Studies toward the oxidative and reductive activation of C-S bonds in 2′-S-aryl-2′-thiouridine derivatives

Article abstract of DOI:10.1016/j.tet.2016.02.063

Studies directed toward the oxidative and reductive desulfurization of readily available 2′-S-aryl-2′-thiouridine derivatives were investigated with the prospect to functionalize the C2′-position of nucleosides. The oxidative desulfurization-difluorination strategy was successful on 2-(arylthio)alkanoate surrogates, while extension of the combination of oxidants and fluoride sources was not an efficient fluorination protocol when applied to 2′-S-aryl-2′-thiouridine derivatives, resulting mainly in C5-halogenation of the pyrimidine ring and C2′-monofluorination without desulfurization. Cyclic voltammetry of 2′-arylsulfonyl-2′-deoxyuridines and their 2′-fluorinated analogues showed that cleavage of the arylsulfone moiety could occur, although at relatively high cathodic potentials. While reductive-desulfonylation of 2′-arylsulfonyl-2′-deoxyuridines with organic electron donors (OEDs) gave predominantly base-induced furan type products, chemical (OED) and electrochemical reductive-desulfonylation of the α-fluorosulfone derivatives yielded the 2′-deoxy-2′-fluorouridine and 2′,3′-didehydro-2′,3′-dideoxy-2′-fluorouridine derivatives. These results provided good evidence of the generation of a C2′-anion through carbon-sulfur bond cleavage, opening new horizons for the reductive-functionalization approaches in nucleosides.

Full text of DOI:10.1016/j.tet.2016.02.063

Tetrahedron xxx (2016) 1e9
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Studies toward the oxidative and reductive activation of CeS bonds
in 20-S-aryl-2ʹ-thiouridine derivatives
,
Ramanjaneyulu Rayala a, Alain Giuglio-Tonolo a b, Julie Broggi b, Thierry Terme b,
b
a
c
,
a,
*
*
ꢀ
Patrice Vanelle , Patricia Theard , Maurice Medebielle , Stanislaw F. Wnuk
a Department of Chemistry and Biochemistry, Florida International University, Miami, FL, USA
Aix Marseille Universite, CNRS, ICR UMR 7273, 13385, Marseille Cedex 05, France
Universite de Lyon & Universite Claude Bernard Lyon 1 (UCBL), Institut de Chimie et Biochimie Moleculaires et Supramoleculaires (ICBMS) UMR
CNRS-UCBL-INSALyon 5246, 43 bd du 11 Novembre 1918, Villeurbanne, France
b
ꢀ
c
ꢀ
ꢀ
ꢀ
ꢀ
a r t i c l e i n f o
a b s t r a c t
Studies directed toward the oxidative and reductive desulfurization of readily available 20-S-aryl-20-
thiouridine derivatives were investigated with the prospect to functionalize the C20-position of nucle-
osides. The oxidative desulfurization-difluorination strategy was successful on 2-(arylthio)alkanoate
surrogates, while extension of the combination of oxidants and fluoride sources was not an efficient
fluorination protocol when applied to 20-S-aryl-20-thiouridine derivatives, resulting mainly in C5-
halogenation of the pyrimidine ring and C20-monofluorination without desulfurization. Cyclic voltam-
metry of 20-arylsulfonyl-20-deoxyuridines and their 20-fluorinated analogues showed that cleavage of the
arylsulfone moiety could occur, although at relatively high cathodic potentials. While reductive-
desulfonylation of 20-arylsulfonyl-20-deoxyuridines with organic electron donors (OEDs) gave pre-
dominantly base-induced furan type products, chemical (OED) and electrochemical reductive-
Article history:
Received 28 January 2016
Received in revised form 25 February 2016
Accepted 26 February 2016
Available online xxx
Keywords:
Cyclic voltammetry
Desulfurizationefluorination
Fluorination
Nucleosides
Organic electron donors
Reductive desulfonylation
desulfonylation of the
hydro-20,30-dideoxy-20-fluorouridine derivatives. These results provided good evidence of the generation
of
C20-anion through carbon-sulfur bond cleavage, opening new horizons for the reductive-
functionalization approaches in nucleosides.
a
-fluorosulfone derivatives yielded the 20-deoxy-20-fluorouridine and 20,30-dide-
a
Ó 2016 Elsevier Ltd. All rights reserved.
1. Introduction
for this approach are known and are based mostly on the combi-
nation of an oxidant [e.g., N-halosuccinimides (NBS, NIS) or 1,3-
dibromo-5,5-dimethylhydantoin (DBH)] and a potentially hazard-
ous fluoride source [e.g., HF-pyridine,19e21 iodine pentafluoride
(IF5),22e24 air- and moisture-stable IF5epyridineeHF reagent,25,26
or BrF3eKHF2].27 In addition to these chemical approaches, direct
and indirect (with the use of a redox mediator) electrochemical
approaches have been developed for some oxidative de-
sulfurization-(di)fluorination reactions, using different sources of
fluorinating reagents, either in organic solvents or in Ionic Liquids
(ILs).28e31
Although, chemical and electrochemical-induced reductive
desulfonylation reactions have been known for years,32e40 in nu-
cleosides they have been limited to reductive dehalogenation or
desulfonylation protocols en route to 20,30-dideoxy-20,30-didehydro
nucleosides.41e47 Reductive desulfonylation/functionalization (in-
cluding (di)fluorination) strategies in nucleosides are to the best of
our knowledge, unknown processes. Our goal was to investigate
alternative methodologies for the modification of nucleosides at
C20 position utilizing 20-S-aryl-20-thionucleosides as convenient
Introduction of fluorine atom(s) into nucleosides dramatically
changes their electronic and steric properties, giving them a wide
range of biological activity.1e3 Prominent examples of C20 fluori-
nated nucleosides with potent biological activities include anti-
cancer drugs gemcitabine,4e6 and clofarabine;7,8 and hepatitis C
virus drug sofosbuvir.9,10 In the last 40 years, numerous methods
for the incorporation of fluorine atoms into organic molecules have
been developed, as summarized in excellent reviews.11e16 Despite
these developments, construction of the tertiary fluorinated ster-
eocenter at the sugar C20 (e.g., sofosbuvir) has been still
challenging.17
Oxidative desulfurization-(di)fluorination is an important fluo-
rination protocol for the preparation of fluoro organic com-
pounds.16,18 Various reagents or reagent-combinations developed
* Corresponding authors. E-mail addresses: maurice.medebielle@univ-lyon1.fr
ꢀ
(M. Medebielle), wnuk@fiu.edu (S.F. Wnuk).
http://dx.doi.org/10.1016/j.tet.2016.02.063
0040-4020/Ó 2016 Elsevier Ltd. All rights reserved.
