Efficient synthesis of 1,2,3-triazole-fused bicyclic compounds from aldoses

Article abstract of DOI:10.1002/ejoc.200500451

We would like to report an expedient synthesis of 1,2,3-triazole-fused bicyclic compounds starting from naturally occurring carbohydrates. These imino sugars were prepared in four steps from glyco-ynitols, readily available from monosaccharides. The title

Full text of DOI:10.1002/ejoc.200500451

FULL PAPER
DOI: 10.1002/ejoc.200500451
Efficient Synthesis of 1,2,3-Triazole-Fused Bicyclic Compounds from Aldoses
Franck Dolhem,[a] Fathia Al Tahli,[a] Catherine Lièvre,*[a] and Gilles Demailly[a]
Keywords: Carbohydrates / Imino sugars / 1,5-Disubstituted 1,2,3-triazoles / glyco-Ynitols / 1,3-Dipolar cycloaddition
We would like to report an expedient synthesis of 1,2,3-tri-
molecular 1,3-dipolar cycloaddition of azidoalkynes in a one-
azole-fused bicyclic compounds starting from naturally oc- pot substitution/thermal cyclization procedure.
curring carbohydrates. These imino sugars were prepared in
four steps from glyco-ynitols, readily available from mono- (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
saccharides. The title compounds were prepared by intra-
Germany, 2005)
sugars, which have been shown to be very potent inhibitors
of glycosidases[10] and glycosyltransferases.[11] These sugar-
derived 1,2,3-triazoles[12–15] can also be regarded as poten-
tial precursors to analogues of some important alkaloid an-
tibiotics.
Introduction
1,2,3-Triazoles are attractive motifs, which, because of
their chemical properties and structure, should find many
applications in organic chemistry. Not present in natural
products, they are remarkably stable to metabolic transfor-
mations. Furthermore, 1,2,3-triazole moieties are emerging
as powerful pharmacophores in their own right.[1] Our
group has now been involved in the synthesis of carbo-
hydrate derivatives for a couple of years[2–7] and, in continu-
ation of our studies on their utilization, we became inter-
ested in the synthesis of polyhydroxylated structures incor-
porating the 1,2,3-triazole motif.
Known methods for the regioselective synthesis of 1,5-
disubstituted 1,2,3-triazoles include the treatment of azides
with active methylene compounds,[8] followed by introduc-
tion of functional groups, and 1,3-dipolar cycloadditions
between azides and alkynes.[9]
Results and Discussion
The 1,2,3-triazole-fused bicyclic carbohydrate-derived
compounds 1–6 were prepared by intramolecular 1,3-di-
polar cycloadditions of azidoalkynes. Such azidoalkynes are
readily available via glyco-ynitols, starting from tritylated
aldoses, through one-carbon chain-elongation without cre-
ation of a new stereogenic center, followed by the activation
and the azido substitution of the primary hydroxy group
(Scheme 2).
We have recently reported the synthesis of 1,1-dibro-
moalkenes from partially protected and unprotected
aldoses[5] and their transformation into glyco-ynitols.[6]
These compounds are interesting scaffolds that can be used
in many transformations. We first used these compounds
to synthesize 1,6- and 1,7-enynes, which in turn afforded
polyhydroxylated 1-vinylcyclopentenes and 1-vinylcyclohex-
enes through ring-closing enyne metathesis.[7] We would
now like to describe the use of the glycol-ynitols for the
rapid preparation of sugar-derived 1,2,3-triazoles.
Here we report the efficient synthesis of glyco-1,2,3-tri-
azoles 1–6, prepared by intramolecular 1,3-dipolar cycload-
ditions of carbohydrate derivatives readily available from al-
dohexoses (type I) and aldopentoses (type II) (Scheme 1).
Such carbohydrate mimics belong to the family of imino
We first devoted our efforts toward the synthesis of com-
pound 1 (Scheme 3). Starting from 2-deoxy-6-O-trityl--
glucose, the dibromo olefin was obtained by treatment of
the hemiacetal with (dibromomethyl)triphenylphospho-
nium bromide in the presence of zinc in 1,4-dioxane under
reflux.[5] Treatment of this olefin with n-butyllithium in
THF at low temperature afforded the corresponding al-
kyne.[6] In the next step, this glyco-ynitol was subjected to
a classical benzylation reaction, followed by deprotection of
the primary hydroxy group by acidic treatment, affording
7.[7] Activation of the primary hydroxy group by a tosylate
was next introduced by treatment of 7 with p-toluenesulfon-
Scheme 1.
