'Click' preparation of carbohydrate 1-benzotriazoles, 1,4-disubstituted, and 1,4,5-trisubstituted triazoles and their utility as glycosyl donors

Article abstract of DOI:10.1071/CH08364

Glycosyl triazoles can be prepared from readily available anomeric azides through various 'click' methodologies: thermal Huisgen cycloaddition with alkynes, strain-promoted Huisgen cycloaddition of benzynes, and Cu ^I-catalyzed azide-alkyne cycloaddition of terminal alkynes (CuAAC reaction). Here we investigate the formation of glycosyl 1-benzotriazoles from anomeric and non-anomeric carbohydrate azides using benzynes derived from substituted anthranilic acids. The reactivity of the resulting anomeric 1-benzotriazoles as glycosyl donors was investigated and compared with 1,4-disubstituted glycosyl triazoles (from the CuAAC reaction) and 1,4,5-trisubstituted glycosyl triazoles (prepared by Huisgen cycloaddition of glycosyl azides and dimethyl acetylene dicarboxylate). The 1,4,5-trisubstituted glycosyl triazoles were activated by Lewis acids and could be converted to O-glycosides, S-glycosides, glycosyl chlorides, and glycosyl azides. By contrast, under all conditions investigated, the 1,4-disubstituted glycosyl triazoles were unreactive as glycosyl donors. Glycosyl 1-benzotriazoles were generally inert as glycosyl donors; however, a tetrafluorobenzotriazole derivative, which bears electron-withdrawing substituents on the benzotriazole group, was a moderate glycosyl donor and could be converted to an S-glycoside by treatment with thiocresol and tin(iv) chloride.

Full text of DOI:10.1071/CH08364

Full Paper
CSIRO PUBLISHING
www.publish.csiro.au/journals/ajc
Aust. J. Chem. 2008, 61, 837–846
‘Click’ Preparation of Carbohydrate 1-Benzotriazoles,
1,4-Disubstituted, and 1,4,5-Trisubstituted Triazoles
and their Utility as Glycosyl Donors∗
Jacinta A. Watt,A Carlie T. Gannon,A Karen J. Loft,A Zoran Dinev,A
and Spencer J. WilliamsA,B
ASchool of Chemistry and Bio21 Molecular Science and Biotechnology Institute,
University of Melbourne, Parkville, Vic. 3010, Australia.
BCorresponding author. Email: sjwill@unimelb.edu.au
Glycosyl triazoles can be prepared from readily available anomeric azides through various ‘click’methodologies: thermal
Huisgen cycloaddition with alkynes, strain-promoted Huisgen cycloaddition of benzynes, and CuI-catalyzed azide-alkyne
cycloaddition of terminal alkynes (CuAAC reaction). Here we investigate the formation of glycosyl 1-benzotriazoles from
anomeric and non-anomeric carbohydrate azides using benzynes derived from substituted anthranilic acids. The reactivity
of the resulting anomeric 1-benzotriazoles as glycosyl donors was investigated and compared with 1,4-disubstituted gly-
cosyl triazoles (from the CuAAC reaction) and 1,4,5-trisubstituted glycosyl triazoles (prepared by Huisgen cycloaddition
of glycosyl azides and dimethyl acetylene dicarboxylate). The 1,4,5-trisubstituted glycosyl triazoles were activated by
Lewis acids and could be converted to O-glycosides, S-glycosides, glycosyl chlorides, and glycosyl azides. By contrast,
under all conditions investigated, the 1,4-disubstituted glycosyl triazoles were unreactive as glycosyl donors. Glycosyl
1-benzotriazoles were generally inert as glycosyl donors; however, a tetrafluorobenzotriazole derivative, which bears
electron-withdrawing substituents on the benzotriazole group, was a moderate glycosyl donor and could be converted to
an S-glycoside by treatment with thiocresol and tin(iv) chloride.
Manuscript received: 29 August 2008.
Final version: 12 September 2008.
(a)
RO
(b)
Introduction
N
N
N
O
O
Since the recent introduction of the CuI-catalyzed azide-terminal
alkyne cycloaddition (CuAAC)[1] and the independent realiza-
tion of improved rates and regioselectivities as reported by the
Meldal[2] and Sharpless[3] groups, there has been a boom in
applications of this reaction in the carbohydrate field. These
include the preparation of triazoles used to both inhibit[4]
and define the substrate specificity[5] of glycosyltransferases,
its application in the detection of azide-bearing cell-surface
carbohydrates,[6] and the synthesis of complex neoglycoconju-
gates including triazole-linked oligosaccharides, glycopeptides
and carbohydrate macrocycles.[7]
The CuAAC reaction yields 1,4-disubstituted 1,2,3-triazoles
in high yields with essentially perfect regioselectivity[8] and the
ready accessibility of glycosyl azides makes them ideal sub-
strates for the reaction. Several other types of N-linked glycosyl
1,2,3-triazoles have been reported in the literature, most notably
1,4,5-trisubstituted 1,2,3-triazoles, and 1- and 2-substituted
benzotriazoles (Fig. 1). 1,4,5-Trisubstituted 1,2,3-triazoles have
been prepared through the classical Huisgen [3 + 2] cyclo-
addition of glycosyl azides and activated symmetrical alkynes
such as dimethyl acetylene dicarboxylate.[9] Glycosyl benzo-
triazoles have been prepared by the glycosidation of benzo-
triazole saltsortrimethylsilylbenzotriazole, resultingin mixtures
N
RO
N
N
(c)
RO
(d)
N
N
O
O
N
N
RO
N
N
R
R
R
Fig. 1. Generic examples of glycosyl triazoles: (a) 1-benzotriazole,
(b) 2-benzotriazole, (c) 1,4,5-trisubstituted triazole, and (d) 1,4-disubstituted
triazole.
of the 1- and 2-substituted regioisomers.[10,11] Each of these
reactions has been described as a ‘click’ process that conforms
to the ideals of modularity, high yield, stereospecificity and ease
of isolation and purification.[12,13]
Although the attractions of the glycosyl triazole group have
mostly been as an inert linker, several reports have inves-
tigated the chemical reactivity of various glycosyl triazoles.
The N-linkage of 1,4-disubstituted glycosyl triazoles is sta-
ble to strong acid or base for prolonged periods,[14] is inert
∗ The present paper is dedicated to Professor Bob Stick to mark the occasion of his retirement and 65th birthday.
© CSIRO 2008 10.1071/CH08364
0004-9425/08/110837

838
J. A. Watt et al.
to enzymatic cleavage by glycosidases,[15] and is stable to a
range of common reaction conditions, such as those used for
the acetylation and benzylation of alcohols, as well as for
the removal of these protecting groups.[16] Moreover, the link-
age is stable to the conditions used for Lewis acid-catalyzed
(BF3·Et2O) and Koenigs–Knorr (AgOTf) glycosidations.[16] By
contrast, Miethchen and coworkers have shown that trisubsti-
tuted triazoles with an electron-withdrawing trifluoromethyl
substituent are acid-sensitive[17] and Bröder and Kunz have
demonstrated that 1,4,5-trisubstituted glycosyl triazoles can act
as glycosyl donors in the presence of Lewis acids including
TMSOTf, ZnCl2, and BF3·Et2O,[9] and can be converted to
glycosyl fluorides by treatment with HF–pyridine.[18,19] Inter-
estingly, 1,4,5-trisubstituted glycosyl triazoles derived from the
thermal cycloaddition of di-t-butyl acetylene dicarboxylate were
found to be better glycosyl donors than those obtained from
dimethyl acetylene dicarboxylate, a result Bröder and Kunz
attributed to loss of the t-butyloxycarbonyl group under the reac-
tion conditions, and the formation of a glycosyl triazole, which
was proposed to be the actual glycosyl donor.[18] Finally, to the
best of our knowledge, the utility of glycosyl benzotriazoles as
glycosyl donors has not been assessed, possibly owing to the
lack of reliable methods for their synthesis and the difficulty of
preparing pure regioisomers.
Table 1. Cycloaddition of benzyne with carbohydrate
azides
Reagents and conditions: azide (1 equiv.), anthranilic acid
(3 equiv.), isoamyl nitrite (5 equiv.); Bt = 1H-benzo[d][1,2,3]
triazol-1-yl
N
N
O
N
Anthranilic acid, dioxane
Isoamyl nitrite, (CH2Cl)2
Carbohydrate
azide
Azide
OAc
Product (yield)
OAc
O
O
AcO
AcO
AcO
AcO
N3
Bt
OAc
OAc
1
2
10 (77%)
OBz
O
OBz
O
BzO
BzO
BzO
BzO
Bt
Bt
Bt
N3
OBz
OBz
11 (80%)
OBn
OBn
O
O
BnO
BnO
BnO
BnO
N3
OBn
12 (62%)
OBn
3
4
Given the current interest in glycosyl triazoles, we sought
to develop a route enabling the synthesis of glycosyl 1-
benzotriazoles as single regioisomers, and to investigate their
reactivity as glycosyl donors relative to 1,4-disubstituted and
1,4,5-trisubstituted glycosyl triazoles.