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2
R. Rayala et al. / Tetrahedron xxx (2016) 1e9
substrates to access well-known fluoro nucleosides (e.g., gemcita-
bine or PSI 6130, a core of Sofosbuvir). Herein we report studies on
the reactivity of 20-S-aryl-20-thiouridine substrates (type I, Fig. 1)
with respect to oxidation processes and 20-arylsulfonyl-20-deoxy-
uridine (type II) with respect to reductive processes. The oxidative
fluorination processes are envisioned to proceed via desulfur-
izationedifluorination of the uridine-20-thioethers (substrate I,
promote the critical second fluorination step.21 The DBH was
proven to be more effective than other halogen oxidants (NBS, NIS)
in these reactions.48
Despite successful desulfurizationedifluorination strategy with
2-arylthioalkanoate surrogates, our attempts to extend this pro-
tocol to sugars and nucleosides met with only limited success. Thus,
treatment
of
(S)-(þ)-2-phenylthio-4-benzyloxymethyl-4-
X¼H) or desulfurizationefluorination of uridine
a
-fluorothioethers
butanolide49 with DBH (4 equiv)/Py.9HF (8 equiv)/CH2Cl2/35 ꢁC/
15 h gave complex reaction mixture.48 Also, attempted fluorination
of readily available50 20-S-aryl-20-thiouridine analogues of type 651
(Scheme 2) or 20-S-aryl-20-fluoro-20-thiouridine analogues of type
851 (Scheme 3) with Py.9HF/DBH failed to give 20,20-difluoro
products yielding instead 5-brominated52 products as well as the
(substrate I, X¼F) using halonium ion (Brþ, Iþ) reagents as oxidants
and a nucleophilic fluorine source (Fꢀ) for quenching the in-
termediary C20-carbocation. The reductive fluorination processes
are proposed to proceed via cleavage of the sulfonyl moiety (from
substrate II, X¼H or F) with single electron transfer reagents or
electrochemically and quenching the resultant C20-carbanion with
electrophiles such as Fþ, Hþ, CH3þ, etc.
corresponding sulfoxides and/or a-fluoro sulfoxides, among other
byproducts. Installing different protection groups on sugar hy-
Fig. 1. Proposed pathways for the C20-functionalization of uridine derivatives.
2. Results and discussion
droxyls (Ac, Bn) and EDG (MeO) or EWG (Cl) in phenyl ring as well
as changing reaction conditions (e.g., halogen source, temperature,
reaction time) did not change the outcome.48
Interestingly, treatment of the 4-methoxyphenyl thioether 6
with NIS (2.1 equiv)/Py.9HF (3 equiv) gave the corresponding 5-
Because of the lack of examples for desulfurizationedifluori-
nation reactions of arylealkyl thioethers with the arylthio group
attached to a secondary internal carbon atom, we initially per-
formed model studies with
a
-arylthio substituted esters (e.g., 2;
iodo 7 (29%) and the
2). Analogous treatment of sulfide 6 with NIS/DAST combina-
tion53,54 produced the mono-
-fluorothioether 8 in 44% isolated
yield without 5-halogenation. In contrast, treatment of 6 with DBH
(3 equiv)/Py.9HF (6 equiv) generated a complex reaction mixture.
These results reiterate the mechanistic assumption that ring acti-
vating groups (e.g., OMe) on the aryl ring promote the first fluori-
nation step.
a-fluorothioether 8 (12%) products (Scheme
Scheme 1) that mimic the 20-postion of the ribose in the nucleoside
targets (e.g., I, X¼H). Using the methodology developed by Haufe
et al.20,21 we found that treatment of ethyl 2-(phenylthio)octanoate
2 with DBH (3 equiv) and Olah’s reagent (Py.9HF, 6 equiv) in CH2Cl2
at 35 ꢁC for 2 h, showed 90% conversion to 2,2-difluorooctanoate 5b
(1H NMR, 19F NMR; Scheme 1). The para-chlorophenylthio
substituted ester 3 provided 2,2-difluorohexanoate 5a in almost
quantitative yield in only 1 h, whereas para-methoxyphenylthio
ester 4 required 16 h to show 70% conversion to 5a.48 These results
illustrated that 4-chlorophenyl thioethers were better substrates
for these difluorination reactions than corresponding phenyl and 4-
methoxyphenyl thioethers, as noted also by Haufe, et al. for the
primary alkylearyl thioethers.21 The EDGs on the phenyl ring are
believed to stabilize the cationic charge on the resonance-stabilized
carbeniumesulfonium ion intermediate and thus promote the first
fluorination step; whereas EWGs are assumed to ease the elimi-
nation of arylsulfenyl bromide in the last step and therefore
a
Moreover, treatment of a-fluorothioether 8 with DBH/Py.9HF at
ꢀ78 ꢁC effected selective bromination of the uracil ring at the C5
position52 yielding the corresponding 5-bromo derivative 9 as
a major product (50%), however with no indication of the geminal
difluoro product formation (Scheme 3). Interestingly, the
rothioether moiety in 9 remained intact under these oxidative
conditions. It was previously noted that oxidation of -fluo-
rothioethers to the -fluoro sulfoxides with m-CPBA required
a-fluo-
a
a
higher temperature and longer reaction time than conversion of
the unfluorinated thioethers to the corresponding sulfoxides.50
Scheme 1. Desulfurizationedifluorinations of a-thioesters 2e4.
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R. Rayala et al. / Tetrahedron xxx (2016) 1e9
3
Conditions A: NIS (2.1 eq), Py.9HF (3 eq); Conditions B: NIS (2.1 eq), DAST (6 eq).
Scheme 2. Attempted fluorination of 20-S-(4-methoxyphenyl)-20-thiouridine analogue 6.
bond was not observed and the unexpected formation of 11 could
not be explained by a sole electron-transfer mechanism. To ra-
tionalize this result, we tried the same reaction with a less pow-
erful
organic
reductant,
the
commercially
available
tetrakis(dimethylamino)ethylene (TDAE) [E1/2 (DMF)¼ꢀ0.62 V
versus SCE]. Treatment of 20-sulfone 10 with an excess of TDAE
gave the 30-acetoxy elimination product 13 (34%), the enol type
(open chain sugar) product 14 (20%) and the same furan derivative
11 (46%).
Scheme 3. Attempted fluorination of 20-fluoro-20-S-(4-methoxyphenyl)-20-thiouridine
derivative 8.
