Homogeneous azidophenylselenylation of glycals using TMSN 3-Ph2Se2-PhI(OAc)2

Article abstract of DOI:10.1016/j.tetlet.2004.10.022

The use of TMSN₃ instead of NaN₃ allows the reaction to be performed under homogeneous conditions, shortens the reaction time, and provides reliable scale-up. An improved preparative method for homogeneous azidophenylselenylation of glycals is described consisting of reaction with TMSN₃ and Ph₂Se₂ in the presence of PhI(OAc)₂. The use of TMSN₃ instead of NaN₃ as in the heterogeneous procedure, allowed both a reduced reaction time and a scale-up that was not possible in the case of the azidophenylselenylation of substituted glycals using NaN₃.

Full text of DOI:10.1016/j.tetlet.2004.10.022

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 9107–9110
Homogeneous azidophenylselenylation of glycals using
TMSN3–Ph2Se2–PhI(OAc)2
Yuri V. Mironov, Andrei A. Sherman and Nikolay E. Nifantiev*
N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Moscow, Leninsky prospect 47,
Moscow 119991, Russian Federation
Received 30 June 2004; revised 1 October 2004; accepted 5 October 2004
Abstract—An improved preparative method for homogeneous azidophenylselenylation of glycals is described consisting of reaction
with TMSN3 and Ph2Se2 in the presence of PhI(OAc)2. The use of TMSN3 instead of NaN3 as in the heterogeneous procedure,
allowed both a reduced reaction time and a scale-up that was not possible in the case of the azidophenylselenylation of substituted
glycals using NaN3.
Ó 2004 Elsevier Ltd. All rights reserved.
Complex carbohydrate chains of natural glycolipid1 and
glycoprotein2 conjugates often contain the 2-amino-2-
deoxy-a-D-galactopyranoside unit. The most convenient
synthesis of such structures uses appropriately substi-
tuted 2-azido-2-deoxy-galactosyl donors. Among differ-
ent methods for their preparation the azidonitration of
triacetylgalactal 1 has been used most widely.3 However,
this method is laborious and also needs extra steps for
the transformation of nitrate adduct A (Scheme 1) into
glycosyl donor B bearing the leaving group X, which
is required for efficient glycosylation. Thus the develop-
ment of alternative, more practical, and shorter routes
to 2-azido-2-deoxy-galactosyl donors is desirable.
synthesis of 2-azido-glycosyl donors when compared
with the azidonitration procedure. Accordingly we in-
tended to apply the APS reaction for the preparation
of selenoglycoside 2 and its derivatives, to be used in
the synthesis of Tn-antigen and blood group A related
oligosaccharide chains.
Unfortunately our attempts to reproduce published pro-
tocols for the preparation of selenoglycoside 2 were
unsuccessful. Thus, using 0.25M of substrate 1 accord-
ing to Czernecki et al.5 we observed the formation of
only traces of selenoglycoside 2 along with many by-
products (Table 1, entry 1). When the concentration of
substrate 1 was lowered to 0.04M according to San-
toyo-Gonzales et al.6 we obtained the desired product
2 together with its minor talo-isomer 3 in a good overall
yield of 88% on a 0.1g scale (entry 2) but only in 53% on
a 2g scale (entry 3). The lower efficiency could be ex-
plained by the heterogeneity of the reaction media due
to the insolubility of sodium azide in dichloromethane,
which complicates the generation of azide radicals, for-
mation of which is the initial step in the proposed mech-
anism for the heterogeneous APS reaction.4
Tingoli and co-workers described the anti-Markovnikov
one-step azidophenylselenylation (APS) of olefins
including tri-O-methyl-D-glucal by treatment with a
mixture of NaN3, PhI(OAc)2, and Ph2Se2.4 This method
was applied by Czernecki et al.5 and with a small varia-
tion of reagent ratio by the Santoyo-Gonzales et al.6 for
the transformation of galactal 1 into phenyl 3,4,6-tri-O-
acetyl-2-azido-2-deoxy-1-seleno-a-D-galactopyranoside
2 in yields of 70–90%.
Selenoglycosides were shown7 to be efficient glycosyl
donors and thus the one-step APS transformation of
glycals can be seen as an advantageous method for the
To overcome this problem we investigated the possibil-
ity of using a soluble azide donor, namely trimethylsilyl
azide (TMSN3). We found that treatment of a solution
of triacetylgalactal 1, Ph2Se2, and PhI(OAc)2 in dichlo-
romethane with TMSN3 under typical conditions8 gave,
in 4h, a 9:1:1 mixture of target adduct 2, its regioisomer
3 and bis-azide 4 in a total yield of 92% (entry 4).
Pure selenoglycoside 2 could be easily obtained after
Keywords: Azidophenylselenylation; Glycal; Trimethylsilyl azide.
*
Corresponding author. Tel./fax: +7 095 1358784; e-mail: nen@
ioc.ac.ru
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.10.022