[a] Laboratoire des Glucides, FRE 2779, Université de Picardie
Jules Verne,
33 rue Saint-Leu, 80039 Amiens, France
Fax: +33-3-22827561
E-mail: catherine.lievre@sc.u-picardie.fr
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F. Dolhem, F. Al Tahli, C. Lièvre, G. Demailly
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Scheme 3. Reagents and conditions: i) Ph3PCHBr3, Zn, 1,4-diox-
ane, reflux, 76%. ii) nBuLi, THF, –70 °C, 92 %. iii) 1) BnBr, TBAI,
NaH, DMF; 2) HCl concd., CHCl3/MeOH, 76%. iv) TsCl, Py,
room temp., 95%. v) NaN3, DMF, 80 °C, 5 min, 60%. vi) Toluene,
reflux, 24 h, 92%. vii) NaN3, DMF, 120 °C, 3 h, 70 %.
Scheme 2.
yl chloride in pyridine at room temperature, with tosylate
8 being obtained in a very good yield (95%). By addition 54% overall yields, respectively. In the case of galacto-de-
of sodium azide in DMF at 80 °C, 8 was transformed into rived 12, we noticed a drop in reactivity, which forced us to
the azido compound 9, which was isolated in moderate increase the reaction time (60 h) and to use an excess of
yield (60%). We think that this modest result could be reagent (NaN3, 6 equiv.). Those measures resulted in a
partly due to the easy cyclization of this intermediate. When slightly poorer yield because of the appearance of unidenti-
the azidoalkyne 9 was heated at reflux in toluene, 1,3-di- fied side products. The structures 2, 3, and 4 were also con-
1
polar cyclization occurred to give the deoxy-gluco-1,2,3-tri- firmed by H and 13C NMR spectroscopy, and characteris-
azole 1 in 92% yield. The structure of bicycle 1 was resolved tic ions at m/z = 584.4 in their respective mass spectra
by NMR spectroscopy experiments, with the characteristic (FAB-MS) were attributed to [M + Na]+.
resonances observed at δ = 135.0, 135.1, and 46.6 ppm at-
tributed to C-3, C-3a, and C-8, respectively, and those at δ
= 7.46 (s) and 4.76 (m) attributed to 3-H and 8a-H and
8b-H, respectively. This structure was also confirmed by a
characteristic ion at m/z = 478.6, attributed to [M + Na]+,
in its mass spectrum (FAB-MS). Since isolation of 9 turned
out to give only a moderate yield, we thought and hoped
that introduction of the azide and direct conversion into
the 1,2,3-triazole in a one-pot procedure might improve the
overall yield of these transformations. Indeed, when 8 was
treated with sodium azide in DMF at 120 °C the reaction
proceeded to completion after 3 h, and 1 was isolated in an
improved 70% overall yield (Scheme 3).
We then decided to extend these reaction conditions to
three other aldohexoses (Scheme 4). Use of p-TsCl in pyri-
dine thus allowed the conversion of 10 into tosylate 13,
which was treated with sodium azide in DMF at 120 °C for
1 h 45 min to provide the triazole 2 in 85% overall yield.
NMR spectroscopy and mass spectrometry were used to
established this structure. We were pleased to note that the
Scheme 4. Reagents and conditions: i) TsCl, Py, room temp., 24 h.
ii) NaN3, DMF, 120 °C.
presence of an alkoxy group on the carbon atom α to the
triple bond did not negatively affect the course of the cycli-
sation. By the same sequence, manno-ynitol 11 and galacto-
ynitol 12 were converted into the corresponding manno-
After our work with hexoses, we turned to the synthetic
1,2,3-triazole 3 and galacto-1,2,3-triazole 4 in 80% and transformation of pentoses into 1,2,3-triazoles. By use of
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Efficient Synthesis of 1,2,3-Triazole-Fused Bicyclic Compounds from Aldoses
FULL PAPER
1 mmol) immersed in a water bath. After having been stirred under
argon at room temperature for 24 h, the reaction mixture was con-
centrated. The crude residue was purified by flash chromatography.
the same synthetic procedure we achieved the synthesis of
two glyco-1,2,3-triazoles and from aldopentoses
5
6
(Scheme 5). The -ribose derivatives 16 and 17 were treated
with p-TsCl in the presence of pyridine at room temperature
for 24 h to afford tosylates 18 and 19 in 96% and 95%
yields, respectively. One-pot SN2 displacement of the corre-
sponding tosylates with NaN3, followed by the 1,3-dipolar
cycloaddition, afforded 1,2,3-triazoles 5 and 6, isolated in
this case in yields of 58% and 74%, respectively.