Cyclic voltammetry analysis showed that sulfone derivative 10
could be reduced in two irreversible reduction steps at potentials of
ꢀ2.42 and ꢀ2.64 V versus SCE (Fig. S1, Table S1, Supplementary
data), with the first reduction step (Epc1) corresponding to the
cleavage of the C20eS bond with the expulsion of the p-methox-
ybenzenesulfinate. This hypothesis was confirmed by the cyclic
voltammetry of an authentic sample59 of sodium p-methox-
ybenzenesulfinate (Fig. S2). While the reduction potential is in the
array of redox potentials that the effective reducing power of SED
could reportedly attain,60 the redox potential gap between TDAE
Since the oxidative desulfurizationefluorination approaches
were not efficient protocols for the utilization of 20-arylthiouridine
derivatives as substrates for the modification of the C20-position,
we turned our attention to the development of a reductive desul-
fonylation approach. This strategy is consisted with the generation
of an intermediary carbanion at the C20-position of uridine de-
rivatives which could be subsequently coupled to an electrophile
(e.g., II; Fig. 1). We assumed that such anion could be obtained
through cleavage of the C20-S bond in 20-arylsulfonyl-20-deoxyur-
idine substrates. Moreover, such sulfones derivatives could be
conveniently synthesized by simple oxidation of the arylthiour-
idine substrates used for the oxidative approach.50,51 Reductive
removal of sulfones is usually mediated by highly aggressive metal-
containing reducing agents, typically alkali metals, not always
compatible with the nucleoside chemistry, as they can cause side
reactions on the diverse functional groups present in the mole-
cule.33 Instead, we opted for the use of recently reported organic
electron donors (OEDs)55e57 that can selectively cleave CeSO2
bonds by stepwise transfer of two electrons under mild reaction
conditions.35,58 The bispyridinylidene SED has a redox potential of
E1/2 (DMF)¼ꢀ1.24 V versus SCE (Fig. 2) and efficiently reduces
sulfones via the formation of anion intermediates.58 Its high tol-
erance to other functional groups, such as ketones, made it par-
ticularly suitable for our 20-deoxyuridine substrates.
and 10 (DE>1.2 V) clearly indicates that reduction of 10 cannot be
achieved by TDAE-promoted electron transfer. Since OEDs can act
as base or as reducing agent,61,62 we assumed that TDAE initially
acted as a base inducing elimination of AcOH by abstracting H20 to
produce 13 (Scheme 5). Judging from the first reduction potential of
13 (Epc1¼ꢀ2.11 V vs SCE; Table S1, Fig. S3), further reduction of 13
by TDAE to produce 11 would also be rather difficult. One can think
that TDAE is only acting as a base and that 13 suffers from base-
induced reactions leading in turn to 14 and 11 (base-induced
pathway, Scheme 5). The hypothesis of a basic behaviour was
supported by the fact that reaction of 10 with 4-
dimethylaminopyridine (DMAP) led to the quantitative formation
of 11. On the other hand, in the case of SED, a mixed base-/electron
transfer-induced mechanism could occur and rapidly lead to 11. We
assumed that under more forced reducing conditions,60 13 could be
reduced in parallel to the base-induced reactions (ET-induced
pathway, Scheme 5). Hence, 13 could be reduced by single-electron
transfer (SET) leading to glycosidic bond cleavage, followed by
trapping of the formed radical by the radical cation of the electron
donor (SEDꢂD).63 A last base-induced reaction would give 11 and
regenerate the SED.
Since the acetyl protection in 10 was base labile in the presence
of OEDs, and prone to elimination from the intermediate C20-
carbanion, we also studied benzylated sulfone substrates. However,
treatment of the fully benzylated 20-[(4-methoxyphenyl)sulfonyl]
uridine 1551 (Epc1¼ꢀ2.42 V vs SCE; Fig. S1, Table S1) with a stoi-
chiometric amount of SED resulted in a similar rapid glycosidic
bond cleavage producing the vinyl sulfone 16 (70%) and 3-N-ben-
zyluracil 17 (69%; Scheme 6). This result indicated that the basic
character of SED was probably predominant over its reducing
Fig. 2. Redox potential and equilibria of bispyridinylidene SED named as “Super-
electron donor”.
When the 20-sulfone 1050 was treated at rt with the organic
reductant SED, the reaction cleanly provided the furan product 11
in 95% yield after 15 min (Scheme 4). The uracil base 12 was
identified (but not isolated) by 1H NMR in the aqueous phase
along with other impurities. To our surprise, cleavage of the C20eS
character with substrates bearing a labile a-hydrogen. Treatment of
15 with an excess of SED gave two inseparable ribose derivatives:
the vinyl sulfone 16 and the furan derivative 18 with possibly the
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R. Rayala et al. / Tetrahedron xxx (2016) 1e9
Scheme 4. Reduction studies of the acetyl-protected sulfone substrate 10 with organic donors.
Scheme 5. Proposed “base-versus electron transfer-induced” mechanism for the reaction of 10 with OEDs.
Scheme 6. Reduction studies of benzyl protected sulfone substrate 15 with the SED.
latter being formed from 16 under reducing and/or basic conditions
as proposed for 10 in Scheme 5.
compound 2165 was obtained in 46% yield when 19 was treated
with 3 equiv of SED at 120 ꢁC. This result indicated that reductive
cleavage of the sulfone took place with excess SED at high tem-
perature. Controlled-potential electrolysis of 19 in DMF at ꢀ1.90 V
versus SCE, a potential more positive to the first potential peak
measured by cyclic voltammetry (see Table S1), gave, after the
consumption of 2.0 F/mole of substrate (1 h, rt), a main fraction that
contained 21 and 19 as an inseparable mixture (ratio w 8:2), with
estimated yield of 21 close to 45% (Scheme 7). Noteworthy to
mention that 20-deoxy-20-fluoridine 22, the diacetylated 23 and
uracil 12 (albeit in low amount) were also detected in the crude
Since the
under the desired reductive conditions,
2451 were chosen for the further studies. Thus, treatment of
a
-hydrogen of 20-sulfone substrates were too labile
a
-fluorosulfones 1950 and
a
-
fluorosulfone 19 (Epc1¼ꢀ2.36 V vs SCE; Fig. S4, Table S1) with the
SED reagent at room temperature gave the mono 30-deacetylated
product 20 (45% conversion) along with unchanged starting ma-
terial but no further degradation or glycosidic bond cleavage were
observed (Scheme 7).64 The reduction of the sulfonyl moiety was
not observed at this temperature. However, known fluorovinyl
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R. Rayala et al. / Tetrahedron xxx (2016) 1e9
5
Scheme 7. Reactivity studies of acetyl protected
a-fluorosulfone 19 with OED and under electrochemical activation.
reaction mixture. These results were in line with the profile of
products obtained with an excess of the SED reagent at 120 ꢁC/3 h,
however it offered an alternative milder approach to prepare 21 by
a reductive approach. The results with SED or the electrochemical
activation provided evidence that the C20 anion was indeed gen-
erated through C20-S bond cleavage. It is important to note that
replacement of SED with other reducing agents such as samarium
iodide did not affect the reduction of the sulfonyl moiety.
favour the formation of reduction product 26 (to enhance proton
abstraction), did not change the outcome of the reaction. The
elimination product 25 and 3-N-benzyluracil 17 were obtained in
80% and 60% isolated yields, respectively.
Controlled-potential electrolysis of 24 in DMF at ꢀ2.20 V versus
SCE, a potential slightly less positive to the first peak potential
measured by cyclic voltammetry (see Table S1), gave, after the
consumption of 2.1 F/mole of substrate (1 h, rt), 17 in 74% isolated
yield and an inseparable mixture containing 24 and 26 (ratio w
2.5:1) with also additional products. The estimated yield of 26 was
roughly 18%, a yield slightly higher compared to the reaction using
the SED reagent (Scheme 8). Although the electrolysis did not go to
complete conversion of starting material, as opposed to the results
obtained with the SED reagent, there was no indication of forma-
tion of furan 25. The electrochemical reductive cleavage of 24
seems to be more complex than 19 since generation of more
products was observed, but formation of 22, 23 and 26 under
milder electrochemical conditions, is again an attractive starting
point for further optimization studies and possible anion trapping.
