Aryl Boronic Acid Catalysed Dehydrative Substitution of Benzylic Alcohols for C?O Bond Formation

Article abstract of DOI:10.1002/chem.201806057

A combination of pentafluorophenylboronic acid and oxalic acid catalyses the dehydrative substitution of benzylic alcohols with a second alcohol to form new C?O bonds. This method has been applied to the intermolecular substitution of benzylic alcohols to form symmetrical ethers, intramolecular cyclisations of diols to form aryl-substituted tetrahydrofuran and tetrahydropyran derivatives, and intermolecular crossed-etherification reactions between two different alcohols. Mechanistic control experiments have identified a potential catalytic intermediate formed between the aryl boronic acid and oxalic acid.

Full text of DOI:10.1002/chem.201806057

A Journal of
Accepted Article
Title: Aryl Boronic Acid-Catalysed Dehydrative Substitution of Benzylic
Alcohols for C-O Bond Formation
Authors: James Edward Taylor, Susana Estopiñá-Durán, Liam J.
Donnelly, Euan B. Mclean, Bryony M. Hockin, and Alexandra
M. Z. Slawin
This manuscript has been accepted after peer review and appears as an
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To be cited as: Chem. Eur. J. 10.1002/chem.201806057
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Aryl Boronic Acid-Catalysed Dehydrative Substitution of Benzylic
Alcohols for C-O Bond Formation
Susana Estopiñá-Durán,[a] Liam J. Donnelly,[a] Euan B. Mclean,[a] Bryony M. Hockin,[a] Alexandra M. Z.
Slawin,[a] and James E. Taylor*[a],[b]
Abstract: A combination of pentafluorophenylboronic acid and
oxalic acid catalyses the dehydrative substitution of benzylic
alcohols with a second alcohol to form new C-O bonds. This method
has been applied to the intermolecular substitution of benzylic
alcohols to form symmetrical ethers, intramolecular cyclisations of
diols to form aryl-substituted tetrahydrofuran and tetrahydropyran
derivatives, and intermolecular crossed-etherification reactions
between two different alcohols. Mechanistic control experiments
have identified a potential catalytic intermediate formed between the
arylboronic acid and oxalic acid.
Introduction
The alkylation of heteroatoms is one of the most widely used
reactions in both academia and industry.[1] Alkylations are
traditionally performed using substitution reactions of alkyl
halides or stoichiometrically-activated alcohols with suitable
nucleophiles. These processes typically require the use of
super-stoichiometric amounts of activating agents and/or
Scheme 1. Catalytic dehydrative substitution of alcohols.
produce potentially hazardous by-products. While a number of
catalytic variants of both the Mitsunobu and Appel reactions has
also been reported,[2] these often use stoichiometric reagents to
Recently, aryl boronic acids have emerged as promising mild
regenerate the active azodicarboxylates or phosphine catalysts,
Lewis acid catalysts for the activation of alcohols towards
respectively.
dehydrative substitution reactions. Aryl boronic acids and/or
The development of completely catalytic, redox neutral
boronate esters are attractive catalysts given that many are
methods of using alcohols directly as electrophiles in alkylation
commercially available or are readily prepared, and they are
reactions is attractive due to the wide availability of tractable
generally stable and easy to handle.[9,10] Aryl boronic acids and
alcohol substrates and the fact that water is the only by-
boronate esters are also known to reversibly interact with both
product.[2c,3,4] Conceptually, one method of activating alcohols is
alcohols and water,[9] enabling suitable equilibria to be
through coordination of the hydroxyl group to a Lewis acid
established that allows for both substrate activation and catalyst
catalyst to enhance its leaving group ability (Scheme 1a).
turnover, without recourse to the addition of stoichiometric
Nucleophilic substitution can then occur via an SN1 or SN2-type
additives.
mechanism, releasing water as the by-product. Various metal-
based catalytic systems have been reported for such
Seminal work by the groups of McCubbin[11] and Hall[12] has
shown that electron-deficient aryl boronic acids catalyse Friedel-
dehydrative
substitution
reactions
using
heteroatom
Crafts alkylation reactions of various arenes and heteroarenes
using simple allylic or benzylic alcohols as the electrophile.