9108
Y. V. Mironov et al. / Tetrahedron Letters 45 (2004) 9107–9110
AcO
AcO
AcO
AcO
AcO
OAc
O
OAc
O
OAc
O
OAc
O
a
b
AcO
AcO
AcO
X
ONO2
N3
N3
N
3 SePh
B
A
1
2
X=Hal, SR, OC(NH))CCl
3
Scheme 1. The synthesis of 2-azido-2-deoxy-galactosyl donors from galactal 1 using azidonitration3 (a) and one-step APS (b) protocols.
Table 1. APS under homogeneous conditions: a typical procedure for entries 4–9 is described in Ref. 8
Entry Olefin substrate
Azide donor Reaction time (h) Products
Yield (product ratio)
1a
2b
1
1 (0.1g)
NaN3
NaN3
48
48
2
5%
88%
OAc
SePh
O
(2:3 = 10:1)
AcO
AcO
2 +
2 + 3
3
N3
3b
1 (2g)
NaN3
144
4
53%
(2:3 = 10:1)
AcO
AcO
OAc
O
4
1
TMSN3
92%
(2:3:4 = 9:1:1)
2 + 3 +
AcO
N
3 N3
4
AcO
AcO
N3
O
OAc
O
AcO
AcO
O
AcO
AcO
AcO
5
TMSN3
4
91%
(6:7 = 8:3)
+
SePh
N
5
3 SePh
6
7
BnO
BnO
BnO
OBn
O
OBn
O
6
7
TMSN3
TMSN3
2.5
3.5
72%
BnO
N
3 SePh
8
9
Ph
O
Ph
O
O
O
O
O
i-Pr3SiO
77%
92%
i-Pr3SiO
N
3 SePh
10
11
SePh
N3
8
TMSN3
TMSN3
TMSN3
2
4
2
12
13
Me
N3
Me
SePh
Me
Me
SePh
+
+
9
73%
(15:16:17 = 10:3:1)
SePh
N3
N3
14
15
17
16
CO2Me
SePh
CO2Me
CO2Me
SePh
+
10
69%
(18:19 = 3:1)
N3
N3
18
19
20
a This experiment was performed under the conditions of Ref. 5, where yields of 70–92% for adduct 2 were reported.
b This experiment was performed under the conditions of Ref. 6, where a yield of 91% for adduct 2 was reported.
crystallization of this mixture from i-PrOH. This APS
transformation of galactal 1 can be reproduced at 5g
and larger scales with the same result.
of gluco- and manno-adducts 6 and 7 (entry 5). Similarly,
from tri-O-benzyl-galactal 8 and 4,6-O-benzylidene-3-O-
tri(isopropyl)silyl-D-glucal 10, the selenoglycosides 9
and 11 were obtained in 72% and 77% yields, respec-
tively (entries 6 and 7). Thus the homogeneous APS
reaction is useful for the transformation of substrates
Treatment of triacetylglucal 5, also for 4h under the
same conditions, gave 91% of an inseparable 8:3 mixture

