Photocatalyzed reductive fluoroalkylation of 2-acetoxyglycals towards the stereoselective synthesis of α-1-fluoroalkyl-: C -glycosyl derivatives

Article abstract of DOI:10.1039/d0ob01914c

A benign, efficient, regio- and stereoselective protocol for the syntheses of α-1-fluoroalkyl-C-glycosyl compounds bearing CF3, C4F9, and C6F13 substituents on the anomeric carbon has been developed by a new methodology starting from 2-acetoxyglycals for the first time. Remarkably, the reactions proceeded in only one step, through the visible light-photocatalyzed reductive fluoroalkylation of 2-acetoxyglycals by means of an Ir photocatalyst and employed commercially available fluoroalkyl iodides n-CnF2n+1-I (n = 1, 4, 6) as a source of fluoroalkyl radicals.

Full text of DOI:10.1039/d0ob01914c

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Page 1 of 22
Organic & Biomolecular Chemistry
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DOI: 10.1039/D0OB01914C
Photocatalyzed reductive fluoroalkylation of
-acetoxyglycals towards the stereoselective synthesis of
α1-fluoroalkyl-C-glycosyl derivatives
2
1
2,3
1
Erwin W. Mora Flores, María Laura Uhrig, * Al Postigo *
1Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Departamento de
Química Orgánica, Junín 954 CP1113-Buenos Aires, Argentina.
2Universidad de Buenos Aires, Facultad de Ciencias Exactas y Naturales, Departamento
de Química Orgánica, Pabellón 2, Ciudad Universitaria, C1428EG Buenos Aires,
Argentina
3Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)-UBA, Centro
de Investigación en Hidratos de Carbono (CIHIDECAR), Buenos Aires, Argentina
*
5
Corresponding authors. Al Postigo, e-mail: apostigo@ffyb.uba.ar; phone: +54 11
2874312, ORCID: https://orcid.org/0000-0002-4177-3689; María Laura Uhrig, e-mail:
mluhrig@qo.fcen.uba.ar; phone: +54 11 528 58535, ORCID: https://orcid.org/0000-
002-6980-4141.
0
Electronic Supplementary Information (ESI) available: General Information and
Experimental section (Preparation of substrates, Mechanistic Probe Experiments,
Calculation of Thermodynamic Parameters, Schemes S1-S5, Figures S1–S6, Tables S1-
S4, and NMR and HRMS spectra of compounds 2 – 9. See DOI: xxx/xxx

Organic & Biomolecular Chemistry
Page 2 of 22
ABSTRACT
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DOI: 10.1039/D0OB01914C
A benign, efficient, regio- and stereoselective protocol for the syntheses of 1-
fluoroalkyl-C-glycosyl compounds bearing CF , C F , and C F substituents on the
3
4
9
6 13
anomeric carbon has been developed by a new methodology starting from 2-
acetoxyglycals for the first time. Remarkably, the reactions proceeded in only one step,
through the visible light-photocatalyzed reductive fluoroalkylation of 2-acetoxyglycals
by means of an Ir photocatalyst and employed commercially available fluoroalkyl iodides
n-CnF2n+1-I (n = 1, 4, 6) as source of fluoroalkyl radicals.
INTRODUCTION
C-glycosyl compounds belong to a particular class of glycomimetics in which the
1
glycosidic oxygen has been replaced by a carbon atom. This structural feature makes
them resistant to acid and enzymatic hydrolysis, and thus, they have been envisaged as
potential tools in the Glycobiology field as inhibitors of glycosidases and/or
glycosyltransferases.2
The synthesis of C-glycosyl derivatives has largely been addressed over the years
and has been extensively reviewed.3,4,5 Polar and concerted mechanisms and a variety of
cross-coupling reactions are shown to be excellent alternatives to obtain this particular
class of sugar derivatives. Radical mechanisms promoted by AlBN and/or Bu SnH using
3
6
suitable precursors were also explored, among other approaches.
Another alternative to obtain modified carbohydrates is related to the substitution
of a hydroxyl group by a fluorine atom. This strategy provided a variety of modified
glycomimetics useful as probes of glycosidase mechanisms, as enzyme inhibitors and
7
also, as lectin ligands. Derivatives having one or several fluorine atoms attached to the
C-linked moieties of either pyranose or furanose monosaccharides have also been
synthesized. In this respect, regio- and stereoselective fluorination reactions of exo-
8
,9
glycals were carried out by Vincent and coworkers, and their activities as inhibitors of
glycosyltransferases were extensively studied.10,11
1
2
Perfluoroalkyl carbohydrates, in turn, display a variety of interesting properties
to be used as emulsifiers in colloidal systems, as they form self-assembled supramolecular
structures. Thus, they are considered as promising compounds in the biomedical field.13,14
Some of them showed excellent properties as co-surfactants for microemulsions.15,16

Page 3 of 22
Organic & Biomolecular Chemistry
On the other hand, sugar derivatives in which the anomeric carbon bears a
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DOI: 10.1039/D0OB01914C
1
7
fluoroalkyl group through a C-C bond, have also been studied and reviewed. Their
syntheses mostly involve reduction of the fluoroalkenyl exoglycals.
Glycals and, to lesser extent 2-acetoxyglycals, have been used as building blocks
1
8
19,20
in glycosylation reactions. As they are easily obtained from glycosylbromides,
they
are valuable precursors at the gram-scale for the synthesis of natural and also modified
carbohydrates. The fluoroalkylation of glycals, which comprises the incorporation of
fluoroalkyl groups onto the carbon-carbon double bonds, has been achieved by the groups
of Ye (trifluoromethylthiolation),21 Miethchen,22 Poisson and Pannecoucke,23 and
Boutureira,24,25 (Scheme 1); in all cases affording fluoroalkyl functionalization at the 2-
2
6
position. Interestingly, Leclerc and Pannecoucke achieved the preparation of -CF -
2
galactosides through an oxygen-to-carbon acyl migration. Particularly, the method from
Boutureira requires 2-iodoglycals as starting material to achieve 2-fluoroalkylglycals in
reasonable yields while the group of Xiong and Ye27 has achieved a facile Ir-
photocatalyzed trifluoromethylation of glycals employing the Umemoto´s reagent
affording 2-trifluoromethylated glycals in good yields (Scheme 1).
Scheme 1. Approaches to fluoroalkylation of glycals
The results shown here combine our joint interests in photocatalyzed
2
8
fluoroalkylation reactions with the development of new synthetic methods towards
2
9
glycomimetics resistant to biological degradations. Inspired by the results from Xiong
and Ye21,30 on the photocatalyzed trifluoromethylation of glycals which are reported to
afford 2-trifluoromethyl-substituted glycals, we began our initial investigation on 2-
3
1
acetoxyglycals. We decided to explore the possibility of obtaining C-perfluoroalkylated

Organic & Biomolecular Chemistry
Page 4 of 22
glycosyl compounds, by treatment 2-acetoxyglycals with commercially-available
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DOI: 10.1039/D0OB01914C
fluoroalkyl iodides under visible light photocatalysis. Fluoroalkyl iodides having 1, 4 and
carbon atoms were used.
6
RESULTS AND DISCUSSION
An initial assessment employing 2,3,4,6-tetra-O-acetyl galactal 1a under Rose
Bengal (5 mol%) visible-light photocatalysis using a commercial compact fluorescent
lamp (CFL), in the presence of n-C F -I and Cs CO in Ar-deoxygenated MeCN, afforded
4
9
2
3
the 1-C-nonafluorobuthyl 2,3,4,6-tetra-O-acetyl-α-galactosyl compound 2 as a single
anomer in 24% yield, although approximately half of the starting glycal was recovered
1
unchanged. The α-galacto configuration was confirmed by H-NMR spectroscopy, as
detailed below (Figure 1). Thus, the photocatalytic addition of the C F moiety took place
4
9
at the anomeric carbon while a hydrogen atom was incorporated on carbon 2. No
perfluoroalkylated glycal-derivatives were detected in the reaction mixture.
We then embarked on the optimization of the reaction conditions under
photocatalysis (Table 1). The crucial role of light was first demonstrated as no product
was obtained in the dark (entry 32, Table 1). Then, the effect of different photocatalysts,
solvents, bases and additives on the transformation of 2-acetoxygalactal to the α-1-C-
perflurobutyl-peracetylated galactose 2 was explored (Table 1) in an attempt to improve
the yield of 2.
As stated above, when Rose Bengal (RB) was used as photocatalyst (entry 1,
Table 1), 2 was obtained in 24% yield. Photocatalyst Eosin Y afforded 28 % yield of 2
(
entry 16, Table 1), whereas with the iridium-complex (i.e.: Ir[dF(CF )PPy] (dtbPy))PF ,
3 2 6
entry 17), a 53% yield of the product was observed. Taking into consideration that part
of starting glycal 1a was recovered unchanged by column chromatography, a corrected
yield value of 87% for compound 2 is re-calculated under these conditions. Using 2,4,6-
tri (9H-carbazol-9-yl)-5-chloroisophthalonitrile (3CzCIIPN) as photocatalyst, the yield
was 11% yield (Table 1, entry 19). In the absence of photocatalyst, product 2 was not
detected (Table S1, entry 30). Also, the presence of air led to a decrease in product yield
(Table S1, entry 33), in agreement with the presence of open-shell radical species.
Both CFL (compact fluorescent lamp) and blue LEDs (λmax = 470 nm) (entries 17
and 18), resulted in suitable irradiation sources as their emission maxima match with the
absorption range of the selected iridium photocatalyst.

