Insight into the Ferrier Rearrangement by Combining Flash Chemistry and Superacids

Article abstract of DOI:10.1002/anie.202010175

The transformation of glycals into 2,3-unsaturated glycosyl derivatives, reported by Ferrier in 1962, is supposed to involve an α,β unsaturated glycosyl cation, an elusive ionic species that has still to be observed experimentally. Herein, while combination of TfOH and flow conditions failed to observe this ionic species, its extended lifetime in superacid solutions allowed its characterization by NMR-based structural analysis supported by DFT calculations. This allyloxycarbenium ion was further exploited in the Ferrier rearrangement to afford unsaturated nitrogen-containing C-aryl glycosides and C-alkyl glycosides under superacid and flow conditions, respectively.

Full text of DOI:10.1002/anie.202010175

A Journal of the Gesellschaft Deutscher Chemiker
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International Edition Chemie
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Accepted Article
Title: Insight into the Ferrier rearrangement by combining flash
chemistry and superacids
Authors: Naresh Bhuma, Ludivine Lebedel, Hiroki Yamashita, Yutaka
Shimizu, Zahra Abada, Ana Ardá, Jérôme Désiré, Bastien
Michelet, Agnès Martin-Mingot, Ali Abou-Hassan, Masahiro
Takumi, Jérôme Marrot, Jesús Jiménez-Barbero, Aiichiro
Nagaki, Yves Blériot, and Sebastien Thibaudeau
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202010175
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Insight into the Ferrier rearrangement by combining flash
chemistry and superacids
[
a]
[a]
[b]
[b]
[a],[c]
Naresh Bhuma, Ludivine Lebedel, Hiroki Yamashita, Yutaka Shimizu, Zahra Abada,
Ana
[d]
[a]
[a]
[a]
[c]
Ardá, Jérôme Désiré, Bastien Michelet, Agnès Martin-Mingot, Ali Abou-Hassan, Masahiro
[b]
[e]
[d]
[b]
[a]
Takumi, Jérôme Marrot, Jesús Jiménez-Barbero,* Aiichiro Nagaki,* Yves Blériot* and Sébastien
Thibaudeau*[a]
In memory of Professor Jun‐ichi Yoshida
[
[
a]
b]
Dr. N. Bhuma, Dr. L. Lebedel, Dr. Z. Abada, Dr. J. Désiré, Dr. B. Michelet, Dr. A. Martin-Mingot, Prof. Y. Blériot, Prof. S. Thibaudeau
IC2MP UMR CNRS 7285, Equipe “Synthèse Organique”, Université de Poitiers, 4 rue Michel Brunet 86073 Poitiers cedex 9, France.
E-mail: sebastien.thibaudeau@univ-poitiers.fr; yves.bleriot@univ-poitiers.fr
Mr. H. Yamashita, Mr. Y. Shimizu, Mr. M. Takumi, Prof. A. Nagaki
Department of Synthetic and Biological Chemistry, Graduate School of Engineering, Kyoto University, Japan.
E-mail: anagaki@sbchem.kyoto-u.ac.jp
[
c]
d]
Dr. Z. Abada, Prof. A. Abou-Hassan
Sorbonne Université, CNRS UMR 8234, PHysico-chimie des Électrolytes et Nanosystèmes InterfaciauX (PHENIX), F-75005 Paris, France.
Dr. A. Ardá, Prof. J. Jiménez-Barbero
[
CIC bioGUNE, Parque technologico de Bizkaia, Edif. 801A-1°, Derio-Bizkaia 48160, and Ikerbasque, Basque Foundation for Science, Maria Lopez de
Haro 3, 48013 Bilbao, Spain.
E-mail: jjbarbero@cicbiogune.es
[
e]
Dr. J. Marrot
Institut Lavoisier de Versailles, UMR CNRS 8180, 45 avenue des Etats-Unis, Versailles 78035 Cedex, France.