BzO
BzO
BzO
BzO
BzO
13 (64%)
OBz
OBz
O
O
N3
BzO
BzO
BzO
BzO
BzO
OBz
O
OBz
O
Results and Discussion
BzO
BzO
N3
Synthesis of Glycosyl Triazoles
Bt
5
14 (76%)
Although there are several extremely mild methods for the gen-
eration of benzyne, most of the precursors require lengthy and
complicated syntheses,[13,20] and modification of the benzo-
triazole nucleus is not trivial. Wittig and Hoffman,[21] and
shortly thereafter Reynolds,[22] reported that the cycloaddition
of benzyne (obtained by thermal decomposition of diazonium
benzenecarboxylate) to azides affords only 1-substituted benzo-
triazoles. This procedure seemed particularly appealing as it
allows the synthesis of glycosyl 1-benzotriazoles from read-
ily available glycosyl azides, avoiding the formation of the
2-substituted regioisomers. However, preparation of benzyne by
thermal decomposition of diazonium benzenecarboxylate can
suffer from a risk of explosion.[23] This has led to the avoidance
of this useful reaction, with a focus instead on the development
of alternative reagents.[13] However, the ready availability of
substituted anthranilic acids and their potential as benzyne pre-
cursors must not be overlooked. The explosive potential of the
intermediate benzenediazonium-2-carboxylates can be readily
minimized by the simple expedient of avoiding the isolation
of the shock-sensitive solid through forming it in situ under
conditions where it can thermally decompose to benzyne. A
convenient procedure involves the syringe-pump addition of a
solution of anthranilic acid to a solution of the carbohydrate
azide and an excess of isoamyl nitrite in 1,2-dichloroethane at
reflux.[24] By this under-appreciated approach, such anthranilic
acids remain experimentally competitive reagents for the for-
mation of benzotriazoles by virtue of their ready availability,
and the potential safety concerns are overcome. As can be seen
in Table 1, good to excellent results were seen for the glyco-
syl azides 1,[25] 2,[26] 3,[25] 4,[27] 5,[27] and 6,[28] protected with
AcO
AcO
OAc
AcO
AcO
OAc
O
O
N3
Bt
OAc
OAc
15 (73%)
6
Bt
AcO
AcO
N3
OAc
OAc
O
O
AcO
AcO
OMe
OMe
7
16 (80%)
O
O
O
N3
O
Bt
O
OMe
OMe
O
OBn
OBn
17 (71%)
8
OAc
O
OAc
O
AcO
AcO
AcO
AcO
OpNP
OpNP
N3
Bt
9
18 (62%)
acetyl, benzoyl, or benzyl groups. In order to extend the scope of
the reaction, the non-anomeric azides 7,[5] 8, and 9 (K. Loft and
S. J. Williams, unpubl. data) were converted to the non-anomeric
1-benzotriazoles 16, 17, and 18. Of particular note is the toler-
ance of the reaction conditions for a range of common protecting
groups including esters, benzyl ethers, an isopropylidene acetal,
and an aromatic nitro group.
Cycloaddition of benzyne and a carbohydrate azide should
result in only the 1-benzotriazole isomer; however, there
is precedent for the thermal rearrangement of 1-substituted

‘Click’ Preparation of Potential Glycosyl Donors
839
Table 2. Cycloaddition of substituted ‘benzyne’ precursors with glycosyl triazoles
Reagents and conditions: 1 equiv. of azide, 3 equiv. of anthranilic acid, 5 equiv. isoamyl nitrite
N
O
N
RO
N
‘Benzyne’ precursor, dioxane
Isoamyl nitrite, (CH2Cl)2
Glycosyl
azide
R
R
R
R
Azide
‘Benzyne’ precursor
Product (yield)
OBn
N
OBn
O
N
O
BnO
F
N
F
F
BnO
BnO
BnO
F
F
CO2H
NH2
OBn
N3
OBn
19 (42%)
F
3
1
F
F
OAc
O
N
N
OAc
AcO
AcO
N
O
AcO
AcO
OAc
20 (66%)
N3
MeO
MeO
CO2H
OAc
OMe
NH2
OMe
N
OAc
N
O
AcO
AcO
OAc
N
O
OAc
AcO
AcO
N3
CO2H
NH2
21 (42%)
OAc
1
OR
O
OR
N
N
MeO2C
CO2Me
RO
RO
O
N
RO
RO
N3
CO2Me
OR
MeO2C
Toluene, reflux
OR
1
2
R ϭ Ac
R ϭ Bz
23 R = Ac (80%)
24 R = Bz (94%)
22 R ϭ Piv
25 R = Piv (53%)
Scheme 1. Preparation of 1,4,5-trisubstituted 1,2,3-triazoles from glycosyl azides.
triazoles to their 2-substituted isomers.[29] In previous work,
the structures of 1- and 2-benzotriazole isomers were deduced
by careful comparison of UV/visible spectra with literature
compounds;[30] here, direct evidence for only the 1-benzo-
triazole was obtained by two-dimensional 1H–15N heteronuclear
multiple quantum coherence (HMQC) analysis of the acetylated
adduct 10, which revealed three nitrogen signals, with coupling
between the anomeric proton H1 and both N1 and N2, and
coupling between H2 and N1.
The potential of this method for the preparation of glyco-
syl 1-benzotriazoles bearing electron-donating and electron-
withdrawing substituents on the benzotriazole nucleus was
explored next (Table 2). Symmetrically substituted anthranilic
acid precursors were chosen to avoid the problem of the for-
mation of regioisomers. Use of 4,5-dimethoxyanthranilic acid,
3-amino-2-naphthoic acid and tetrafluoroanthranilic acid as
benzyne precursors afforded the corresponding benzo- and
naphtho-triazoles in good yields. This facile entry into substi-
tuted glycosyl 1-benzotriazoles may be of potential value for
medicinal chemistry investigations and, as will be seen, can be
used to tune the reactivity of the benzotriazole group.
of 1,4,5-trisubsituted glycosyl triazoles and 1,4-disubstituted
glycosyl triazoles were prepared. 1,4,5-Trisubstituted glyco-
syl triazoles were synthesized from glycosyl azides 1, 2, and
22[18] by thermal Huisgen [3 + 2] cycloaddition with dimethyl
acetylene dicarboxylate in refluxing toluene (Scheme 1).[9]
1,4-Disubstituted glycosyl triazoles were prepared by the
CuAAC reaction from the glycosyl azides 2 or 4 and phenyl-
acetylene, t-butyl propiolate, or methyl propiolate (Table 3). The
last two alkynes were chosen as they afforded 1,4-disubstituted
triazoles with substituents that matched the 1,4,5-trisubsituted
triazoles prepared here and by Bröder and Kunz.[9] CuI was
produced in situ by reduction of CuSO4 with sodium ascor-
bate in DMSO/water or t-butanol/water[3] and reactions were
conducted in the presence of the CuI-stabilizing ligand tris-
(benzyltriazolylmethyl)amine (TBTA).[31]
Investigation of the Ability of Glycosyl Triazoles
to Act as Glycosyl Donors
With a series of glycosyl triazoles in hand, their ability to act as
glycosyl donors was investigated (Table 4). Initially, we sought
to reinvestigate the work of Bröder and Kunz, who had shown
that various Lewis acids can activate 1,4,5-trisubstituted glyco-
syl triazoles towards O-glycosidation. Glycosyl triazole 24 and
In order to allow comparison of the reactivity of the gly-
cosyl 1-benzotriazoles with other glycosyl triazoles, a series

840
J. A. Watt et al.
Table 3. CuI-catalyzed cycloaddition of glycosyl azides and terminal alkynes
N
O
CuSO4, sodium ascorbate
HCCR, solvent
N
RO
N
Glycosyl
azide
R
Azide
Alkyne
Product (yield)
OBz
O
OBz
N
N
N
O
BzO
BzO
BzO
BzO
N
OBz
N3
Ph
Ph
OBz
2
4
26 (95%)
BzO
BzO
BzO
OBz
N
OBz
O
N
O
BzO
BzO
N3
BzO
27 (65%)
OBz
O
OBz
N
N
O
BzO
BzO
BzO
N
N3
BzO
CO2Me
OBz
OBz
28 (87%)
CO2Me
2
2
OBz
O
OBz
O
N
N
N
BzO
BzO
BzO
BzO
N3
CO2t-Bu
OBz
OBz
CO2t-Bu
29 (60%)
Table 4. 1,4,5-Trisubstituted glycosyl triazoles as glycosyl donors
OR
O
OR
O
N
N
Acceptor
RO
RO
RO
X
N
RO
Lewis acid
CO2Me
OR
OR
MeO2C
Glycosyl donor
Reagents
Product (yield)
OBz
O
OBz
O
BzO
BzO
N
N
BzO
BzO
BzO
OC8H17
N
1-Octanol, TMSOTf
Thiocresol, SnCl4
CO2Me
BzO
MeO2C
24
30 (50%)
OAc
O
OAc
AcO
AcO
N
N
O
STol
AcO
AcO
N
AcO
CO2Me
AcO
31 (77%)
α:β 1:5
MeO2C
23
OAc
O
OAc
O
N
N
N
AcO
AcO
AcO
AcO
N
AcO
TMSCl, SnCl4
TMSN3, SnCl4
CO2Me
CO2Me
AcO
AcO
Cl
MeO2C
23
32 (51%)
OAc
OAc
N
O
O
AcO
AcO
N
AcO
AcO
AcO
N3
MeO2C
23
33 (38%)

‘Click’ Preparation of Potential Glycosyl Donors
841
OBn
anthranilic acids), without formation of the 2-substituted regio-
isomer. In contrast to the introduction of the benzotriazole
group by nucleophilic substitution, this cycloaddition approach
allows the direct preparation of non-anomeric benzotriazoles.