(2R,3S,4R)-2,3,4-Tri-O-benzyl-1-O-(tolyl-4-sulfonyl)hept-6-yne-
1,2,3,4-tetrol (8): Compound 8 was prepared from 7 (129 mg,
0.3 mmol) by General Procedure 1. The crude residue was purified
by flash chromatography (hexane/EtOAc, 9:1), and 8 was obtained
as a colorless oil in 95% yield (170 mg). Rf = 0.36 (hexane/EtOAc,
8:2). [α]2D7 = –14 (c = 0.5, CHCl3). 1H NMR (CDCl3): δ = 7.40–
7.30 (m, 19 H, C6H5), 4.84–4.42 (d, 6 H, PhCH2), 4.50 (dd, J1a,1b
= 10.5, J1a,2 = 5.0 Hz, 1 H, 1a-H), 4.28 (dd, J1a,1b = 10.5, J1b,2
=
2.3 Hz, 1 H, 1b-H), 3.96 (ddd, J1a,2 = 5.0, J1b,2 = 2.3, J2,3 = 8.6 Hz,
1 H, 2-H), 3.94 (dd, J2,3 = 8.6, J3,4 = 2.8 Hz, 1 H, 3-H), 3.85 (dt,
J3,4 = J4,5a = 2.8, J4,5b = 6.7 Hz, 1 H, 4-H), 2.61 (m, 2 H, 5a-H,
5b-H), 2.08 (t, J
= J
= 2.7 Hz, 1 H, 7-H), 1.21 (s, 3 H,
7,5a
7,5b
SO2PhCH3) ppm. 13C NMR (CDCl3): δ = 145.1, 138.5, 133.3,
128.9, 128.8, 128.7, 128.5, 128.1 (C6H5), 81.1 (C-6), 79.1 (C-2), 77.7
(C-4), 77.6 (C-3), 75.4–72.6 (PhCH2), 71.4 (C-1, C-7), 22.0
(SO2PhCH3), 20.6 (C-5) ppm. MS: m/z = 607.7 [M + Na]+.
C35H36O6S (584.72): calcd. C 71.89, H 6.21, S 5.48; found C 72.03,
H 6.43, S 5.72.
(2R,3R,4R,5S)-2,3,4,5-Tetra-O-benzyl-1-O-(tolyl-4-sulfonyl)hept-6-
yne-1,2,3,4,5-pentol (13): Compound 13 was prepared from 10
(134 mg, 0.25 mmol) by General Procedure 1. The crude residue
was purified by flash chromatography (hexane/EtOAc, 87:13) and
13 was obtained as a colorless oil in 95% yield (165 mg). Rf = 0.45
(hexane/EtOAc, 8:2). [α]2D7 = +22 (c = 0.25, CHCl3). 1H NMR
(CDCl3): δ = 7.40–7.30 (m, 24 H, C6H5), 5.07–4.43 (d, 8 H,
PhCH2), 4.55 (dd, J4,5 = 7.3, J5,7 = 2.0 Hz, 1 H, 5-H), 4.49 (dd,
J1a,1b = 10.7, J1a,2 = 2.3 Hz, 1 H, 1a-H), 4.26 (dd, J1a,1b = 10.7,
J1b,2 = 5.5 Hz, 1 H, 1b-H), 4.18 (dd, J2,3 = 5.5, J3,4 = 3.4 Hz, 1 H,
3-H), 3.93 (dt, J1a,2 = 2.3, J2,3 = J1b,2 = 5.5 Hz, 1 H, 2-H), 3.89
(dd, J4,5 = 7.3, J3,4 = 3.4 Hz, 1 H, 4-H), 2.64 (d, J5,7 = 2.0 Hz, 1
H, 7-H), 1.21 (s, 3 H, SO2PhCH3) ppm. 13C NMR (CDCl3): δ =
145.0, 138.6, 138.5, 133.3, 128.9, 128.7, 128.5, 128.2 (C6H5), 81.1
(C-4), 80.6 (C-6), 79.3(C-3), 77.8 (C-2), 77.2 (C-7), 75.0, 74.9, 72.4,
71.0 (PhCH2), 71.4 (C-5), 69.9 (C-1), 22.2 (SO2PhCH3) ppm. MS:
m/z = 713.9 [M + Na]+. C42H42O7S (690.84): calcd. C 73.02, H
6.13, S 4.64; found C 73.31, H 6.29, S 4.75.
Scheme 5. Reagents and conditions: i) TsCl, Py, room temp., 24 h.
ii) NaN3, DMF, 120 °C, 1 h.
Conclusions
In summary, we have achieved the synthesis of several
new chiral 1,2,3-triazole-fused bicyclic compounds in a few
steps from commercially available monosaccharides (pen-
toses and hexoses). Those 1,2,3-triazole-fused bicyclic
carbohydrate-derived compounds possess a predefined ste-
reochemistry and were obtained in satisfactory overall
yields by a versatile procedure. We have it in mind to investi-
gate other preparations of new bi- and polycyclic com-
pounds derived from carbohydrates by such an approach.