To avoid the elimination of the acetate anion from C30 position,
the benzyl protected 20-
a-fluorosulfone derivative 24 was
employed to study the reduction of the sulfone moiety with SED.
However, treatment of 24 with SED under analogous conditions
(3 equiv; DMF, 120 ꢁC, 3 h) produced a complex reaction mixture
(Scheme 8), from which two major products were isolated: furan 25
and 3-N-benzyluracil 17. Also observed by LC-MS was trace
amounts of sulfone cleavage product 26, providing again evidence
of the C20-anion generation, trapped by proton abstraction. In-
triguingly, in the furan derivative 25, sulfone moiety was present
and elimination of fluorine was observed. Furan derivative 25 could
have been formed from either the reduction of the glycosidic bond
followed by base induced fluoride elimination or vice versa. Anal-
ogous treatment of 24 with SED at room temperature gave only
trace amounts of 25 and 17 along with unchanged starting material.
Reaction in the presence of deoxygenated water at 80 ꢁC, in order to
3. Conclusion
In conclusion, new methods for the modification of nucleosides
at the C20-position via oxidative and reductive activation of carbon-
Scheme 8. Reactivity studies of benzyl protected
a-fluorosulfone 24 with SED and under electrochemical activation.
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6
R. Rayala et al. / Tetrahedron xxx (2016) 1e9
sulfur bonds in readily available 20-thionucleosides were studied.
The oxidative desulfurization-difluorination of arylealkyl thio-
ethers including 20-S-aryl-20-thiouridine substrates, using the
protocol of Haufe et al. was studied with mixed results. Although
successful on 2-(arylthio)alkanoate surrogates, combination of
oxidants and fluoride sources was not an efficient fluorination
protocol when applied to 20-thiouridine derivatives, resulting
mainly in C5-halogenation of the pyrimidine ring and C20-mono-
fluorination without desulfurization. Our reductive desulfonylation
approach using Organic Electron Donors (OEDs) was hampered by
competitive base-induced mechanisms in the case of substrates
4.1. Ethyl 2-(phenylthio)octanoate (2)
Thiophenol (260 L, 280 mg, 2.54 mmol) was added to a stirred
solution of NaH (60%, dispersion in paraffin liquid; 100.4 mg,
4.18 mmol) in anhydrous DMF (4 mL) at 0 ꢁC. The resulting sus-
pension was stirred at 0 ꢁC for 30 min and at ambient temperature
for 30 min, until bubbling (H2 gas) ceased. The reaction flask was
m
chilled again and ethyl 2-bromooctanoate (540
mL, 630 mg,
2.51 mmol) was added at 0 ꢁC. The resultant clear, colourless so-
lution was stirred at 0 ꢁC for 20 min and at ambient temperature for
2 h, by which time TLC showed exclusive conversion to a slightly
more polar spot. Volatiles were evaporated and co-evaporated with
toluene (1ꢃ) (vacuum pump) and the resulting pale gum was
partitioned between CHCl3 (20 mL) and NH4Cl/H2O (20 mL). The
aqueous layer was extracted with CHCl3 (2ꢃ5 mL) and the com-
bined organic phase was washed with NaHCO3/H2O (25 mL), brine
(25 mL), and dried (MgSO4). Volatiles were evaporated in vacuo and
the residue was column chromatographed (10% EtOAc in hexanes)
bearing a labile
uracil moieties. On the other hand, reduction of
a
-hydrogen, resulting in the elimination of the
-fluorosulfone
a
derivatives with OED or by electrochemical activation provided
good evidence that the C20-anion was indeed generated through
C20eS bond cleavage. The major benefit of the electrochemical ac-
tivation was the milder conditions of the protocol (rt, no base, short
time) leading to the formation of 20,30-unsaturated-20-fluorouridine
and 20-fluorinated products. These results open new horizons for
the reductive desulfonylationefunctionalization strategies, which,
although, are still not fully developed in nucleosides, have the
potential to be utilized in the synthesis of highly substituted nu-
cleoside analogues including C20-difluoro analogues.
to give 266 (633 mg, 90%) as a pale oil: 1H NMR (CDCl3)
d 7.49e7.46
(m, 2H, Ph), 7.35e7.25 (m, 3H, Ph), 4.16e4.09 (m, 2H, CH2), 3.66 (dd,
J¼6.6, 8.4 Hz, 1H, H2), 1.96e1.87 (m, 1H, H3), 1.82e1.73 (m, 1H, H30),
1.51e1.37 (m, 2H, H4, H40), 1.36e1.26 (m, 6H, H5, H50, H6, H60, H7,
H70), 1.19 (t, J¼7.1 Hz, 3H, CH3), 0.90 (‘t’, J¼6.8 Hz, 3H, CH3); 13C NMR
(CDCl3)
d 172.4, 133.8, 132.7, 128.9, 127.7, 61.0, 50.9, 31.7, 31.5, 28.8,
4. Experimental section
27.2, 22.5, 14.1, 14.0.
Reagent grade chemicals were used and solvents were dried by
reflux and distillation from CaH2 under N2 unless otherwise spec-
ified, and an atmosphere of N2 was used for reactions. The MBraun
glove box used for some reactions contained dry argon and less
than 1 ppm oxygen and water. Reaction progress was monitored by
TLC on Merck Kieselgel 60-F254 sheets with product detection by
254-nm light. Products were purified by column chromatography
using Merck Kiselgel 60 (230e400 mesh) or by automated flash
chromatography using a CombiFlash system. UV spectra were
recorded with a Varian Cary 100 Bio UVevisible spectrophotome-
ter. 1H (400 MHz), 13C (100.6 MHz), and 19F (376 MHz) NMR spectra
were recorded at ambient temperature in solutions of CDCl3 or
DMSO-d6. MS and HRMS spectra were recorded in ESIþ or ESI-
mode, unless otherwise noted. The bispyridinylidene SED was
synthesized following reported procedure,58 stored in a glove box
and used as a well-defined dark purple solid.
Electrochemical measurements were performed using an EG &
G-Princeton Applied Research 263A all-in-one potentiostat, using
a standard three-electrode setup with a glassy carbon electrode
(working electrode, diameter¼3 mm), platinum wire auxiliary
electrode and a non-aqueous Ag/Agþ (0.01M AgNO3þ0.1M n-
Bu4NClO4) system in MeCN as the reference electrode. All solutions
under the study were 0.1 M in the supporting electrolyte n-Bu4NPF6
(Fluka, electrochemical grade) with the voltage scan rate of
0.2 V sꢀ1. Solutions (2.5 mL) were thoroughly bubbled with dry Ar
for 15 min to remove oxygen before any experiment and kept under
positive pressure of Ar. Under these experimental conditions the
ferrocene/ferricinium couple, used as internal reference for po-
tential measurements, was located at E1/2¼þ 0.05 V in DMF.
