NaBH3CN and other systems as substitutes of tin and silicon hydrides in the light or heat-initiated reduction of halosugars: A tunable access to either 2-deoxy sugars or 1,5-anhydro-itols

Article abstract of DOI:10.1016/j.tet.2013.09.032

UV light-promoted reduction of acetobromoglucose by NaBH₃CN in t-BuOH afforded 1,3,4,6-tetra-O-acetyl-2-deoxy-α-d-arabino-hexopyranose in high yield and purity, via a Surzur-Tanner rearrangement, while, with 10 mol % thiophenol added, acetylated 1,5-anhydro-d-glucitol was cleanly obtained. Such tin-free and mild reductions, presumed to proceed via radical pathways, were more efficient with NaBH₃CN compared to NaBH₄ or NaBD ₄, and do not occur with acetochloroglucose. Similar reductions to 1,3,4,6-tetra-O-acetyl-2-deoxy-α-d-arabino-hexopyranose were achieved upon heating to 80 C t-BuOH or CH₃CN solutions of NaBH₃CN and AIBN, but with a lower selectivity due to competing ionic reactions. With other pyranosyl bromides, reductions by NaBH₃CN could be tuned similarly (d-galacto), but some (d-manno, 5-thio-d-xylo) gave mainly or exclusively 1,5-anhydro-itols. Other conditions, or reagents promoting SET process, afforded also reduced products, but with lower rates or selectivities. Primary iodides were reduced readily with NaBH₃CN under UV light.

Full text of DOI:10.1016/j.tet.2013.09.032

Tetrahedron 69 (2013) 9656e9662
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
NaBH3CN and other systems as substitutes of tin and silicon
hydrides in the light or heat-initiated reduction of halosugars:
a tunable access to either 2-deoxy sugars or 1,5-anhydro-itolsq
a
,
b
,
c
a
,
b
,
,
b
,
,b,c
ꢀ
ꢁ
Isabelle Bruyere
, Zoltan Toth c, Hamida Benyahia a c, Jia Lu Xue a
,
Jean-Pierre Pralya
,b,c,
*
a
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
Universite de Lyon, Institut de Chimie et Biochimie Moleculaires et Supramoleculaires (ICBMS) associe au CNRS, UMR 5246, equipe de Chimie
Organique 2, CPE Lyon, 43 boulevard du 11 Novembre 1918, F-69622 Villeurbanne, France
b
ꢁ
Universite Lyon 1, F-69622 Villeurbanne, France
c
ꢁ
ꢁ
ꢁ
CNRS, UMR 5246, Institut de Chimie et Biochimie Moleculaires et Supramoleculaires (ICBMS), equipe de Chimie Organique 2, CPE Lyon, 43 boulevard
du 11 Novembre 1918, F-69622 Villeurbanne, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 13 June 2013
Received in revised form 4 September 2013
Accepted 9 September 2013
Available online 16 September 2013
UV light-promoted reduction of acetobromoglucose by NaBH3CN in t-BuOH afforded 1,3,4,6-tetra-O-
acetyl-2-deoxy-
a
-
D
-arabino-hexopyranose in high yield and purity, via a SurzureTanner rearrangement,
-glucitol was cleanly obtained. Such tin-
while, with 10 mol % thiophenol added, acetylated 1,5-anhydro-
D
free and mild reductions, presumed to proceed via radical pathways, were more efficient with NaBH3CN
compared to NaBH4 or NaBD4, and do not occur with acetochloroglucose. Similar reductions to 1,3,4,6-
tetra-O-acetyl-2-deoxy-
CH3CN solutions of NaBH3CN and AIBN, but with a lower selectivity due to competing ionic reactions.
With other pyranosyl bromides, reductions by NaBH3CN could be tuned similarly ( -galacto), but some
-manno, 5-thio- -xylo) gave mainly or exclusively 1,5-anhydro-itols. Other conditions, or reagents
a-D
-arabino-hexopyranose were achieved upon heating to 80 ꢀC t-BuOH or
Keywords:
Glycosyl bromides
NaBH3CN
Radical reduction
SurzureTanner rearrangement
1,5-Anhydro-glucitol
2-Deoxy sugar
D
(
D
D
promoting SET process, afforded also reduced products, but with lower rates or selectivities. Primary
iodides were reduced readily with NaBH3CN under UV light.
