 °C
4 h
entry
arene
alcohol
product
yieldb
p:o
40%
1
2
3
1.6:1
97%
3:1
7
8
80 °C
4 h
46%
1:1
α:β
29
29
62%
97%
1.2:1
8.4:2.0:1.0
80 °C
5 h
1,2,4:1,2,6:1,3,5
55%
4
5
28
2.8:1
56%
98%
2.8:1
p:o
35
1
2.2:1
9
80 °C
24 h
56%
2:1
6
7
31
31
a Reactions proceeded with pentafluorobenzyl alcohol (1 equiv), the nucleophilic
53%
arene (3-5 equiv), and crystalline Re2O7 in HFIP at the indicated temperatures and
1.8:1
b
for the indicated times.
determined by 1H NMR.
Yields refer to purified materials. Ratios were
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43%
1:0
became a minor competitive pathway. Although HFIP is not an
inherently green solvent,16 the capacity to conduct these
reactions at high concentrations and removing the solvent
through distillation without an aqueous work-up improves the
process mass intensity17 and mitigates concerns of using a
halogenated solvent for these processes.
8
29
a All reactions were run with 10% Re2O7•SiO2 (1 mol%) in HFIP (0.5 M) with three
equiv of the nucleophile. b Isolated yields of regioisomeric mixtures. Ratios were
determined by 1H NMR.
The concentration studies led us to study the role of HFIP
in promoting the transformation. Ghorai and co-workers
showed18 in related processes that Re2O7-mediated Friedel-
Crafts reactions with highly activated benzylic alcohols in
CH3CN are significantly slower than the reactions that we have
studied, indicating that the efficiencies of our processes can be
attributed to the solvent. The roles of fluorinated alcohols in
promoting chemical reactions is a topic of significant interest,
and has been reviewed thoroughly.19 HFIP is an extremely
polar solvent as determined by solvatochromism studies.20
This can be attributed to its exceptional capacity as a hydrogen
bond donor.21 HFIP is also a highly effective sequestering agent
for H2O,22 which can have a strong influence on equilibrium
concentrations of the intermediate benzylic cations. We
conducted the reaction of highly reactive alcohol 45 with 46 in
solvent mixtures containing varying fractions of HFIP to
determine its role in promoting the coupling reactions
(Scheme 4). We observed no qualitative difference in moving
from 100% HFIP to 75% HFIP:25% 1,2-dichloroethane (DCE),
50% HFIP:50% DCE, and 25% HFIP:75% DCE. A reaction in 90%
DCE:10% HFIP proceeded rapidly, but provided dialkylated
product 48 in 14% yield in addition to 83% of 47, indicating
that this solvent system actually enhances reactivity relative to
pure HFIP. Notably, conducting the reaction in pure DCE
resulted in the formation of 47 in 68% yield and ether 49 in
We next tested whether the catalyst loading could be
lowered below 1 mol% (Scheme 3). Initial experiments using
0.1 mol% Re2O7•SiO2 showed that m-fluorobenzyl alcohol
reacted with p-xylene to yield
6 in 73% yield after 3.5 h. The
less reactive substrate p-trifluoromethyl benzyl alcohol (44),
however, only provided diarylmethane 11 in 9% yield after 24
h. These results indicate that success with very low catalyst
loading is dependent upon the ease of carbocation formation.
This led us to investigate the limits of catalyst loading with a
substrate that readily undergoes ionization and an active
nucleophile. The reaction of p-methoxybenzyl alcohol (45) with
mesitylene (46) proceeds to completion in <20 min at rt to
yield 47 in 90% yield in the presence of 1 mol% Re2O7•SiO2, in
accord with predictions about the influence of cation stability
on reaction rates. Lowering the catalyst loading by a factor of
100 (0.01 mol%) resulted in the reaction proceeding to
complete conversion after 7 h at rt and a 93% isolated yield of
47. Lowering the catalyst loading by another factor of 3
(0.0033 mol%, 33 ppm) resulted in the need for gentle heating,
with the reaction requiring 9 h at 45 °C to proceed to
completion with a 96% yield of 47. The concentration of the
reaction was increased in consideration of large scale reactions
being the likely applications of extremely low catalyst loading.