Page 5 of 22
Organic & Biomolecular Chemistry
Among the solvent systems explored (i.e.: DMF, DMA, MeCN, MeOH, and THF,
View Article Online
DOI: 10.1039/D0OB01914C
see Table S1, ESI), MeCN (Table 1, entries 1 and 17) showed to be the most appropriate
one (entry 17). The use of MeOH (Table 1, entry 3), DMA, THF, or DMF (see Table S1,
ESI) as solvents afforded no product or low product 2 yields.
Experiments involving the addition of hydrogen atom donors to the reaction
mixture were performed, with the aim to improve the yield of the reduced C-
perfluorobutylated product. Thus, the use of tris(trimethylsilyl)silane, (Me Si) SiH,
3
3
THF), or H PO (see Table S1, ESI) afforded lower yields of product 2 when using the
2
3
Ir-photocatalyst. Similar experiments were attempted with diverse hydrogen atom donors
using Rose Bengal as photocatalyst (entries 5-12), obtaining lower yields or discrete yield
enhancements of product 2. In the presence of thiols as hydrogen atom donors, the
corresponding perfluorobutylthio ethers were obtained. These products were
characterized by standard spectroscopic techniques (see below and SI).32
By addition of oxidant species (entries 13-15) such as K [Fe(CN) ] or Cu(AcO) ,
3
6
2
the α-1-C-perflurobutyl-peracetylated galactose 2 was not formed. This result indicated
that the presence of an oxidant species in the reaction medium did not promote the re-
generation of the glycal double bond. All these attempts ultimately led to diminished
yields of 2 or even prevent its formation.
+
+
+
+
The sequential use of inorganic bases M CO (where M = Li , Na , K , Cs ) and
2
3
organic bases such as N,N,N´,N´-tetramethylethylethylenediamine (TMEDA) were then
+
+
+
introduced in the optimization of the reaction conditions. The use of Li , K , or Na
counterions in the carbonate salt afforded very low reaction yields (< 10%) of product 2
Table S1, ESI). However, the presence of cesium carbonate salt turned out to be
(
beneficial in terms of product yield. The use of TMEDA as organic base (entry 4), was
not effective.
In summary, the optimal reaction conditions found entail the use of 2-
acetoxyglycals (0.2 mmol), n-CnF2n+1-I (4 equiv.), Cs CO
(1 equiv.),
2
3
(
Ir[dF(CF )PPy] (dtbPy))PF (0.5 mol%) as photocatalyst, in Ar-deoxygenated MeCN as
3
2
6
solvent, irradiating with blue LEDs (λmax = 470nm, 10 watts) under vigorous stirring for
0 hrs. at room temperature (Table 1, entries 16 and 17). Thus, a 87% yield of -
2
perfluorobutyl-2,3,4,6-tetra-O-acetyl-galactose 2 was obtained under the optimized
conditions (Table 1, entries 17 and 18).

Organic & Biomolecular Chemistry
Page 6 of 22
Table 1. Reaction Optimizations. Reactions of substrate 1a (0.2 mmol) with C F -I (4
4
9
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DOI: 10.1039/D0OB01914C
equiv) in the presence of additives (1 equiv), photocatalyst (RB, Eosin Y, and 3CzCIIPN,
mol%, Ir-photocatalyst, 0.5 mol%) under irradiation or otherwise noted in indicated
5
solvent (3 mL) for 20 hrs under Ar-atmosphere or otherwise specified
additive/catalyst
OAc
AcO
AcO
solvent/photocatalyst
Ar
OAc
O
AcO
AcO
O
+
n-C F -I
4 9
h, 20 hrs
AcO
OAc
C4F
9
1a
2
0.2 mmol
4.0 equiv
Entry Additive (equiv)/ Catalysta
PC: RB, baseb2 & solvent
CFL
Irradiation sources Solvent Yield (%)b1
1
2
3
4
Cs
Cs
Cs
2
2
2
CO
CO
CO
3
3
3
(1)/RB
(1)/RB
(1)/RB
MeCN 24% (82%)
c
CFL
CFL
MeCN
20% (57%)
MeOH 0%
TMEDA (1)/RB
CFL
MeCN
0%
PC RB, H donor
d
5
6
7
8
9
1
1
1
Cs
Cs
Cs
Cs
Cs
Cs
Cs
Cs
2
2
2
2
CO
CO
CO
CO
CO
CO
CO
CO
3
3
3
3
(1), TTMSS (0.3)/RB
CFL
CFL
CFL
CFL
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
33% (78%)
37% (86%)
16%
8%
22%
0%
7%
4%
d
(1), TTMSS (1)/RB
(1), isopropanol (1)/RB
(1), methanol (1)/RB
(1), acetone (1)/RB
2
2
2
2
3
3
3
3
CFL
e
0
1
2
(1), 1-adamantanethiol (1)/ RB CFL
(1), 2-mercaptoethanol (1)/ RB CFL
(1), H
2
PO
3
(1)/RB
CFL
Oxidant & PC
CFL
1
1
1
3
4
5
Cs
Cs
Cs
2
2
2
CO
CO
CO
3
3
3
(1), K
(1), Cu(AcO)
(1), Cu(AcO)
3
[Fe(CN)
6
] (1)/RB
MeCN
MeCN
MeCN
5%
0%
2%
2
2
(1)/ RB
(1)/ Ir PC
CFL
Blue LED
f
PC / light source
1
1
1
1
6
7
8
9
Cs
Cs
Cs
Cs
2
CO
3
(1)/EY
CFL
CFL
Blue LED
Blue LED
MeCN
MeCN 53% (87%)
MeCN 53% (87%)
28%
g
2
2
CO
CO
3
3
(1)/ Ir PC
(1)/ Ir PC
g
2
CO
3
(1)/ 3CzCIIPN PC
MeCN
11%
a
3 2 6
)PPy] (dtbPy))PF
(0.5 mol%). bThe yields of
RB: Rose Bengal (3 mol%), EY: Eosin Y (3 mol%), Ir PC: (Ir [dF(CF
chromatographically isolated products are indicated, corrected values obtained after subtraction of remaining unreacted glycals are
indicated in brackets. 48h-reaction. TTMSS = tris(trimethylsilyl)silane.. Yields obtained with Ir PC: 2%, with RB PC: 0%.
c
d
e
Having established the optimum reaction conditions, we subsequently proceeded
to study the scope of the photocatalyzed perfluoroalkylation reactions of other easily
available 2-acetoxyglycals (Table 2).