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
phosphofructose, thereby blocking glycolysis at an early stage. This
causes depletion of ATP as well as of glucose derivatives required
1,5-Anhydro-
D
-glucitol is a naturally-occurring glucose de-
for protein glycosylation,4 making 2-deoxy-
D-glucose a candidate
rivative present in meat and cereals, also found in humans, due to
food intake and a marginal (w10%) endogenous synthesis. Being
for anticancer5 and antiviral6 therapies, among other potential
applications.
generally not metabolized, 1,5-anhydro-
healthy subjects, a stable plasma concentration that reflects
a steady balance between ingestion and urinary excretion. As hy-
D
-glucitol achieves, in
Moreover, as several important antibiotic families display 2-
deoxyglycosyl moieties, the synthesis of 2-deoxyglycosides is an
important niche in the field of carbohydrate chemistry.7 Earlier
perglycemia may enhance the rate of excretion of 1,5-anhydro-
D
-
-
routes to 2-deoxy-3,4,6-tetra-O-acetyl-a-D-glycopyranoses in-
glucitol, its plasma concentration drops, making 1,5-anhydro-
D
volved the corresponding glycals, which, under controlled condi-
tions can undergo acid-catalyzed addition of water8 or acetic acid9.
Similarly, by addition of cationic intermediates (mercuric ion,
positive halogen) in the presence of alcohols, glycals have been
converted into various 2-deoxy-2-substituted derivatives, which
have been smoothly reduced to the corresponding 2-
deoxyglycosides under various conditions (sodium amalgam,7a
catalytic hydrogenation,10 KBH4,11 NaBH4,12 Na2S2O4,13 or under
photolytic,14 and other conditions15). A related synthesis of 2-
glucitol a short-term glycemic marker.1 It is also considered as
a biomarker for monogenic diabetes,2 and for drug-induced
nephrotoxicity.3 2-Deoxy-
D-glucose (2-deoxy-D-arabino-hexopyr-
anose) also displays interesting bioactivities as it inhibits phos-
phohexose isomerase, the enzyme that converts phosphoglucose to
q
The other co-authors, who performed the research at the University of Lyon are
living abroad (Isabelle BRUYERE: Belgium; Zoltan TOTH: Hungary; Xue Jia LUE: PR
China), and their present addresses are unfortunately unknown to me.
* Corresponding author. Tel.: þ33(0)472431161; fax: þ33(0)472448109; e-mail
address: jean-pierre.praly@univ-lyon1.fr (J.-P. Praly).
deoxy-D-arabino-hexopyranose upon treatment of D-glucal with
N-bromosuccinimide and methanol, then reduction with Raney
nickel, and hydrolysis has been recently patented.16 The photo-
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.09.032

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I. Bruyere et al. / Tetrahedron 69 (2013) 9656e9662
9657
induced addition of radical species to glycals is also documented.17
Due to the development of free-radical methods,18 tin hydride-
mediated dehalogenation or deoxygenation and similar radical-
based reductions became very popular, as documented by com-
prehensive reviews.19 It is well-known that free-radical methods
have opened new possibilities in this field due to radical rear-
rangement. As first reported by Giese, 2-acylated (acetyl, chlor-
oacetyl, benzoyl as acyl groups) glycopyranosyl bromides/chlorides
can be reduced to 2-deoxy sugars with tri-n-butyl tin hydride
(slowly added to keep its concentration low)20 or with the less
reactive tris(trimethylsilyl)silane added at once.21 Under these
poorly reductive conditions, the initially formed glycosyl radicals
undergo a slow 2/1-acyloxy migration (the SurzureTanner/Giese
rearrangement), to produce C2-centered radicals, precursors of fi-
nal 2-deoxy products. When tin hydride and PhSH or PhSeH
(10 mol %) are used, the direct reduction of glycos-1-yl radicals is
fast enough to afford predominantly 1,5-anhydro-itols with sup-
pression of the migration reaction.22 We have reviewed earlier the
structure of glycosyl radicals ant their transformations under re-
ductive conditions.23
hypothesis. In particular, the reduction of 1 with NaBH3CN in the
presence of 10 mol % PhSH was gratifying beyond our expectations
as the resulting reduced products (79% yield after chromatogra-
phy) contained mainly the anhydro-
reduction,22 and practically no rearranged 2-deoxy sugar 3 (4/3
ratio: w98/2). Interestingly, attempts to reduce the more stable
D
-glucitol 4 formed by direct
a
-
chloride 2 either alone or as a 1:1 mixture with 1 failed and
unreacted 2 was recovered, thus showing a high chemoselectivity
(Scheme 1).25,26
While preparing C-glycosyl compounds according to Giese’s
method24 by addition of glycosyl radicals to acrylonitrile or diethyl
vinylphosphonate under mild photo-induced conditions, we could
achieve a good control of competing reactions and minimize radical
reduction, using catalytic amount of tri-n-butyl tin chloride and
excess NaBH3CN dissolved in tert-butanol.25 Our protocol proved to
be somewhat more efficient than those reported for the syntheses
Scheme 1. Tunable photoreductions of 1 in the presence of NaBH3CN.