Conducting the reaction at 2.5 M and 45 °C with 33 ppm Re2O7
provided results that were essentially identical to those from
the corresponding reaction at 0.5 M. Notably, increasing the
concentration further to 5.0 M led to a slightly less efficient
process, presumably due to the change in solvent properties as
the reaction approaches being solvent free, and dialkylation
29% yield. Moderately reactive alcohol 29 reacted with
25% DCE:75% HFIP with at 80 °C to yield in 64% yield after 17
h, and somewhat unreactive alcohol 44 reacted with under
2 in
6
2
these conditions to yield 11 in just 14% yield. These results
Scheme 3. Reactions at lower catalyst loading.
Scheme 4. Solvent effects.
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efficient than the result shown in Figure 1 for Re2O7. Several
aspects of these results are noteworthy. The loading of
rhenium with HOReO3 is half of what is required for the
Re2O7 reactions for most substrates, making its use
significantly more economical since Re2O7 is approximately
5 times more expensive than HOReO3 on a per mole
comparison.24 Additionally, HOReO3 is a liquid that can be
handled readily. Thus utilizing HOReO3 provides the
reactivity of crystalline Re2O7 and the handling ease of
Re2O7•SiO2 while being much less expensive. We conclude
based on these results and those described later that
reactions with Re2O7 and HOReO3 most likely proceed
through the same fundamental mechanism. HOReO3 is also
an extremely effective catalyst at low loadings, with 0.01
mol% sufficing to provide 47 from 45 and 46 in 92% yield
within 9 h at rt.
indicate that the polarity of HFIP is very important for
reactions in which the intermediate carbocation is not highly
stabilized, and slight changes in the solvent mixture can have a
pronounced effect on reaction efficiency. Additionally HFIP's
hydrogen bonding capacity is important for blunting the
nucleophilicity of the hydroxy groups in the substrates,
consistent with Mayr's studies on the nucleophilicity of
HFIP/H2O mixtures,23 and eliminating dehydrative ether
formation.
Additionally we conducted studies to determine whether
the unusual efficiency of these reactions could be attributed to
the reaction medium or to the nucleofugacity of perrhenate.
The pKa of perrhenic acid is –1.25 in water, which is
significantly higher than those of HCl and HBr. Therefore
carbocation formation through the loss of perrhenate should
be less efficient than through the loss of chloride or bromide.
We compared (Scheme 5) the Friedel-Crafts reactions of p-
fluorobenzyl alcohol (
absence of Re2O7•SiO2 to the reactions of the corresponding
benzylic chloride (50) and bromide (51). The reaction of with
in the presence of 1 mol% Re2O7•SiO2 in HFIP at rt, as
1) with p-xylene (2) in the presence and
1
2
described above, delivered diarylmethane
3 in 85% isolated
yield. No reaction was observed in the absence of Re2O7•SiO2
or in the presence of SiO2, thereby confirming the need for
Re2O7. Only 60% of chloride 50 was consumed after 6 h at rt,
giving
3
in 43% yield. The reaction of bromide 51 with
2 in HFIP
provided
3
in 69% yield after 6 h. Therefore the Re2O7-
mediated conditions generate a significantly better leaving
group than bromide or chloride. The rate difference is
particularly striking in consideration of the low concentrations
of the intermediate perrhenate esters and indicates that these
species are unexpectedly effective leaving groups.
Scheme 6. Catalyst comparison.
These results, coupled with Moran's observation of
catalysis by TfOH activation,4 lead to questions about the
mechanism of the alcohol activation. Although HOReO3 is a
much weaker Brønsted acid (pKa of –14 for TfOH) we
cannot eliminate the possibility that HFIP causes an
anomalous increase in the acidity of HOReO3, resulting in
these reactions proceeding through protonation rather than
perrhenate ester formation. We addressed this issue (Figure
2) initially through comparing the rates of Re2O7 (1 mol%),
TfOH (10 mol% and 2 mol%), HOReO3 (2 mol% and 1
mol%), and Re2O7•SiO2 (1 mol%) in the conversion of 53 to
11. These experiments showed that 1 mol% Re2O7, 10 mol%
TfOH, and 2 mol% HOReO3 promoted the transformation
at approximately the same rate. Lowering the loading of
TfOH to 2 mol% resulted in a reaction that was even slower
than the Re2O7•SiO2 catalyzed process. Thus if the
oxorhenium catalysts act solely as Brønsted acids then the
HFIP environment must cause HOReO3 to be a stronger
acid than TfOH. Notably, p-TsOH (pKa = –2.8) does not
promote the coupling reaction, indicating that the potential
acidity enhancement by HFIP is not a general phenomenon.