Page 7 of 22
Organic & Biomolecular Chemistry
Table 2. Substrate scope of perfluoroakylation of 2-acetoxyglycals. Reaction time 20 hrs.
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DOI: 10.1039/D0OB01914C
The yields of chromatographically isolated products are indicated, corrected values
obtained after subtracting the remaining unreacted glycals are indicated in brackets
Ir[dF(CF )PPy] (dtbPy))PF
R3
3
2
6
R3
2
(0.5mol%)
R
O
2
R
O
AcO
+
F2n+1Cn-I
AcO
blue LED / MeCN (3mL)
Cs CO3 (1Equiv) / Ar / 20h
2
AcO
OAc
C F
n
2n+1
0
.2 mmol
4 equiv
n= 1, 4 or 6
1a-c
OAc
OAc
O
AcO OAc
AcO OAc
O
AcO
AcO
O
AcO
O
AcO
AcO
AcO
AcO
AcO
AcO
AcO
C4F9
C4F9
3. 36% (87%)
C6F13
C6F13
2. 53% (87%)
4. 39 % (98%)
5. 32% (82%)
OAc
AcO OAc
AcO
O
AcO
AcO
O C4F
9
AcO
AcO
O
O
AcO
AcO
AcO
AcO
OAc
AcO
CF3
CF3
C4F
9
8
8
and 9 34% (70%)
: 9 = 0.7:1.0
6. 59% (82%)
7. 59% (90%)
The photocatalyzed perfluorobutylation and perfluorohexylation reactions of
peracetylated galactal 1a afforded products 2 and 4 in 53, and 36% yields respectively,
as single -anomers (Figure 1, C-perfluoroalkylated glycosyl derivatives). Accordingly,
the photocatalyzed perfluorobutylation and perfluorohexylation reactions of
peracetylated glucal 1b gave products 3 and 5 in 39, and 32% yields respectively, also as
unique  anomers. In accordance with Miethchen’s report,22b the purification of these
perfluoroalkyl derivatives was difficult to achieve and a final purification step by
preparative TLC was required. Yields of products in brackets (Table 2), calculated based
on recovered starting materials, attest to the excellent mass balance of the reactions.
The α-configuration together with the equatorial disposition of the O-acetate
group at C-2, were confirmed by observing the coupling constant values of products 2 -
7
. For example, in the case of 2, the values for J1,2 = 5.2 Hz and a J2,3 = 9.7 Hz were
consistent with equatorial-axial and axial-axial disposition, respectively. Also, they were
in good agreement with those observed for other gluco-configured α-C-glycosyl
compounds.33,34 Moreover, H-1 appeared as a complex multiplet at 4.87 ppm, deshielded
as a result of the effect of the perfluoroakyl chain. Strong heteronuclear coupling of H-1
3
3
with the two proximal diastereotopic fluorine atoms was observed ( J ≈ 5.2 and J =
1,F’
1
,F
3
5
2
8.3 Hz). Similar values were obtained for galactosyl derivatives 4 and 6, and for the
glucosyl derivatives 3, 5 and 7.

Organic & Biomolecular Chemistry
Page 8 of 22
View Article Online
DOI: 10.1039/D0OB01914C
H-1
A
B
J1,2=5.2 Hz
H2
R
R
J2,3=9.7 Hz
O
H1
H4
R
H5
J1,F=5.2 Hz
R
H
J3,4=3.3 Hz
J1,F'=28.3 Hz
3
C
F
CF2
J4,5=2.2 Hz
F
C2F5
R = OAc
3
Figure 1. A.-Coupling constants ( J) analysis for the -galacto-configured compound 2.
B.-Multiplicity observed for H-1.
When we treated the 2-acetoxy glycal derived from xylose 1c with n-C F -I under
4
9
the above reaction conditions (Table 2), a mixture of the -xylo and -lyxo pyranoses 8
and 9 in 0.7 : 1.0 ratio was obtained in a combined 34% yield.
Efforts at separating products 8 and 9 from the reaction mixture failed, as standard
column chromatography techniques were ineffective, nor preparative HPLC methods
achieved separation. Nevertheless, ulterior purification of the mixture of 8 and 9 and
thorough spectroscopic characterization allowed the full spectral identification of each
anomer in the mixture.
The β-xylo configuration of the minor component 8, was determined based on
1
1
1
1
their H- H coupling (Figure 2). The H- H COSY experiment was crucial to determine
the coupling pattern of both compounds 8 and 9. The large constant values between H-2
and both, H-1 and H-3 (J1,2 ≈ J2,3 = 9.4 Hz) were consistent with their trans-diaxial
3
6
4
disposition. Thus, H-2 at 5.41 ppm was axially disposed in the C conformation, which
1
is stabilized in this case by all the substituents equatorially located.
The α-lyxo configuration of the major component 9, instead, was determined as
the axially disposed H-3, appeared as a doble-doublet with J3,4 = 10.2 Hz (due to the
coupling with the axial H-4) and J = 3.3 Hz indicating an equatorial disposition of H-
2
,3
2
. On the other hand, the J , J4,5eq, J4,5ax and J5eq,5ax (10.2, 5.8, 10.4 and 11.3 Hz,
3,4
respectively), are in good agreement with those described by Durette and Horton for
4
37
peracetylated α-lyxopyranosides and consistent with a C conformation.
1

Page 9 of 22
Organic & Biomolecular Chemistry
J4,5eq=5.6Hz
J4,5ax=10.4Hz
J4,5eq=5.8Hz
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DOI: 10.1039/D0OB01914C
H
J2,3=9.4 Hz
H4
4
H2
R
H
eq
Heq
O
O
J3,4=9.9 Hz
J4,5ax=10.1Hz
F
F
R
R
J1,2=9.4 Hz
J1,2= 2.5Hz
H
1J1,F=18.2Hz
R
C
R
R
H2
H5ax
CF2
C2F5
J3,4=10.2 Hz
H5ax
H
H1
3
H
3
C
F
9
J2,3=3.3 Hz
8
F
CF
2
C2F5
R = OAc
R = OAc
3
Figure 2. Figure 2. Coupling constants ( J) analysis for the β-xylo-configured compound
8
and for the α-lyxo-configured compound 9.
The pyranose flexibility in xylose 1c could account for the mixture of the α-lyxo
and β-xylo diastereoisomers found in the Ir-photocatalyzed reactions Also, 1c can suffer
fluoroalkyl radical attack from both faces of the double bond, as compared to hexose-
derived 2-acetoxyl glycals 1a and 1b (Table 2). Noteworthy, the OAc at 2-position and
the anomeric R group maintain a trans-disposition in the products derived from xylose
F
1
c (products 8 and 9 Table 2).
Considering the relevance of trifluoromethylated compounds in industry and
medicinal chemistry, we undertook the analogous trifluoromethylation reactions of 2-
acetoxy-glycal derivatives of galactose and glucose employing this time commercially-
available CF -I (see ESI for handling of this reagent).
3
The trifluoromethylation reaction of peracetylated galactal 1a afforded product 6
in 64% yield, again as a single -anomer, where the incorporation of the CF moiety took
3
place at the anomeric carbon, and a H atom at carbon-2. The Ir-photocatalyzed
trifluoromethylation of peracetylated glucal 1b gave product 7 in 59% yield, also as a
single -anomer.
We pursued deprotecting products 2 and 3 under the standard Zemplén’s
3
8
conditions (MeONa/MeOH). However, an unidentified product mixture was recovered.
Intrigued by the different reaction course shown in the photocatalyzed
trifluoromethylation of glycals reported by Ye and colleagues21,30 employing the
Umemoto´s reagent and fac-Ir(ppy) as photocatalyst in an oxidative quenching cycle
3
towards the synthesis of 2-trifluoromethylglycosides, we decided to explore the reaction
mechanism of our 2-acetoxyglycals with commercial n-perfluoroalkyl iodides and
+
Ir[(dF(CF )ppy] (dtbbpy) (PC-1) as photocatalyst. The redox properties of
3
2
+
39
Ir[(dF(CF )ppy] (dtbbpy) , and similar metal-organo-photoredox catalysts, can behave
3
2
4
0
both in oxidative or reductive quenching manners, or simultaneously in both. However,
as fluorescence of PC-1* does not seem to be suppressed by addition of n-C F -I (Figures
4
9