The method was used for the synthesis of substituted benzo-
triazoles from the corresponding substituted anthranilic acid
precursors.Theanomeric1-benzotriazolederivativesarenucleo-
side analogues, and have previously been investigated as
anticancer agents;[34] the non-anomeric 1-benzotriazoles are
isonucleosides, and may also prove to have interesting biological
activities.[35]
Investigation of the ability of glycosyl triazoles to act as
glycosyl donors revealed that 1,4,5-trisubstituted glycosyl tri-
azoles bearing two electron-withdrawing groups were effec-
tive glycosyl donors and could be converted to O-glycosides,
S-glycosides, glycosyl chlorides, and glycosyl azides. By con-
trast, 1,4-disubstituted glycosyl triazoles were unreactive as
glycosyl donors under all of the conditions investigated. Finally,
glycosyl 1-benzotriazoles were typically inert as glycosyl
donors; however, a glycosyl tetrafluorobenzotriazole could be
converted to an S-glycoside. Thus, the number and nature of
electron-withdrawing substituents on the triazole group appears
to dictate their ability to act as leaving groups.
N
N
O
BnO
BnO
OBn
O
N
F
F
Thiocresol
SnCl4
BnO
BnO
OBn
STol
OBn
34 (20%)
F
F
19
Scheme 2. Use of a tetrafluorobenzotriazole as a glycosyl donor.
octanol, in the presence of TMSOTf, afforded the β-glycoside
30 in 50% yield. In order to broaden the potential applicabil-
ity of these triazoles as synthetic intermediates, their conversion
into a range of other known glycosyl donors was investigated.
Thus, treatment of 23 with thiocresol and SnCl4 afforded the
corresponding S-glycoside 31 (77%) as a mixture of anomers.
Similarly, the triazole 23 could be converted to the glycosyl
chloride 32 (51%) by treatment with chlorotrimethylsilane and
SnCl4. Finally, in an example of an N-glycosidation, the triazole
23 was converted to the glycosyl azide 33 (38%), with inversion
of configuration, by treatment with TMSN3 and SnCl4.
Theabilityof1,4-disubstitutedglycosyltriazolestoactasgly-
cosyl donors was investigated next. Not unexpectedly, in light of
previous work,[14,16] no reaction was observed on treatment of
the phenyltriazole 26 and 1-octanol with a range of Lewis acids
such as Cu(OTf)2, AgOTf, TfOH, or TMSOTf. The poor reac-
tivity observed here is somewhat at odds with the reactivity seen
for 1,4,5-trisubstituted glycosyl triazoles, especially in light of
the mechanism proposed by Bröder and Kunz wherein unsub-
stituted glycosyl triazoles were proposed to be intermediates
in Lewis acid-catalyzed glycosidations.[18] Thus, the ability of
the methoxycarbonyl- and t-butyloxycarbonyl-substituted 1,4-
triazoles 28 and 29 to act as glycosyl donors was investigated.
Notably, TfOH was unable to activate either of these triazoles
towards glycosidation. This result suggests that the ability of the
trisubstituted triazoles to act as glycosyl donors is simply due to
the presence of the strongly electron-withdrawing ester groups,
and not due to loss of the t-butyloxycarbonyl group.
Finally, we examined the ability of the glycosyl 1-
benzotriazoles to act as glycosyl donors. Katritzky has published
extensively on the ability of benzotriazoles to act as syn-
thetic auxiliaries in organic synthesis, including as ‘tamed’
halogen equivalents in nucleophilic substitutions.[32] However,
to the best of our knowledge, the reactions of glycosyl 1-
benzotriazoles have not been systematically investigated. Sur-
prisingly, the unsubstituted glycosyl 1-benzotriazoles 10 and
11 proved refractory as glycosyl donors in the presence of
a range of Lewis acids including TMSOTf, TfOH, SnCl4,
BF3·Et2O, or AgOTf. Katritzky has shown that tetrahydro-
pyranyl 1-benzotriazole reacts with Grignard reagents to afford
2-aryl-tetrahydropyrans.[32] However, 12 was inert to either
PhMgBr or diethylzinc. Having established the requirement for
electron-withdrawing groups to effect glycosidation with tri-
substituted glycosyl triazoles, we investigated the ability of the
‘armed’[33] benzylated tetrafluorobenzotriazole 19 to act as a
glycosyl donor (Scheme 2). Gratifyingly, this could be converted
to the S-glycoside 34 using thiocresol and SnCl4, albeit in low
yield (20%).
Experimental
General Methods
Petroleum spirits refers to a mixed fraction boiling at 40–60◦C.
TLC was performed with Merck silica gel 60 F254, using mix-
tures of petroleum spirits/ethyl acetate unless otherwise stated.
Detection was effected by either charring in a mixture of 5%
sulfuric acid/MeOH or by visualization in UV light. Melting
points were obtained on a Reichert–Jung hot-stage apparatus
and are corrected. NMR spectra were obtained on Varian Inova
400 or 500 instruments. Flash chromatography was performed
according to the method of Still et al. with Merck silica gel 60,
using adjusted mixtures of ethyl acetate/petroleum spirits unless
otherwise stated.[36] Dichloromethane and pyridine were dried
over CaH2. Solvents were evaporated under reduced pressure
using a rotary evaporator. High resolution mass spectrometry
(HRMS) was performed on a Finnigan hybrid LTQ-FT mass
spectrometer. Elemental analysis was performed by Chemical
and Microanalytical Services, Belmont, Victoria. [α]D values
are given in 10−1 degrees cm2 g−1. J values are given in Hz. The
two-dimensional HMQC spectrum was obtained on an Inova
400 with pulse sequence delays optimized for nJ(H,N) = 8 Hz;
pulse width (N) 44 ms, (H) 7.4 ms; relaxation delay (N) 2.5 s.
Nitromethane (0 ppm) was used as an external reference for the
15N spectrum.
Representative Procedure for the Preparation
of 1-Benzotriazoles
A solution of anthranilic acid (3 equiv.) in dioxane (10 mL
per mmol of azide) was added over 30 min to a refluxing solu-
tion of the azide (1 equiv.) and isoamyl nitrite (5 equiv.) in
1,2-dichloroethane (20 mL per mmol of azide) under N2. The
reaction mixture was heated for a further 1 h, then diluted
with CH2Cl2 and washed with water (2 × 50 mL) and brine
(1 × 50 mL).The solvent was removed under reduced pressure to
give a dark residue, which was purified by flash chromatography
to give the benzotriazole.
Conclusions
Carbohydrate 1-benzotriazoles can be readily accessed by
cycloaddition of benzynes (derived by diazotization of

842
J. A. Watt et al.
1-(2,3,4,5-Tetra-O-acetyl-β-D-glucosyl)-
1H-benzo[d][1,2,3]triazole 10
(1H, dd, J1,2 1.5, J2,3 3.0, H2), 6.83 (1H, d, J1,2 1.5, H1), 6.96–
8.23 (24H, m, Ar). δC (125.6 MHz; CDCl3) 62.06, 65.78, 70.62,
71.60, 75.76 (5C, C2,3,4,5,6), 86.62 (1C, C1), 112.46–146.09
(30C, Ar), 164.54, 165.35, 165.93 (4C, C=O).