Scheme 5. Leaving group comparison.
2,6-Di-tert-butylpyridine completely suppresses these
reactions. This led us to speculate that HOReO3 is the
relevant catalyst. We tested the viability of perrhenic acid
(76.5 weight % in H2O) as a catalyst by comparing its
efficacy in the coupling of the slow-reacting substrate
pentafluorobenzyl alcohol (18) and p-xylene with crystalline
Re2O7 and Re2O7•SiO2 (Scheme 6) to yield 9. This study
showed that HOReO3 is comparable to crystalline Re2O7 and
is significantly superior to Re2O7•SiO2 in promoting these
reactions. The highly deactivated substrate 3,5-bis-
trifluoromethylbenzyl alcohol (52) provided a 51% yield of 16
after 23 h with 2 mol% HOReO3, which is somewhat less
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disubstitution product 57. TfOH produced a 21% yield of 56
and a 14% yield of 47 at 36% conversion. At 95% conversion
the reaction with Re2O7 provided a 78% yield of 56 and only
a 17% yield of 57, while TfOH produced a 5% yield of 56 and
a 75% yield of 57 at 90% conversion. These results are
consistent with Re2O7 showing a strong preference for
alcohol ionization over acetate ionization while TfOH shows
little to no selectivity. This system provides a very stringent
challenge for the systems because the cation arising from
product ionization is more stable than that derived from the
starting material, as σm values for benzylic groups increase
as the electronegativity of the substituent increases.9 Thus
monosubstitution at high conversion is
a challenging
transformation that requires selective catalyst. The
a
absence of the monoalkylation product resulting from
preferential acetate ionization suggests that this species is
significantly more reactive than the starting material, which
is consistent with the more positive σm value for the
acetoxymethyl group relative to the hydroxymethyl group.9
This study further supports our hypothesis that the
oxorhenium-catalyzed reactions do not proceed by simple
alcohol protonation by a Brønsted acid with solvent-
promoted enhanced acidity, and suggest that a perrhenate
ester is likely to be relevant intermediate. A secondary role
for a Brønsted acid cannot be discarded by our studies,
however, with the highly non-basic nature of HFIP
potentially allowing for protonated perrhenate esters to be
the direct precursors to benzylic cations. The heightened
selectivity for activating hydroxy groups by oxorhenium
catalysts, however, demonstrates an advantage for these
agents over strong Brønsted acids with respect to
chemoselectivity.
Figure 2. Reaction kinetics as a function of catalyst.
We then compared the rates of HOReO3, Re2O7 and
TfOH in the conversion of acetate 54 to 11 (Figure 3) under
the assumption that Brønsted acid catalysis will promote
ionization even more effectively for this substrate relative to
the corresponding alcohol while perrhenate ester formation
would be suppressed. The reaction with TfOH proceeded to
a significant extent within 2 h but, surprisingly, was slower
than the reaction of the corresponding alcohol. We attribute
this to acetic acid being sequestered less effectively than
water, leading to lower concentrations of the intermediate
benzylic cation. The reactions with HOReO3 and Re2O7,
however, proceeded to <5% conversion at the same time
and temperature. This result is inconsistent with a simple
solvent-mediated
acidity
enhancement
since
the
oxorhenium catalysts are approximately equivalent to TfOH
in their abilities to promote alcohol ionization.
Scheme 7. Reactions with a difunctionalized substrate.