Controlled-potential electrolyses were run in a cylindrical divided
cell (see Fig. S5) using a porous reticulous carbon electrode (S w
2.5 cm2) as working electrode, a platinum wire as counter electrode
separated from the cathodic compartment with a frit glass (po-
rosity 4) and Ag wire as a pseudo reference. Cyclic voltamograms
were recorded before the electrolysis and during the electrolysis
using a glassy carbon electrode (diameter¼1 mm). The solutions
containing the substrate and the supporting electrolyte (n-Et4NBF4
0.1 M) were thoroughly bubbled with dry Ar for 15 min to remove
oxygen before any experiment and kept under positive pressure of
Ar.
4.2. Ethyl 2-((4-chlorophenyl)thio)hexanoate (3)
Treatment of ethyl 2-bromohexanoate (500
mL, 610.5 mg,
2.74 mmol) with 4-chlorothiophenol/NaH/DMF, as described for 2,
gave 367 as a pale yellow oil (763.6 mg, 97%): 1H NMR (CDCl3)
d
7.41e7.37 (m, 2H, Ph), 7.30e7.26 (m, 2H, Ph), 4.17e4.09 (m, 2H,
CH2), 3.61 (dd, J¼6.6, 8.4 Hz, 1H, H2), 1.94e1.84 (m, 1H, H3),
1.81e1.69 (m, 1H, H30), 1.51e1.27 (m, 4H, H4, H40, H5, H50), 1.19 (t,
J¼7.1 Hz, 3H, CH3), 0.91 (‘t’, J¼7.1 Hz, 3H, CH3); 13C NMR (CDCl3)
d
172.1, 134.11, 134.10, 132.1, 129.0, 61.1, 51.0, 31.3, 29.4, 22.2, 14.1,
13.8.
4.3. Ethyl 2-((4-methoxyphenyl)thio)hexanoate (4)
Treatment of ethyl 2-bromohexanoate (500
mL, 610.5 mg,
2.74 mmol) with 4-methoxythiophenol/NaH/DMF, as described for
2, gave 468 as a colourless oil (739.3 mg, 96%): 1H NMR (CDCl3)
d
7.36e7.31 (m, 2H, Ph), 6.78e6.74 (m, 2H, Ph), 4.02 (‘q’, J¼7.2 Hz,
2H, CH2), 3.41 (dd, J¼6.6, 8.5 Hz, 1H, H2), 1.82e1.75 (m, 1H, H3),
1.68e1.59 (m,1H, H30),1.42e1.32 (m,1H, H4),1.30e1.21 (m, 3H, H40,
H5, H50), 1.10 (t, J¼7.1 Hz, 3H, CH3), 0.82 (t, J¼7.1 Hz, 3H, CH3); 13C
NMR (CDCl3)
d 172.2, 160.1, 136.2, 123.4, 114.4, 60.7, 55.2, 51.6, 31.1,
29.3, 22.3, 14.1, 13.8.
4.4. General procedure for the preparation of ethyl di-
fluoroalkanoates (5)
DBH (1.5 mmol) was added to a stirred solution of esters 2 or 3
or (0.5 mmol) and Py.9HF (3 mmol) in CH2Cl2 (2 mL) in a poly-
propylene vessel at ambient temperature. The resulting brown
solution was stirred at 35 ꢁC for 2 h (2), 1 h (3) or 16 h (4). The
reaction flask was cooled to room temperature, quenched by ad-
dition of ice-cold water, diluted with CH2Cl2, and neutralized with
drop-wise addition of conc. NH4OH. Organic layer was separated
and aqueous layer was back extracted (2ꢃCH2Cl2). Combined or-
ganic layer was washed with 1N HCl, brine, dried (MgSO4) and
concentrated in vacuo to give crude difluorinated product 5b (95%
conversion from 2) or 5a (95% conversion from 3; 70% conversion
from 4) as a brown oil, with data as reported.69
Please cite this article in press as: Rayala, R.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.02.063

R. Rayala et al. / Tetrahedron xxx (2016) 1e9
7
3
5a69 had: 1H NMR (CDCl3)
d
4.25 (q, JH,H¼7.2 Hz, 2H, CH2),
(MeOH) lmax 253, 280 nm, lmin 239, 271 nm; 1H NMR (CDCl3)
d
7.84
2.09e1.88 (m, 2H, H3, H30), 1.42e1.30 (m, 4H, H4, H40, H5, H50),
(s, 1H, H6), 7.81 (d, J¼2.1 Hz, 0.2H, Ph), 7.66 (d, J¼2.2 Hz, 0.8H, Ph),
7.49e7.23 (m, 17H, Ph), 6.78 (d, J¼8.7 Hz, 0.8H, Ph), 6.75 (d,
J¼8.7 Hz, 0.2H, Ph), 6.44 (d, J¼13.9 Hz, 0.8H, H10), 6.27 (br s, 0.2H,
H10), 5.09 (‘d’, J¼13.6 Hz, 1H, benzylic), 4.92e4.80 (m, 1H, benzylic),
4.73e4.65 (m, 1H, benzylic), 4.62e4.41 (m, 3H, benzylic), 4.18e4.09
(m, 2H, H30, H40), 3.92 (s, 0.6H, CH3), 3.91 (s, 2.4H, CH3), 3.82e3.72
(m, 1H, H50), 3.61e3.53 (m, 1H, H500); 19F NMR (CDCl3)
3
3
1.28 (t, JH,H¼7.1 Hz, 3H, CH3), 0.85 (t, JH,H¼7.2 Hz, 3H, H6, H60,
H600); 13C NMR (CDCl3)
d
164.4 (t, JF,C¼33.2 Hz, C1), 116.4 (t,
2
1JF,C¼249.8 Hz, C2), 63.0 (CH2), 34.5 (t, JF,C¼23.2 Hz, C3), 23.5 (t,
2
3JF,C¼4.3 Hz, C4), 22.2 (C5), 13.9 (CH3), 13.7 (C6); 19F NMR (CDCl3)
3
d
ꢀ105.92 ppm (t, JFeH¼16.8 Hz); GCeMS (tR¼7.5 min) 151 (Mþ-
Et, 1.1), 87 (100).
3
5b69 had: 1H NMR (CDCl3)
d
4.25 (q, JH,H¼7.2 Hz, 2H, CH2),
d
ꢀ133.52 ppm (br s, 0.8F), e131.57 ppm (br s, 0.2F); 13C NMR
2.03e1.91 (m, 2H), 1.45e1.18 (m, 11H), 0.81 (‘t’, 3JH,H¼6.8 Hz, 3H, H6,
(CDCl3) for major isomer: d 158.4, 157.2, 149.4, 138.1, 137.79, 137.76,
H60, H600); 13C NMR (CDCl3)
d
164.5 (t, JF,C¼33.0 Hz, C1), 116.4 (t,
137.3, 136.8, 135.9, 134.1, 134.0, 129.3, 128.6, 128.5, 128.4, 128.3,
128.2, 128.1, 128.0, 127.9, 120.24, 120.23, 112.2, 112.0, 108.7 (d,
2
1JF,C¼249.7 Hz, C2), 62.7 (CH2), 34.5 (t, 2JF,C¼23.2 Hz, C3), 31.4, 28.7,
22.4, 21.4 (t, 3JF,C¼4.3 Hz, C4), 13.9; 19F NMR (CDCl3)
d
ꢀ105.89 ppm
JC2 eF¼239.1 Hz, C20), 96.9, 90.4 (d, JC1 eF¼47.3 Hz, C10), 80.3 (C40),
1
2
0
0
(t, JFeH¼17.0 Hz); GCeMS (tR¼7.4 min) 179 (Mþ-Et, 60.8), 144
79.7 (d, 2JC3 eF¼17.7 Hz, C30), 73.5 (CH2), 73.1 (CH2), 67.0 (C50), 56.4
3
0
(100).