(2R,3R,4R,5R)-2,3,4,5-Tetra-O-benzyl-1-O-(tolyl-4-sulfonyl)hept-6-
yne-1,2,3,4,5-pentol (14): Compound 14 was prepared from 11
(303 mg, 0.56 mmol) by General Procedure 1. The crude residue
was purified by flash chromatography (hexane/EtOAc, 87:13) and
14 was obtained as a colorless oil in 95% yield (370 mg). Rf = 0.47
(hexane/EtOAc, 8:2). [α]2D7 = –32 (c = 0.5, CHCl3). 1H NMR
(CDCl3): δ = 7.40–7.30 (m, 24 H, C6H5), 5.07–4.43 (d, 8 H,
PhCH2), 4.58 (m, 1 H, 1a-H), 4.53 (dd, J4,5 = 4.7, J5,7 = 2.7 Hz, 1
H, 5-H), 4.30 (dd, J1a,1b = 10.8, J1b,2 = 5.4 Hz, 1 H, 1b-H), 4.29
(dd, J2,3 = 5.4, J3,4 = 3.4 Hz, 1 H, 3-H), 3.47 (dt, J1a,2 = 2.1, J2,3
= J1b,2 = 5.4 Hz, 1 H, 2-H), 3.44 (dd, J4,5 = 4.7, J3,4 = 3.4 Hz, 1
H, 4-H), 2.65 (d, J5,7 = 2.7 Hz, 1 H, 7-H), 1.21 (s, 3 H, SO2PhCH3)
ppm. 13C NMR (CDCl3): δ = 145.2, 138.6, 138.5, 133.3, 128.9,
128.8, 128.7, 128.2 (C6H5), 81.6 (C-6), 80.8 (C-4), 78.3 (C-3), 77.7
(C-2), 76.7 (C-7), 75.0–71.0 (PhCH2), 69.8 (C-1), 69.3 (C-5), 22.0
(SO2PhCH3) ppm. MS: m/z = 713.9 [M + Na]+. C42H42O7S
(690.84): calcd. C 73.02, H 6.13, S 4.64; found C 73.28, H 6.41, S
4.82.
Experimental Section
General Remarks: Unless otherwise specified, materials were pur-
chased from commercial suppliers and were used without further
purification. Reactions with moisture-sensitive materials were con-
ducted in oven-dried glassware under argon. Flash chromatography
was carried out on Kieselgel 60 (230–400 mesh, Merck) and analyt-
ical thin-layer chromatography (TLC) was performed on E. Merck
glass-backed silica gel sheets (Silica Gel 60 F254). Melting points
are uncorrected. Optical rotations were measured with a sodium
lamp (λ = 589 nm) and are uncorrected. 1H and 13C NMR spectra
were recorded at 300 and 75 MHz, respectively. Spectra were re-
corded in CDCl3 or [D6]DMSO and chemicals shifts (δ) are ex-
pressed in ppm relative to residual CHCl3 or an internal standard.
All signals in the 13C NMR spectra were assigned through C,H-
correlated spectra. IR spectra were recorded with neat films (NaCl
cell) and KBr pellets (solids). Infusion electrospray mass spectra in
the positive-ion mode were obtained with an updated (3.6 GHz
TDC) Q-TOF hybrid quadrupole/time-of-flight instrument, fitted
with a pneumatically assisted electrospray ion source (Z-spray).
(2R,3S,4R,5S)-2,3,4,5-Tetra-O-benzyl-1-O-(tolyl-4-sulfonyl)hept-6-
yne-1,2,3,4,5-pentol (15): Compound 15 was prepared from 12
(410 mg, 0.76 mmol) by General Procedure 1. The crude residue
was purified by flash chromatography (hexane/EtOAc, 87:13) and
General Procedure 1 for the Synthesis of Compounds 8, 13–15, and
18–19: p-Toluenesulfonyl chloride (2 equiv.) was added to a pyri-
dine (1 mL) solution of the starting material (7, 10–12, 16–17;[7] 15 was obtained as a colorless oil in 95% yield (500 mg). Rf = 0.42
Eur. J. Org. Chem. 2005, 5019–5023
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F. Dolhem, F. Al Tahli, C. Lièvre, G. Demailly
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(hexane/EtOAc, 8:2). [α]2D9 = +24 (c = 0.4, CHCl3). 1H NMR
ppm. MS: m/z = 478.4 [M + Na]+. C28H29N3O3 (455.55): calcd. C
(CDCl3): δ = 7.40–7.30 (m, 24 H, C6H5), 5.07–4.43 (d, 8 H, 73.82, H 6.42, N 9.22; found C 73.89, H 6.59, N 9.35.
PhCH2), 4.55 (dd, J4,5 = 7.3, J5,7 = 2.2 Hz, 1 H, 5-H), 4.54 (dd,
General Procedure 2 for the Synthesis of Compounds 1–6: Sodium
J1a,1b = 10.7, J1a,2 = 3.0 Hz, 1 H, 1a-H), 4.27 (dd, J1a,1b = 10.7,
azide (2 equiv.) was added to a DMF (7 mL) solution of one of the
J1b,2 = 4.0 Hz, 1 H, 1b-H), 4.08 (m, 3 H, 2-H, 3-H, 4-H), 2.70 (d,
tosylated compounds (8, 13–15, 18–19; 0.05 mmol). The reaction
mixture was stirred under argon at 120 °C. The reaction was moni-
tored by TLC, and after completion, the solvent was evaporated.