Supporting information for this article is given via a link at the end of the document
Abstract: The transformation of glycals into 2,3-unsaturated glycosyl
derivatives, reported by Ferrier in 1962, is supposed to involve an α,β
unsaturated glycosyl cation, an elusive ionic species that has still to
be observed experimentally. Herein, while combination of TfOH and
flow conditions failed to observe this ionic species, its extended
lifetime in superacid solutions allowed its characterization by NMR-
based structural analysis supported by DFT calculations. This
allyloxycarbenium ion was further exploited in the Ferrier
rearrangement to afford unsaturated nitrogen-containing C-aryl
glycosides and C-alkyl glycosides under superacid and flow
conditions respectively.
preferred pseudoaxial orientation of the leaving group at C-3 in
the starting glycal.[9]
The Ferrier I rearrangement (or Ferrier reaction),[1-2] first reported
in 1962 by Ferrier[3] and earlier observed by Fischer,[4] is
considered as the prevalent route to hex-2-enopyranoses or
pseudoglycals, species that hold a great synthetic potential in
carbohydrate chemistry.[5,6] Typically, this reaction is carried out
with a glycal 1 having a good leaving group (e.g., acetate,
carbonate, or trichloroacetimidate) at C-3 position, which after
activation and allylic rearrangement,[7] generates the
corresponding pseudoglycal 2 (Figure 1A). It is now accepted
that, in reactions involving alcohols as nucleophiles under acidic
conditions, the resulting pseudoglycals are very labile and
anomerize, favoring the α-O-glycosides as a reflection of a
thermodynamic control. On the opposite, the stereoselective
formation of C-glycosides, unlikely to be a reversible process, is
supposed to be under kinetic control.[8] Undoubtedly, the
Figure 1. A. Ferrier rearrangement; B. Accumulation of allyloxycarbenium ion I
under flash conditions and its reaction with C-nucleophiles in flow; C. Superacid-
promoted generation, low-temperature in situ NMR characterization,
conformational analysis and use in C-arylation of the short-lived protonated
allyloxycarbenium ion I’.
conformation of glycal 1 plays an all-important role in the Ferrier
rearrangement. The vinylogous anomeric effect, the anomeric
effect extended through a C=C double bond, must dictate a
1
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The conformation of the postulated oxocarbenium ion
intermediate (adopting the preferred conformation
I
over
as well as the
5
over B) must also contribute
[
10,11]
conformation II according to calculations)
O
1,4
favored product conformation ( H
to the α-selectivity (Figure 1A).[12] The anchimeric assistance by
the protecting group at C-4 to ease the departure of the leaving
group at C-3 has also been postulated to rationalize the
stereochemical outcome of the Ferrier rearrangement.[13] In
comparison with a classical glycosyl cation, the additional
conjugation into the vinyl group enhances the stabilization of the
allyloxycarbenium ion, suggesting its classification as a stabilized
[
14]
ion,
thus theoretically favoring its direct observation by
spectroscopic methods. Surprisingly, despite its crucial role in the
Ferrier reaction, this species remains however hypothetical to the
best of our knowledge. We report herein our efforts to
characterize this elusive ion combining flow microreactors (Figure
Figure 3. Effects of temperature (T) and residence time in R1 (tR1) on the yield
1B), superacid chemistry, NMR analysis and DFT calculations
(%) of 2a from the reaction of the glucal 1a with triflic acid (TfOH) and
and its use as a glycosyl donor to generate unprecedented
nitrogen-containing C-aryl hex-2-enopyranosides (Figure 1C).
The cation-flow method,[ in which highly reactive cations
are rapidly generated in the absence of nucleophiles using the
integrated flow microreactor, is quite effective for the generation
of alkoxycarbenium ions[16] and for performing glycosylation
reactions involving glycosyl cation intermediates based on an
indirect method.[17] To evaluate the ability of this method to
generate and exploit the related Ferrier cation, the commercially
available tri-O-acetyl-D-glucal 1a was chosen as a model
substrate. Using an integrated flow microreactor system
consisting of two micromixers (M1 and M2) and two microtube
reactors (R1 and R2), the treatment of a dichloromethane solution
of 1a with triflic acid (TfOH) followed by allyltrimethylsilane to
generate the known C-glycoside 2a[18] was examined (Figure 2).
subsequent reaction with allyltrimethylsilane in the flow microreactor system.