Moran and co-workers further optimised the reaction conditions
for the Friedel-Crafts alkylation process using a rapid screening
nucleophiles.[3b] For example, the nucleophilic substitution of
allylic, propargylic,[5,6] and benzylic alcohols[7] has been explored
using
a variety of metal-based Lewis acids. Dehydrative
substitution can also be performed using strong Brønsted acid
catalysts, typically via an SN1 mechanism.[8]
technique,[13]
which
identified
a
combination
of
pentafluorophenylboronic acid (1 mol%) and oxalic acid (2
mol%) in nitromethane as the most effective. Hall and co-
workers have reported that tetrafluorophenylboronic acid 1 is an
effective catalyst for intramolecular heterocyclisation reactions
of pendent oxygen and nitrogen nucleophiles onto tertiary allylic
alcohols (Scheme 1b),[14] with two examples of intramolecular
cyclisations onto benzylic alcohols. The same catalytic system
has also been applied to the transposition of allylic alcohols[15]
and the intermolecular alkylation of sulfonamide nucleophiles
using benzylic alcohols.[16,17]
[a]
[b]
S. Estopiñá-Durán, L. J. Donnelly, E. B. Mclean, B. M. Hockin, Prof.
A. M. Z. Slawin, Dr J. E. Taylor
EaStCHEM, School of Chemistry, University of St Andrews, North
Haugh, St Andrews, KY16 9ST (UK)
Dr J. E. Taylor
Department of Chemistry, University of Bath, Claverton Down, Bath,
BA2 7AY (UK)
E-mail: j.e.taylor@bath.ac.uk
Supporting information for this article is given via a link at the end of
the document.
To date, arylboronic acid-catalysed intermolecular
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dehydrative substitution using readily available benzylic alcohols
as the electrophilic component in combination with a second
alcohol as the nucleophile has yet to be reported. Herein, we
report that commercially available pentafluorophenylboronic acid
is an efficient catalyst for such intermolecular dehydrative
substitutions of benzylic alcohols, allowing formation of both
symmetrical and unsymmetrical ether products.[18] The method
has also been applied to the intramolecular dehydrative
cyclisation of diols to form aryl-substituted tetrahydrofuran (THF)
the reactivity, with 67% 4 isolated after 16 h at 70 °C (Table 1,
entry 5). Reducing the ligand loading to 5 mol% resulted in a
lower yield (Table 1, entry 6), however increasing the
temperature to 90 °C using 10 mol% 8 gave ether 4 in 67% yield
after only 3 h (Table 1, entry 7). A control experiment in the
absence of boronic acid 3 under the otherwise optimal reaction
conditions resulted in no product formation (Table 1, entry 8).
Similarly, the use of other solvents, including various mixtures
with nitromethane, led to no reactivity.[19]
and
tetrahydropyran
(THP)
derivatives.
Preliminary
The scope of the aryl boronic acid-catalysed intermolecular
dehydrative etherification process was then investigated using
substituted benzylic alcohols (Table 2). Benzhydrol was highly
reactive and gave ether 9 in excellent 99% yield at rt. The use of
4-methylbenzyl alcohol under the previously optimised
conditions at 90 °C gave several undesired side products,
including those arising from Friedel-Crafts alkylation. However,
reducing the reaction temperature to 40 °C allowed 10 to be
obtained in 53% yield. In contrast, the reaction with 3-
methylbenzyl alcohol required heating at 90 °C for an extended
time (48 h) to form ether 11 in 62% yield. Halogen-substituted
benzyl alcohols were particularly well tolerated, with 4-fluoro, 4-
chloro- and 4-bromobenzyl alcohols giving the corresponding
ethers 12–14 in excellent yields. However, the use of more
sterically demanding 2-chloro- and 2-bromobenzyl alcohol led to
reduced reactivity, with increased reaction times required to
obtain ethers 15 and 16 in low 35% and 28% yield, respectively.
Limitations of this methodology include the presence of highly
investigations into the reaction mechanism and the nature of the
active catalytic species are also reported.
Results and Discussion
Investigations began using a single benzylic alcohol substrate as
both the electrophile and nucleophile in a catalytic dehydrative
substitution reaction. The intermolecular etherification of benzyl
alcohol 2 into dibenzyl ether 4 was chosen as a model reaction,
however an initial screen using various electron deficient aryl
boronic acids as catalysts in nitromethane at 70 °C returned
starting material in all cases (Table 1, entry 1).[19] Next, several
ligands (10 mol%) were screened in combination with
commercially-available pentafluorophenylboronic acid
3
(5
mol%). The use of catechol 5 gave no reactivity (Table 1, entry
2), but the use of either tartaric acid 6 or mandelic acid 7 gave
modest amounts of the desired dibenzyl ether 4 after 16 h
(Table 1, entries 3 and 4). Oxalic acid 8 significantly enhanced
Table 2. Intermolecular dehydrative etherification of benzylic alcohols.