Y. V. Mironov et al. / Tetrahedron Letters 45 (2004) 9107–9110
9109
Randriamandimby, D. Tetrahedron Lett. 1993, 34, 7915–
7916.
6. Santoyo-Gonzales, F.; Calvo-Flores, F. G.; Garcia-Men-
doza, P.; Hernandez-Mateo, F.; Isac-Garcia, J.; Robles-
Diaz, R. J. Org. Chem. 1993, 58, 6122–6125.
containing benzyl and benzylidene groups which were
reported5,6 to be unstable under the conditions of the
heterogeneous APS reaction. In particular, the low yield
in the preparation of selenide 9 from 8 under heteroge-
neous conditions was explained by the low stability of
the nonacyl O-blocking groups in the presence of azide
radicals in the reaction media.5,6
7. (a) Mehta, S.; Pinto, B. M. J. Org. Chem. 1993, 58, 3269–
3276; (b) Mehta, S.; Pinto, B. M. In Modern Methods in
Carbohydrate Synthesis; Khan, S. H., OÕNeill, R. A., Eds.;
Harwood Academic Publishers, 1996; pp 107–129; (c)
Yamago, S.; Yamada, T.; Hara, O.; Ito, H.; Mino, Y.;
Yoshida, J. Org. Lett. 2001, 3, 3867–3870; (d) Jiaang,
W.-T.; Chang, M.-Y.; Tseng, P.-H.; Chen, S.-T. Tetrahedron
Lett. 2000, 41, 3127–3130; (e) Tseng, P.-H.; Jiaang, W.-T.;
Chang, M.-Y.; Chen, S.-T. Chem. Eur. J. 2001, 7, 585–590.
8. Typical procedure: The solution of alkene (1mmol) and
Ph2Se2 (1mmol) in CH2Cl2 (5ml) was cooled to ꢀ30°C
under argon and PhI(OAc)2 (1mmol) and TMSN3
(2mmol) were added sequentially. After stirring for
5min the flask was sealed and was placed in a freezer at
a constant temperature of ꢀ10°C. When the conversion of
starting material was completed (TLC: Silica Gel 60 F254
(E. Merck, Darmstadt, Germany), eluent petroleum
ether–toluene (1:2) for compounds 8, 10, 12 and 14 or
ethyl acetate–toluene (1:5) for compounds 1 and 5) the
reaction mixture was warmed to room temperature, the
solvent was evaporated and the resulting solid was
subjected to column chromatography (Silica Gel 60 (E.
Merck, Darmstadt, Germany), gradient elution from
petroleum ether to ethyl acetate). The structures of
the products of APS reactions (Table 1) were assessed
using 1H (500MHz, CDCl3) and 13C NMR (12 5MHz, CDC3l)
spectroscopy. NMR data for compounds 2, 4, 6, 7 and 13
were in good agreement with published data. Mixtures of
compounds 15, 16 and 17 and of 19 and 20 were not
separated because of their instability and partial decom-
position within several days even if stored at ꢀ20°C.
Selected NMR data for new compounds: 3: 1H NMR: 7.55
(d, 2H, o-Ph, J = 7.4Hz), 7.30–7.40 (m, 3H,
m- and p-Ph), 5.72(br s, 1H, H-1), 5.37 (m, H2 , H-3
It is noteworthy that the APS transformation of tribenz-
ylgalactal 8 under homogeneous conditions proceeds
slightly faster than that of its triacetyl analog 1 (entries
4 and 6). Additionally, the APS reaction under homoge-
neous conditions proceeds not only with higher yield but
also much more rapidly (2–4h) than the heterogeneous
one (several days).5,6,9 Reaction of silylated glucal 10
was not accompanied by the formation of enone side
products, which were observed when 3-O-silylated glu-
cal derivatives were treated with PhI(OAc)2 and TMSN3
but in the absence of Ph2Se2.10
The APS reaction with the use of TMSN3 can be applied
to the transformation of noncarbohydrate olefins as
well. Thus styrene 12 gave anti-Markovnikov adduct
13 exclusively (entry 8) whereas methylcyclopentene 14
gave the adduct 15 with smaller amounts of its isomers
16 and 17 (entry 9). The transformation of the elec-
tron-deficient alkene 18 also proceeded effectively and
regiospecifically to give isomeric 2-azido-1-phenylse-
leno-adducts 19 and 20 (entry 10).
In conclusion, we have demonstrated the advantageous
use of TMSN3 instead of NaN3 in APS reactions in pro-
viding shorter reaction times and reliable scale-ups. Sub-
strate specificity in the APS transformation of glycals
with regard to their stereochemistry and blocking
groups as well as a study of the mechanism of the homo-
geneous APS reaction and uses of the phenyl 2-azido-2-
deoxy-1-selenoglycosides prepared in a- and b-glycosyl-
ation reactions will be reported elsewhere.
0
and H-4), 4.41(br d, 1H, H-5, J5,6 = J5,6 = 6.5Hz), 4.22 (d,
2H, H-6 and H-60, J6,5 = J6 ,5 = 6.5Hz), 3.44 (br d, 1H, H-
0
2, J2,3 = 5.0Hz), 2.23, 2.11, 2.08 (3s, 9H, Ac); 13C NMR:
169.5–170.0 (C@O), 128.1–136.6 (Ar), 91.5 (C-1), 69.2 (C-
5), 66.6 (C-3), 66.0 (C-4), 61.8 (C-6), 45.8 (C-2), 20.5–20.7
(MeC@O). 11: 1H NMR: 7.10–7.80 (10H, m, Ar), 5.95
(1H, d, H-1, J1,2 = 5.4Hz), 5.50 (1H, s, PhCH), 4.35 (1H,
Acknowledgements
0
m, H-5), 4.17 (1H, dd, H-6, J6,5 = 4.9Hz, J6,6 = 11.7Hz),
4.12(1H, t, H-3, J3,2 = J3,4 = 9.3Hz), 3.84 (1H, dd, H-2,
J1,2 = 5.4Hz, J2,3 = 9.3Hz), 3.80 (1H, br d, H-6,
This work was supported by the Russian Foundation
for Basic Research (grant 03-03-06290), DCMS RAS
(project 1.3). A.A.S. is grateful to INTAS for a YS fel-
lowship (grant 03-55-1026). We also thank L. O. Kono-
nov and A. I. Zinin for helpful discussions and A. S.
Shashkov and A. A. Grachev for recording NMR
spectra.
0
J6 ,6 = 11.7Hz), 3.58 (1H, t, H-4, J4,3 = J4,5 = 9.2Hz) 1.05
(21H, m, i-Pr); 13C NMR: 137.6 (ipso-Ph), 126.7–131.0
(Ar), 102.6 (PhCH), 85.3 (C-1), 82.2 (C-4), 72.6 (C-3), 68.5
(C-6), 67.1 (C-2), 65.5 (C-5), 18.1, 12.9. 15: 1H NMR
(CDCl3), d: 7.72(2H, d, o-Ph, J = 7.3Hz), 7.40 (3H, m, p-
and m-Ph), 3.86 (1H, dd, H-2, J = 3.2Hz and J = 6.8Hz),
2.37 (1H, m, H-3), 1.92 (2H, m, H-5, H-50), 1.83 (3H, m,
H-30, H-4, H-40), 1.56 (3H, s, CH3); 13C NMR, d: 137.9
(ipso-Ph), 127.1–129.3 (Ph), 70.4 (C-2), 56.0 (C-1), 38.2 (C-
5), 29.6 (C-3), 23.4 (CH3), 21.1 (C-4). 16: 1H NMR
(CDCl3), d: 7.74 (2H, d, o-Ph, J = 7.5Hz), 7.40 (3H, m, p-
and m-Ph), 3.70 (1H, t, H-2, J = 7.7Hz), 2.18 (1H, m, H-
3), 2.11 (1H, m, H-30), 1.95 (1H, m, H-4), 1.70 (1H, m, H-
40), 1.57 (2H, m, H-5, H-50), 1.56 (3H, s, CH3); 13C NMR,
d: 138. 1 (ipso-Ph), 127.1–129.3 (Ph), 72.1 (C-2), 58.1 (C-
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1
1), 38.0 (C-5), 29.3 (C-3), 28.0 (CH3), 20.1 (C-4). 17: H
NMR (CDCl3), d: 7.30–7.90 (5H, m, Ar), 3.62(1H, t, H-2,
J = 7.5Hz), 2.33 (2H, m, H-3, H-30), 1.95 (1H, m, H-4),
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CH3); 13C NMR, d: 137.7 (ipso-Ph), 127.1–129.3 (Ph), 64.8