Variations of the initial reduction protocol25,26 showed that
while the 3/4 ratio (w95:5) was essentially constant for most
reductions of 1 (Table 1), an optimized yield of reduced products
(82%, entry 5) was achieved provided (a) pure recrystallized 1 was
used, (b) argon was bubbled for w30 min into the liquid phase
maintained at w30 ꢀC to remove oxygen prior to the reaction, (c)
good quality NaBH3CN from recent batches was used, (d) a Vycor
of
a-configured C-glycosyl compounds. Moreover, applied to
anomeric dihalides having both chlorine and bromine atoms bound
to the C1 position, radical-based reactions proved to be chemo-,
and stereoselective, so that combining two radical steps (glycosyl
filter (
lamp used. Otherwise, either longer reaction times [1 get trans-
formed slowly if a Pyrex filter ( >300 nm) was used (entry 3)], or
yields decreased by ca. 10e20% due in part to hydrolysis to 2,3,4,6-
tetra-O-acetyl- -glucopyranose 5, were observed (entries 4, 6e8).
l>254 nm) was adapted to the medium-pressure mercury
addition to an alkene, then
cosyl chloride produced) led to the corresponding
glycosyl compounds (w40% yield). Besides the desired C-glyco-
sides, 1,3,4,6-tetra-O-acetyl- -arabino-hexopyranose and
2,3,4,6-tetra-O-acetyl-1,5-anhydro- -glucitol were found as
byproducts (w10% yield from 2,3,4,6-tetra-O-acetyl- -glucopyr-
a-stereoselective reduction of the gly-
b
-configured C-
l
a
-D
3
D
D
4
This was also the case when t-BuOH was replaced by CH3CN as the
solvent (entry 10), thus affording 3 (57%, 3/4 ratio 86:14) after
2.25 h, probably because CH3CN has a nitrile chromophore whose
absorption should limit the energy transfer to NaBH3CN (CH3CN,
NaBH3CN, and n-Bu4NBH3CN absorb in the range 250e300 nm).
Moreover, compared to t-BuOH, the higher polarity of CH3CN
should favor ionic pathways, as hydrolysis to 5, and the ionic re-
duction of 1 into 4, entailing the lower 3/4 selectivity observed. If
a-D
anosyl bromide 1). Therefore, a few assays were conducted without
alkene added so as to favor reduction. To our delight, preliminary
experiments aiming at reducing 1 with NaBH3CN in the absence of
tri-n-butyl tin hydride, revealed simple and tunable conditions to
tightly control the reaction paths and outcome of photo-initiated
reductions (vide infra).25 This was the first report showing that
NaBH3CN alone can be a substitute to tin or silicon hydrides, for
tunable reductions under mild and simple conditions. We now report
on further tests carried out under light and heat-promoted condi-
tions for the NaBH3CN-mediated reductions of various halosugars,
as well as attempted reductions of protected glycosyl bromides
based on SET process.
0.6 equiv of UV-active AIBN (lmax¼360 nm, ¼11.9 mol/cm at
3
18.03 mM) was added to the mixture in t-BuOH, even higher yield
(85%) and selectivity (3/4 ratio 98:2) were observed (entry 9) but
the reaction was surprisingly slower (2.5 h). Probably, the pres-
ence of AIBN as a radical initiator favored free radical pathways
(with rearrangement), over direct ionic reduction. The intimate
mechanism of the rearrangement of b-(acyloxy)alkyl radical (ei-
2. Results and discussion
ther concerted or via rapid collapse of contact ion pair) is still not
fully clarified.27 As said before, photoreduction of 1 by NaBH3CN in
the presence of PhSH (10 mol %) led to 4 in high yield and purity
(entry 11).