Table 1. Reaction optimisation.
Entry
Ligand (mol%)
T (°C)
t (h)
Yield (%)[a]
1
–
70
70
70
70
70
70
90
90
16
16
16
16
16
16
3
0
2
5 (10)
6 (10)
7 (10)
8 (10)
8 (5)
0
3
38
23
67
55
67
0
4
5
6
7
8 (10)
8 (10)
8[b]
3
[a] Isolated yields after purification by column chromatography. [b] Reaction
performed without F5C6B(OH)2 3.
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electron-withdrawing aryl substituents, for example 4-
trifluoromethylbenzyl alcohol 17 returned only starting material
even after extended reaction times. Conversely, electron-rich 4-
methoxybenzyl alcohol 18 was highly reactive, resulting in a
complex mixture of products including those from undesired
Friedel-Crafts alkylation processes.[20] Lowering the temperature
to either rt or –10 °C did not improve the selectivity of the
reaction with 18, with only minimal amounts of ether formation
observed.[19] The use of heterocyclic alcohols, such as 3-
pyridylcarbinol 19, also resulted in a complex mixture under the
standard reaction conditions.
Table 3. Intramolecular dehydrative etherification.
Having demonstrated the desired reactivity using a single
benzylic alcohol, the use of two different alcohols was next
investigated. It was envisioned that selective activation of a
benzylic alcohol would allow dehydrative substitution with a
second, non-benzylic alcohol. First, the intramolecular
dehydrative substitution of secondary benzylic alcohols bearing
a pendant primary alcohol substituent to form THF derivatives
was studied (Table 3). Under the previously optimised conditions,
the intramolecular cyclisation of 1-phenylbutane-1,4-diol
proceeded smoothly at 40 °C, forming THF 20 in 92% yield with
no products from competing intermolecular processes observed.
This reaction was also performed on a preparative 11 mmol
scale, giving 1.4 g of THF 20 in 87% yield. The presence of a
mildly electron-donating 4-methyl substituent was well tolerated,
affording THF 21 in 86% yield. Notably, in contrast with the
intermolecular substitution, incorporation of a strongly electron-
donating 4-methoxy aryl substituent was tolerated in the
intramolecular substitution to give 22 in good yield. In addition,
cyclisation in the presence of an electron-withdrawing 4-
trifluoromethyl substituent was also possible, with THF 23
isolated in 54% yield after an extended 48 h reaction time.
Halogen substituents were again well tolerated, with products 24
and 25 obtained in good yield after reaction at 90 °C.
Next, the synthesis of 2-aryl substituted THP derivatives
from 1,5-diols was investigated under the standard reaction
conditions. The same trends in reactivity were observed, with
neutral and electron-rich aryl substituents reacting to give
products 26-28 in good yield. In this case, incorporation of an
electron-withdrawing 4-trifluoromethyl substituent resulted in
lower reactivity, with THF 29 obtained in only 29% yield after 48
h at 90 °C. As before, 4-chloro and 4-bromo-aryl substitution
was well tolerated, with THP products 30 and 31 isolated in 87%
and 62% yield, respectively. The formation of larger 2-
phenyloxepane 32 from the corresponding 1,6-diol was only
moderately successful, giving 30% yield after 48 h at 40 °C.
Attempts to apply this methodology to the formation of smaller
ring sizes was unsuccessful, with 1,2-diol substrate 33 giving a
complex mixture under the standard reaction conditions while
efforts to form oxetanes from 1,3-diol 34 returned only starting
materials.
[a] Reaction performed on an 11 mmol scale.
pentafluorophenylboronic acid 3 (5 mol%) and oxalic acid 8 (10
mol%) in MeNO2 at room temperature (Table 4). Complete
conversion of benzhydrol was observed, with a 70:30 mixture of
the desired crossed ether product 36 and the benzhydrol derived
symmetrical ether 9 obtained as determined by 1H NMR
spectroscopic analysis. The ratio of product 36 to 9 could be
improved by lowering the reaction concentration (Table 4,
entries 2 and 3), with the reaction starting with 0.05
M
benzhydrol 35 giving 90:10 36/9 after 16 h. However, further
lowering the concentration gave no additional improvement
(Table 4, entry 4), and similarly using 10 equiv. MeOH led to no
further increase in product ratio (Table 4, entry 5).