According to the representative procedure, the azide 1[25]
(165 mg, 0.5 mmol) gave, after flash chromatography (30–40%
EtOAc/pet. spirits), the benzotriazole 10 as a yellow oil (152 mg,
77%). A portion was recrystallized to give pale brown needles,
mp 133–135.5◦C (from EtOH; lit.[11,37] 118–119◦C). [α]2D4 −61
(c ∼0.8 in CHCl3; lit.[37] [α]D −61.7, lit.[11] [α]D −61). δH
(500 MHz; CDCl3) 1.77, 2.04, 2.09, 2.11 (4 × 3H, 4s, Me), 4.10
(1H, ddd, J4,5 10.0, J5,6 2.0, J5,6 5.0, H5), 4.22 (1H, dd, J5,6 2.5,
J6,6 13.0, H6), 4.33 (1H, dd, J5,6 5.0, J6,6 13.0, H6), 5.38 (1H,
dd, J3,4 9.5, J4,5 10.0, H4), 5.52 (1H, dd, J2,3 9.5, J3,4 9.5, H3),
5.78 (1H, dd, J1,2 9.5, J2,3 9.5, H2), 6.21 (1H, d, J1,2 9.5, H1),
7.43 (1H, dd, J 8.0, 7.5, Ar), 7.57 (1H, dd, J 7.5, 8.0, Ar), 7.73
(1H, d, J 8.0,Ar), 8.08 (1H, d, J 8.5,Ar). δC (125.6 MHz; CDCl3)
20.08, 20.57, 20.60, 20.70 (4C, Me), 61.64, 67.78, 69.22, 72.68,
75.01 (5C, C2,3,4,5,6), 86.03 (1C, C1), 10.65, 120.32, 124.79,
128.38, 131.70, 146.53 (6C,Ar), 168.62, 169.45, 170.05, 170.51
(4C, C=O).
1-(2,3,4,5-Tetra-O-benzoyl-α-D-mannosyl)-
1H-benzo[d][1,2,3]triazole 14
According to the representative procedure, the azide 5[27]
(311 mg, 0.5 mmol) gave, after flash chromatography (30–50%
EtOAc/pet. spirits), the benzotriazole 14 as a dark yellow gum
(264 mg, 76%). A portion was recrystallized to give yellow nee-
dles, mp 159–162◦C (from EtOH). [α]D24 +7 (c ∼0.8 in CHCl3).
δH (400 MHz; CDCl3) 4.12 (1H, ddd, J4,5 10.0, J5,6 2.4, J5,6 4.8,
H5), 4.51 (1H, dd, J5,6 5.2, J6,6 12.4, H6), 4.57 (1H, dd, J5,6
2.8, J6,6 12.4, H6), 6.31 (1H, dd, J3,4 10.0, J4,5 10.0, H4), 6.61
(1H, s, H1), 6.72–6.76 (2H, m, H2,3), 7.25–8.18 (24H, m, Ar).
δC (100.5 MHz; CDCl3) 62.44, 66.92, 69.76, 70.27, 71.69 (5C,
C2,3,4,5,6), 83.27 (1C, C1), 110.33–146.17 (30C, Ar), 165.19,
165.43, 165.58, 165.98 (4C, C=O).
1-(2,3,4,5-Tetra-O-acetyl-β-D-galactosyl)-
1H-benzo[d][1,2,3]triazole 15
1-(2,3,4,5-Tetra-O-benzoyl-β-D-glucosyl)-
1H-benzo[d][1,2,3]triazole 11
According to the representative procedure, the azide 6[28]
(0.19 g, 0.50 mmol) gave, after flash chromatography (30–50%
EtOAc/pet. spirits), the benzotriazole 15 (0.16 g, 73%) as a
brown gum. [α]D22 −56.3 (c ∼1.00 in CHCl3; lit.[11] [α]D −53.2).
δH (400 MHz; CDCl3) 1.75, 1.98, 2.00, 2.27 (4 × 3H, s, Ac),
4.15–4.17, 4.21–4.26 (2H, 2m, J5,6 6.4, H6,6), 4.31 (1H, t, J5,6
6.4, H5), 5.33 (1H, dd, J1,2 3.2, J2,3 10.0, H2), 5.60 (1H, d, J1,2
3.2, H1), 5.85 (1H, t, J3,4 9.6, H3), 6.17 (1H, d, J3,4 9.6, H4),
7.38, 7.53 (2H, 2t, J 7.6, Ar), 7.66, 8.03 (2H, 2d, J 8.4, Ar).
δC (125.6 MHz; CDCl3) 20.37, 20.80, 20.91, 21.03 (4C, CH3),
61.63, 66.97, 67.33, 71.23, 73.95 (5C, C2,3,4,5,6), 86.90 (1C,
C1), 111.12, 120.56, 124.97, 128.50, 132.02, 146.77 (6C, Ar),
169.01, 170.19, 170.21, 170.66 (4C, C=O).
According to the representative procedure, the azide 2[26]
(311 mg, 0.5 mmol) gave, after flash chromatography (30–40%
EtOAc/pet. spirits), the benzotriazole 11 as a yellow gum
(280 mg, 80%). This was recrystallized to give an orange pow-
der, mp 98–100◦C (from EtOH). [α]D24 −74 (c ∼1.2 in CHCl3).
(Found: C 68.91, H 4.52, N 6.07. C40H31N3O9 requires C 68.86,
H 4.48, N 6.02%). δH (400 MHz; CDCl3) 4.51–4.55 (2H, m,
H6,6), 4.77 (1H, m, H5), 5.99 (1H, dd, J1,2 9.2, J2,3 9.2, H2),
6.19 (1H, dd, J3,4 9.6, J4,5 9.2, H4), 6.26 (1H, dd, J2,3 9.2, J3,4
9.6, H3), 6.59 (1H, d, J1,2 8.8, H1), 7.24–8.06 (24H, m, Ar).
δC (100.5 MHz; CDCl3) 62.40, 68.87, 69.93, 73.17, 75.51 (5C,
C2,3,4,5,6), 86.61 (1C, C1), 110.06–133.76 (30C, Ar), 164.46,
165.21, 165.68, 165.99 (4C, C=O).
1-(Methyl 2,3,4,-Tri-O-acetyl-6-deoxy-α-D-mannosid-6-yl)-
1H-benzo[d][1,2,3]triazole 16
1-(2,3,4,5-Tetra-O-benzyl-β-D-glucosyl)-
1H-benzo[d][1,2,3]triazole 12
According to the representative procedure, the azide 7[5]
(173 mg, 0.500 mmol) gave, after flash chromatography (25–
55% EtOAc/pet. spirits), the benzotriazole 16 (169 mg, 80%) as
a brown oil. [α]2D3 +41.2 (c ∼1.91 in CHCl3). (Found: C 54.2, H
5.65, N 10.0. C19H23N3O8 requires C 54.15, H 5.5, N 10.0%). δH
(400 MHz; CDCl3) 2.00, 2.12, 2.13 (3 × 3H, 3s, Ac), 2.85 (3H,
s, OCH3), 4.30–4.36 (1H, m, H5), 4.57 (1H, d, J1,2 1.6, H1),
4.75–4.85 (2H, m, H6,6), 5.20 (1H, dd, J2,3 3.6, J1,2 1.6, H2),
5.26 (1H, dd, J3,4 9.6, J4,5 9.6, H4), 5.35 (1H, dd, J3,4 9.6, J2,3 3.2,
H3), 7.38 (1H, dd, J 7.6, 7.6, Ar), 7.50 (1H, dd, J 7.6, 7.6, Ar),
7.67 (1H, d, J 8.4, Ar), 8.05 (1H, d, J 8.4, Ar). δC (100.5 MHz;
CDCl3) 20.56, 20.73 (×2), (3C, CH3), 49.21 (1C, C6), 54.86
(1C, OCH3), 67.66, 68.70, 69.35, 69.64 (4C, C2,3,4,5), 98.13
(1C, C1), 110.12, 119.76, 123.86, 127.33, 133.65, 145.77 (6C,
Ar), 169.68, 169.81, 170.11 (3C, C=O).
According to the representative procedure, the azide 3[25]
(196 mg, 0.347 mmol) gave, after flash chromatography (15%
EtOAc/pet. spirits), the benzotriazole 12 (137 mg, 62%) as a
brown gum. [α]D25 −15.1 (c ∼0.59, CHCl3; lit.[38] [α]D20 −22.8).
δH (400 MHz; CDCl3) 3.74–3.87, 3.93–3.96 (6H, 2m), 4.29–
4.35 (2H, m), 4.48 (1H, d, J 12.0, CH2Ph), 4.55 (1H, d, J
12.0, CH2Ph), 4.67 (1H, d, J 10.6), 4.91 (1H, d, J 10.6), 4.91–
4.98 (2H, m), 5.96 (1H, d, J1,2 9.2, H1), 6.73–8.09 (20H,
Ar). δC (100.5 MHz; CDCl3) 68.55, 73.65, 74.67, 75.51, 76.08
(5C, C2,3,4,5,6), 78.23, 79.64, 85.81, 87.45 (5C, PhCH2,C1),
110.91–146.57 (Ar).