Attempts to reduce 1 upon heating a t-BuOH solution in a flask
wrapped with an aluminum foil afforded 3 in 78% yield and high
purity (3/4 ratio 95:5) but via an extremely slow process (10 and 15
days at 80 and 60 ꢀC, respectivelydentries 13, 14), with no reaction
observed after 17.5 h at 30 ꢀC. After 15 days at 40e50 ꢀC, 1 get
partially reduced (entry 12) and afforded 3 and 4 in w12% yield, the
3/4 ratio being 2:3. This suggested the radical rearrangement rate
was slow at this temperature range, a fact, which has been estab-
lished recently by others in the case of the BEt3/air-mediated re-
Isolation of 3 and 4 as byproducts formed in the course of the
radical synthesis of C-glucosides25,26 initiated a study of the re-
duction of 1 by NaBH3CN and related borohydrides under a variety
of conditions and that of glycosyl halides by NaBH3CN. Preliminary
assays with filtered UV-light (Vycor filter,
reduction of 2,3,4,6-tetra-O-acetyl- -glucopyranosyl bromide 1
was fast (w35 min) and clean, with only one spot visible on TLC
plates. Column chromatography afforded homogeneous fractions
(82% yield) shown by 1H NMR spectroscopy to contain essentially
the 2-deoxy product 3, with low amounts of 1,5-anhydro-D-glu-
citol 4 (3/4 ratio>95:5). The reduction of bromide 1 into the 2-
deoxy product 3 was strongly suggesting a radical pathway with
l>254 nm) showed that
a-D
duction of a b-anomeric xanthate, shown to afford mainly either
a
2/1-acyloxy migration taking place under unprecedented
the directly reduced product 4 (at ꢁ20 ꢀC) or the rearranged one 3
conditions and further assays (vide infra) supported this

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I. Bruyere et al. / Tetrahedron 69 (2013) 9656e9662
9658
Table 1
Light-, and heat-promoted reduction of glucosyl bromide 1 by NaBH3CN25,31
Entry
Solvent
Argona
UV light-promoted
Heat-promoted
conditions ꢀC
Reagents additives
NaBH3CN: A
AIBN: B
Reaction
time
Products: % and ratio
cond./filterb
1
3
4
5
6
7
3/4
4/3
a
/
b
R/S
PhSH: C
1
2
3
t-BuOH
CH3CN
t-BuOH
d
Vycor
Vycor
Pyrex
d
6.5 h
6.5 h
8.5 h
55
50
89
20
8
d
d
Yes
A, 2 equiv
11
w1:1
61
88:12
8225
>95:5
73
93:7
61
>95:5
61
4
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
CH3CN
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
CH3CN
CH3NO2
CH3NO2
Yes
Yes
Yes
Yes
No
d
Corex
Vycor
No filter
Vycor
Vycor
Vycor
Vycor
Vycor
d
A, 2 equiv
A, 2 equiv
A, 2 equiv
A, 2 equivc
A, 2 equiv
2 h
5
35 min
35 min
1 h
6
7
9
8
30 min
2.5 h
10
>95:5
85
98:2
57
9
A, 2 equiv
B, 0.6 equiv
A, 2 equiv
B, 0.6 equiv
A, 2 equiv
C, 10 mol %
A, 2 equiv
10
11
12
13
14
15
16
17e
18
d
2.25 h
1.75 h
15 days
15 days
10 days
36 h
12
86:14
Yes
d
7925
98:2
12
40e50
60
12
3:2
d
d
A, 2 equiv
A, 2 equiv
77
95:5
78
95:5
53d
96:4
69d
95:5
d
d
80
d
d
80
A, 2 equiv
B, 0.6 equiv
A, 2 equiv
B, 0.6 equiv
A, 2 equiv
2
4
8
8d
w1:2
91:9
d
d
80
6.5 h
12d
77:23
46.5d
95:5
36d
d
d
100
100
10.5 h
5 h
17.5d
100:0
33d
12
13
d
d
A, 3 equiv
100:0
85:15
a
Unless otherwise indicated, argon was usually bubbled through the solution, but in some cases this detail was not marked in the experimental report.
b
The minimum transmission wavelengths for Vycor, Corex, and Pyrex filters are, respectively, 210, 258, and 292 nm; they are transparent above 254, 280, 320 nm,
respectively.
c
An old batch of NaBH3CN was used.
d
e
Product ratio estimated by 1H NMR spectroscopy.
Compound 1 was not transformed (TLC) after stirring the mixture for 21 h at rt.
(at þ60 ꢀC) depending on the temperature applied.28a While the
reduction under thermal conditions was accelerated in the pres-
ence of AIBN (36 h at 80 ꢀCdentry 15), its selectivity was surpris-
ingly decreased, as 3 was isolated in 53% yield only (3/4 ratio 96:4),
complete within <6.5 h (entry 16) to produce 3 (69% yield, 3/4 ratio
95:5), 5 (4%), 7(R) and 7(S) (12%, 7(R)/7(S) ratio 77:23). Reductions
of 1 by NaBH3CN in CH3NO2 heated to 100 ꢀC afforded most
probably by ionic pathways 4, 5, 7(R), and 7(S), the amount of 4
being dependent on that of NaBH3CN, while 3 was not observed
(entries 17, 18).
Notably, when the reduction of 1 was performed under normal
atmosphere, hemiacetal 5 was isolated in ca. 10% amounts. This
suggested a mode of formation by radical coupling with oxygen30
although 5, also detected in other assays, may arise from reaction
with water and/or oxygen nucleophiles: 5 was isolated in 9% yield
when using an old batch of NaBH3CN, containing moisture due to
hygroscopicity. Blank experiments with only 1 dissolved in either t-
BuOH or CH3CN also produced 5 in 20 and 8% yield, respectively, if
irradiation was continued for 6.5 h. While CH3CN and t-BuOH might
contain trace amounts of water, formation of 5 in higher amounts in
t-BuOH is surprising but 5 may be produced via the t-butyl gluco-
side 6, which could undergo acid-catalyzed cleavage of the O-gly-
cosidic bond.