Organic & Biomolecular Chemistry
Page 10 of 22
S4 and S5), electron transfer oxidation of Ir(III)* to Ir(IV) and concomitant reduction of
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DOI: 10.1039/D0OB01914C
n-C F -I to C F radicals is precluded, ruling out an oxidative photocatalytic quenching
4
9
4 9
cycle with PC-1. On the other hand, the emission spectra of PC-1* are quenched upon
addition of a DMF solution of Cs CO (Figure 1 below, and Figures S2 & S3), indicating
2
3
that an electron transfer takes place between PC-1* and Cs CO , affording Ir(II) and the
2
3
.
-
-1
radical anion of CO , with a Stern Volmer rate constant K = 402 M .
3
SV
A
B
8
00
00
00
00
0
Ir + Q= 0
2.1
6
4
2
1.9
Ir+Q= 24.5E-2 mM
Ir + Q= 48.9E-2 mM
Ir + Q= 73.4E-2 mM
Ir + Q= 97.9E-2 mM
Ir + Q= 1.59 mM
1.7
1.5
1.3
1.1
0.9
0
0.5
1
CO
1.5
2
400
500
600
700
[
Cs
2
3
] mM
Wavelength (nm)
Figure 1. A. Suppression of the fluorescence of the photocatalyst, in the presence of DMF
solution of Cs CO (Q) B. Fluorescence Quenching. Stern-Volmer Plot
2
3
The photocatalytic reactions of 1 with PC-1 is suppressed in the presence of 1,4-
dinitrobenzene (Scheme 2A), confirming the presence of an electron transfer process
involving reducing species. Mechanistic evidence, such as the quenching of the
photoreactions with 1-methyl-1-phenyl-ethylene, a good radical acceptor, (Scheme 2B)
and TEMPO (Scheme 2C), are also in accordance with the presence of radicals (Table
S2).

Page 11 of 22
Organic & Biomolecular Chemistry
AcO OAc
O
Ir[dF(CF )PPy] (dtbPy))PF
3 2 6
NO2
AcO
OAc
O
View Article Online
DOI: 10.1039/D0OB01914C
(0.5mol%)
A
AcO
n-C F -I
4
9
AcO
X
AcO
OAc
LED Azul / MeCN (3mL)
C4F9
O N
2
0.2mmol
0.8mmol
Cs CO (1 equiv) / Ar / 20h
2 3
AcO OAc
Ir[dF(CF )PPy] (dtbPy))PF
3
2
6
O
AcO
C4F9
n-C F -I
(0.5mol%)
B
4 9
OAc
LED Azul / MeCN (3mL)
95%
0
.2mmol
0.8mmol
Cs CO / Ar / 20h
(1 equiv)
3
2
AcO OAc
O
Ir[dF(CF )PPy] (dtbPy))PF
3
2
6
AcO
(0.5mol%)
C
n-C F -I
4
9
N
O
N
O
LED Azul / MeCN (3mL)
Cs CO (1 equiv) / Ar / 20h
OAc
99%
C4F9
0.2mmol
0.8mmol
2
3
Scheme 2. Mechanistic probe experiments
The reaction of 1a according to the standard reaction conditions in CD CN as
3
solvent afforded 3 % yield of product 2, purporting that a large isotope effect is operating,
and that the H-transfer step from the solvent can be rate-determining. Other sources of H-
atom donor in the reaction medium cannot be discarded at this time, and this step of the
reaction mechanism is being thoroughly investigated at present in our laboratory.
We also measured the quantum yield of the reaction, and found a value of 0.196

0.05, suggesting the lack of a reaction propagation chain (see ESI for quantum yield
4
1
calculation). According to the results from Yoon and co-workers we estimated the
length of the propagation chain in our photoinitiated reaction and found a value of 0.20,
well below that expected in a self-propagation chain mechanisms (see ESI).
We also conducted an on/off light experiment (Figure S1) aimed at
revealing/discarding the presence of chains in photoredox processes. A plot of product
formation versus photoreaction time revealed that during dark periods (absence of
irradiation), no accumulation of product was encountered, indicating the necessity of
constant illumination.39,42 However, ordinary lifetimes for radical chain events may
4
3
commonly be on the second or sub-second time scale; therefore, the lack of product
accumulation during dark intervals is only consistent with chains ceasing faster than the
timescale of the analytical measurement employed.44,45
The proposed mechanism is illustrated in Scheme 3.

Organic & Biomolecular Chemistry
Page 12 of 22
View Article Online
DOI: 10.1039/D0OB01914C
AcO OAc
O
AcO
OAc
O
AcO
Ir(III)
Ir(III)*
CO32-
AcO
reductive
quenching
OAc
AcO
C F
n
2n+1
C F
n n+1
I
I
Ir(II)
C F
n 2n+1
-I
CO3
H-Donor

G = -1.37V + 1.27V = -0.1V
I
OAc
AcO
AcO
H
O
AcO
C F
n
2n+1
Scheme 3. Proposed reaction mechanism
In the proposed mechanism, the visible-light -excited photocatalyst PC-1* accepts
an electron from Cs CO , affording the PC in its reduced form (Ir(II)). The reductive
2
3
quenching cycle for the production of C F radicals has a Gibbs energy value of 0.1 V,
4
9
as calculated from the Rehm Weller equation (Figure S7). This Ir(II) has enough reductive
potential to reduce the perfluoroalkyl iodide R -I to R radicals (see section 2.4.2.- ESI),
F
F
which add to the C-1 position of 1 affording radical adduct intermediate I. This
intermediate I cannot be oxidized to a carbocation intermediate (no Ir(IV) present), as in
the case of the work by Ye and co-workers21,30 but instead traps a H atom to afford the
C -glycoside product. This H-atom donation step is being investigated at the moment.
RF
This latter is probably a sluggish process, with a slow rate determining step, as opposed
to the trifluoromethylation of glycals with the Umemoto´s reagent, where oxidation of
the intermediate radical adduct to an oxonium ion by Ir(IV) regenerates the PC in its
original oxidation step. In the present case, two-bimolecular steps are involved in the
generation of product 2, i.- radical addition and ii.- subsequent H-abstraction. The lack of
an ATRA (atom transfer radical addition) reaction product, that would result from
concomitant introduction of an iodine atom and a R group into the double bond moiety,
F
re-enforces the lack of chain propagation, the low quantum yield observed and the short
length chain obtained.
It should be noted that despite that two stereogenic centers are formed in the
reductive fluoroalkylation of 2-acetoxygalactal and glucal derivatives, only one mayor

Page 13 of 22
Organic & Biomolecular Chemistry
product is obtained in each case (i.e.: 2 and 3, respectively), as strong selectivity towards
View Article Online
DOI: 10.1039/D0OB01914C
the α-galacto/α-gluco-configured products was observed. These results can be interpreted
4
on the basis of steric effects, also called the α-effect. In the preferred H conformation
5
of the substrates (vide infra Scheme 4), the quasi-equatorial disposition adopted for the -
CH OAc substituents at position 5-, permits the in-coming R radical to approach from
2
F
the bottom α-face, a fact that is reinforced in the galacto-derivative (53% of product 2)
which bears an axial OAc group at position 4 exerting remarkable steric influence towards
the R radical approximation from the upper β-face. Moreover, an addition on the β-face
F
would lead to an unfavorable twist-boat transition state. Finally, the incoming hydrogen
atom-donor occurs from the β-face, leaving the AcO-group in equatorial disposition
(Scheme 4).
AcO OAc
OAc
AcO
OAc
O
AcO
AcO
O
H
AcO
O
AcO
OAc
AcO
AcO
C F
n
2n+1
C F
n 2n+1
1a
2
C F
n
2n+1
X
CH OAc
2
OAc
AcO
AcO
AcO
O
O
AcO
AcO
CH OAc
2
4H5
5H4
C F
n
2n+1
1a
4
Scheme 4. α-Attack of the perfluoroakyl radical to 1a in the preferred H conformation.
5
On the other hand, the higher flexibility of the pyranose 1c could account for the
mixture of the α-lyxo and β-xylo diastereoisomers found in the Ir-photocatalyzed
4
reactions. 1c, in the preferred H conformation, can suffer unimpeded fluoroalkyl radical
5
attack at C-1 from both faces of the double bond as a result of absence of any substituent
at C-5 (allowing bottom approach of R radical) or the advantageous equatorial
F
disposition of the substituent at C-4 (which permits approximation of R radical from the
F
top face), as compared to galacto-derived glycal 1a. H-atom donation in the resulting
radical intermediates takes place from the same face leading to compounds 8 and 9.