15]
This result was further exemplified by applying the method to
several nucleophiles and D-glucals to produce
a set of
pseudoglucals 2 (Table 1).
Table 1 : Flow microreactor synthesis of functionalized pseudo glucals 2 from
D-glucals 1a and 1b.
Entry
1
1 (glycal)
nucleophile
2 (product)
Yield
(%)
(α/β)
83
(91:9)
2
3
91
78:22)
(
quant.
(91:9)
Figure 2. Integrated flow microreactor system for the production of C-allyl
pseudo-glycal 2a from glycal 1a. T-shaped micromixers: M1 and M2, microtube
reactors: R1 and R2.
4
5
quant.
(70:30)
57
The reactions were carried out at a range of residence times in
R1 (tR1) and a variety of temperatures (T). The results are
summarized in Figure 3, in which the yield of 2a is plotted against
T and tR1 as a contour map with a scattered overlay. The yield of
(58:42)
Under the optimized reaction conditions, the known[19]
pseudoglycal 2a’ could be generated in 91% yield from 1a and 1-
phenyl-1-trimethylsiloxyethylene (Table 1, entry 2). The reactivity
of trimethoxy D-glucal 1b was also examined using the flow
microreactor system. As summarized in Table 1, trimethoxy D-
glucal 1b was also effective as a glycosyl donor, allowing the
coupling of several nucleophiles. Allyltrimethylsilane, 1-phenyl-1-
trimethylsiloxyethylene and n-BuLi gave the corresponding C-
alkyl glycosides 2b,[20] 2b’ and 2b” in good to excellent yields. In
all cases, an  stereochemical outcome was observed that can
be tentatively explained by the pseudo-axial attack on the -face
2a strongly depends on the residence time and the temperature.
At high temperatures with longer residence times, the yield was
low presumably because of the decomposition of the generated
cation. At low temperatures, the yield was also low for a short tR1
probably because of the incomplete generation of the cation.
However, 2a was obtained in 83% yield (α/β = 91:9) by choosing
T = -30 °C and tR1 = 0.6 second as the optimized conditions.
Whatever the conditions used, it is worth noting that the α anomer
is formed as the major isomer, in accordance with the kinetic
trapping of cation of type I from the lower face of the sugar ring.
of the 4
H conformer of the transient 2-deoxyglucopyranosyl
3
2
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COMMUNICATION
oxycarbenium ion as previously observed[22a] while a long-range
participation by the ester or ether at C-6 can not be
excluded.[13c,13d] We finally evaluated the ability of the flow
microreactor system to generate and accumulate ion I to allow its
observation by NMR. Unfortunately, treatment of glucal 1 with
TfOH failed to afford clean NMR spectra under these conditions
presence of Brønsted acid catalysts, glycals undergo nucleophilic
displacement (Ferrier-type reaction) but can also experience
functionalization at C1 to yield 2-deoxy derivatives, via postulated
oxycarbenium ions.[ Here, the observation of ion IIIa further
reinforces this hypothesis. Performing the reaction at higher
temperatures increased the Ia/ IIIa ratio suggesting that ion IIIa is
a precursor of ion Ia in this process (see SI). To drive the reaction
to the exclusive formation of conjugated glycosyl cation, we
switched to trimethoxy D-glucal 1b and submitted it to the same
superacid conditions (Figure 4B). Unlike in a classical organic
environment,[24] the methoxy substituent has proved to be a
superior leaving group under superacid activation compared to
the acetyl group. Satisfyingly, one major polycationic species was
observed by NMR whose signals were in good agreement with
the conjugated glycosyl cation Ib displaying an anomeric proton
at δ = 8.45 ppm and an anomeric carbon at δ = 203.0 ppm (Figure
4C). The protonation of the methoxy groups was evidenced by a
23]
(
see SI).