together with 5 (2%), tert-butyl 2,3,4,6-tetra-O-acetyl-
anoside 6 (8%, ratio w1:2), plus the 3,4,6-tri-O-acetyl-1,2-O-
ethylidene- -glucopyranoses 7(R) and 7(S) (8%, R/S ratio 91:9)
D-glucopyr-
a/b
a-
D
(Scheme 2). Similar 1,2-ethylidene products observed previously25
were assumed to result from ionic rather than radical pathways,
which is in accordance with their synthesis from 1 upon reaction
with NaBH4.29 tert-Butyl glucosides 6 are also assumed to result
from ionic pathways favored by heating. Attempts to reduce 1 in
CH3CN heated to 80 ꢀC resulted in an even faster thermal reduction
Other borohydrides, such as n-Bu4NBH3CN, NaBH4, and NaB-
H(OAc)3 were tested, in either t-BuOH, CH3CN or C6H6 (Table 2). n-
Bu4NBH3CN used in benzene led after 4.25 h irradiation to a mix-
ture of 3, 4, 7R (47% yield, 3/4/7R ratio 67:28:5 by 1H NMR), and
hemiacetal 5 (17%). Similarly NaBH(OAc)3 (6 equiv used) gave 3 in
37% yield, 3/4 ratio 95:5, after 24 h irradiation in t-BuOH, whereby
the reduction was partial with 7% 1 recovered. Compared to t-BuOH
Scheme 2. Byproducts and others formed from 1 upon attempted reduction with
NaBH3CN, NaBH4, or NaBD4.

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I. Bruyere et al. / Tetrahedron 69 (2013) 9656e9662
9659
and CH3CN (Table 1), benzene appeared (Table 2, entry 1) to be
galacto, 12 5-thio-
D-xylo, 13
D
-ribo) and 6-halogeno-
a-
D-glucopyr-
a less favorable solvent, probably for polarity reasons and its UV
absorbing ability. While n-Bu4NBH3CN shows an absorption band
in the range 250e300 nm, NaBH4 does not. All assays carried out
with NaBH4 in different solvents (CH3CN, t-BuOH) and conditions
(thermal or photo-induced) were poorly effective (entries 3e5),
anose derivatives 14aed was investigated. The photo-induced re-
ductions (Vycor filtered light) were carried out in t-BuOH with
excess NaBH3CN (conditions i), with NaBH3CN and PhSH 10 mol %
(conditions ii). Reduction was also possible by heating with excess
NaBH3CN (conditions iii) (Table 3).31 For solubility reason, 9 was
dissolved in CH3CN and its transformation (conditions i) was found
complete after 345 min to afford 15 and 16 (70% crude yield, 44%
after chromatography, 15/16 ratio w4:1) and appreciable amount of
affording 3 at best in 40% yield, 3/4 ratio 89:11 (hn, CH3CN, entry 4).
NaBD4 was even a less effective reducing agent compared to NaBH4,
as judged from the longer reaction times observed (entries 6, 7).
While the presence of 4D32 among the reduced products isolated
by chromatography could not be confirmed, homogeneous mix-
tures were shown by NMR to contain mainly the 2-deoxy reduced
products 3 and 3D,33 in w1:1 ratio, due to incomplete labeling
(entry 7). Our results resemble those obtained with a complex of
deuterated borane and N-heterocyclic carbene that pointed to
a substantial isotope effect.34a
2,3,4,6-tetra-O-benzoyl- -glucopyranose 17. Under conditions ii, 9
D
reacted faster to afford the corresponding itol 16 isolated in 56%
yield and 16/15 ratio w85:15, besides a low amount of the hemi-
acetal 17. These two reactions resembled those achieved with 1,
although their selectivity was lower. Under conditions i and al-
though a reduced amount of NaBH3CN was used (1.5 instead of
2 equiv), the
18 in 7% yield only and the corresponding itol 19 in 70% yield. This
was not surprising as -mannopyranosyl radicals are less prone to
D-manno bromide 10 afforded the 2-deoxy derivative
Being simple, inexpensive, easily tunable, environmentally be-
nign, these unprecedented tin-free conditions were attractive, and
D
offered an alternative protocol to known routes to 1,5-anhydro-
D-
2/1 acetyloxy rearrangement in accordance to the fact that the
itols or 2-deoxy sugars. As the
the reduction of benzoylated
a
-chloride 2 was found unreactive,
-glucopyranosyl bromide 9 and
products with an equatorial OAc group at C1 do not gain stabili-
a-
D
zation by the anomeric effect.35 Bromide 11 (
D-galacto) was reduced
other differently configured glycosyl bromides (10
D-manno, 11 D-
under both conditions i and ii within 90 min to afford, besides low
Table 2
Light-, and heat-promoted reduction of 1 by other borohydridesa
Entry
Conditions: h
solvent
n/D
(ꢀC),
Reducing
agent
Reaction
time (h)
Products %
1
3
4
5
6
7
8
1
2
3
4
5
h
n
, Vycor
Benzene
, Vycor
t-BuOH
, Vycor
t-BuOH
, Vycor
n-Bu4NBH3CN
2 equiv
NaBH(OAc)3
6 equiv
NaBH4
2 equiv
NaBH4
2 equiv
NaBH4
2 equiv
4.25
24
9
d
47
17
Mixed with 3, 4
3/4/7R¼67:28:5
hn
7
37
12
3/4>95:5
hn
1þ3þ4¼w40
57:31:12 ratio
hn
3.5
5
d
40
8
CH3CN
80 ꢀC
3/4¼89:11
Mixture of 3, 4, 7(R), 7(S), and 8
CH3CNb
1
30
3þ3D
10
4þ4D
6
7
h
n
, Vycor
t-BuOH
, Vycor
CH3CN
NaBD4
2 equiv
NaBD4
2 equiv
6.25
7.45
>95:5
25
1:1 Traces
hn
d
a
Bromide 1 (205 mg, 0.5 mmol) and the selected borohydride were dissolved in the chosen solvent.31
Heat-induced reductions were carried out in the presence of AIBN (0.6 equiv).