Organic & Biomolecular Chemistry
Page 14 of 22
View Article Online
DOI: 10.1039/D0OB01914C
H
O
AcO
AcO
C F
n
2n+1
8
AcO
AcO
AcO
O
CnF2n+1
X
AcO
AcO
O
AcO
AcO
-face attack
C F
n
2n+1
H
C F
n
AcO
O
2n+1
OAc
5
5
CnF2n+1
O
AcO
AcO
4
4
AcO
AcO
O
AcO
O
4
H
O
5
AcO
AcO
AcO
C F
OAc
5H4
n
2n+1
1c
4H5
4
5
AcO
C F
X
AcO
n
2n+1
AcO
AcO
C F
n
2n+1
-face attack
AcO
AcO
AcO
O
9
H
OAc
5
C F
n 2n+1
O
4
C F
n
2n+1
AcO
AcO
Scheme 5. α- and β-attack of the perfluoroakyl radical to 1c.
CONCLUSIONS
Perfluoroalkylation of 2-acetoxy-glycals towards the synthesis of 1-
fluoroalkyl-C-glycosyl compounds was achieved through visible-light photocatalytic
techniques employing an Ir(F) photocatalyst (PC-1) and commercially available
perfluoroalkyl iodides n-CnF2n+1-I (n = 1,4,6) in reasonably good yields.
The synthetic strategy studied in this work represents important advantages over
the reported methods for obtaining C-fluoroalkylglycosides, as it involves a single
process starting from laboratory-available 2-acetoxyglycals, employs inexpensive
commercial sources of perfluoroalkylated chains, and uses light in the visible region of
the electromagnetic spectrum to initiate the reaction. The reactions were clean and
proceeded with good yields and excellent mass balance.
As for the reaction mechanism, we provide evidence on the fact that PC-1 acts in
a reductive quenching cycle producing R radicals as determined by fluorescence
F
quenching experiments in a non-chain radical process as evidence by the lower-than-unity
quantum yield observed (i.e.: 0.196).
The reactions showed to be highly stereoselective since for the 2-acetoxygalactal
and 2-acetoxyglucal substrates, only α-galacto/α-gluco-configured products were
observed, respectively. On the other hand, in the case of the pentopyranose-derived glycal

Page 15 of 22
Organic & Biomolecular Chemistry
1
c, a mixture of the α-lyxo and β-xylo diastereoisomers were obtained in the Ir-
View Article Online
DOI: 10.1039/D0OB01914C
photocatalyzed reactions.
In summary, we herein report the first visible-light-photocatalyzed one-step- C-
fluoroalkylation procedure of glycal derivatives towards the synthesis of C-
perfluoroalkylated-glycosyl compounds. These results encourage further investigations
on alternative radical methods for the introduction of fluorinated groups into glycals and
2
-acetoxyglycals.
EXPERIMENTAL
General Procedure for Photocatalytic Reactions
In a 5 mL-reaction vial provided with a screw-cap septum and a micro stir bar, the glycal
(
1a-c, 0.2 mmol), Cs CO (65 mg, 0.2 mmol), and the selected photocatalyst (0.36 mol%,
2 3
4
1
.5 × 10-2 mmol Eosin Y), 4.5 × 10-2 mmol RB (0.36 mol%), or Iridium catalyst, (1 ×
0-3 mmol, 0.5 mol%) were suspended in deoxygenated acetonitrile (3 mL). The mixture
was stirred and an Argon atmosphere was flushed into the solution for 3 min. Then, the
perfluoroalkyl iodide (n-C F I, 138 µL (0.8 mmol); n-C F I, 173 µL (0.8 mmol); or CF I,
4
9
6
13
3
2
83 µL (0.8 mmol) of the stock solution) was introduced through the septum with a
syringe. After brief ulterior deoxygenation with Argon, the vial was placed on a stir plate
and the solution stirred vigorously for 24 hrs at room temperature under constant
illumination under 5-Watt-blue LEDs (10-Watt total, distance from the lamp: 1 cm from
a blue LED). The mixture was then extracted with DCM or Et O (3 × 5 mL), and the
2
extracts, dried over MgSO (anh.) and concentrated in vacuo. TLC analyses were
4
performed employing ethyl acetate:iso-octane (1:1) as the mobile phase. The crude
residues were analyzed by H-NMR, and a 19F-NMR by adding benzotrifluoride as
internal standard for quantification of the products. Yields were also determined by
weight after purification of the products, under the conditions described above.
1

Organic & Biomolecular Chemistry
Page 16 of 22
1
-(2,3,4,6-Tetra-O-acetyl-α-D-galactopyranosyl)-1,1,2,2,3,3,4,4,4-nonafluorobutane (2)
View Article Online
DOI: 10.1039/D0OB01914C
OAc
O
AcO
AcO
AcO
C4F9
Purification by column chromatography (8:2 Hexane / EtOAc) followed by preparative
TLC, gave compound 2 (58 mg, 53%) as a white powder, 26 mg of starting glycal 1a
were recovered from the column (87% corrected yield for 2). R = 0.50 (1.5:1 iso-octane
f
EtOAc). [α]20 = 5.81 (c 0.97, CH Cl ). H NMR (600 MHz, CDCl ) δ: 5.53 (dd, 1 H,
1
/
D
2
2
3
J = 3.3, J = 2.2 Hz, H-4), 5.50 (dd, 1 H, J = 9.7, J = 3.3 Hz, H-3), 5.46 (dd, 1 H,
3
,4
4,5
2,3
3,4
J = 5.2, J = 9.7, H-2), 4.88 (ddd, 1 H, J = 5.2, J = 5.2, J1,F ’= 28.3 Hz, H-1), 4.30
1
,2
2,3
1,2
1,F
(
m, 1 H, H-5) 4.22 (dd, 1 H, J5,6’ = 7.5, J6,6’ = 11.7 Hz, H-6’), 4.11 (dd, 1 H, J = 5.2, J
5,6 6,6`
1
3
1
=
11.7 Hz, H-6), 2.16, 2.13, 2.07, 2.05 (4 s, 3 H each, CH CO). C { H} NMR (150.9
3
MHz, CDCl ) δ: 170.3, 169.9, 169.7, 169.4 (CO), 71,6 (C-5), 69.0 (dd, J = 20.0, 2JC,F’
2
3
C-F
=
27.5 Hz, C-1), 67.4 (d, 4JC,F’ = 3.2 Hz, C-3) 66.6 (C-4), 65.5 (d, 3JC,F’ = 7.8 Hz, C-2),
1
9
6
3
2
0.9 (C-6), 20.6, 20.5, 20.4 (×2) (CH CO). F NMR (470.592 MHz, CDCl ) δ: 80.9 (t,
3
3
1
’
F, J = 10.6 Hz, CF ), 112.1, 116.1 (2brd, 1 F each, J = 302.4 Hz, C F ), 123.4 (m,
3
2
3
2’
F, C F ), 124.6 (m, 1 F, J = 5.1, J = 23.9, J = 293 Hz, C F ), 127.6 (m, 1 F, J = 8.5,
2
2
2
’
+
J = 17.5 Hz, C F ). ESI-HRMS: [M+H ] calcd for C H F O : 551.0958, Found:
2
18 20
9
9
+
+
5
51.09636, [M+Na ] calcd for C H F NaO : 573.07776, Found: 573.07870, [M+K ]
1
8
19
9
9
calcd for C H F KO : 589.05169, Found: 589.05194.
1
8
19
9
9
1
-(2,3,4,6-Tetra-O-acetyl-α-D-glucopyranosyl)-1,1,2,2,3,3,4,4,4-nonafluorobutane (3)
OAc
O
AcO
AcO
AcO
C4F9
Purification by column chromatography (8:2 Hexane / EtOAc) followed by preparative
TLC, gave compound 3 (40 mg, 32%) as white syrup, 40 mg of starting glycal 1b were
recovered from the column (87% corrected yield for 3). R = 0.60 (1:1 Hexane / EtOAc).
f
α]20 = +4.3 (c 1, CH Cl ). H NMR (600 MHz, CDCl ) δ: 5.55 (t, 1 H J = 9.1, J =
1
[
D
2
2
3
2,3
3,4
9
.6 Hz, H-3), 5.26 (dd, 1 H, J = 6.1, J = 9.1 Hz, H-2), 5.05 (dd, 1 H, J =9.6, J 8.5,
1,2 2,3 3,4 4,5
H-4), 4.84 (ddd, 1 H, J = 6.1, J = 5.4, J = 27.5 Hz, H-1), 4.30 (dd, 1 H, J = 5.8,
1
,2
1,F
1,F ’
5,6
J6,6’ = 13.0, Hz H-6) 4.12 (m, 1 H, H-5, H-6’), 2.12, 2.09 (×2), 2.08 (4 s, 3 H each,
1
3
1
CH CO). C { H} NMR (150.9 MHz, CDCl ) δ: 170.4, 169.6, 169.4, 169.3 (CO), 72.7
3
3
(
C-5), 69.7 (C-3), 69.0 (t, 2JC-F = 24.0 C-1), 67.6 (×2, C-2, C-4), 61.6 (C-6), 20.5, 20.4