The scope of the intermolecular crossed etherification
process was investigated through variation of the alkyl alcohol
component in combination with benzhydrol 35 (Table 5). Various
alkyl-substituted alcohols were applicable under the previously
optimised conditions, with complete conversion of benzhydrol 35
observed in all cases. Crossed ethers 37-41 were all obtained
as the major product as a mixture with a minor amount of
symmetric ether 9 derived from benzhydrol 35. The use of
The use of two different alcohols in an intermolecular
crossed etherification process via selective catalytic dehydrative
substitution was then investigated. Initially, the reaction of
benzhydrol 35 as the electrophile in combination with an excess
of methanol as the nucleophilic component was studied using
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scale, allowing the isolation of 2.52 g of ether 44. Substrates
bearing pendant functional groups including esters and allyl
ethers were also tolerated, forming ethers 45 and 46 in good
yields. Next, the benzylic alcohol component was varied using
hex-5-en-1-ol as the standard nucleophile. Alkyl-substituted
secondary benzylic alcohols reacted to give ethers 47-49 in
good yields. Importantly, the reaction was completely selective
for the crossed-intermolecular substitution process, with no
symmetrical ether formation or unwanted elimination to form
styrene derivatives observed. The presence of an alkynyl
substituent on the secondary carbinol centre did not affect the
reactivity, with ether 50 isolated in 83% yield after reaction at
90 °C. Substitution on the aryl ring was also possible, with
electron-donating or halogen-substituted 4-methoxy-, 2-
methoxy- 4-fluoro- and 4-bromophenyl ethanol well tolerated to
form ethers 51-54 in high yields. The use of both 3-bromo- and
2-bromophenyl ethanol as electrophiles gave ethers 55 and 56
in 38% and 61% yield, respectively after 48 h at 90 °C. However,
the presence of an electron-withdrawing 4-trifluoromethyl
substituent gave no reactivity and returned only starting
materials. The reaction of primary benzyl alcohol 2 with alkyl
alcohols such as methanol or hex-5-en-1-ol under the standard
conditions were also unsuccessful, returning only unreacted
starting materials.
Table 4. Optimisation of intermolecular dehydrative crossed etherification.
Entry
[35] / M
Conv. (%)[a]
36:9[a]
1[b]
2
0.2
97
70:30
75:25
90:10
88:12
90:10
0.1
>98
3
0.05
0.03
0.05
>98 (71[c]
>98
)
4
5[d]
>98
[a] Determined by 1H NMR analysis. [b] Reaction using 5 mol% oxalic acid. [c]
Isolated yield of 90:10 mixture. [d] Reaction using 10 equiv. MeOH.
trifluoroethanol as a nucleophile was less well tolerated, forming
a 63:37 mixture of ether 42 to 9. Pleasingly, the use of hex-5-en-
1-ol resulted in selective crossed dehydrative substitution, with
ether 43 isolated as the sole product in 84% yield. Alkynyl
substitution was also well tolerated, with ether 44 obtained in an
excellent 97% yield. The synthetic utility of this procedure was
further demonstrated by performing this reaction on an 11 mmol
Table 5. Intermolecular dehydrative crossed etherification.
[a] Combined yield. [b] Reaction performed on an 11 mmol scale.
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A series of control experiments was performed to investigate
the mechanistic pathway and to probe the nature of any catalytic
species formed between pentafluorophenylboronic acid 3 and
oxalic acid 8. First, the intermolecular crossed-dehydrative
substitution using hex-5-en-1-ol was performed under the
standard reaction conditions using both α-vinylbenzyl alcohol 57
and isomeric cinnamyl alcohol 58 (Scheme 2a). In both cases,
linear ether product 59 was obtained as a single regioisomer in
good yield, consistent with the formation of
a common
intermediate. Next, the dehydrative substitution protocol was
performed using enantiomerically pure (R)-1-phenylethan-1-ol
60 and ethyl glycolate (Scheme 2b). Ether product 61 was
formed in 87% yield, but with complete erosion of
enantiopurity.[21] These experiments are therefore consistent
with a catalytic SN1-type substitution pathway proceeding via a
planar carbocation intermediate, and is in line with the proposed
mechanisms for aryl boronic acid-catalysed Friedel-Crafts
alkylation processes.[11,12]
Scheme 3. Nature of the catalytic species.