1-(2,3,4,5-Tetra-O-benzoyl-β-D-mannosyl)-
1H-benzo[d][1,2,3]triazole 13
According to the representative procedure, the azide 4[27]
(311 mg, 0.5 mmol) gave, after flash chromatography (30–
50% EtOAc/pet. spirits) the benzotriazole 13 as a yellow gum
(224 mg, 64%).A portion was recrystallized to give an off-white
powder, mp 207–211◦C (from EtOH). [α]2D4 −104 (c ∼0.8 in
CHCl3). (Found: C 68.8, H 4.35, N 5.9. C40H31N3O9 requires
C 68.9, H 4.5, N 6.0%). δH (500 MHz; CDCl3) 4.56 (1H, ddd,
J4,5 10.0, J5,6 2.5, J5,6 3.5, H5), 4.62 (1H, dd, J5,6 4.0, J6,6 12.5,
H6), 4.99 (1H, dd, J5,6 2.5, J6,6 12.5, H6), 6.00 (1H, dd, J2,3
3.0, J3,4 10.0, H3), 6.38 (1H, dd, J3,4 10.0, J5,6 10.0, H4), 6.41
1-(Methyl 2-O-Benzyl-6-deoxy-3,4-O-isopropylidene-
β-D-galactosid-6-yl)-1H-benzo[d][1,2,3]triazole 17
(i) Methyl 6-Azido-2-O-benzyl-6-deoxy-3,4-O-
isopropylidene-β-D-galactopyranoside 8
A mixture of methyl 2-O-benzyl-6-deoxy-6-iodo-3,4-O-
isopropylidene-β-D-galactopyranoside[39] (0.76 g, 1.74 mmol)
and sodium azide (0.17 g, 2.57 mmol) in DMF (50 mL) was
stirred at 100◦C for 24 h. The reaction mixture was then

‘Click’ Preparation of Potential Glycosyl Donors
843
poured over ice (100 mL) and extracted with dichloromethane
(3 × 50 mL). The organic extract was washed with brine
(3 × 75 mL) and water (3 × 75 mL), then dried (MgSO4), fil-
tered and concentrated under reduced pressure to give a crude
brown gum.The gum was purified by flash chromatography (10–
40% EtOAc/pet. spirits) to give the azide 8 as a pale yellow gum
(309 mg, 51%) that crystallized on standing. Recrystallization
afforded a fluffy white solid, mp 81–83◦C (from EtOH/H2O).
[α]2D3 +17.9 (c ∼0.89 in CHCl3). (Found: C 58.5, H 6.7, N 12.0.
C17H23N3O5 requires C 58.4, H 6.6, N 12.0%). δH (500 MHz;
CDCl3) 1.33, 1.36 (2 × 3H, 2s, CMe2), 3.29–3.32 (1H, dd, J5,6
4.0, J6,6 13.0, H6), 3.40 (1H, t, J2,3 7.5, H2), 3.59 (3H, s, OMe),
3.72 (1H, dd, J5,6 4.0, J6,6 13.0, H6), 3.88–3.91 (1H, m, H5),
4.08 (1H, dd, J2,3 2.5, J3,4 6.0, H3), 4.20 (1H, t, J3,4 6.0, H4),
4.27 (1H, d, J1,2 8.0, H1), 4.78–4.85 (2H, app. q, CH2Ph), 7.28–
7.41 (5H, m, Ph). δC (125.6 MHz; CDCl3) 26.59, 27.91 (2C,
CMe2), 51.40 (1C, CH2Ph), 57.22 (1C, OMe), 72.92, 73.78,
74.08, 79.12, 79.52 (5C, C2,3,4,5,6), 104.10 (1C, C1), 110.53
(1C, CMe2), 127.87, 128.44, 128.51, 138.36 (Ph). νmax(thin
film)/cm−1 2097 (N3).
1-(2,3,4,5-Tetra-O-benzyl-β-D-glucosyl)-3,4,5,6-
tetrafluoro-1H-benzo[d][1,2,3]triazole 19
According to the representative procedure, the azide 3[25]
(283 mg, 0.50 mmol) and 2-amino-3,4,5,6-tetrafluorobenzoic
acid (314 mg, 1.5 mmol) gave, after flash chromatography
(5–20% EtOAc/pet. spirits), a yellow residue, which was
recrystallized to give the tetrafluorobenzotriazole 19 as a white
solid (150 mg, 42%), mp 113.5–116.5◦C (from EtOH). [α]2D7
−59 (c ∼1.18 in CHCl3). (Found: C 67.4, H 5.0, N 5.9.
C40H35F4N3O9 requires C 67.3, H 4.9, N 5.9%). δH (400 MHz;
CDCl3) 3.68–5.02 (14H, m, H1,2,3,4,5,6,6,OCH2Ph), 5.94 (1H,
d, J1,2 8.8, H1), 6.77–7.38 (20H, m,Ar). δC (100.5 MHz; CDCl3)
68.35, 73.36, 74.55, 75.29, 76.00 (5C, C2,3,4,5,6), 78.12, 78.26,
86.09, 87.61 (5C, C1,OCH2Ph), 127.55–128.58, 136.60, 137.73,
137.81, 137.97 (Ar). HRMS (electrospray ionization (ESI+),
m/z) calc. for C40H35F4N3O9Na [M + Na]+ 736.2407, found
736.2411.
1-(2,3,4,5-Tetra-O-acetyl-β-D-glucosyl)-5,6-dimethoxy-
1H-benzo[d][1,2,3]triazole 20
According to the representative procedure, the azide 1[25]
(165 mg, 0.500 mmol) and 4,5-dimethylanthranilic acid gave,
after flash chromatography (25–45% EtOAc/pet. spirits), the
benzotriazole 20 (169 mg, 66%) as a brown solid. A portion was
recrystallized to afford a pink powder, mp 139–141◦C (from
EtOH). [α]2D3 −82.1 (c ∼1.25 in CHCl3). (Found: C 51.8, H
5.3, N 8.3. C22H27N3O11 requires C 51.9, H 5.3, N 8.25%). δH
(500 MHz; CDCl3) 1.80, 2.05, 2.08, 2.11 (4 × 3H, 4s, Ac), 3.97,
4.05 (2 × 3H, 2s, OCH3), 4.07–4.12 (1H, m, H5), 4.19 (1H, dd,
J6,6 12.5, J5,6 2.0, H6), 4.39 (1H, dd, J6,6 12.5, J5,6 5.0, H6),
5.37 (1H, dd, J 10.0, 10.0, one of H2,3,4), 5.50 (1H, dd, J 9.5,
9.5, one of H2,3,4), 5.69 (1H, dd, J 9.5, 9.5, one of H2,3,4), 6.13
(1H, d, J1,2 9.0, H1), 7.00, 7.36 (2 × 1H, 2s,Ar). δC (100.5 MHz;
CDCl3) 20.09, 20.55, 20.58, 20.64 (4C, COCH3), 56.20, 56.40
(2C, OCH3), 61.65, 67.81, 69.09, 72.89, 75.10 (5C, C2,3,4,5,6),
86.12, 90.91, 99.13, 126.97, 140.98, 149.02, 152.00 (7C, C1,Ar),
168.68, 169.51, 169.96, 170.35 (4C, C=O).
(ii) 1-(Methyl 2-O-Benzyl-6-deoxy-3,4-O-
isopropylidene-β-D-galactosid-6-yl)-
1H-benzo[d][1,2,3]triazole 17
According to the representative procedure, the azide 8
(140 mg, 0.41 mmol) gave, after flash chromatography (20–
50% EtOAc/pet. spirits), the benzotriazole 17 as a brown
plates (120 mg, 71%), mp 155–156◦C. [α]D22 +16.1 (c ∼0.91 in
CHCl3). (Found: C 65.0, H 6.5, N 9.9. C19H23N3O8 requires C
64.9, H 6.4, N 9.9%). δH (500 MHz; CDCl3) 1.30, 1.44 (2 × 3H,
2s, CMe2), 3.19 (3H, s, OMe), 3.42 (1H, t, J1,2 7.5, H2), 4.06–
4.11 (2H, m, H1,3), 4.18 (1H, t, J3,4 6.0, H4), 4.24–4.27 (1H,
m, H5), 4.77 (2H, app. q, CH2Ph), 4.92 (1H, dd, J5,6 8.0, J6,6
14.5, H6), 5.10 (1H, dd, J5,6 4.5, J6,6 14.5, H6,6), 7.24–7.38
(6H, m, Ar), 7.49 (1H, t, J 7.0, Ar), 7.73, 8.04 (2H, 2d, J 8.5,
8.5, Ar). δC (125.6 MHz; CDCl3) 26.60, 28.02 (2C, CMe2),
48.89 (1C, CH2Ph), 56.95 (1C, OMe), 72.74, 73.74, 73.77,
79.10, 79.44 (5C, C2,3,4,5,6), 103.94 (1C, C1), 110.64, 110.85
(2C, CMe2,Bt), 119.90, 124.24, 127.53, 127.87, 128.36, 128.50,
134.14, 138.29, 145.97 (Ar).