9110
Y. V. Mironov et al. / Tetrahedron Letters 45 (2004) 9107–9110
(C-1), 52.8 (C-2), 36.2 (C-5), 32.2 (C-3), 24.3 (C-4), 21.7
m-Ph, J = 7.5Hz), 4.30 (1H, t, H-2, J = 7.9Hz), 3.64 (3H,
s, OMe), 2.17 (1H, m, H-5), 2.05 (2H, m, H-3, H-30), 1.90
(CH3). 19: 1H NMR (CDCl3), d: 7.59 (2H, d, o-Ph,
J = 7.4Hz), 7.42(1H, t, p-Ph, J = 7.5Hz), 7.35 (2H, t, m-
Ph, J = 7.4Hz), 3.97 (1H, d, H-2, J = 5.5Hz), 3.70 (3H, s,
OMe), 2.51 (1H, m, H-3), 2.30 (1H, m, H-5), 1.91 (1H, m,
H-30), 1.88 (2H, m, H-4, H-40), 1.85 (1H, m, H-50); 13C
NMR, d: 172.0 (C@O), 137.5 (ipso-Ph), 126.8–129.7 (Ph),
69.1 (C-2), 59.9 (C-1), 51.9 (OMe), 31.1 (C-5), 30.0 (C-3),
20.7 (C-4). 20: 1H NMR (CDCl3), d: 7.63 (2H, d, o-Ph,
J = 7.5Hz), 7.50 (1H, t, p-Ph, J = 7.6Hz), 7.32(H2 , t,
(2H, m, H-4, H-50), 1.62(1H, m, H-4 ); 13C NMR, d: 173.2
0
(C@O), 137.9 (ipso-Ph), 128.8–129.4 (Ph), 67.6 (C-2), 60.3
(C-1), 52.3 (OMe), 33.4 (C-5), 30.2 (C-3), 20.4 (C-4).
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