acid
8 (1:2 3/8) in d3-MeNO2, which includes the non-
coordinated arylboronic acid 3 (δB = 26.8 ppm) and two
tetrahedral sp3-hybridised boron species (δB = 7.4 and 5.4
ppm).[25,26] These signals are analogous to the signal observed
for 62 in d6-DMSO (δB = 5.7 ppm) and may be the result of
different hydrated forms of 62 in solution.[27,28] This is consistent
with the increased Lewis acidity of the boron atom upon
complexation with oxalic acid resulting in a greater affinity for the
both water and the solvent.[29]
Further control experiments were performed to probe
whether the active boron species in solution acts as either a
Lewis acid or Brønsted acid catalyst. Isolated complex 62 was a
competent pre-catalyst for the intermolecular etherification of
benzylic alcohol 63, forming ether 14 is 95% yield after 3 h
(Table 6, entry 1). The use of alternative strong Brønsted acids
as catalysts resulted in minimal product formation. For example,
trifluoroacetic acid (TFA) gave a complex mixture of products
after 3 h (Table 6, entry 2), while (+)-camphorsulfonic acid ((+)-
CSA) gave no reactivity (Table 6, entry 3). However, the use of
4-toluenesulfonic acid (p-TsOH∙H2O) did show some reactivity,
giving 36% conversion into ether 14 (Table 6, entry 4). Therefore,
while alternative Brønsted acid catalysts show some reactivity,
Scheme 2. Control experiments.
Although the use of pentafluorophenylboronic acid 3 in
combination with oxalic acid 8 has been reported for dehydrative
Friedel-Crafts reactions,[13,16] the exact nature of the intermediate
catalytic species has not previously been studied. A preparative
experiment reacting pentafluorophenylboronic acid 3 with oxalic
acid 8 (2 equiv.) in MeNO2 at 90 °C followed by removal of the
solvent yielded a white powder, from which small crystals could
be obtained. X-Ray crystallographic analysis showed the
formation of hydrated boronate ester 62 (Scheme 3a),[22,23] with
11B, 19F and 13C{1H,19F} NMR spectroscopic analysis in d6-
DMSO consistent with this structure.[19,24] Boronate ester
complex 62 is a competent pre-catalyst for the crossed-
etherification, forming product 47 in comparable yields to in situ
catalyst formation (Scheme 3b). However, boronate ester 62
cannot be unambiguously identified as the active catalytic
species in solution, as NMR analysis in d3-MeNO2 shows the
formation of a dynamic equilibrium between at least three
species.[19] The same equilibrium is established between a
mixture of pentafluorophenylboronic acid 3 and oxalic
Table 6. Brønsted acid catalysis control experiments.
Entry
Catalyst (mol%)
Additive (mol%)
Conv. (%)[a]
>98 (95[b]
1
2
3
4
5
62 (5)
–
)
TFA (5)
–
Complex mixture
(+)-CSA (5)
p-TsOH∙H2O (5)
–
0
–
36
0
C6F5B(OH)2 3 (5)
(CO2H)2 8 (10)
2,6-(t-Bu)2C5H3N (5%)
[a] Determined by 1H NMR analysis. [b] Isolated yield
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the arylboronic acid catalyst system provides both increased
reactivity and selectivity. Performing the reaction under the
standard conditions in the presence of sterically demanding 2,6-
di-tert-butyl pyridine (5 mol%) results in complete inhibition, with
no ether product formed within 3 h (Table 6, entry 5). This result
suggests that the active aryl boron species formed in solution
acts as a Brønsted acid catalyst.
generally formed in good yields and water formed as the only
by-product. Preliminary mechanistic investigations suggest a
catalytic SN1 substitution process is likely to occur. Boronate
ester 62, formed from the reaction of 3 and 8 under the reaction
conditions, has been fully characterised and is a competent
precatalyst for the reaction. Ongoing studies within our
laboratory are aimed at further investigating the scope and
Based upon the above evidence,
a
possible reaction
mechanism
of
arylboronic
acid-catalysed
dehydrative
mechanism for dehydrative nucleophilic substitution using
arylboronic acid catalysis is outlined in Scheme 4. A dynamic
equilibrium between pentafluorophenylboronic acid 3 and oxalic
acid 8 in solution forms complex 62, which is likely to act as a
strong Brønsted acid catalyst. Protonation of a benzylic alcohol
forms ion pair 64, which is sufficiently activated to dissociate into
ion pair 65. Reaction of carbocation 65 with a suitable alcohol
nucleophile gives the substitution product, with the released
boronate species 66 is likely to be in equilibrium with other
hydrated forms in the presence of water.[27] Reversible
protonation of the different alcohols rationalise the selectivity in
the crossed-etherification processes, with only benzylic alcohols
capable of forming a stabilised carbocation for onwards reaction.