The residue was diluted with EtOAc and washed with H2O. The
combined organic layers were dried (Na2SO4) and concentrated.
The crude residue was purified by flash chromatography to give the
desired compounds 1–6.
J5,7 = 2.2 Hz, 1 H, 7-H), 1.21 (s, 3 H, SO2PhCH3) ppm. 13C NMR
(CDCl3): δ = 145.0, 138.6, 138.5, 133.3, 128.8, 128.7, 128.5, 128.2
(C6H5), 81.7 (C-4), 81.6 (C-6), 77.9, 77.4 (C-2, C-3), 76.9 (C-7),
75.0, 74.9, 72.4, 71.0 (PhCH2), 71.3 (C-1), 69.6 (C-5), 22.2
(SO2PhCH3) ppm. MS: m/z = 713.9 [M + Na]+. C42H42O7S
(690.84): calcd. C 73.02, H 6.13, S 4.64; found C 73.33, H 6.29, S
4.82.
(5R,6S,7R)-5,6,7-Tris(benzyloxy)-5,6,7,8-tetrahydro-4H-[1,2,3]tri-
azolo[1,5-a]azepine (1): Compound 1 was prepared from 8 (166 mg,
0.28 mmol) by General Procedure 2. The crude residue was purified
by flash chromatography (hexane/EtOAc, 70:30) and 1 was ob-
tained as a colorless oil in 70% yield (90 mg). Rf = 0.25 (hexane/
(2R,3S)-2,3-Di-O-benzyl-1-O-(tolyl-4-sulfonyl)hex-5-yne-1,2,3-triol
(18): Compound 18 was prepared from 16 (143 mg, 0.46 mmol) by
General Procedure 1. The crude residue was purified by flash
chromatography (hexane/EtOAc, 9:1) and 18 was obtained as a so-
lid in 96% yield (200 mg). Rf = 0.20 (hexane/EtOAc, 9:1). [α]2D7
=
EtOAc 6:4). [α]2D7 = –57 (c = 0.8, CHCl3). H NMR (CDCl3): δ =
1
1
+1 (c = 1, CHCl3). M.p. 87–92 °C. H NMR (CDCl3): δ = 7.40–
7.30 (m, 14 H, C6H5), 4.71–4.48 (d, 4 H, PhCH2), 4.38 (dd, J1a,1b
7.46 (s, 1 H, 3-H), 7.40–7.30 (m, 15 H, C6H5), 4.84–4.42 (d, 6 H,
PhCH2), 4.76 (m, 2 H, 8a-H, 8b-H), 4.06 (brd, J5,6 = 5.9 Hz, 1 H,
= 10.6, J1a,2 = 2.6 Hz, 1 H, 1a-H), 4.25 (dd, J1a,1b = 10.6, J1b,2
=
6-H), 3.92 (ddd, 1 H, 7-H), 3.85 (dt, J4a,5 = 1.3, J4b,5 = 5.9, J5,6
=
4.7 Hz, 1 H, 1b-H), 3.84 (ddd, J1a,2 = 2.6, J1b,2 = 4.7, J2,3 = 8.0 Hz,
1 H, 2-H), 3.70 (dt, J2,3 = 8.0, J3,4a = 2.6, J3,4b = 8.0 Hz, 1 H, 3-
H), 2.61 (m, 2 H, 4a-H, 4b-H), 2.04 (t, J4a,6 = J4b,6 = 2.6 Hz, 1 H,
6-H), 1.24 (s, 3 H, SO2PhCH3) ppm. 13C NMR (CDCl3): δ = 145.2,
138.0, 130.3, 128.9, 128.4, 128.3 (C6H5), 80.6 (C-5), 77.6 (C-2), 75.7
(C-3), 73.3, 72.5 (PhCH2), 71.1 (C-6), 69.1 (C-1), 22.0 (SO2PhCH3),
20.7 (C-4) ppm. MS: m/z = 487.6 [M + Na]+. C27H28O5S (464.57):
calcd. C 69.80, H 6.07, S 6.90; found C 70.12, H 6.25, S 7.20.
5.9 Hz, 1 H, 5-H), 3.18 (dd, J4a,5 = 1.3, J4a,4b = 15.6 Hz, 1 H, 4a-
H), 3.06 (dd, J4b,5 = 5.9, J4a,4b = 15.6 Hz, 1 H, 4b-H) ppm. 13C
NMR (CDCl3): δ = 138.9, 138.0, 137.8, 128.9, 128.8, 128.7, 128.5,
128.2 (C6H5), 135.1 (C-3a), 135.0 (C-3), 79.0 (C-6), 75.1 (C-7), 74.7
(C-5), 75.5, 72.4, 72.3 (PhCH2), 46.6 (C-8), 22.1 (C-4) ppm. IR
(CHCl ): ν = 3050, 1460, 1239, 1060, 800 cm–1. MS: m/z = 478.6
˜
3
[M + Na]+. C28H29N3O3 (455.55): calcd. C 73.82, H 6.42, N 9.22;
found C 73.91, H 6.50, N 9.30.