Conclusions
We have described an efficient protocol for diarylmethane
synthesis through Friedel-Crafts reactions between benzene
derivatives and benzylic alcohols. Re2O7, either in its crystalline
form or adsorbed onto silica gel, is an exceptionally effective
catalyst for these processes. The transformation has a very
broad scope, including electron deficient benzylic alcohols, and
requires low catalyst loading. The use of highly polar HFIP as
the reaction solvent is important for enhancing rates and for
minimizing the nucleophilicity of the hydroxy groups of the
benzylic alcohols. The intermediates in these reactions are
exceptional leaving groups, proving to be superior to chlorides
and bromides. Re2O7 can be replaced by perrhenic acid to
Figure 3. Acetate ionization by different catalysts.
Additionally we exposed difunctional compound 55 and
2 to Re2O7 and TfOH at partial (1 h) and nearly complete
(2.25 h) conversion (Scheme 7). We observed selective
formation of 56, the product of alcohol activation, in 52%
yield with Re2O7 at 54% conversion, with only 2% of the
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forming processes using a different oxorhenium catalyst,
see: (b) B. D. Sherry, A. T. Radosevich and F. D. Toste, J. Am.
Chem. Soc. 2003, 125, 6076; (c) M. R. Luzung and F. D. Toste,
J. Am. Chem. Soc. 2003, 125, 15760.
minimize cost and facilitate handling. Mechanistic studies
confirmed that the mechanism of these reactions does not
proceed through simple protonation, with the perrhenate
ester or protonated perrhenate ester being the most likely
reactive intermediate. This leads to unique chemoselectivity in
which alcohols can be activated in preference to superior
leaving groups. This work shows the capacity of oxorhenium
species to promote important carbon–carbon bond forming
reactions from readily available substrates while mitigating
environmental impact.25
9
While σ+ values would be more appropriate for several of
the substituents we use
σ values to remain consistent
between substituents that can influence cation stability
through resonance and induction. For a comprehensive
listing of
Taft, Chem. Rev. 1991, 91, 165.
10 S. L. Scott and J.-M. Basset, J. Am. Chem. Soc. 1994, 116
σ
and σ+ values, see C. Hansch, A. Leo and R. W.
,
12069.
11 J. Wang, M. Sánchez-Roselló, J. L. Aceñal, C. del Pozo, A. E.
Sorochinsky, S. Fuestro, V. A. Soloshonok and H. Liu, Chem.
Rev. 2014, 114, 2432.
12 Please see the Supporting Information for experimental
validation of regioisomer assignments.
Conflicts of interest
The authors declare no competing interests.
13 M. F. Gotta and H. Mayr, J. Org. Chem. 1998, 63, 9769.
14 (a) V. N. Ipatieff and H. Pines, J. Am. Chem. Soc. 1937, 59, 56;
(b) R. M. Roberts, E. K. Baylis and G. J. Fonken, J. Am. Chem.
Soc. 1963, 85, 3454.
Acknowledgements
15 For an elegant recent example of this strategy, see: S. Jaracz,
M. Kozlowski, L. Y. Eun and S. M. Kim, US Pat. 2016058258,
2016, Colgate-Palmolive Company and the Trustees of the
University of Pennsylvania.
We thank the National Institutes of Health (R01GM103886) for
generous funding of this project.
16 L. J. Diorazio, D. R. J. Hose and N. K. Adlington, Org. Process
Res. Dev. 2016, 20, 760.
Notes and references
17 C. Jiminez-Gonzalez, C. S. Ponder, Q. B. Broxterman and J. B.
Manley, Org. Process Res. Dev. 2011, 15, 912.
18 R. Nallagonda, M. Rehan and P. Ghorai, J. Org. Chem. 2014,
79, 2934.
19 (a) I. Colomer, A. E. R. Chamberlain, M. B. Haughey and T. J.
1
D. J. C. Constable, P. J. Dunn, J. D.Hayler, G. R. Humphrey, J.
L. Leazer, Jr., R. J. Linderman, K. Lorenz, J. Manley, B. A.
Pearlman, A. Wells, A. Zaks and T. Y. Zhang, Green Chem.
2007, 9, 411.
Donohoe, Nature Rev. Chem. 2017, 1, 0088; (b) I. A. Shuklov,
2
(a) M. Dryzhakov, E. Richmond and J. Moran, Synthesis 2016,
48, 935; (b) L. Chen, A.-P. Yin, C.-H. Wang and J. Zhou, Org.