Although the proposed mechanism is consistent with the
observed reaction scope and control experiments, alternative
mechanisms involving different boronate intermediates and/or
Lewis acid catalysis cannot be unequivocally ruled-out at this
stage.
substitution processes.
Experimental Section
1
General: For general experimental details, characterisation data, and H
and 13C{1H} NMR traces for novel compounds, see the Supporting
Information.[30]
Representative procedure for intermolecular dehydrative crossed
etherification: The required nucleophilic alcohol (5.0 equiv.) was added
to a solution of pentafluorophenylboronic acid 3 (5 mol%) and oxalic acid
8 (10 mol%) in MeNO2 (0.05 M) and was stirred at rt for 5 mins. The
required benzylic alcohol (1.0 equiv.) was added and the reaction stirred
at the stated temperature until complete by TLC analysis. The reaction
was cooled to rt, diluted with toluene and concentrated under reduced
pressure to give the crude product, which was further purified by silica-
gel column chromatography.
Acknowledgements
We thank the University of St Andrews and the EPSRC for the
award of a DTA studentship (S.E.-D.). We would also like to
thank the EPSRC, University of St Andrews, and CRITICAT
Centre for Doctoral Training for financial support [Ph.D.
studentships to B.M.H, E.B.M and L.J.D; Grant code:
EP/L016419/1]. J.E.T thanks the Leverhulme Trust for the award
of an Early Career Fellowship (Grant code: ECF-2014-005). We
also thank the EPSRC National Mass Spectrometry Facility at
Swansea University.
Keywords: alcohols • homogeneous catalysis • boronic acids •
etherification • substitution
[1]
[2]
S. D. Roughley, A. M. Jordan, J. Med. Chem. 2011, 54, 3451-3479.
a) T. Y. S. But, P. H. Toy, J. Am. Chem. Soc. 2006, 128, 9636-9637; b)
K. C. K. Swamy, N. N. B. Kumar, E. Balaraman, K. V. P. P. Kumar,
Chem. Rev. 2009, 109, 2551-2651; c) J. An, R. M. Denton, T. H.
Lambert, E. D. Nacsa, Org. Biomol. Chem. 2014, 12, 2993-3003; d) S.
Fletcher, Org. Chem. Front. 2015, 2, 739-752; e) R. H. Beddoe, H. F.
Sneddon, R. M. Denton, Org. Biomol. Chem., 2018, 16, 7774-7781.
For reviews on catalytic alcohol activation, see: a) E. Emer, R. Sinisi, M.
G. Capdevila, D. Petruzziello, F. D. Vincentiis, P. G. Cozzi, Eur. J. Org.
Chem. 2011, 2011, 647-666; b) M. Dryzhakov, E. Richmond, J. Moran,
Synthesis 2016, 48, 935-959; c) P. H. Huy, T. Hauch, I. Filbrich, Synlett
2016, 27, 2631-2636.
Scheme 4. Plausible reaction mechanism.
Conclusions
[3]
[4]
Catalytic inter- and intramolecular dehydrative substitution of
benzylic alcohols with a second alcohol to form C-O bonds can
be
achieved
using
commercially
available
pentafluorophenylboronic acid 3 (5 mol%) and oxalic acid 8 (10
mol%). The method is applicable to the synthesis of various
symmetrical and non-symmetrical ethers, as well as aryl
substituted THF and THP derivatives, with the products
D. J. C. Constable, P. J. Dunn, J. D. Hayler, G. R. Humphrey, J. J. L.
Leazer, R. J. Linderman, K. Lorenz, J. Manley, B. A. Pearlman, A.
Wells, A. Zaks, T. Y. Zhang, Green Chem. 2007, 9, 411-420.
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[5]
[6]
B. Sundararaju, M. Achard, C. Bruneau, Chem. Soc. Rev. 2012, 41,
4467-4483.