(2R,3S,4S)-2,3,4-Tri-O-benzyl-1-O-(tolyl-4-sulfonyl)hex-5-yne-
1,2,3,4-tetrol (19): Compound 19 was prepared from 17 (327 mg,
0.78 mmol) by General Procedure 1. The crude residue was purified
by flash chromatography (hexane/EtOAc, 9:1) and 19 was obtained
as a colorless oil in 95% yield (420 mg). Rf = 0.35 (hexane/EtOAc,
8:2). [α]2D7 = +32 (c = 0.6, CHCl3). 1H NMR (CDCl3): δ = 7.40–
(4S,5R,6S,7R)-4,5,6,7-Tetrakis(benzyloxy)-5,6,7,8-tetrahydro-4H-
[1,2,3]triazolo[1,5-a]azepine (2): Compound 2 was prepared from 13
(153 mg, 0.24 mmol) by General Procedure 2. The crude residue
was purified by flash chromatography (hexane/EtOAc, 75:25) and
2 was obtained as a solid in 90% yield (120 mg). Rf = 0.15 (hexane/
EtOAc, 8:2). M.p. 105–108 °C. [α]2D8 = +14 (c = 1.2, CHCl3). 1H
NMR (CDCl3): δ = 7.71 (s, 1 H, 3-H), 7.40–7.30 (m, 20 H, C6H5),
7.35 (m, 19 H, C6H5), 4.92–4.52 (d, 6 H, PhCH2), 4.56 (dd, J3,4
=
8.8, J4,6 = 2.1 Hz, 1 H, 4-H), 4.42 (dd, J1a,1b = 10.5, J1a,2 = 4.7 Hz,
1 H, 1a-H), 4.25 (dd, J1a,1b = 10.5, J1b,2 = 2.1 Hz, 1 H, 1b-H), 3.91
(m, 2 H, 2-H, 3-H), 2.58 (d, J4,6 = 2.1 Hz, 1 H, 6-H), 2.50 (s, 3 H,
SO2PhCH3) ppm. 13C NMR (CDCl3): δ = 145.2, 138.2, 137.9,
137.8, 130.8, 128.9, 128.8, 128.7, 128.5, 127.4 (C6H5), 80.0 (C-5),
79.5, 77.1 (C-2, C-3), 76.6 (C-6), 74.6, 73.1, 71.5 (PhCH2), 70.7
(C-4), 69.8 (C-1), 22.2 (SO2PhCH3) ppm. MS: m/z = 593.7
[M + Na]+. C34H34O6S (570.70): calcd. C 71.56, H 6.00, S 5.62;
found C 71.82, H 6.23, S 5.82.
5.12 (dd, J8a,8b = 14.1, J7,8a = 8.3 Hz, 1 H, 8a-H), 4.99 (d, J4,5
5.8 Hz, 1 H, 4-H), 4.84–4.62 (d, 8 H, PhCH2), 4.58 (dd, J8a,8b
=
=
14.1, J7,8b = 2.0 Hz, 1 H, 8b-H), 4.12 (m, J6,7 = 5.8 Hz, 2 H, 6-H,
7-H), 4.08 (t, J4,5 = J5,6 = 5.8 Hz, 1 H, 5-H) ppm. 13C NMR
(CDCl3): δ = 139.4, 139.0, 138.7, 138.6, 128.6, 128.2, 128.0, 127.9,
127.7 (C6H5), 135.5 (C-3a), 134.6 (C-3), 82.5, 78.6 (C-6, C-7), 74.6
(C-5), 74.5, 74.0, 73.1, 71.6 (PhCH2), 73.9 (C-4), 47.2 (C-8) ppm.
IR (KBr): ν = 3050, 1460, 1239, 1060, 800 cm–1. MS: m/z = 584.4
˜
[M + Na]+. C35H35N3O4 (561.67): calcd. C 74.84, H 6.28, N 7.48;
(2R,3S,4R)-1-Azido-2,3,4-tri-O-benzylhept-6-yne-2,3,4-triol (9): So-
dium azide (40 mg, 0.62 mmol) was added to a DMF (7 mL) solu-
tion of 8 (200 mg, 0.34 mmol). After having been stirred at 80 °C
under argon for 5 min, the reaction mixture was concentrated. Af-
ter extraction with EtOAc/H2O, the combined organic extracts
were dried (Na2SO4) and concentrated. The crude residue was puri-
fied by flash chromatography (hexane/EtOAc, 94:6) and 9 was ob-
tained as a colorless oil in 60% yield (90 mg). Rf = 0.71 (hexane/
found C 75.02, H 6.50, N 7.54.