Page 17 of 22
Organic & Biomolecular Chemistry
1
9
(
×2), 20.3 (CH CO). F NMR (470.592 MHz, CDCl ) δ: 80.9 (t, 3F, J = 10.7 Hz, CF
3
View Article Online
)
,
3
3
DOI: 10.1039/D0OB01914C
1
’
3’

1
113.0, 115.2 (2brd, 1 F each, J = 304.3 Hz, C F ), 123.4 (m, 2 F, C F ), 124.6 (m,
2
2
2
’
2’
F, J = 22.7, J = 293.1 Hz, C F ), 127.5 (m, 1 F, J = 4.5, J = 293.1 Hz, C F ). ESI-
2
2
+
+
HRMS: [M+Na ] calcd for C H F NaO : 573.0778, Found: 573.0784.
1
8
19
9
9
1
-(2,3,4,6-Tetra-O-acetyl-α-D-galactopyranosyl)-1,1,2,2,3,3,4,4,5,5,6,6,6-
tridecafluorohexane (4)
OAc
AcO
O
AcO
AcO
C6F
13
Purification by preparative thin-layer chromatography (8:2 Hexane / EtOAc) followed by
preparative TLC, gave compound 4 (52 mg, 39%) as yellowish syrup, 40 mg of starting
glycal 1a were recovered from the column (98% corrected yield for 4). R = 0.60 (1:1 iso-
f
octane / EtOAc). [α]20 = +14.8 (c 1, CH Cl ). H NMR (600 MHz, CDCl ) δ: 5.53 (dd,
1
D
2
2
3
1
1
4
H, J = 3.5, J = 2.5 Hz, H-4), 5.51 (dd, 1 H, J = 9.6, J = 3.5 Hz, H-3), 5.46 (dd,
3,4 4,5 2,3 3,4
H, J = 5.2, J = 9.6, H-2), 4.88 (ddd, 1 H, J = 5.2, J =5.2, J1,F ’= 28.2 Hz, H-1),
1
,2
2,3
1,2
1, F
.30 (m, 1 H, H-5) 4.23 (dd, 1 H, J = 7.5, J = 11.7 Hz, H-6’), 4.11 (dd, 1 H, J = 5.2,
5
,6’
6,6’
5,6
1
3
1
J6,6` = 11.7 Hz, H-6), 2.16, 2.13, 2.07, 2.06 (4 s, 3 H each, CH CO). C { H} NMR (150.9
3
MHz, CDCl ) δ: 170.4, 170.0, 169.8, 169.5 (CO), 71.5 (C-5), 69.2 (C-1), 67.4 C-3) 66.6
3
1
9
(
C-4), 65.5 (C-2), 61.0 (C-6), 20.6, 20.5, 20.4 (×2) (CH CO). F NMR (470.592 MHz,
3
CDCl ) δ: 80.8 (t, 3 F, J = 10.6 Hz, CF ), 112.5, 124.2 (m, 6 F, 3× CF ), 125.4,
3
3
2
2
’
+

126.9 (2m, 1 F each, C F ). ESI-HRMS: [M+H ] calcd for C H F O : 651.0894,
2 20 20 13 9
Found: 651.0909.
1
-(2,3,4,6-Tetra-O-acetyl-α-D-glucopyranosyl)-1,1,2,2,3,3,4,4,5,5,6,6,6-
tridecafluorohexane (5)
OAc
O
AcO
AcO
AcO
C6F
13
Purification by preparative thin-layer chromatography (8:2 Hexane / EtOAc) followed by
preparative TLC, gave compound 5 (42 mg, 32%) as yellowish syrup, 40 mg of starting
glycal 1b were recovered from the column (82% corrected yield for 5). R = 0.60 (1:1
f
Hexane / EtOAc). [α]20 = +3.7 (c 1, CH Cl ). H NMR (600 MHz, CDCl ) δ: 5.52 (t, 1
1
D
2
2
3

Organic & Biomolecular Chemistry
Page 18 of 22
H, J = J = 9.6 Hz, H-3), 5.24 (dd, 1 H, J = 6.0, J = 9.6 Hz, H-2), 5.03 (t, 1 H, J
3V,ie4w Article Online
2
,3
3,4
1,2
2,3
DOI: 10.1039/D0OB01914C
=
J = 9.0, H-4), 4.81 (ddd, 1 H, J = 5.4, J = 5.4, J1,F ’= 27.5 Hz, H-1), 4.31 (dd, 1 H,
4,5 1,2 1,F
J = 5.7, J = 12.9 Hz H-6) 4.13 (m, 1 H, H-5, H-6’), 2.12, 2.10 (×2), 2.08 (4 s, 3 H
5
,6
6,6’
1
3
1
each, CH CO). C { H} NMR (150.9 MHz, CDCl ) δ: 169.5, 169.4, 169.3 (×2) (CO),
3
3
7
2
2.6 (C-5), 69.7 (C-3), 69.0 (t, 2JC-F = 54.4 C-1), 67.6 (C-2), 67.5 (C-4), 61.5 (C-6), 20.6,
1
9
0.5, 20.4, 20.3 (CH CO). F NMR (470.592 MHz, CDCl ) δ: 80.7 (t, 3 F, J = 10.1 Hz,
3
3
2
’
CF ), 120.0, 124.2 (m, 6 F, 3× CF ), 125.2, 126.9 (2m, 1 F each, J = 293 Hz, C F ).
3
2
2
+
ESI-HRMS: [M+H ] calcd for C H F NaO : 673.0714, Found: 673.0707.
2
0
19 13
9
(2,3,4,6-Tetra-O-acetyl-α-D-galactopyranosyl)trifluoromethane (6)
OAc
O
AcO
AcO
AcO
CF3
Purification by preparative thin-layer chromatography (8:2 Hexane / EtOAc) followed by
preparative TLC, gave compound 6 (48 mg, 59%) as a yellowish syrup, 19 mg of starting
glycal 1a were recovered from the column (82% corrected yield for 6). R = 0.70 (1:1
f
Hexane / EtOAc). [α]20 = 4.5 (c 1.0, CH Cl ). H NMR (600 MHz, CDCl ) δ: 5.49 (dd,
1
D
2
2
3
1
H, J = 3.3, J = 1.8 Hz, H-4), 5.38 (dd, 1 H, J = 6.2, J = 9.6, H-2), 5.20 (dd, 1 H,
3,4 4,5 1,2 2,3
J = 9.6, J = 3.3 Hz, H-3), 4.65 (ddd, 1 H, J = 6.2, J = 8.7, J1, F = 11.7 Hz, H-1),
2
,3
3,4
1,2
1, F
4
2
1
6
3
.22 (m, 2 H, H-5 + H-6’), 4.10 (dd, 1 H, J = 8.4, J = 14.3 Hz, H-6), 2.14, 2.09, 2.06,
5,6 6,6’
1
3
1
.04 (4 s, 3 H each, CH CO). C { H} NMR (150.9 MHz, CDCl ) δ: 170.4, 170.1, 169.9,
3
3
69.6 (CO), 71.2 (C-5), 70.2 (q, JC-F = 29.2, C-1), 67.3 (C-3), 66.74 (C-4), 65.0 (C-2),
1
9
1.1 (C-6), 20.6 (×2), 20.5 (×2) (CH CO). F NMR (470.592 MHz, CDCl ) δ: 67.6 (s,
3
3
+
F, CF ). ESI-HRMS: [M+Na ] calcd for C H F NaO : 423.0873, Found: 423.0885.
3
15 19
3
9
(2,3,4,6-Tetra-O-acetyl-α-D-glucopyranosyl)trifluoromethane (7)
OAc
O
AcO
AcO
AcO
CF3
Purification by preparative thin-layer chromatography (8:2 Hexane / EtOAc) followed by
preparative TLC, gave compound 7 (47 mg, 59%) as white syrup, 23 mg of starting glycal
1
b were recovered from the column (90% corrected yield for 7). R = 0.70 (1:1 iso-octane
f
EtOAc). [α]20 = +6.3 (c 1, CH Cl ). H NMR (600 MHz, CDCl ) δ: 5.51 (t, 1 H, J =
1
/
D
2
2
3
2,3