Biomol. Chem. 2014, 12, 6033; (c) A. Baeza and C. Nájera,
Synthesis 2014, 25; (d) R. R. Naredla and D. A. Klumpp, Chem.
Rev. 2013, 113, 6905.
X. Mo, J. Yakiwchuk, J. Dansereau, J. A. McCubbin and D. G.
Hall, J. Am. Chem. Soc. 2015, 137, 9694.
V. D. Vuković, E. Richmond, E. Wolf and J. Moran, Angew.
Chem., Int. Ed. 2017, 56, 3085.
N. V. Dubrovina and A. Börner, Synthesis 2007, 2925; (c) J.-P.
Bégué, D. Bonnet-Delphon and B. Crouse, Synlett 2004, 18.
20 C. Reichert, Chem. Rev. 1994, 94, 2319.
21 L. Eberson, M. P. Hartshorn, O. Persson and F. Radner, Chem.
Commun. 1996, 2105.
22 K. P. Dockery, J. P. Dinnocanzo, S. Farid, J. L. Goodman, I. R.
Gould and W. P. Todd, J. Am. Chem. Soc. 1997, 119, 1876.
23 S. Minegishi, S. Kobayashi and H. Mayr, J. Am. Chem. Soc.
2004, 126, 5174.
24 Based on current pricing from Sigma-Aldrich.
25 P. Anastas and N. Eghbali, Chem. Soc. Rev. 2010, 39, 301.
3
4
5
(a) H. H. Jung, J. R. Seiders, II and P. E. Floreancig, Angew.
Chem., Int. Ed. 2007, 46, 8464; (b) Y. Xie and P. E. Floreancig,
Chem. Sci. 2011, 2, 2423; (c) Y. Xie and P. E. Floreancig,
Angew. Chem., Int. Ed. 2013, 52, 625; (d) Y. Xie and P. E.
Floreancig, Angew. Chem., Int. Ed. 2014, 53, 4926.
6
For reviews of Re2O7-mediated transformations, see: (a) I.
Volchkov and D. Lee, Chem. Soc. Rev. 2014, 43, 4381; (b) S.
Bellemin-Laponnaz, ChemCatChem 2009, 1, 357. For relevant
examples, see: (c) K. Narasaka, H. Kusama and Y. Hiyashi,
Tetrahedron 1992, 48, 2059; (d) S. Bellemin-Laponnaz, Gisie,
J. P. Le Ny and J. A. Osborn, Angew. Chem., Int. Ed. 1997, 36
,
976; (e) C. Morrill and R. H. Grubbs, J. Am. Chem. Soc. 2006,
128, 8142; (f) B. M. Trost and F. D. Toste, J. Am. Chem. Soc.
2000, 122, 11262; (g) J. M. Hutchison, H. A. Lindsay, S. S.
Dormi, G. D. Jones, D. A. Vivic and M. C. McIntosh, Org. Lett.
2006, 8, 3663; (h) E. C. Hansen and Lee, D., J. Am. Chem. Soc.
2006, 128, 8142; (i) A. T. Herrmann, T. Saito, C. E. Stivala, J.
Tom and A. Zakarian, J. Am. Chem. Soc. 2010, 132, 5962; (j) S.
Y. Yun, E. C. Hansen, I. Volchkov, W. Y. Lo and D. Lee, Angew.
Chem., Int. Ed. 2010, 49, 4261; (k) J. Hu, D. Xu, Q. Zhang, Y.
Shang, M. Shi, Y. Huangfu, L. Liu, R. Liang, Y. Lai, Y. He, J.-m.
Gao and W. Xie, RSC Adv. 2016, 6, 52583.
T. M. Rohrs, Q. Qin and P. E. Floreancig, Angew. Chem., Int.
Ed. 2017, 56, 10090.
For a related example, see: (a) X. Wan, J. Hu, D. Xu, Y. Shang,
Y. Zhen, C. Hu, F. Xiao, Y.-P. He, Y. Lai and W. Xie,
Tetrahedron Lett. 2017, 58, 1090. For dehydrative bond-
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