1-(2,3,4,5-Tetra-O-acetyl-β-D-glucosyl)-1H-
naphtho[2,3-d][1,2,3]triazole 21
According to the representative procedure, the azide 1[25]
(165 mg, 0.500 mmol) and 3-amino-2-naphthoic acid gave,
after flash chromatography (25–55% EtOAc/pet. spirits), the
naphthotriazole 21 (106 mg, 42%) as a brown oil. [α]2D5 −92
(c ∼0.27 in CHCl3). (Found: C 57.6, H 5.1, N 8.5. C24H25N3O9
requires C 57.7, H 5.05, N 8.4%). δH (400 MHz; CDCl3) 1.76,
2.05, 2.11, 2.13 (4 × 3H, 4s, Ac), 4.13–4.18 (1H, m, H5), 4.25
(1H, dd, J6,6 12.8, J5,6 2.4, H6), 4.37 (1H, dd, J6,6 12.4, J5,6 4.8,
H6), 5.46 (1H, dd, J 10.0, 10.0, one of H2,3,4), 5.57 (1H, dd, J
10.4, 10.4, oneofH2,3,4), 5.92(1H, dd, J9.6, 9.6, oneofH2,3,4),
6.33 (1H, d, J1,2 9.6, H1), 7.48 (1H, dd, J 7.2, 7.2, Ar), 7.56 (1H,
dd, J 7.2, 7.2, Ar), 8.02 (1H, d, J 8.4, Ar), 8.06 (1H, d, J 8.4,
Ar), 8.14 (1H, s, Ar), 8.65 (1H, s, Ar). δC (100.5 MHz; CDCl3)
20.02, 20.52, 20.56, 20.66 (4C, CH3), 61.66, 67.84, 69.00, 73.01,
74.90 (5C, C2,3,4,5,6), 85.99 (1C, C1), 106.57, 118.59, 125.08,
127.13, 128.01, 129.35, 129.87, 130.89, 133.31, 145.55 (10C,
Ar), 168.57, 169.45, 170.01, 170.44 (4C, C=O).
1-(p-Nitrophenyl 3,4,6-Tri-O-acetyl-2-deoxy-β-D-glucosid-
2-yl)-1H-benzo[d][1,2,3]triazole 18
According to the representative procedure, the azide 9
(63.9 mg, 0.141 mmol) gave, after flash chromatography (20%
EtOAc/toluene), the benzotriazole 18 (46.3 mg, 62%). This was
recrystallized to give off-white needles, mp 240–241.5◦C (from
EtOH). [α]2D5 +55.6 (c ∼0.57 in CHCl3). (Found C 54.65, H
4.6, N 10.5. C24H24N4O10 requires C 54.55, H 4.6, N 10.6%).
δH (400 MHz; CDCl3) 1.66, 2.07, 2.14 (3 × 3H, 3s, Ac), 4.23
(1H, ddd, J5,6 1.9, J5,6 5.2, H5), 4.28 (1H, dd, J5,6 1.9, J6,6
12.4, H6), 4.46 (1H, dd, J5,6 5.2, J6,6 12.4, H6), 5.06 (1H, dd,
J 8.2, 10.6, one of H3,4), 5.38 (1H, t, J 9.4, one of H3,4),
6.01–6.06 (2H, m, H1,2), 6.85–8.11 (8H, Ar). δC (100.5 MHz;
CDCl3) 20.36, 20.81, 20.95 (3C, 3 × CH3), 61.48, 61.94, 68.63,
72.89, 98.89 (5C, C2,3,4,5,6), 109.12 (1C, C1), 117.18, 120.68,
124.79, 125.89, 128.46, 134.44, 143.73, 145.72, 160.79 (Ar),
169.03, 169.94, 170.63 (3C, C=O). νmax(thin film)/cm−1 1049,
1072, 1205 (C–O), 1226 (C–O), 1347 (NO2), 1520 (NO2), 1750
(C=O).
3,4-Bis-(methoxycarbonyl)-1-(2,3,4,6-tetra-O-acetyl-
β-D-glucosyl)-1H-1,2,3-triazole 23
A solution of the azide 1[25] (1.02 g, 2.73 mmol) and dimethyl
acetylene dicarboxylate (0.60 mL, 4.91 mmol) in toluene

844
J. A. Watt et al.
(30 mL) was heated at reflux overnight. The solvent was evap-
orated under reduced pressure and the residue was dissolved
in EtOAc (30 mL), washed with water (3 × 30 mL), and dried
(MgSO4). The solvent was evaporated under reduced pressure
and the crude residue was recrystallized to give the triazole 23
as light yellow cubic crystals (1.12 g, 80%), mp 148–151.5◦C
(from EtOH; lit.[40] 153◦C). [α]D25 −24.9 (c ∼0.8 in CHCl3). δH
(400 MHz; CDCl3) 1.90, 2.05, 2.07, 2.08 (4 × 3H, s, Ac), 3.97,
4.04(2 × 3H, 2s, OMe), 4.79(1H, ddd, J4,5 10.0, J5,6 2.0, J5,6 4.8,
H5), 4.14 (1H, dd, J5,6 2.0, J6,6 12.8, H6), 4.29 (1H, dd, J5,6 4.8,
J6,6 12.8, H6), 5.25 (1H, dd, J3,4 9.6, J4,5 10.0, H4), 5.42 (1H, dd,
J 9.2, 9.6), 5.94 (1H, dd, J 9.2, 9.6, H2,3) 6.13 (1H, d, J1,2 9.2,
H1). δC (100.5 MHz; CDCl3) 20.26, 20.53, 20.55, 20.65 (4C,
COCH3), 52.84, 53.68 (2C, OMe), 61.37, 67.36, 69.75, 72.87,
75.23 (5C, C2,3,4,5,6), 85.60 (C1), 130.85, 140.10 (2C, Ar),
158.51, 159.97 (2C, CO2Me), 168.53, 169.21, 170.14, 170.40
(4C, C=O).
39.11 (4C, C(CH3)3), 61.69, 67.61, 70.72, 72.15, 74.67
(5C, C2,3,4,5,6), 88.48 (C1), 176.50, 176.73, 177.31, 178.23
(4C, C=O).
3,4-Bis-(methoxycarbonyl)-1-(2,3,4,6-tetra-O-pivalyl-
β-D-glucosyl)-1H-1,2,3-triazole 25[18]
A solution of the azide 22 (506 mg, 0.93 mmol) and dimethyl
acetylene dicarboxylate (207 µL, 1.68 mmol) in refluxing
toluene (10 mL) was heated under reflux overnight. The solvent
was evaporated under reduced pressure and the residue was dis-
solved in EtOAc (40 mL) and washed with water (3 × 30 mL).
Theorganicphasewasdried(MgSO4)andthesolventevaporated
under reduced pressure. The crude crystalline residue was puri-
fied by flash chromatography (30% EtOAc/pet. spirits) to give
the triazole 25 as white needles (338 mg, 53%), mp 131–133◦C.
[α]2D5 −22.1 (c ∼0.7 in CHCl3). δH (400 MHz; CDCl3) 0.95,
1.13, 1.18 (48H, 3s, t-Bu), 3.97, 4.02 (2 × 3H, 2s, CO2CH3),
4.01 (1H, ddd, J4,5 10.0, J5,6 2.0, J5,6 5.2, H5), 4.12 (1H, dd,
J5,6 5.2, J6,6 12.8, H6), 4.18 (1H, dd, J5,6 2.0, J6,6 12.8, H6),
5.30 (1H, dd, J3,4 10.0, J4,5 9.8, H4), 5.52 (1H, dd, J2,3 9.6,
J3,4 9.6, H2), 6.03 (1H, dd, J2,3 9.2, J3,4 9.2, H3), 6.18 (1H, d,
J1,2 9.6, H1). δC (125.6 MHz; CDCl3) 26.71, 26.98, 27.10 (12C,
C(CH3)3), 38.56, 38.76, 38.80 (4C, C(CH3)3), 52.78, 53.62
(CO2CH3), 61.29, 66.97, 69.45, 72.42, 75.75 (5C, C2,3,4,5,6),
85.56 (C1), 130.60, 140.11 (2C, Ar), 158.37, 159.95 (CO2Me),
175.59, 176.19, 177.15, 177.86 (4C, C=O).
3,4-Bis-(methoxycarbonyl)-1-(2,3,4,6-tetra-O-benzoyl-
β-D-glucosyl)-1H-1,2,3-triazole 24
A solution of the azide 2[26] (2.01 g, 3.24 mmol) and dimethyl
acetylene dicarboxylate (0.71 mL, 5.83 mmol) in toluene
(50 mL) was heated at reflux overnight. The solvent was evap-
orated under reduced pressure and the residue dissolved in
EtOAc (60 mL) and washed with water (3 × 50 mL) and dried
(MgSO4). The solvent was evaporated under reduced pres-
sure and the residue was purified by flash chromatography
(30–40% EtOAc/pet. spirits) to give the triazole 24 as a yel-
low foam (2.32 g, 94%). A portion was crystallized from
EtOH to give a white solid, mp 97–101◦C. [α]D25 +5.5 (c
∼0.8 in CHCl3). (Found: C 63.0, H 4.4, N 5.6. C40H33N3O13
requires C 62.9, H 4.4, N 5.5%). δH (500 MHz; CDCl3) 3.88,
3.92 (2 × 3H, 2s, Me), 4.47–4.53 (2H, m, H5,6), 4.64–4.68
(1H, m, H6), 5.89, 6.14, 6.51–6.56 (4H, 3m, H1,2,3,4), 7.26–
8.07 (20H, m, Ph). δC (125.6 MHz; CDCl3) 52.72, 53.57
(2C, Me), 62.44, 68.53, 70.35, 73.10, 75.63 (5C, C2,3,4,5,6),
86.08 (C1), 128.23–140.15 (Ar), 158.62, 159.93 (2C, CO2Me),
164.30, 164.98, 165.69, 165.97 (4C, C=O). HRMS (ESI+,
m/z) calc. for C40H33N3O13Na [M + Na]+ 786.1906, found
786.1907.