Page 19 of 22
Organic & Biomolecular Chemistry
J = 8.9 Hz, H-3), 5.19 (dd, 1 H, J = 7.1, J = 8.9, H-2), 5.05 (t, 1 H, J = J = 8.9
3
,4
1,2
2,3
3,4
3,4
View Article Online
DOI: 10.1039/D0OB01914C
Hz, H-4), 4.60 (ddd, 1 H, J = 7.0, J = 8.7, J1, F = 17.3 Hz, H-1), 4.29 (m, 1 H, J5,6’
=
1
,2
1, F
5
.0, J6,6’ = 12.5 Hz, H-6’), 4.12 (dd, 1 H, J = 2.4, J = 12.5 Hz, H-6), 4.02 (m, 1 H,
5,6 6,6’
1
3
1
H-5), 2.10, 2.09, 2.05, 2.04 (4 s, 3 H each, CH CO). C { H} NMR (150.9 MHz, CDCl )
3
3
δ: 170.6, 169.7, 169.5, 169.4 (CO), 72.3 (C-5), 70.4 (C-1), 69.8 (C-3), 67.7 (C-4), 67.2
1
9
(
C-2), 61.6 (C-6), 20.7 (×2), 20.6, 20.4 (CH CO). F NMR (470.592 MHz, CDCl ) δ:
3
3
+

67.3 (s, 3 F, CF ). ESI-HRMS: [M+Na ] calcd for C H F NaO : 423.0873, Found:
3 15 19 3 9
4
23.0863
1
-(2,3,4-tri-O-acetyl-β-xylopyranosyl)-1,1,2,2,3,3,4,4,5,5,6,6,6-tridecafluorobutane
and 1-(2,3,4-Tri-O-acetyl-α-lyxopyranosyl)-1,1,2,2,3,3,4,4,5,5,6,6,6-
tridecafluorobutane (9)
(8)
AcO
O
O
AcO
AcO
C4F9
AcO
AcO
OAc
C4F9
Isomeric compounds 8 and 9 were obtained from 2-acetoxy-xylal 1c (52 mg) as an
unresolved mixture. The mixture was purified from other minor contaminants by
preparative thin-layer chromatography (8:2 Hexane / EtOAc) and 33 mg (34% combined
yield) were obtained as a white syrup, 26 mg of starting glycal 1c were recovered from
the column (70% corrected yield for 8 + 9). R = 0.60 (1:1 Hexane / EtOAc).
f
Further attempts to separate both compounds by HPLC (RP-18 column, MeOH / H O
2
mixtures) were unsuccessful. Nevertheless, the signals of both compounds could be
1
clearly seen in the H-NMR spectrum, and a 0.7 : 1.0 ratio of 8 : 9 could be determined
1
by integration of the signals. H NMR (600 MHz, CDCl ) δ: 5.77 (br. dd., 1 H, J = 2.5,
3
1,2
J2,3 = 3.3 Hz, H-2-lyxo), 5.41 (t, 0.7 H, J1,2 = J2,3 = 9.4 Hz, H-2-xylo), 5.30 (ddd, 1 H,
J4,5eq = 5.8, J4,5ax = 10.4 Hz, J = 10.2, H-4-lyxo), 5.28 (m, 0.7 H, H-3-xylo), 5.05 (dd, 1
3,4
H, J = 3.3, J = 10.2 Hz, H-3-lyxo), 5.01 (dd, 0.7 H, J = 5.6, J4,5ax = 10.1 Hz, J3,4
4,5eq
2
,3
3,4
=
9.9, H-4-xylo), 4.33 (dd, 1 H, J4,5eq = 5.8, J5eq,5ax = 11.3 Hz, H-5eq-lyxo), 4.22 (dd, 0.7
H, J4,5eq = 5.6, J5eq,5ax = 11.3 Hz, H-5eq-xylo), 4.07 (m, 1 H, JH,F = 18.2 Hz, H-1-lyxo),
.93 (m, 0.7 H, H-1-xylo), 3.33 (t, 1.7 H, J4,5ax = 10.4, J5eq,5ax = 11.3 Hz, H-5ax-lyxo +
H-5-ax-xylo), 2.16 (s, 2.1 H, CH CO, xylo), 2.15, 2.05 (2 s, 3 H each, 2 × CH CO, lyxo),
3
3
3
1
3
1
2
.04, 2.03 (2 s, 2.1 H each, 2 × CH CO, xylo), 2.02 (s, 3 H, CH CO, lyxo). C { H}
3 3
NMR (150.9 MHz, CDCl ) δ: 170.3, 170.2, 169.9, 169.7, 169.6, 169.3 (CO), 74.2 (m, C-
3
1
-xylo), 73.5 (m, C-1-lyxo), 73.0 (C-3-xylo), 71.0 (C-3-lyxo), 68.0 (C-4-xylo), 67.6 (C-5-
xylo), 66.9 (C-5-xylo), 66.2 (m, C-2-xylo), 65.6 (C-5-lyxo), 65.3 (m, C-2-lyxo), 21.07,

Organic & Biomolecular Chemistry
Page 20 of 22
1
9
2
0.88, 20.81, 20.73, 20.71, 20.54, 20.29 (COCH ). F NMR (470.592 MHz, CDCl ) δ:
3 3
View Article Online
DOI: 10.1039/D0OB01914C
+

80.92 (t, 3 F, J = 10.7 Hz, CF ), 116.5 - 128.0 (m, 6 F, 3 × CF ). ESI-HRMS: [M+H ]
3
2
calcd for C H F NaO : 501.0566, Found: 501.0568
1
5
15
9
7
CONFLICTS OF INTEREST
There are no conflicts to declare.
Acknowledgements
Support for this work from the Universidad de Buenos Aires (UBA), the Consejo
Nacional de Investigaciones Científicas y Técnicas (CONICET) and the Agencia
Nacional de Promoción Científica y Tecnológica (ANPCyT), Argentina, are gratefully
acknowledged. AP and MLU are research members of CONICET. EM is a recipient of a
doctoral scholarship from CONICET.
REFERENCES
1
M. Brito-Arias, Chapter 5, C-Glycosides, Synthesis and Characterization of Glycosides,
nd
Springer, 2 Edition, 2016, 281-310.
2
W. Zou, Curr. Top. Med. Chem., 2005, 5, 1363-1391.
3
L. Liu, M. McKee, M. H. D. Postema, Curr. Org. Chem., 2001, 5, 1133-1167.
4
Y. Yang, B. Yu, Chem. Rev., 2017, 117, 12281−12356.
5
K. Lalitha, K. Muthusamy, Y. S. Prasad, P. K. Vemula, S. Nagarajan, Carbohydr. Res., 2015,
4
02, 158-171.
6
B. Giese, H.-G. Zeitz, Chapter 23, C-Glycosyl compounds from free radical reactions,
Preparative Carbohydrate Chemistry, Stephen Hanessian Ed., Marcel Dekker Inc. Eds,
1
997, 507-525.
7
8
9
M. L. Uhrig, B. Lantaño, A. Postigo, Org. Biomol. Chem., 2019, 17, 5173-5189.
A. Caravano, H. Dohi, P. Sinaÿ, S. P. Vincent, Chem. Eur. J., 2006, 12, 3114–3123.
L. Dumitrescu, G. Eppe, A. Tikad, W. Pan, S. El Bkassiny, S. S. Gurcha, A. Ardá, J. Jiménez-
Barbero, G. S. Besra, S. P. Vincent, Chem. Eur. J., 2014, 20, 15208-15215.
1
1
0
S. P. Vincent, M. D. Burkart, C.-Y. Tsai, Z. Zhang, C.-H. Wong, J. Org. Chem., 1999, 64,
264-5279.
P. Vincent, A. Tikad, Isr. J. Chem., 2015, 55, 392-397.
5
1