(OCH3), 45.7 (CH2). HRMS (ESI) m/z 755.1182 [MþNa]þ, calcd for
C
37H3479BrFN2NaO6Sþ 755.1197.
4.5. 3-N-Benzyl-30,50-di-O-benzyl-5-iodo-20-S-(4-
methoxyphenyl)-20-thiouridine (7) and 3-N-benzyl-30,50-di-O-
benzyl-20-fluoro-20-S-(4-methoxyphenyl)-20-thiouridine (8)
4.7. 50-O-Acetyl-20,30-dideoxy-20,30-didehydro-20-[(4-
methoxyphenyl)sulfonyl]uridine (13), 1-[5-acetyl-4-hydroxy-
2-((4-methoxyphenyl)sulfonyl)-1,3-pentadien-1-yl]uracil (14)
and [4-[(4-methoxyphenyl)sulfonyl]furan-2-yl]methyl acetate
(11)
NIS (95 mg, 0.42 mmol) was added to a stirred solution of 6
(128 mg, 0.2 mmol) and Py.9HF (138 mL, 0.6 mmol) in anhydrous
CH2Cl2 (3 mL) at ꢀ78 ꢁC in a polypropylene vessel and the resulting
brown solution was brought to w5 ꢁC overnight (16 h). Stirring was
continued at ambient temperature for 7 h (total reaction time:
23 h). The reaction was quenched by addition of ice-cold water
(10 mL), diluted with CH2Cl2 (5 mL), neutralized with drop-wise
addition of conc. NH4OH. Organic layer was separated and aque-
ous layer was back extracted (2ꢃCH2Cl2). Combined organic layer
was washed with 1N HCl (10 mL), brine (10 mL), dried (MgSO4), and
filtered. Volatiles were evaporated in vacuo and the brown residue
was column chromatographed (5% / 20% EtOAc in hexanes) to
give 7 (44 mg, 29%) as a colourless oil and 851 (20-R/SeS, w1:1;
16 mg, 12%) as a pale-yellow oil.
TDAE (0.24 mL, 1.04 mmol) was added to a stirred solution of 10
(100 mg, 0.207 mmol) in anhydrous DMF (2 mL) at ꢀ78 ꢁC under
argon. The reaction mixture was brought to ambient temperature
over 1 h 15 min and a 10% HCl solution (2 mL) was then added. The
crude was extracted with EtOAC (3ꢃ) and the combined organic
phase was dried over anhydrous Na2SO4. Volatiles were evaporated
in vacuo and the residue was column chromatographed (PE 100%/
EtOAc/PE 2/1/EtOAc 100%) to give 11 (29.5 mg, 46%), 14 (17.5 mg,
20%), and 13 (30 mg, 34%), all as colourless oils.
13 had: 1H NMR (CDCl3)
d 9.23 (br, 1H, NH), 7.79e7.75 (m, 2H,
Ph), 7.24 (d, J¼8.4 Hz, 1H, H6), 7.18 (t, J¼1.6 Hz, 1H, H30), 7.03e6.99
(m, 3H, Ph, H10), 5.55 (dd, J¼2, 8.4 Hz, 1H, H5), 5.12e5.09 (m, 1H,
H40), 4.41 (dd, J¼4, 12.4 Hz, 1H, H50), 4.29 (dd, J¼3.6, 12.4 Hz, 1H,
H500), 3.87 (s, 3H, OCH3), 2.09 (s, 3H, Ac); 13C NMR (50 MHZ,
7 had: UV (MeOH) lmax 253, 283 nm, lmin 246, 273 nm; 1H NMR
(CDCl3) d 7.66e7.63 (m, 2H, Ph), 7.56 (s, 1H, H6), 7.44e7.31 (m, 13H,
Ph), 7.12e7.10 (m, 2H, Ph), 6.51 (d, J¼8.9 Hz, 1H, H10), 6.33e6.30 (m,
2H, Ph), 5.15 (‘d’, J¼13.4 Hz, 1H, benzylic), 5.02 (‘d’, J¼13.3 Hz, 1H,
benzylic), 4.68e4.52 (m, 4H, benzylic), 4.33e4.25 (m, 2H, H40, H30),
3.76e3.67 (m, 2H, H20, H50), 3.66 (s, 3H, OCH3), 3.51 (dd, J¼2.0,
CDCl3)
d
170.1 (C]O), 164.9 (CPh), 162.9 (C4), 150.3 (C2), 142.1
(C6), 141.9 (C20), 139.5 (C30), 130.8 (CHPh), 129.1 (CPh), 115.2 (CHPh),
103.2 (C5), 87.5 (C10), 82.8 (C40), 63.9 (C50), 56.1 (OCH3), 20.8 (Ac).
HRMS (ESI) m/z 423.0856 [MþH]þ, calcd for C18H19N2O8Sþ
423.0857.
10.5 Hz, 1H, H500); 13C NMR (CDCl3)
d 159.8, 159.1, 150.8, 142.2 (C6),
137.22, 137.16, 136.2, 135.2, 130.4, 128.8, 128.6, 128.4, 128.2, 128.1,
128.06, 127.8, 127.7, 123.0, 114.7, 90.2 (C10), 82.1 (C30), 80.7 (C40),
73.8 (CH2), 72.3 (CH2), 70.5 (C5), 68.9 (C50), 56.4 (C20), 55.5 (OCH3),
46.0 (CH2). HRMS (ESI) m/z 785.1119 [MþNa]þ, calcd for
14 had: 1H NMR (CDCl3)
d
9.00 (br s, 1H, NH), 7.76 (d, J¼8.8 Hz,
2H, Ph), 7.58 (s, 1H, H10), 6.97e6.99 (m, 3H, Ph, H6), 5.69 (br, 1H,
OH), 5.62 (dd, J¼1.2, 8.0 Hz, 1H, H5), 4.93e4.79 (m, 1H, H30), 4.27
(dd, J¼4.4, 12.4 Hz, 1H, H50), 4.21 (dd, J¼4.8, 12.4 Hz, 1H, H500), 3.86
C
37H35IN2NaO6Sþ 785.1133.