b
Table 3
Light and heat-promoted reduction of various halosugars with NaBH3CNa in t-BuOHb
Substrates
Concdc,31
Products/yields/ratiod
ie 345 min or ii 105 min
9 D
-glucob
1535
1638,39
i: 70%,f44 %;g15/16 w4:1
ii: 56 %;g 16/15 w85:15
i 40 min or iiie 6.5 h
10
D
-manno
1835
i, 7 %g
iii, 0%h
1940e42
i, 70%g
iii, 0%h
(continued on next page)

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I. Bruyere et al. / Tetrahedron 69 (2013) 9656e9662
9660
Table 3 (continued )
Substrates
Concdc,31
Products/yields/ratiod
ii 90 min or ii 90 min or iii 3 h
11
D
-galacto
2043
2138,40,41
i: 55%;g 20/21 >85/15
iii: 37%;g 20/21 w6:4
ii: 65%;g 21/20 >98/2
i 40 min or iiie 3.25 h
12 5-Thio-
D
-xylo44
2336
i: 81%j
iii: 3.25 h, 73%g
i 60 min see Text
13
D
-ribo
24, 12%g
25(R) exo-H: 24%g
25(S) endo-H: 8%g
ik
X R R0
Time %g
14a Br H Me
14b I H Me
14c I Ac Me
14d I Ac Ac
26a45 4.5 h 88 from 14a
26a 1.5 h 79 from 14b
26c46 2 h 82 from 14c
26d47 2 h 66 from 14d
a
b
c
2 equiv, unless otherwise indicated.
Compound 9 was reduced in CH3CN.
Typical conditions: (i) NaBH3CN 1.2/2 equiv, hn/Vycor, argon; (ii) NaBH3CN 2 equiv, C6H5SH 10 mol %, hn/Vycor, argon; (iii) NaBH3CN 2 equiv, AIBN 0.6 equiv, argon, reflux.
The corresponding glycopyranose was isolated from 9 or 11 under conditions i or ii (17: 20 and 9% yield; 22: 7 and 9% yield, respectively); under conditions iii, 11 and 12
d
afforded also reduced products of the 1,2-ethylidene type29 (<9 and 4% yield, respectively), analogous to 7(R) and 7(S) formed from 1. From 10 these products predominated.
e
NaBH3CN: 1.5 equiv.
Crude yield.
After chromatography.
f
g
h
Under conditions iii, 10 ledd to (S)-3,4,6-tri-O-acetyl-1,2-O-ethylidene- -mannopyranose29 (54% yield).g
b-D
i
NaBH3CN: 1.2 equiv.
After crystallization.
50 mg scale assay.31
j
k
amounts of 2,3,4,6-tetra-O-acetyl-
pected reduced products 20 and 21. Compared to the data for the
gluco series, 20 was contaminated by 21 to a higher extend (85:15
ratio) indicating a lower selectivity. The reduction of 5-thio- -xylo
bromide 12 afforded 23 (conditions i) without rearrangement,36
D
-galactopyranose 22, the ex-
a benzoate, a trifluorobenzoate, a diphenyloxyphosphonyloxy
D
-
group attached to C2, has been observed by ESR only for the last
group,33 and also for a benzoate group, with a ribosyl phenyl-
selenide as the radical precursor.35 With 10, 11, and 12, thermal
reduction was attempted. Compared to the light-promoted condi-
tions, the 1,5-anhydro-itols and/or 2-deoxy reduced products were
formed in lower amounts from 11 and 12, even not at all from 10,
which was converted to reduced products of the 1,2-ethylidene
D
similarly to data reported for 2,3,4,6-tetra-O-acetyl-5-thio-a-D-
glucopyranosyl bromide.37 Attempted reduction of thermolabile
1335 (under conditions i) resulted, immediately after adding
NaBH3CN, in spontaneous gas evolution and formation of a white
precipitate. The structures of the isolated compounds 24 and 25 are
best explained by ionic reactions. Cis-rearrangement of ribosyl
type (see Table 3, note d). Finally, various 6-halogenated a-D-glu-
copyranose derivatives, with free or acetylated hydroxyl groups
(14aed) were subjected to light-induced reduction (50 mg scale,
2:1 t-BuOH/CH3CN).31 Compared to bromide 14a, the reaction was
radicals generated from
D-ribofuranosyl bromides with either

ꢀ
I. Bruyere et al. / Tetrahedron 69 (2013) 9656e9662
9661
faster in the case of iodides but the yields did not change signifi-
cantly depending on whether the OH groups were acetylated or
not. In all cases, the corresponding 6-deoxy product was obtained
in good to excellent yield (unoptimized).