[16] T. Verdelet, R. M. Ward, D. G. Hall, Eur. J. Org. Chem. 2017, 2017,
5729-5738.
a) Y. Nishibayashi, I. Wakiji, M. Hidai, J. Am. Chem. Soc. 2000, 122,
11019-11020; b) B. D. Sherry, A. T. Radosevich, F. D. Toste, J. Am.
Chem. Soc. 2003, 125, 6076-6077; c) M. Georgy, V. Boucard, J.-M.
Campagne, J. Am. Chem. Soc. 2005, 127, 14180-14181; d) C. Defieber,
M. A. Ariger, P. Moriel, E. M. Carreira, Angew. Chem. Int. Ed. 2007, 46,
3139-3143; Angew. Chem. 2007, 119, 3200-3204; e) Y. Yamashita, A.
Gopalarathnam, J. F. Hartwig, J. Am. Chem. Soc. 2007, 129, 7508-
7509.
[17] a) M. Hellal, F. C. Falk, E. Wolf, M. Dryzhakov, J. Moran, Org. Biomol.
Chem. 2014, 12, 5990-5994; b) M. Dryzhakov, M. Hellal, E. Wolf, F. C.
Falk, J. Moran, J. Am. Chem. Soc. 2015, 137, 9555-9558.
[18] For a review on ether synthesis, see: S. Mandal, S. Mandal, S. K.
Ghosh, P. Sar, A. Ghosh, R. Saha, B. Saha, RSC Adv. 2016, 6, 69605-
69614.
[19] See the Supporting Information for more details.
[20] M. Salmón, N. Zavala, A. Cabrera, J. Cárdenas, R. Gaviño, R. Miranda,
M. Martínez, J. Mol. Catal. A: Chem. 1995, 104, L127-L129.
[21] For an example of Brønsted acid-catalysed intramolecular dehydrative
substitution with chirality transfer, see: [8e]. For recent examples of
catalytic intermolecular dehydrative subsitutions with stereochemical
inversion, see: a) E. D. Nacsa, T. H. Lambert, Org. Lett. 2013, 15, 38-
41; b) P. H. Huy, I. Filbrich, Chem. Eur. J. 2018, 24, 7410-7416; c) T.
Stach, J. Dräger, P. H. Huy, Org. Lett. 2018, 20, 2980-2983.
[22] CCDC 1871925 contains the supplementary crystallographic data for
62. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[23] For structural analysis of related boronate esters derived from
coordination with diacids, see: a) P. I. Paetzold, W. Scheibitz, E. Scholl,
Z. Naturforsch. B 1971, 26, 646-649; b) P. Paetzold, P. Bohm, A.
Richter, E. Scholl, Z. Naturforsch., B: Anorg. Chem., Org. Chem. 1976,
31B, 754-764; c) W. Kliegel, U. Schumacher, S. J. Rettig, J. Trotter,
Can. J. Chem. 1992, 70, 1188-1194; (d) K. Ishihara, Y. Lu, Chem. Sci.
2016, 7, 1276-1280.
[7]
a) J. Y. Gauthier, F. Bourdon, R. N. Young, Tetrahedron Lett. 1986, 27,
15-18; b) B. G. Das, R. Nallagonda, P. Ghorai, J. Org. Chem. 2012, 77,
5577-5583; c) T. Ohshima, J. Ipposhi, Y. Nakahara, R. Shibuya, K.
Mashima, Adv. Synth. Catal. 2012, 354, 2447-2452; d) S. Biswas, J. S.
M. Samec, Chem. Asian J. 2013, 8, 974-981; e) A. K. Maity, P. N.
Chatterjee, S. Roy, Tetrahedron 2013, 69, 942-956; f) G. Sathaiah, A.
C. Shekhar, A. R. Kumar, K. Raju, P. S. Rao, M. Sridhar, B. Narsaiah,
Chem. Lett. 2013, 42, 1522-1524; g) P. Khedar, K. Pericherla, A.
Kumar, Synlett 2014, 25, 515-518; h) B. V. Rokade, K. Gadde, K. R.
Prabhu, Eur. J. Org. Chem. 2015, 2015, 2706-2717; i) H. Hikawa, Y.
Ijichi, S. Kikkawa, I. Azumaya, Eur. J. Org. Chem. 2017, 2017, 465-468;
j) M. Liang, S. Zhang, J. Jia, C.-H. Tung, J. Wang, Z. Xu, Org. Lett.
2017, 19, 2526-2529.
[8]
a) R. Sanz, A. Martínez, D. Miguel, J. M. Álvarez‐Gutiérrez, F.