Analogous treatment of 6 (128 mg, 0.2 mmol) with NIS (95 mg,
(s, 3H, OCH3), 1.95 (s, 3H, Ac); 13C NMR (CDCl3)
d 170.4 (C]O), 164.2
0.42 mmol) and DAST (160
m
L, 1.2 mmol) followed by aqueous
(CPh), 162.6 (C4), 160.3 (C10), 150.3 (C2), 140.2 (broad, C6), 131.5
(CPh), 129.9 (CHPh), 116.9 (broad, C20), 114.9 (CHPh), 103.7 (C5), 88.7
(broad, C30), 63.4 (C50), 55.6 (OCH3), 20.5 (CHA3c). HRMS (ESI) m/z
423.0864 [MþH]þ, calcd for C18H19N2O8Sþ 423.0857; 440.1119
[MþNH4]þ, calcd for C18H22N3O8Sþ 440.1122.
workup (satd Na2S2O3, satd NaHCO3, brine, MgSO4) and column
chromatography gave 851 (20-R/SeS, w1:1; 58 mg, 44%) as a pale-
yellow oil.
4.6. 3-N-Benzyl-30,50-di-O-benzyl-5-bromo-20-fluoro-20-S-(4-
11 had: 1H NMR (CDCl3)
d
7.93 (d, J¼0.8 Hz, 1H, H1), 7.85e7.89
methoxyphenyl)-20-thiouridine (9)
(m, 2H, Ph), 6.96e7.00 (m, 2H, Ph), 6.56 (s, 1H, H3), 4.97 (s, 2H, H5,
H50), 3.85 (s, 3H, OCH3), 2.05 (s, 3H, Ac); 13C NMR (CDCl3)
d 170.3
Py.9HF (62
mL, 0.27 mmol) was added to a chilled solution of
(C]O), 163.8 (CPh), 152.4 (C4), 145.7 (C1), 132.9 (C2), 131.1 (CPh),
129.8 (CHPh), 114.7 (CHPh), 108.7 (C3), 57.4 (C5), 55.8 (OCH3), 20.8
(CHA3c); HRMS (ESI) m/z 328.0852 [MþNH4]þ, calcd for C14H18NO6Sþ
328.0849.
DBH (19 mg, 0.066 mmol) in dry CH2Cl2 (1 mL) at ꢀ78 ꢁC. The
resulting pale solution was stirred at ꢀ78 ꢁC for 10 min and a so-
lution of substrate 8 (40 mg, 0.06 mmol) in dry CH2Cl2 (2 mL) was
added via syringe. The resultant orange solution was stirred at
ꢀ78 ꢁC for 2 h and was brought to ꢀ30 ꢁC over 45 min. The reaction
mixture was diluted with CH2Cl2 (5 mL), washed with NaHCO3/H2O
(5 mL), H2O (5 mL), brine (5 mL), dried (MgSO4). Volatiles were
evaporated in vacuo and the yellow residue was column chroma-
tographed (15% EtOAc in hexanes) to give 9 as mixture of di-
astereomers (20-R/SeS, w4:1) (pale-yellow oil, 22 mg, 50%): UV
4.8. [4-[(4-Methoxyphenyl)sulfonyl]furan-2-yl]methyl ace-
tate (11) and uracil (12)
In a glove box, SED (31 mg, 0.1 mmol) was added to a solution of
10 (50 mg, 0.1 mmol) in anhydrous DMF (4 mL) and the resulting
mixture was stirred at ambient temperature for 15 min. Then the
Please cite this article in press as: Rayala, R.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.02.063

8
R. Rayala et al. / Tetrahedron xxx (2016) 1e9
reaction flask was brought out of the glove box and water was
added to the crude reaction mixture. The aqueous phase was
extracted with CH2Cl2 (3ꢃ), the combined organic phase was dried
over anhydrous Na2SO4 and volatiles were evaporated in vacuo to
give 11 (29.4 mg, 95%) as a colourless oil.
Acidification of the aqueous phase (pH w5e6) followed by ex-
traction (2ꢃCH2Cl2) gave a white solid. 1H NMR (MeOD) of the
white solid revealed the presence of uracil 12 along with other
impurities.
4.11. 3-(Benzyloxy)-2-[(benzyloxy)methyl]-4-[(4-methox-
yphenyl)sulfonyl]furan (25)
In a glove box, SED (62 mg, 0.22 mmol, 3 equiv) was added to
a solution of 24 (50 mg, 7.3ꢃ10ꢀ5 mol) in anhydrous DMF (4 mL)
and the resulting solution was stirred at 120 ꢁC for 3 h. Reaction
flask was brought out of the glove box, and water was added to the
crude reaction mixture. The aqueous phase was extracted with
CH2Cl2 (3ꢃ) and the combined organic phase was dried with
Na2SO4. Volatiles were evaporated in vacuo and the residue was
column chromatographed (PE/EtOAc 9/1/EtOAc 100%) to give 25
(19.6 mg, 58%) as a white gum and 3-N-benzyluracil (17; 12.4 mg,
84%) as white solid.
4.9. 3,5-Di-O-Benzyl-1,2-dideoxy-1,2-didehydro-2-[(4-
methoxyphenyl)sulfonyl]ribose (16), 2-[(benzyloxy)methyl]-4-
[(4-methoxyphenyl)sulfonyl]furan (18) and 3-N-benzyluracil
(17)
Analogous treatment, in
a glove box, of 24 (58.3 mg,
8.5ꢃ10ꢀ5 mol) with SED (72 mg, 0.25 mmol, 3 equiv) at ambient
temperature for 4 h showed only trace amounts of 25 and 17 on
TLC. Addition of degassed water (0.5 mL, 500 mg, 27.75 mmol)
followed by heating at 80 ꢁC for 30 min gave, after workup and
silica gel chromatography, 25 (31.7 mg, 80%) and 17 (10.1 mg, 60%).
In a glove box, SED (22 mg, 7ꢃ10ꢀ5 mol, 1.05 equiv) was added
to a solution of 15 (45 mg, 6.7ꢃ10ꢀ5 mol) in DMF (4 mL) and the
reaction mixture was stirred at ambient temperature for 15 min.
Then the reaction flask was brought out of the glove box and water
was added to the crude reaction mixture. The aqueous phase was
extracted with CH2Cl2 (3ꢃ) and the combined organic phase was
dried over anhydrous Na2SO4. Volatiles were evaporated in vacuo
and the residue was column chromatographed (PE 100%/PE/
EtOAc 9/1/EtOAc 100%) to give 16 (22 mg, 70%) as a white gum
and 17 (9.4 mg, 69%) as a white solid.
25 had: 1H NMR (200 MHz, CDCl3)
d
7.94e7.87 (m, 2H, Ph), 7.83
(s, 1H, H1), 7.37e7.24 (m, 10H, Ph), 6.95e6.88 (m, 2H, Ph), 5.07 (s,
2H, CH2), 4.41 (s, 2H, CH2), 4.17 (s, 2H, CH2), 3.84 (s, 3H, OCH3); 13
C
NMR (50 MHz, CDCl3)
d
163.6 (C3), 144.8 (C1), 142.4 (CPh), 140.7
(CPh), 137.4 (CPh), 136.2 (CPh), 132.8 (C4), 130.0 (CHPh), 128.55(CHPh),
128.53 (CHPh), 128.48 (CHPh), 128.0 (CHPh), 127.9 (CHPh), 125.6 (C2),
114.3 (CHPh), 77.3 (CH2), 72.4 (CH2), 61.1 (CH2), 55.7 (OCH3). HRMS
(ESI) m/z 482.1632 [MþNH4]þ, calcd for C26H28NO6Sþ 482.1632.