(4R,5R,6S,7R)-4,5,6,7-Tetrakis(benzyloxy)-5,6,7,8-tetrahydro-4H-
[1,2,3]triazolo[1,5-a]azepine (3): Compound 3 was prepared from 14
(360 mg, 0.52 mmol) by General Procedure 2. The crude residue
was purified by flash chromatography (hexane/EtOAc, 75:25) and
3 was obtained as a colorless oil in 84% yield (247 mg). Rf = 0.14
(hexane/EtOAc, 8:2). [α]2D8 = –71 (c = 0.3, CHCl3). 1H NMR
(C2D6OS): δ = 7.75 (s, 1 H, 3-H), 7.40–7.30 (m, 20 H, C6H5), 5.01
(d, J4,5 = 2.1 Hz, 1 H, 4-H), 4.80–4.62 (d, 8 H, PhCH2), 4.78 (dd,
J8a,8b = 13.1, J7,8a = 8.1 Hz, 1 H, 8a-H), 4.62 (dd, J8a,8b = 13.1,
J7,8b = 1.8 Hz, 1 H, 8b-H), 4.22 (m, 2 H, 6-H, 7-H), 4.08 (m, 1 H,
1
EtOAc, 8:2). [α]3D0 = +3 (c = 0.9, CHCl3). H NMR (CDCl3): δ =
7.40–7.30 (m, 15 H, C6H5), 4.84–4.42 (d, 6 H, PhCH2), 3.98 (dd,
J2,3 = 6.3, J3,4 = 3.0 Hz, 1 H, 3-H), 3.88 (dt, J3,4 = J4,5a = 3.0, J4,5b
= 6.7 Hz, 1 H, 4-H), 3.69 (dd, J1a,1b = 13.3, J1a,2 = 5.2 Hz, 1 H,
1a-H), 3.48 (dd, J1a,1b = 13.3, J1b,2 = 2.7 Hz, 1 H, 1b-H), 3.85 (m, 5-H) ppm. 13C NMR (C2D6OS): δ = 139.2, 139.0, 138.9, 138.5,
1 H, 2-H), 2.63 (dd, J4,5a = 3.0, J5a,7 = 2.6 Hz, 1 H, 5a-H), 2.61
128.9, 128.7, 128.6, 128.5, 128.3 (C6H5), 134.9 (C-3a), 134.6 (C-3),
82.5, 78.6 (C-6, C-7), 74.6 (C-5), 74.5, 74.0, 73.1, 71.6 (PhCH2),
(dd, J4,5b = 6.7, J5b,7 = 2.6 Hz, 1 H, 5b-H), 2.09 (t, J5a,7 = J5b,7
=
2.6 Hz, 1 H, 7-H) ppm. 13C NMR (CDCl3): δ = 138.9, 138.8, 128.8, 73.8 (C-4), 47.8 (C-8) ppm. IR (CHCl ): ν = 3050, 1460, 1239,
˜
3
128.7, 128.5, 128.2 (C6H5), 81.2 (C-6), 79.2, 79.1 (C-2, C-3), 77.8 1060, 800 cm–1. MS: m/z = 584.4 [M + Na]+. C35H35N3O4 (561.67):
(C-4), 75.6, 72.7, 72.1 (PhCH2), 71.3 (C-7), 51.3 (C-1), 20.7 (C-5) calcd. C 74.84, H 6.28, N 7.48; found C 75.12, H 6.55, N 7.54.
5022
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© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2005, 5019–5023

Efficient Synthesis of 1,2,3-Triazole-Fused Bicyclic Compounds from Aldoses
FULL PAPER
(4S,5R,6R,7R)-4,5,6,7-Tetrakis(benzyloxy)-5,6,7,8-tetrahydro-4H-
[1,2,3]triazolo[1,5-a]azepine (4): Compound 4 was prepared from 15
(500 mg, 0.72 mmol) by General Procedure 2. The crude residue
was purified by flash chromatography (hexane/EtOAc, 75:25) and
4 was obtained as a colorless oil in 57% yield (230 mg). Rf = 0.2
(hexane/EtOAc, 7:3). [α]2D7 = +18 (c = 0.4, CHCl3). 1H NMR
(CDCl3): δ = 7.74 (s, 1 H, 3-H), 7.40–7.30 (m, 20 H, C6H5), 4.90
(d, J4,5 = 5.8 Hz, 1 H, 4-H), 4.80–4.62 (d, 8 H, PhCH2), 4.70 (m,
J8a,8b = 14.1, J7,8a = 8.3, J7,8b = 2.0 Hz, 2 H, 8a-H, 8b-H), 4.15 (m,
J7,8a = 8.3, J7,8b = 2.0, J5,6 = 3.0 Hz, 2 H, 6-H, 7-H), 4.08 (dd, J4,5
= 5.8, J5,6 = 3.0 Hz, 1 H, 5-H) ppm. 13C NMR (CDCl3): δ = 139.4,
139.0, 138.7, 138.6, 129.2, 129.0, 128.7, 128.2, 127.6 (C6H5), 135.5
(C-3a), 134.0 (C-3), 82.5, 78.6 (C-6, C-7), 74.6 (C-5), 74.5, 74.0,
(PhCH ), 72.6 (C-4), 71.7 (C-5), 46.2 (C-7) ppm. IR (KBr): ν =
˜
2
3050, 1450, 1250, 1060, 800 cm–1. MS: m/z = 464.5 [M + Na]+.