Rodríguez, Adv. Synth. Catal. 2006, 348, 1841-1845; b) M. Rueping, U.
Uria, M.-Y. Lin, J. Am. Chem. Soc. 2011, 133, 3732-3735; c) F. Han, L.
Yang, Z. Li, C. Xia, Adv. Synth. Catal. 2012, 354, 1052-1060; d) E.
Barreiro, A. Sanz‐Vidal, E. Tan, S. H. Lau, T. D. Sheppard, S.
Díez‐González, Eur. J. Org. Chem. 2015, 2015, 7544-7549; e) A. Bunrit,
C. Dahlstrand, S. K. Olsson, P. Srifa, G. Huang, A. Orthaber, P. J. R.
Sjöberg, S. Biswas, F. Himo, J. S. M. Samec, J. Am. Chem. Soc. 2015,
137, 4646-4649.
[24] It is likely that in solution, boronate ester 62 is coordinated with d6-
DMSO in place of H2O.
[25] In d3-MeNO2 the three boron-containing species are present in an
approximate 7:7:1 ratio at equilibrium, as determined by 19F{1H} NMR
spectroscopic analysis. The addition of water, which is formed during
the etherification process, does not affect the position of equilibrium.
[26] For calculated and experimental 11B NMR chemical shifts of various
organoboron compounds, see: H. S. Rzepa, S. Arkhipenko, E. Wan, M.
T. Sabatini, V. Karaluka, A. Whiting, T. D. Sheppard, J. Org. Chem.,
2018, 83, 8020-8025.
[9]
D. G. Hall in Boronic Acids: Preparation and Applications in Organic
Synthesis, Medicine and Materials, Vol. 2, Wiley-VCH Verlag GmbH &
Co. KGaA, Weinheim, 2011.
[10] For reviews on organoboron acids as catalysts, see: a) K. Ishihara, H.
Yamamoto, Eur. J. Org. Chem. 1999, 1999, 527-538; b) I. Georgiou, G.
Ilyashenko, A. Whiting, Acc. Chem. Res. 2009, 42, 756-768; c) E.
Dimitrijević, M. S. Taylor, ACS Catal. 2013, 3, 945-962.
[27] C. Bergquist, B. M. Bridgewater, C. J. Harlan, J. R. Norton, R. A.
Friesner, G. Parkin, J. Am. Chem. Soc. 2000, 122, 10581-10590.
[28] We thank the reviewers for insightful suggestions regarding the catalyst
speciation and reaction mechanism.
[11] a) J. A. McCubbin, H. Hosseini, O. V. Krokhin, J. Org. Chem. 2010, 75,
959-962; b) J. A. McCubbin, O. V. Krokhin, Tetrahedron Lett. 2010, 51,
2447-2449.
[29] Attempts to characterise the trigonal complex formed between
pentafluorophenyl boronic acid 3 and oxalic acid 8 in non-coordinating
solvents such as CHCl3 or CD2Cl2 were unsuccessful due poor
solubility.
[12] a) X. Mo, J. Yakiwchuk, J. Dansereau, J. A. McCubbin, D. G. Hall, J.
Am. Chem. Soc. 2015, 137, 9694-9703; b) C. L. Ricardo, X. Mo, J. A.
McCubbin, D. G. Hall, Chem. Eur. J. 2015, 21, 4218-4223.
[13] E. Wolf, E. Richmond, J. Moran, Chem. Sci. 2015, 6, 2501-2505.
[14] H. Zheng, S. Ghanbari, S. Nakamura, D. G. Hall, Angew. Chem. Int. Ed.
2012, 51, 6187-6190; Angew. Chem. 2012, 124, 6291-6294.
[30] The data underpinning this research can be found at DOI:
https://doi.org/10.15125/BATH-00561.
[15] H. Zheng, M. Lejkowski, D. G. Hall, Chem. Sci. 2011, 2, 1305-1310.
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10.1002/chem.201806057
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S. Estopiñá-Durán, L. J. Donnelly, E. B.
Mclean, B. M. Hockin, A. M. Z. Slawin,
J. E. Taylor*
Page No. – Page No.
Aryl Boronic Acid-Catalysed
Dehydrative Substitution of Benzylic
Alcohols for C-O Bond Formation
Take some water: Pentafluorophenylboronic acid catalyses the inter- and
intramolecular dehydrative substitution of benzylic alcohols with a second alcohol
as the nucleophile to form ether products.
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