16 had: 1H NMR (CDCl3)
d 7.83e7.79 (m, 2H, Ph), 7.42 (s, 1H, H1),
7.37e7.31 (m, 3H, Ph), 7.26e7.24 (m, 5H, Ph), 7.09e7.07 (m, 2H, Ph),
6.86e6.84 (m, 2H, Ph), 4.86 (d, J¼3.2 Hz, 1H, H3), 4.77 (td, J¼3.2,
5.6 Hz, 1H, H4), 4.49 (d, J¼2.4 Hz, 2H, CH2), 4.40 (s, 2H, CH2), 3.81 (s,
3H, OCH3), 3.48 (dd, J¼5.6, 10.4 Hz, 1H, H5), 3.40 (dd, J¼5.6, 10.4 Hz,
4.12. General procedure for the electrolysis of 19 and 24
Under argon was introduced in the cathodic compartment,
10 mL of an anhydrous DMF solution containing n-Et4NBF4 0.1M
and 2.5 mL of the same solution in the anodic compartment (see
Fig. S5 for the cell). The cathodic solution was deoxygenated with
argon bubbling for 15 min and then was introduced 19 or 24. So-
lution was stirred and deoxygenated further for 10 min. A cyclic
voltamogram was then recorded using a glassy carbon electrode in
order to determine the reduction potential of starting material. A
constant potential of ꢀ2.21 V for 19 or ꢀ2.51 V for 24 was then
applied at room temperature, with an initial current close to
12e18 mA. The progress of the electrolysis was followed by cyclic
voltammetry. After 2.0e2.1 F/mole of starting material (1 h), the
electrolysis was stopped and quenched with an aqueous NH4Cl
solution and extracted with EtOAc (3ꢃ), the combined organic
phase were washed with H2O (3ꢃ), dried over Na2SO4 and filtered.
Concentration under vacuo left a residue that was purified by silica
gel chromatography.
1H, H5); 13C NMR (CDCl3) 163.3 (CPh), 159.7 (C1), 137.4 (CPh), 137.3
d
(CPh), 133.6 (CPh), 129.8 (2 CHPh), 128.7 (2 CHPh), 128.4 (2 CHPh),
128.1 (3 CHPh), 128.0 (CHPh), 127.9 (2 CHPh), 119.7 (C2), 114.2 (2
CHPh), 90.3 (C3), 80.7 (C4), 73.7 (CH2), 70.8 (CH2), 68.9 (C5), 55.7
(OCH3); HRMS (ESI) m/z 484.1789 [MþNH4]þ, calcd for
C
26H30NO6Sþ 484.1788.
Analogous treatment of 15 (50 mg, 7.5ꢃ10ꢀ5 mol) with SED
(64 mg, 2.2ꢃ10ꢀ4 mol, 3 equiv) in DMF (4 mL) for 30 min at room
temperature gave 18 as a mixture with 16 (colourless oil; 7.4 mg;
ratio of 16:18 is 33/67) and 17 (13 mg, 86%) as a white solid.
18 had: 1H NMR (200 MHz, CDCl3)
d 7.93 (s, 1H, H1), 7.91e7.84
(m, 2H, Ph), 7.36e7.30 (m, 5H, Ph), 7.01e6.96 (m, 2H, Ph), 6.49 (s,
1H, H3), 4.53 (s, 2H, CH2), 4.42 (s, 2H, H5), 3.86 (s, 3H, OCH3); MS
(ESI) m/z 376.17 [MþNH4]þ, calcd for C19H22NO5Sþ 376.12.
4.10. 50-O-Acetyl-20,30-didehydro-20,30-dideoxy-20-fluorour-
idine (21)
From 0.09 g (0.180 mmol) of 19, 75.1 mg of a viscous yellow oil
was obtained as a crude product. Column chromatography (5%
MeOH in CHCl3) gave a fraction (31.2 mg) that contained an in-
separable mixture of 21 and 19 (ratio 8:2) with estimated yields of
21 (45%) and 19 (6%) from 1H and 19F NMR. Further elution gave
traces amount of 22 and 23 along with other fluorinated impurities
as confirmed by mass spectrometry and NMR.
From 0.09 g (0.131 mmol) of 24, 89.6 mg of a viscous yellow oil
was obtained as crude product. Column chromatography (5% MeOH
in CHCl3) gave a fraction (50 mg) that contained an inseparable
mixture of 24 and 26 (ratio w 2.5:1) with estimated yields of 24
(43%) and 26 (18%) from 1H and 19F NMR. Further elution gave 17
(74%) in addition to other fluorinated impurities.
In a glove box, SED (68 mg, 0.24 mmol, 3 equiv) was added to
a stirred solution of 19 (40 mg, 0.08 mmol) in anhydrous DMF
(4 mL) and the resulting dark brown solution was stirred at 120 ꢁC
for 18 h. Reaction flask was brought out of the glove box, and 10%
HCl solution was added to the crude reaction mixture. Aqueous
layer was extracted with CH2Cl2 (2 ꢃ). Combined organic layer was
dried (Na2SO4), filtered, and concentrated in vacuo to give a brown
solid. Et2O was added to the solid and was filtered. Filtrate was
concentrated in vacuo to give 21 (<10 mg, w46%) along with other
impurities. 1H NMR of the black solid (DMSO-d6) showed similar
peaks to the ones obtained for the oxidized form of the SED
(SED2þ).58
2165 had: 1H NMR (CDCl3)
d
8.47 (br s, 1H, NH), 7.52 (dd, J¼1.0,
Acknowledgements
8.1 Hz, 1H, H6), 6.90e6.88 (m, 1H, H10), 5.78 (d, J¼8.1 Hz, 1H, H5),
5.69 (m, 1H, H30), 5.06e5.02 (m, 1H, H40), 4.35e4.21 (m, 2H, H50,500),
This investigation was supported by SC1CA138176 (NIH/NCI;
SFW) award, Centre National de la Recherche Scientifique (CNRS)
through ‘Action CNRS-USA nꢁ 4020’, and Aix-Marseille and Claude
2.11 (s, 3H, Ac); 19F NMR (CDCl3)
d
ꢀ133.76 (t, J¼4.6 Hz, F20); MS (EI)
m/z 271.09 [MþH]þ, calcd for C11H12FN2Oþ5 271.07.
Please cite this article in press as: Rayala, R.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.02.063

R. Rayala et al. / Tetrahedron xxx (2016) 1e9
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9
Bernard Lyon 1 Universities. We also thank FIU Graduate School for
the Dissertation Year Fellowship (RR), and NIH MARC U*STAR
(GM083688-02) scholarship program (PT) as well as Romain Si-
mon, Christian Duchet and Nathalie Enriques from the Centre
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