Page 21 of 22
Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/D0OB01914C
1
1
2
3
C. Zur, A. O. Miller, R. Miethchen, Liquid Crystals, 1998, 24, 695- 699.
T. Schuster, S. Schellenberger, R. Friedrich, M. Klapper, K. Müllen, J. Fluorine Chem., 2013,
54, 30–36.
1
1
1
1
4
5
6
J. G. Riess, J. Greiner, Carbohydr. Res., 2000, 27, 147-168
C. Zur, R. Miethchen, Eur. J. Org. Chem., 1998, 531-539.
V. Círikva, R. Polák, O. Paleta, K. Kefurt, J. Moravcová, M. Kodíčekc, S. Forman,
Carbohydr. Res., 2004, 339, 2177–2185.
1
1
7
8
R. Plantier-Royon, C. Portella, Carbohydr. Res., 2000, 327, 119-146.
D. W. Gammon, B. F. Sels, Other Methods for Glycoside Synthesis: Dehydro and Anhydro
Derivatives, Handbook of Chemical Glycosylation: Advances in Stereoselectivity and
Therapeutic Relevance, Alexei V. Demchenko Ed., WILEY-VCH Verlag GmbH & Co.
KGaA, 2008, pp 416.
1
9
(
a) M. Sharma, R. K. Brown, Can. J Chem. 1966, 44, 2825-2835; (b) R. U. Lemieux, E.
Fraga, K. A., Watanabe, Can. J Chem., 1968, 46, 61-69; (c) S. J. Danishefsky, M. T.
Bilodeau, Angew. Chem. Int. Ed. Engl., 1996, 35, 1380-1419; (d) H. H. Kinfe, Org. Biomol.
Chem., 2019, 17, 4153-4182.
2
0
(
a) G. M. De Fina, O. Varela, R. M. de Lederkremer, Synthesis, 1988, 891-893; (b) O. Varela,
G. M. De Fina, R. M. de Lederkremer, Carbohydr. Res., 1993, 246, 371-376; (c) V. E.
Manzano, E. Repetto, M. L. Uhrig, M. Baráth, O. Varela, Carbohydrate Proven Methods,
Vol. 1, Pavol Kováč Ed., CRC Press 2012, 295-301.
2
2
1
2
Y. Yu, D.-C. Xiong, X.-S. Ye, Org. Biomol. Chem., 2016, 14, 6403-6406.
(a) R. Miethchen, M. Hein, H. Reinke, Eur. J. Org. Chem.,1998, 919-923. (b) A. Wegert, R.
Miethchen, M. Hein, H. Reinke, Synthesis, 2005, 11, 1850-1858.
2
2
2
2
3
4
5
6
M.-C. Belhomme, T. Poisson, X. Pannecoucke, Org. Lett., 2013, 15, 3428-3431.
J. Mestre, A. Lishchynskyi, S. Castillón, O. Boutureira, J. Org. Chem., 2018, 83, 8150–8160.
J. Mestre, S. Castillón, O. Boutureira, J. Org. Chem., 2019, 84, 15087–15097.
S. Colombel, M. Sanselme, E. Leclerc, J.-C. Quirion, X. Pannecoucke, Chem. Eur. J., 2011,
1
7, 5238-5241.
2
2
7
8
B. Wang, D.-C. Xiong, X.-S. Ye, Org. Lett., 2015, 17, 5698–5701.
(
a) D. E. Yerien, M. V. Cooke, M. C. García Vior, S. Barata-Vallejo, A. Postigo, Org.
Biomol. Chem., 2019, 17, 3741-3746; (b) B. Lantaño, S. Barata-Vallejo, A. Postigo, Org.
Biomol. Chem., 2018, 16, 6718-6727; (c) S. Barata-Vallejo, M. V. Cooke, A. Postigo, ACS
Catal., 2018, 8, 7287−7307.
2
9
(
a) V. E. Manzano, M. L. Uhrig, O. Varela Org. Biomolec. Chem., 2012, 10, 8884-8894; (b)
A. J. Cagnoni, J. Kovensky, M. L. Uhrig, J. Org. Chem., 2014, 79, 6456-6467; (c) A. J.
Cagnoni, J. Kovensky, M. L. Uhrig, J. Org. Chem. 2014, 79, 6456-6467; (d) M. E. Cano, O.

Organic & Biomolecular Chemistry
Page 22 of 22
View Article Online
DOI: 10.1039/D0OB01914C
Varela, M. I. García-Moreno, J. M. García Fernández, J. Kovensky, M. L. Uhrig, Carbohydr.
Res., 2017, 443-444, 58-67; (e) H. O. Montenegro, P. H. Di Chenna, C. C. Spagnuolo, M. L.
Uhrig, Carbohydr. Res., 2019, 479, 6–12.
3
3
0
1
B. Wang, D.-C. Xiong, X.-S. Ye, Org. Lett., 2015, 17, 5698–5701.
W. Priebe, I. Fokt, G. Grynkiewicz, Glycal Derivatives, Glycoscience, B. Fraser-Reid, K.
Tatsuta, J. Thiem Eds., Springer-Verlag Berlin Heidelberg, 2008, 699-735.
D. E. Yerien, S. Barata-Vallejo, B. Camps, A. E. Cristófalo, M. E. Cano, M. L. Uhrig, A.
Postigo, Cat. Science & Tech., 2017, 7, 2274-2282.
3
2
3
3
3
4
D. Horton, T. Miyake, Carbohydr. Res., 1988, 184, 221-229.
H. Shao, Z. Wang, E. Lacroix, S.-H. Wu, H. J. Jennings, W Zou, J. Am. Chem. Soc., 2002,
1
24, 2130-2131.
3
3
5
6
W. R. Dolbier Jr., Guide to Fluorine NMR for Organic Chemists, 2nd Edition, Wiley, 2016.
(a) A. De Bruyn, M. Anteunis, R. van Rijsbergen, M. Claeyssens, P. Kováč, J. Carbohydr.
Chem., 1982-83, 1, 301-309; (b) H. Paulsen, M. Brenken, Liebigs Ann. Chem., 1988, 649-
6
54.
3
3
7
8
P. L. Durette, D. Horton, Carbohyd. Res., 1971, 18, 403-418.
Z. Wang, Comprehensive Organic Name Reactions and Reagents, John Wiley & Sons Inc.,
2
010, page 3123-3128.
3
4
4
4
4
4
4
9
0
1
2
3
4
5
R. C. McAtee, E. J. McClain, C. R. J. Stephenson, Trends in Chem., 2019, 1, 111-125.
W. Wang, S. Zhang, H. Zhao, S. Wang, Org. Biomol. Chem., 2018, 16, 8565-8568.
M. A. Cismesia, T. P. Yoon, Chem. Sci., 2015, 6, 5426-5434.
D. Liu, M.-J. Jiao, X.-Z. Wang, P.-F. Xu, Org. Lett., 2019, 21, 4745-4749.
G. M. Burnett, H. W. Melville, Chem. Rev., 1954, 54, 225-288.
L. Buzzetti, G. E. M. Crisenza, P. Melchiorre, Angew. Chem. Int. Ed., 2019, 58, 3730-3747.
S. P. Pitre, C. D. McTiernan, W. Vine, R. DiPucchio, M. Grenier, J. C. Scaiano, Sci. Rep.,
2
015, 5, 16397.