1-(2,3,4,6-Tetra-O-benzoyl-β-D-glucosyl)-4-phenyl-
1H-1,2,3-triazole 26
Sodium ascorbate (60.0 mg, 0.302 mmol) was added to a mix-
ture of the azide 2[26] (2.18 g, 3.52 mmol), phenylacetylene
(0.598 mL, 5.44 mmol), CuSO4 (9.6 mg, 0.06 mmol) and TBTA
(32.0 mg, 0.06 mmol) in t-BuOH/water (2:1, 22.5 mL). After
4 days, TLC showed consumption of starting material. The reac-
tion was extracted with CHCl3 and the organic phase washed
with H2O (3 × 100 mL). The solvent was evaporated under
reduced pressure and the resulting residue was purified by pas-
sage through a plug of silica (95% CHCl3/MeOH) to give the
triazole 26 as a yellow flaky solid (2.41 g, 95%). [α]2D1 −21.8
(c ∼0.8 in CHCl3). δH (400 MHz; CDCl3) 4.51–4.72 (3H, m,
H5,6,6), 5.93 (1H, dd, J3,4 9.6, J4,5 10.0, H4), 6.08 (1H, dd, J1,2
9.2, J2,3 9.6, H2), 6.17 (1H, dd, J2,3 9.6, J3,4 9.6, H3), 6.35 (1H,
d, J1,2 9.2, H1), 7.24–8.03 (30H, m, Ph), 8.17 (1H, s, triazole).
δC (100.5 MHz; CDCl3) 62.89, 69.11, 71.12, 73.25, 75.23 (5C,
C2,3,4,5,6), 86.34 (C1), 118.09–133.85, 148.64 (Ph), 165.01,
165.34, 165.76, 166.22 (4C, C=O).
2,3,4,6-Tetra-O-pivalyl-β-D-glucosyl Azide 22[18]
The azide 1[25] (485 mg, 1.3 mmol) was stirred with a small piece
of sodium metal in MeOH until TLC indicated conversion to a
less polar product. Cation exchange resin (Amberlyst IR-120,
H+ form) was used to neutralize the solution and the solvent was
evaporated under reduced pressure. Pivalyl chloride (1.57 mL,
10.4 mmol) and 4-dimethylaminopyridine (DMAP) (0.195 mg,
1.3 mmol) were added to a solution of the crude tetraol (267 mg,
1.3 mmol) in pyridine (10 mL) and the mixture was stirred at
room temperature for 20 h. A further 4 equiv. of pivalyl chlo-
ride were added (0.78 mL, 5.2 mmol) and the temperature was
raised to 50◦C and the reaction stirred for a further 24 h. The sol-
vent was co-evaporated with toluene and the remaining residue
was crystallized to give the azide 22 (707 mg, 83%), mp 103–
109◦C (from EtOH/water). [α]D24 −9.9 (c ∼0.6 in CHCl3). δH
(500 MHz; CDCl3) 1.10–130 (36H, m, t-Bu), 3.82 (1H, ddd, J4,5
10.0, J5,6 2.0, J5,6 5.0, H5), 4.10 (1H, dd, J5,6 5.0, J6,6 12.0, H6),
4.24 (1H, dd, J5,6 2.0, J6,6 12.0, H6), 4.63 (1H, d, J1,2 8.6, H1),
4.99 (1H, dd, J1,2 9.0, J2,3 9.5, H2), 5.16 (1H, dd, J3,4 10.0, J4,5
10.0, H4), 5.33 (1H, dd, J2,3 9.5, J3,4 9.5, H3). δC (125.6 MHz;
CDCl3) 27.22, 27.28, 27.33 (12C, CH3), 38.94, 38.97, 39.00,
1-(2,3,4,6-Tetra-O-benzoyl-β-D-mannosyl)-4-phenyl-
1H-1,2,3-triazole 27
Sodium ascorbate (62.0 mg, 0.313 mmol) was added to a mixture
of the azide 4[25] (194 mg, 0.31 mmol), phenylacetylene (62 µL,
0.56 mmol), CuSO4 (1.0 mg, 0.006 mmol) and TBTA (3.3 mg,
0.006 mmol) in DMSO (9:1, 5 mL). After 24 h, water was added
to the reaction mixture and the precipitate was collected to give
the triazole 27 as a pale blue solid (148 mg, 65%). A portion was
recrystallized from EtOH to give white crystals, mp 219–221◦C
(from EtOH and water). [α]2D1 −103.2 (c ∼0.750 in CHCl3).
δH (500 MHz; CDCl3) 4.54 (1H, ddd, J4,5 10.5, J5,6 2.5, J5,6
4.5, H5), 4.61 (1H, dd, J5,6 4.5, J6,6 12.5, H6), 4.91 (1H, dd,
J5,6 2.5, J6,6 12.5, H6), 5.92 (1H, dd, J2,3 3.0, J3,4 10.0, H3),
6.25 (1H, dd, J3,4 10.0, J4,5 10.5, H4), 6.30 (1H, dd, J1,2 1.0,
J2,3 3.0, H2), 6.66 (1H, d, J1,2 1.0, H1), 7.26–8.18 (31H, m,

‘Click’ Preparation of Potential Glycosyl Donors
845
Ar). δC (125.6 MHz; CDCl3) 62.68, 66.03, 70.13, 71.93, 76.06
(5C, C2,3,4,5,6), 85.82 (C1), 118.00–148.17 (32C, Ar), 164.51,
165.51, 165.58, 166.29 (4C, C=O). HRMS (ESI+, m/z) calc. for
C42H33N3O9Na [M + Na]+ 746.2109, found 746.2118.
in CHCl3). δH (400 MHz; CDCl3) 0.80–1.56 (15H, m, hep-
tyl), 3.54, 3.92 (2H, 2 × ddd, OCH2), 4.17 (1H, ddd, J4,5 9.6,
J5,6 3.2, J5,6 4.8, H5), 4.52 (1H, dd, J5,6 5.2, J6,6 12.0, H6),
4.64 (1H, dd, J5,6 3.2, J6,6 12.0, H6), 4.85 (1H, d, J1,2 7.6,
H1), 5.54 (1H, dd, J1,2 8.0, J2,3 9.6, H2), 5.69 (1H, dd, J2,3
9.6, J3,4 10.0, H3), 5.92 (1H, dd, J3,4 10.0, J4,5 9.6, H4),
7.24–8.03 (20H, m, Ar). δC (100.5 MHz; CDCl3) 14.24, 22.77,
25.94, 29.28, 29.36, 29.56, 21.88 (7C, OCH2(CH3)6CH3), 63.42
(OCH2(CH3)6CH3), 70.05, 70.55, 72.09, 72.61, 73.12 (5C,
C2,3,4,5,6), 101.48 (C1), 128.45–133.58 (24C, Ar), 165.26,
165.38, 166.02, 166.34 (4C, C=O).
1-(2,3,4,6-Tetra-O-benzoyl-β-D-glucosyl)-
4-methoxycarbonyl-1H-1,2,3-triazole 28
Sodium ascorbate (9.7 mg, 0.049 mmol) was added to a stirred
suspension of the azide 2[26] (305 mg, 0.49 mmol), methyl
propiolate (61.5 µL, 0.74 mmol), CuSO4 (0.0098 mmol), and
TBTA (5.2 mg, 9.8 µmol) in a mixture of t-BuOH/water (4:1,
10 mL).Additionalsodiumascorbate(0.2 equiv.)wasaddedafter
24 and 48 h and stirring was continued for a total of 72 h. Water
was added, resulting in the formation of a precipitate. The solid
was collected and recrystallized, to give the triazole 28 as a yel-
low solid (300 mg, 87%), mp 201–203.5◦C (from EtOAc/pet.
spirits). [α]2D1 −33.3 (c ∼0.95 in CHCl3). (Found: C 64.35, H
4.6, N 6.1. C38H31N3O11 requires C 64.7, H 4.4, N 5.95%). δH
(400 MHz; CDCl3) 3.91 (3H, s, Me), 4.45–4.68 (3H, m, H5,6,6),
5.85 (1H, dd, J3,4 9.6, J4,5 9.6, H4), 5.91 (1H, dd, J2,3 10.0,
J3,4 9.4, H3), 6.11 (1H, dd, J1,2 9.6, J2,3 10.0, H2), 6.29 (1H,
d, J1,2 9.6, H1), 7.24–8.00 (20H, m, Ar), 8.47 (s, 1H, triazole
CH). δC (100.5 MHz; CDCl3) 52.52 (1C, CH3), 62.69, 68.85,
71.33, 72.87, 76.03 (5C, C2,3,4,5,6), 86.54 (C1), 127.86, 129.42
(2C,Ar), 128.61–134.04 (24C,Ar), 160.77 (MeOC=O), 164.94,
165.27, 165.72, 166.20 (4C, PhC=O). HRMS (ESI+, m/z) calc.
for C38H31N3O11Na [M + Na]+ 728.1849, found 728.1884.