reagents promoting SET process, afforded also reduced products,
but with lower rates or selectivities. Primary iodides were reduced
readily with NaBH3CN under UV light. Further work planned in the
line of sustainable chemistry, with cheap and environment-friendly
conditions has yielded new recent results, to be reported soon.
These experiments are best interpreted on the basis of radical
reaction pathways, which depending on the conditions applied
(light vs heat activation), should differ, at least at the initiation
stage. Further work is needed for establishing firmly a mechanism,
which for now remains speculative on the basis of our work and
literature data. The photoreduction of aryl halides with NaBH4 has
been explained based on SET and formation of borꢁon-centered
radicals.48 UV photolysis of solutions containing BH4 or H3BCNꢁ
in liquid ammonia has been interpreted based on an electron de-
tachment from the anion to give a solvated electron and transient
H3BXꢂ radicals (X¼H, CN) that undergo rapid proton loss leading to
4. Experimental section
4.1. General
The solvents (tert-butanol, CH3CN, and CH3NO2) were distilled
over CaH2 and under argon atmosphere. NaBH3CN (95% grade),
Bu4NBH3CN, and NaBH(OAc)3 (95% grade) purchased from Aldrich,
were used as received, and stored in an exicator. Air was generally
removed from the reaction media by bubbling argon into organic
solutions for 0.5e1.5 h. Acetobromoglucose (95% grade) was pur-
chased from Fluka, and was recrystallized from Et2O. The other
sugar halides were purified similarly, whenever possible. NMR
spectra were recorded with Bruker spectrometers AC 200, DRX 300,
and DRX 500 for solutions in CDCl3.
ꢁ
BH3 ꢂ or H2BCNꢁꢂ radical anions (produced from either NaBH3CN or
n-Bu4BH3CN) observed by ESR.49 Interestingly, while no signals
were obtained when the UV beam was filtered through a Pyrex
glass,49a H2BCNꢁꢂ was observed to react only rapidly with bromides
and iodides.49b Recently, these boron salts have been shown to
react under UV-light irradiation with alkyl iodides (chlorides and
bromides were found inappropriate) and unsaturated esters to
achieve tin-free Giese reactions.50 The continuing interest in this
field51 as well as in boron-centered radicals52 prompted us to dis-
close our observations on a very simple tin-free reductive dehalo-
genation reaction.51g
4.2. Typical procedure for light-promoted reduction25
(Conditions i): a t-BuOH solution (8 mL) containing 1 (200 mg,
0.486 mmol) and 95% NaBH3CN (60.3 mg, 1 mmol) (see Table 1 for
specific details and additives) was introduced in a quartz tube
(w94 mL volume; 27 mm diameter) mounted at a close distance
(w1 cm) of a medium-pressure mercury lamp (Hanovia, 450 W)
inserted in a quartz jacket cooled down with tap-water and
equipped with a filter (Vycor, Corex, Pyrex, see caption, Table 1).
The tube was equipped with a magnetic stirring bar and argon was
bubbled through the solution for at least 30 min prior irradiation.
After completion of the reaction as indicated by TLC monitoring, or
when judged appropriate, the solution was concentrated and the
residue was dissolved in 30 mL CH2Cl2. After aqueous workup,
drying of the organic phase over MgSO4, and concentration under
reduced pressure, the residue was resolved by silica gel column
chromatography. Compounds of identical mobilities led to mix-
tures that were examined by 1H NMR to estimate the product
distribution. Similar assays with PhSH 10 mol % added were car-
ried out (conditions ii). Reduction of compounds 14aed was
achieved similarly, using a quartz tube (13 mm diameter) equip-
ped with a stirring bar. Compounds 14aed (50 mg) and 95%
NaBH3CN (2 equiv) were dissolved in a 2:1 t-BuOH/CH3CN mixture
(6 mL) that was poured in the tube (argon atmosphere) prior to
UV-light irradiation (Vycor filter).