C27H27N3O3 (441.52): calcd. C 73.45, H 6.16, N 9.52; found C
73.62, H 6.20, N 9.54.
Acknowledgments
We thank the Conseil Régional de Picardie for financial support.
F. D. is grateful to the French Ministry of Education, Research and
Technology (MENRT) for a doctoral fellowship.
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73.1, 71.6 (PhCH ), 73.9 (C-4), 52.0 (C-8) ppm. IR (CHCl ): ν =
˜
2
3
3050, 1460, 1239, 1060, 800 cm–1. MS: m/z = 584.4 [M + Na]+.
C35H35N3O4 (561.67): calcd. C 74.84, H 6.28, N 7.48; found C
75.12, H 6.60, N 7.64.
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pyridine (5): Compound 5 was prepared from 18 (200 mg,
0.43 mmol) by General Procedure 2. The crude residue was purified
by flash chromatography (hexane/EtOAc, 4:6) and 5 was obtained
as a solid in 58% yield (120 mg). Rf = 0.25 (hexane/EtOAc, 6:4).
[α]2D7 = –5 (c = 0.85, CHCl3). M.p. 108–111 °C. 1H NMR (CDCl3):
δ = 7.48 (s, 1 H, 3-H), 7.40–7.30 (m, 10 H, C6H5), 4.75 (m, 4 H,
PhCH2), 4.62 (dd, J7a,7b = 13.5, J6,7a = 5.6 Hz, 1 H, 7a-H), 4.39
(dd, J7a,7b = 13.5, J6,7b = 4.0 Hz, 1 H, 7b-H), 4.15 (ddd, J6,7a = 5.6,
6467–6471.
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J6,7b = 4.0, J5,6 = 1.6 Hz, 1 H, 6-H), 4.05 (ddd, J4b,5 = 4.8, J4a,5
=
7.5, J5,6 = 1.6 Hz, 1 H, 5-H), 3.20 (dd, J4a,5 = 7.5, J4a,4b = 16.3 Hz,
1 H, 4a-H), 2.99 (dd, J4b,5 = 4.8, J4a,4b = 16.3 Hz, 1 H, 4b-H) ppm.
13C NMR (CDCl3): δ = 138.1, 138.0, 129.0, 128.5, 128.4, 128.1,
128.0 (C6H5), 132.0 (C-3a), 131.5 (C-3), 73.3 (C-5), 73.1 (C-6), 72.4,
71.9 (PhCH ), 48.0 (C-7), 23.6 (C-4) ppm. IR (CHCl ): ν = 3050,
˜
2
3
1450, 1250, 1060, 800 cm–1. MS: m/z = 358.4 [M + Na]+.
C20H21N3O2 (335.40): calcd. C 71.62, H 6.31, N 12.53; found C
71.32, H 6.27, N 12.40.
(4S,5R,6R)-4,5,6-Tris(benzyloxy)-4,5,6,7-tetrahydro[1,2,3]triazolo-
[1,5-a]pyridine (6): Compound 6 was prepared from 19 (448 mg,
0.78 mmol) by General Procedure 2. The crude residue was purified
by flash chromatography (hexane/EtOAc, 6:4) and 6 was obtained
as a solid in 74% yield (260 mg). Rf = 0.22 (hexane/EtOAc, 6:4).
[α]2D3 = –15 (c = 1.2, CHCl3). M.p. 114–116 °C. 1H NMR (CDCl3):
δ = 7.75 (s, 1 H, 3-H), 7.40–7.30 (m, 15 H, C6H5), 4.75 (d, 6 H,
PhCH2), 4.63 (m, J7a,7b = 12.0, J6,7a = 10.5 Hz, 1 H, 7a-H), 4.58
(dd, J4,5 = 3.0, J5,6 = 5.8 Hz, 1 H, 5-H), 4.44 (dd, J7a,7b = 12.0,
J6,7b = 2.0 Hz, 1 H, 7b-H), 4.37 (d, J4,5 = 3.0 Hz, 1 H, 4-H), 3.91
(ddd, J6,7a = 10.5, J6,7b = 2.0, J5,6 = 5.8 Hz, 1 H, 6-H) ppm. 13C
NMR (CDCl3): δ = 138.3, 137.6, 138.1, 129.1, 128.8, 128.6, 128.3,
128.1 (C6H5), 134.5 (C-3a), 132.2 (C-3), 74.7 (C-6), 74.0, 72.3, 72.0
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Received: June 21, 2005
Published Online: October 12, 2005
Eur. J. Org. Chem. 2005, 5019–5023
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5023