Strongly inspired by the work of Olah and Prakash, who
unlocked large areas of carbocation chemistry exploiting non
nucleophilic superacid conditions,[21] our team has used HF/SbF
5
superacid as both reagent and solvent to generate and
characterize several glycosyl cations in the condensed phase.[22]
Following this strategy, we challenged the generation of ion I in
superacid solutions and its observation by low-temperature NMR
spectroscopy. The tri-O-acetyl-D-glucal 1a was first submitted to
5
HF/SbF and furnished a mixture of two polycationic species
which were analyzed by NMR spectroscopy (Figure 4A).
1
signal at 9.81 ppm ( H-NMR) and two signals at 70.6 and 71.6
1
3
3
ppm ( C-NMR). The departure of the CH O group at C-3 was
confirmed by the observation of the methyloxonium ion at 60.0
ppm,[25] and the formation of a C=C bond evidenced by two
doublets of doublets at 6.86 ppm (J = 9.8 Hz and J = 4.2 Hz) and
1
6
.48 ppm (J = 9.9 Hz and J = 1.9 Hz) in the H-NMR spectrum
1
3
and two signals at 149.4 and 127.0 ppm ( C-NMR). The quality
of the recorded NMR spectra allowed complete analysis of the
homonuclear H-NMR coupling constants for both species Ia and
1
Ib, enabling access to their conformational preferences in solution,
3
by comparing the experimental J(H,H) coupling constants with
those predicted for DFT calculated structural models (see SI). The
planarity of the sugar ring at the O5-C1-C2-C3 moiety was thus
confirmed, while the situation around the C3-C4-C5-O5 bonds
was demonstrated to be more flexible. Indeed, for both species
3
3
the experimental values J(H3,H4) = 4.3-4.5 Hz, and J(H4,H5) =
.0-5.2 Hz (see SI) necessarily entailed the existence of a
5
conformational equilibrium. DFT calculations (see SI) identifed
two enery minima very close in energy (0.8 and 3.2 kJ/mol for Ia
and Ib respectively) for which the combination of their NMR
parameters fulfill the experimentally observed ones (Figures 4A
and 4B and SI).
Figure 4. A. Generation of conjugated allyloxycarbenium ion Ia (conformations
in solution confirmed by DFT analysis) and glycosyl cation IIIa from tri-O-acetyl-
Because of the potential bioactivity as well as the synthetic
challenges associated with aryl C-glycosides, this class of
carbohydrates has attracted considerable interest and extensive
research aiming at developing new chemical strategies and
tactics toward this class of compounds.[ The carbon-Ferrier
rearrangement is considered as one of the most prevalent and
straightforward approaches to access C-glycosides,[2c] that are
D-glucal 1a in HF/SbF
tri-O-methyl-D-glucal 1b in HF/SbF
confirmed by DFT analysis); C. Low-temperature 13C NMR spectrum of cation
Ib in HF/SbF solution.