We also envisaged reduction by means of electron donors, or
light-promoted SET process. Attempted reduction of 1 with sodium
dithionite13 under a variety of conditions (Na2S2O4 reacts faster in
basic aqueous medium) led in our hands to hemiacetal 5, with
variable amounts of 3 and 4 (60 % yield at best ; 5:1 ratio). Other
reducing reagents and conditions [10-methylacridinium iodide
(AcrHþIꢁ) or 9,10-dihydro-10-methylacridine (AcrH2) with
NaBH3CN/hn; NEt3/hn; tetrakis(dimethylamino)ethylene (TDAE)]
were tested in view of reducing 1, but multicomponent mixtures
were obtained in all cases and none of these reagents was found
more selective than NaBH3CN (see Supplementary data for details).
Our efforts in the 2-amino-2-deoxy-
ries met no success, as 3,4,6-tri-O-acetyl-2-deoxy-2-N-acetamido-
-glucopyranosyl bromide reacted immediately upon addition of
D-glucose/D-glucosamine se-
D
NaBH3CN (as shown by gas evolution), to afford a mixture of
products, identified as the corresponding tert-butyl glycosides
(6e8%), the isoxazoline (50e54%), and the corresponding hemi-
acetal (8e10%), isolated in quite similar amounts, whatever the
conditions (stirring at 25 ꢀC, UV-light irradiation with and without
AIBN). TDAE and sodium tetraphenyl borate were the only reagents
that afforded modest amounts of product reduced at C-1 from
3,4,6-tri-O-acetyl-2-deoxy-2-N-trifluoroacetamido-a-D-glucopyr-
anosyl bromide (see Supplementary data).
4.3. Typical procedure for heat-promoted reduction
3. Conclusion
(Conditions iii): 1 (200 mg, 0.486 mmol), 95% NaBH3CN
(60.3 mg, 1 mmol), and AIBN (48.2 mg, 0.29 mol, 0.6 equiv) (see
Tables for specific details) were dissolved in 8 mL of solvent upon
stirring and argon was bubbled through the solution for at least
30 min. The mixture protected from light with an aluminum foil
was heated with a sandbath under reflux, with TLC monitoring.
Workup, treatment, and analysis were as indicated for the light-
promoted reactions.
UV light-promoted reduction of acetobromoglucose by
NaBH3CN in t-BuOH afforded 1,3,4,6-tetra-O-acetyl-2-deoxy-
arabino-hexopyranose in high yield and purity, via a SurzureTanner
rearrangement, while with 10 mol % thiophenol added, acetylated
1,5-anhydro-D-glucitol was cleanly obtained. Such tin-free and mild
reductions, presumed to proceed via radical pathways, were more
efficient with NaBH3CN compared to NaBH4 or NaBD4, and do not
occur with acetochloroglucose. Similar reductions to 1,3,4,6-tetra-
a-D-
O-acetyl-2-deoxy-
a
-
D
-arabino-hexopyranose were achieved upon
Acknowledgements
heating to 80 ꢀC t-BuOH or CH3CN solutions of NaBH3CN and AIBN,
but with a lower selectivity due to competing ionic reactions. With
other pyranosyl bromides, reductions by NaBH3CN could be tuned
ꢀ
I.B. and Z.T. thank the French Ministere de la Recherche et de
ꢁ
l’Enseignement Superieur for a Ph.D. stipend and a post-doctoral
similarly
(
D
-galacto), but some
(
D
-manno, 5-thio-
D
-xylo) gave
fellowship, respectively. Other support from CNRS and Claude-
Bernard University Lyon1 are also acknowledged.
mainly or exclusively 1,5-anhydro-itols. Other conditions, or

ꢀ
9662
I. Bruyere et al. / Tetrahedron 69 (2013) 9656e9662
debated: Zavitsas, A. A.; Chatgilialoglu, C. J. Am. Chem. Soc. 1995, 117,
Supplementary data
10645e10654; Zavitsas, A. A. J. Chem. Soc., Perkin Trans. 1 1998, 499e502.
23. Praly, J.-P. Adv. Carbohydr. Chem. Biochem. 2000, 56, 65e151.
24. Radicals in Organic Synthesis: Giese, B. Formation of Carbonecarbon Bonds;
Pergamon: Oxford, 1986.
Data and results on attempted reductions of 1, 3,4,6-tri-O-ace-
tyl-2-deoxy-2-N-acetamido-
tri-O-acetyl-2-deoxy-2-N-trifluoroacetamido-
D
-glucopyranosyl bromide, or 3,4,6-
-glucopyranosyl
ꢀ
25. Praly, J.-P.; Ardakani, A. S.; Bruyere, I.; Marie-Luce, C.; Qin, B. B. Carbohydr. Res.
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26. Bruyere, I. Ph.D. Thesis n 146-2002; University of Lyon: Villeurbanne, France.
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ꢀ
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