4-Methylphenyl 2,3,4,6-Tetra-O-acetyl-
1-thio-β-D-glucoside 31
SnCl4 (117 µL, 2.0 mmol) was added to a stirred solution of
the trisubstituted triazole 23 (258 mg, 0.50 mmol) and thiocresol
(93 mg, 0.75 mmol) in dry CH2Cl2 (5 mL) at room temperature.
After 75 min, the reaction mixture was extracted with CH2Cl2
and the organic phase was washed with 1 M HCl (3 × 30 mL)
and H2O (2 × 30 mL).The organic layer was dried (MgSO4) and
the solvent was evaporated under reduced pressure. The crude
yellow residue was purified by flash chromatography (30–40%
EtOAc/pet. spirits) to give the thioglycoside 31 as a yellow oil
(165 mg, 77%; 1:5 α:β). δH (500 MHz; CDCl3) 4.64 (1H, d, J1,2
10.0, H1β), 6.29 (1H, d, J1,2 4.5, H1α). δC (125.7 MHz; CDCl3)
85.78 (C1β), 90.05 (C1α).
2,3,4,6-Tetra-O-acetyl-α-D-glucosyl Chloride 32
SnCl4 (240 µL, 2.0 mmol) was added to a stirred suspension
of the trisubstituted triazole 23 (258 mg, 0.50 mmol), TMSCl
(255 µL, 2.0 mmol), and 4-Å molecular sieves in CH2Cl2 (5 mL)
withundernitrogenatroomtemperature.Themixturewasstirred
for 2 h and was diluted with CH2Cl2 and filtered through Celite.
The filtrate was washed with 1 M HCl (3 × 40 mL) and water
(2 × 40 mL), dried (MgSO4) and the solvent evaporated under
reduced pressure. The residue was purified by flash chromato-
graphy (35–40% EtOAc/pet. spirits) to give 32 as a pale yellow
crystalline residue (92.9 mg, 51%).A portion was recrystallizsed
from diethyl ether/pet. spirits to give white needles, mp 72–
75◦C (lit.[41] 72–73.5). [α]D27 166 (c ∼0.8 in CHCl3; lit.[42] [α]2D7
166). δH (400 MHz; CDCl3) 1.99–2.06 (4 × 3H, m, Ac), 4.08–
4.11 (1H, m, H6), 4.25–4.30 (2H, m, H5,6), 4.97 (1H, dd, J1,2
4.0, J2,3 10.0, H2), 5.09 (1H, dd, J3,4 9.6, J4,5 9.6, H4), 5.52
(1H, dd, J2,3 10.0, J3,4 9.6, H3), 6.25 (1H, d, J1,2 4.0, H1). δC
(100.5 MHz;CDCl3)20.56, 20.59, 20.63, 20.68(4C, Me), 61.13,
67.44, 69.44, 70.40, 70.75 (5C, C2,3,4,5,6), 169.35, 169.88,
170.53 (4C, C=O).
1-(2,3,4,6-Tetra-O-benzoyl-β-D-glucosyl)-
4-t-butyloxycarbonyl-1H-1,2,3-triazole 29
Sodium ascorbate (16.2 mg, 0.082 mmol) was added to a stirred
mixture of the azide 2[26] (506 mg, 0.815 mmol), t-butyl propio-
late (179 µL, 1.47 mmol), CuSO4 (2.6 mg, 0.016 mmol), and
TBTA (8.6 mg, 0.016 mmol) in t-BuOH/water (2:1, 12 mL) and
DMSO (1 mL). After 2 days, TLC showed consumption of the
starting material. Water (10 mL) was added, resulting in the
formation of a precipitate. The solid was collected and recrys-
tallized from EtOH to give the triazole 29 as white crystals
(368 mg, 60%). [α]1D9 −26.6 (c ∼0.7 in CHCl3). δH (400 MHz;
CDCl3) 1.57 (9H, s, t-butyl), 4.46–4.52 (2H, m, H5,6), 4.66
(1H, m, H6), 5.86 (1H, dd, J3,4 9.6, J4,5 9.6, H4), 5.94 (1H,
dd, J1,2 9.2, J2,3 9.6, H2), 6.11 (1H, dd, J2,3 9.6, J3,4 9.6, H3),
6.29 (1H, d, J1,2 9.2, H1), 7.26–8.00 (20H, m, Ar), 8.38 (1H,
s, triazole CH). δC (125.5 MHz; CDCl3) 28.42 (3C, C(Me)3),
62.79, 68.92, 71.32, 73.09, 76.01 (5C, C2,3,4,5,6), 82.90 (C1),
86.49 (C(Me)3), 125.90–134.04 (24C, Ar), 128.01, 129.48 (2C,
Ar), 164.92, 165.27, 165.72, 166.22 (4C, C=O). HRMS (ESI+,
m/z) calc. for C41H37N3O11Na [M + Na]+ 770.2317, found
770.2320.
2,3,4,6-Tetra-O-acetyl-α-D-glucosyl Azide 33
TMSN3 (66.4 µL, 0.50 mmol) and SnCl4 (73 µL, 0.50 mmol)
were added to a suspension of the trisubstituted triazole 23
(129 mg, 0.25 mmol) and 4-Å molecular sieves in dry 1,2-
dichloroethane (8 mL) and the mixture was stirred at 50◦C.After
2 h, additionalSnCl4 (1 equiv.)andTMSN3 (1 equiv.)wereadded
and the reaction stirred for another 2 h.At this point,TLC showed
consumption of the starting material and the reaction was fil-
tered. The filtrate was washed with 1 M HCl (3 × 40 mL) and
H2O (2 × 40 mL), dried (MgSO4) and the solvent evaporated
under reduced pressure. The crystalline residue was purified by
flash chromatography (30–45% EtOAc/pet. spirits) to give the
azide 33 as an off-white solid (35.3 mg, 38%), mp 52.5–55◦C.
Octyl 2,3,4,6-Tetra-O-benzoyl-β-D-glucoside 30
TMSOTf (97.5 µL, 0.54 mmol) was added to a stirred suspen-
sion of the trisubstituted triazole 24 (206 mg, 0.269 mmol),
1-octanol (51 µL, 0.32 mmol), and 4-Å molecular sieves in
dry 1,2-dichloroethane (10 mL) at room temperature. After
24 h, additional TMSOTf (97.5 µL, 0.539 mmol) was added and
the reaction stirred for a further 24 h. The mixture was fil-
tered through Celite and the filtrate was washed with water
(3 × 30 mL) and dried (MgSO4). The solvent was evaporated
under reduced pressure and the residue was purified by flash
chromatography (20–30% EtOAc/pet. spirits) to give the glyco-
side 30 as a yellow oil (95.7 mg, 50%). [α]2D0 15.7 (c ∼0.4
[α]D25 +2.9 (c ∼0.6 in CHCl3). H NMR and 13C NMR data
1
were consistent with the literature.[43]

846
J. A. Watt et al.
4-Methylphenyl 2,3,4,6-Tetra-O-benzyl-
1-thio-D-glucoside 34
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A solution of the tetrabenzylated tetrafluorobenzotriazole
19 (64.6 mg, 0.09 mmol), SnCl4 (21.7 µL, 0.18 mmol), and
thiocresol (16.8 mg, 0.14 mmol) in dry CH2Cl2 (5 mL) was
stirred under nitrogen at room temperature. After 4 h, further
SnCl4 (21.7 µL, 0.18 mmol) was added. At 6 h, the reaction
mixture was diluted with CH2Cl2 and washed with 1 M HCl
(3 × 20 mL) and H2O (2 × 20 mL). The organic layer was dried
(MgSO4) and the solvent was evaporated under reduced pres-
sure. The crude residue was purified by flash chromatography
(10–20% EtOAc/pet. spirits) to give the thioglycoside 34 as yel-
low residue (12.0 mg, 20%). δH (400 MHz; CDCl3) 4.88 (1H, d,
J1,2 10.8, H1β), 5.58 (1H, d, J1,2 4.4, H1α). The 1H NMR data
for the β-anomer are consistent with the literature.[44]
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Acknowledgements
The Australian Research Council is thanked for financial support. J.A.W.
and K.J.L. were partially supported by the University of Melbourne. High
resolution mass spectrometry (HRMS) was performed by Messrs Hadi Loie,
Chris Barlow, and Adrian Lam.
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