5
at -40 °C; B. Generation of allyloxycarbenium ion Ib from
5
at -40 °C (conformations in solution
26]
5
distinct motifs embedded in various biologically active natural
products.[
6d,26]
Acid-promoted reaction of glycals with good
Detailed NMR analysis confirmed the presence of the resonance-
nucleophiles such as alkynyl and allylsilanes, silyl enol ethers or
organometallics is especially efficient to generate C-glycosides.[
However, standard procedures to generate C-aryl glycosides
through acid-promoted Ferrier rearrangement with aromatics is
scarcely reported[27] and subject to the undesired formation of
rearranged products when dealing with functionalized aromatics
due to heteroatom nucleophilicity.[28] Capitalizing on our ability to
stabilized glycosyl cation Ia (anomeric proton at δ = 8.30 ppm and
anomeric carbon at δ = 202.4 ppm). The shielding of the anomeric
carbon and proton compared to the 2-deoxyglucosyl cation IIIa[22a]
2c]
can be rationalized by the increased stabilization of the
carbocation by conjugation. The presence of a C=C bond in this
species was evidenced by two signals at 6.29 and 6.75 ppm in
1
the H NMR spectrum and two peaks at 152.3 and 125.4 ppm in
the 13C NMR spectrum. In addition, the protonated acetates are
generate Ferrier cation of type I in HF/SbF solution, on previous
5
Friedel-Crafts type reactions achieved in superacid[29] and on the
protection of the nitrogen atom(s) by protonation in superacid, the
generation of nitrogen-containing aryl C-glycosides from Ferrier
cation precursor in superacid was explored. In batch conditions,
1
characterized by two singlets at 12 ppm < δ < 14 ppm in the H
NMR spectrum. Beside ion Ia, the presence of the known 2-
deoxyglucosyl cation IIIa was also detected in the reaction crude
according to characteristic NMR signals (see SI).[22a] In the
3
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COMMUNICATION
the tri-O-acetyl-D-glucal 1a was submitted to HF/SbF
5
in the
function must be in equilibrium with its protonated form and the
methyl group therefore orientates the electrophilic addition.[31] The
reaction is also stereoselective, the α-isomer being formed
predominantly through this process, whatever the conditions used
(α/β ratio = 85:15). As demonstrated by following the reaction by
low-temperature NMR analysis, 4a results from the concomitant
nucleophilic trapping of Ia and IIIa (followed by elimination) in
solution (see SI). To define the scope of this reaction, we
screened a set of substituted arenes and heteroarenes (Figure 5).
As previously observed for the formation of product 4a, the
reaction proceeded regioselectively and efficiently in the
presence of methylated acetanilides (products 4b and 4c). The
structure of 4b was also confirmed by X-ray analysis of the
collected crystals obtained after reaction of substrate 3 (see
SI).[32] Gratifyingly, halogenated aromatics could also be coupled
to pseudo glycals, as shown by the formation of α-product 4d.
Here again, the fluorine atom orientates the regioselectivity. More
importantly, the Ferrier cation I was found to react with aniline with
excellent stereoselectivity, albeit in a moderate yield (product 4e).
Considering that anilines must react in their protonated form in
superacid solutions, and thus acting as very poor ammonium-
substituted nucleophiles, this result emphasizes the
presence of p-methylacetanilide as a model arene, affording the
desired C-aryl hex-2-enopyranoside 4a albeit in low yield with the
formation of several side products with undetermined structure. A
similar trend was observed with other arenes, definitely discarding
the use of glycals as glycosyl donors to generate C-aryl
5
glycosides in HF/SbF . As mentioned above, the glycosyl cation
IIIa can lead to a conjugated ion Ia upon acid activation and
subsequent elimination of the C-3 acetate group. This suggests
that the treatment of a 2-deoxy glycosyl donor in the presence of
an arene under superacid conditions at a temperature above -40
°C might generate a C-aryl glycoside intermediate that would
undergo further elimination to afford the desired C-aryl-hex-2-
enopyranoside. This hypothesis was confirmed by the direct
observation of Ia (and IIIa) when submitting 2-deoxy glucosyl
donor 3 to superacid solution, the Ia/IIIa ratio increasing with time
and temperature (see SI). A preliminary trial at -40 °C with donor
3
and p-methylacetanilide yielded 4a in 16% yield (Table 2, entry
1). Performing the reaction at lower acidity failed to furnish the
desired compound even on a prolonged reaction time (Table 2,
entry 2).[30] However, carrying out the reaction at slightly higher
temperature and at a lower concentration proved beneficial (Table
2
, entries 3-5). Conducting the reaction with a substrate
superelectrophilic character of the protonated Ferrier cation in
-1
[33]
concentration in solution of 0.038 mol.L was found to be the best
compromise for good conversion and selective
superacid.
The reaction was also operative with a protected
a
a
phenol, expanding the method to oxygenated aromatics (product
transformation, decreasing the amount of undetermined side
products formation (Table 2, entries 6-7). The amount of
nucleophilic partner could even be reduced to 1.5 equiv. by
performing the reaction at -20 °C for 10 min, affording the desired
C-aryl hex-2-enopyranoside 4a in 72% yield (Table 2, entry 8).
4f).
Table 2. Optimization of C-arylation conditions applied to 2-deoxyglucosyl
donor 3 to access pseudoglycal 4a.
Entry
[3][a]
mol.L )
[SbF
(mol%)
5
][b]
n
Conditions
Yield (%)[c]
-
1
(
1
2
3
4
5
6
7
8
0.15
0.15
8
4
8
8
8
8
8
8
3
3
-40 °C, 10 min
-40 °C, 4 h
16
-[d]
19
38
46
71
66
72
0.075
0.019
0.019
0.038
0.038
0.038
3
-20 °C, 10 min
-20 °C, 10 min
-20 °C, 2 min
-20 °C, 4 min
-20 °C, 5 min
-20 °C, 10 min
3
3
3
2
1.5
Figure 5. Scope of the C-arylation of peracetylated 2-deoxyglucopyranose
5
mediated by HF/SbF . Conditions from Table 2, entry 8.
[
a] Substrate concentration in HF/SbF
5
solution. [b] Concentration of SbF
5
relative to HF in HF/SbF
5
solution. [c] Isolated yield. [d] No reaction.
The direct modification of nitrogen-containing natural products at
a late stage of a synthetic plan is now considered as a tool of
choice in drug discovery programs.[34] To test the potential of our
methodology in this context, the reactivity of the Ferrier cation Ia
with several nitrogen containing heteroaromatics was explored.
To our delight, tetrahydroisoquinoline, indoline, oxindole as well
as functionalized oxindoles could be stereoselectively and
Interestingly,
this
Friedel-Crafts
reaction
proved
regioselective, as the carbohydrate unit is selectively inserted in
ortho position to the methyl group of the acetanilide. This result
can be correlated to the behavior of nitrogen containing species
5
in superacid solutions including HF/SbF . Neutral acetamide
4
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COMMUNICATION
[
10] Allyl oxocarbenium ion intermediate I generated from tri-O-acetyl-D-glucal has
efficiently C-glycosylated in a regioselective manner (products
-1
been recently estimated to be favored by 19.58 kJ.mol over II, see: N. Huang,
H. Liao, H. Yao, T. Xie, S. Zhang, K. Zou, X. -W. Liu Org. Lett. 2018, 20, 16-
19.
4g-k). Noteworthy, the β-isomer is predominantly formed when
glycosyl cation is trapped by oxindoles, a stereochemical
outcome that is difficult to rationalize.
[
11] Calculations performed on allyl oxocarbenium ion interemediates generated from
di-O-acetyl-L-arabinal also indicated a predominant axial orientation of the 4-
OAc group, see: S. Hosokawa, B. Kirschbaum, M. Isobe Tetrahedron Lett. 1998,
In conclusion, this study enabled to convert the cyclic
allyloxycarbenium ion I, the key intermediate in the Ferrier
rearrangement, from an elusive species to a well-defined
molecule. This cation was suggested to accumulate in the
presence of triflic acid under flow conditions, and was further
trapped by anionic C-nucleophiles. Exploiting non-nucleophilic
3
9, 1917-1920.
[
12] K. Le Mai Hoang, W. -L. Leng, Y. -J. Tan, X. -W. Liu Stereoselective C-
glycosylation from glycal scaffolds, in Selective Glycosylations: Synthetic
methods and catalysts; Wiley-VCH, 2017, pp 135-153.
[
13] a) R. J. Ferrier, N. J. Prasad, J. Chem. Soc. 1969, 570-575. b) D. P. Curran, Y.-
G. Suh, Carbohydr. Res. 1987, 171, 161–191. For recent work on long-range
participation by protecting groups see c) Hansen, T.; Elferink, H.; van Hengst,
J. M. A.; Houthuijs, K. J.; Remmerswaal, W. A.; Kromm, A.; Berden, G.; van
der Vorm, S.; Rijs, A. M.; Overkleeft, H. S.; Filippov, D. V.; Rutjes, F. P. J. T.;
van der Marel, G. A.; Martens, J.; Oomens, J.; Codée, J. D. C.; Boltje, T. J.
Nature Communications 2020, 11 (1). d) Marianski, M.; Mucha, E.; Greis, K.;
Moon, S.; Pardo, A.; Kirschbaum, C.; Thomas, D. A.; Meijer, G.; Helden, G.;
Gilmore, K.; Seeberger, P. H.; Pagel, K. Angew. Chem. Int. Ed. 2020, 59,
6166–6171.
5
HF/SbF superacid solution, this cation was fully characterized by
combining low-temperature NMR spectroscopy and DFT
calculations. Its synthetic application in Ferrier rearrangements
starting from 2-deoxyglucosyl donor produced a series of
unprecedented nitrogen-containing C-aryl pseudoglycals.
[
[
14] F. Marchetti, G. Pampaloni, S. Zacchini, Dalton. Trans. 2009, 8096-8106.
15] S. Suga, M. Okajima, K. Fujiwara, J. -I. Yoshida, J. Am. Chem. Soc. 2001, 123,
7
941-7942.
16] S. Suga, K. Matsumoto, K; Ueoka, J. -I. Yoshida, J. Am. Chem. Soc. 2006, 128,
710-7711.
17] K. Saito, K. Ueoka, K. Matsumoto, S. Suga, T. Nokami, J. -I. Yoshida, Angew.
Chem. Int. Ed. 2011, 50, 5153-5156.
[
[
Acknowledgements
7
LL, NB and ZA thank the Agence Nationale de la Recherche (ANR
SweetCat) for PhD and post-doctoral grants. ST and YB
acknowledge the European Union (ERDF), Région Nouvelle
Aquitaine and the University of Poitiers for financial support. YB
thanks the PRC CNRS JSPS program number 1706 for funding.
JJB acknowledges the European Research Council for generous
support (ERC-2017-AdG to JJB - Project number 788143-
RECGLYCANMR). AA and JJB thank Agencia Estatal de
Investigación (Spain) for grants CTQ2015-64597-C2-1-P and
Severo Ochoa Excellence Accreditation SEV‐2016‐0644. AN was
partially supported by the Grant-in-Aid for Scientific Research on
Innovative Areas 2707 Middle molecular strategy from MEXT (no.
[
[
[
[
18] P. Chen, J. Su, Tetrahedron 2016, 72, 84-94.
19] H. Y. Tong, S. Xiang, W. L. Leng, X. -W. Liu, RSC Adv. 2014, 4, 34816-34822.
20] P. Tiwari, G. Agnihotri, A. K. Misra, Carbohydr. Res. 2005, 340, 749-752.
21] G. A. Olah, G. K. S. Prakash, A. Molnar, J. Sommer, Superacids, 2nd edn, Wiley
Intersciences, New York, 2009.
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•
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Angewandte Chemie International Edition
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Entry for the Table of Contents
It’s Ferrier today: The cyclic allyloxycarbenium ion, the key intermediate in the Ferrier rearrangement, has been generated and
accumulated under TfOH flow conditions. It has also been shown to be stable in superacid HF/SbF solutions. Its long-lived character
5
in these non-nucleophilic conditions allowed its full characterization by low-temperature NMR supported by DFT calculations. This ionic
species proved to be synthetically useful and produced a range of original C-aryl and C-heteroaryl pseudoglycals.
6
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