Functionalization of 2H-1,2,3-Triazole C-Nucleoside Template via N2 Selective Arylation

Article abstract of DOI:10.1021/acs.joc.6b00323

C-Nucleosides are an underexplored and important class of nucleosides with antiviral and anticancer activity. In addition, triazole heterocycles are well employed as a strategy to modify nucleobase in nucleoside analogues, although rare examples were described for triazoyl C-nucleosides. N²-Aryl-1,2,3-triazole C-nucleoside compounds that could be obtained by selective 1,2,3-triazole heterocycle N² arylation in 1-β-d-ribofuranosyl-2H-1,2,3-triazole substrate were designed in this study. The optimized condition used AdBrettPhos/[PdCl(allyl)]₂ as the catalyst system. This transformation was accomplished by aryl halides bearing an electron donor and withdrawing groups, as well as by heterocyclic halides in good to excellent yields. The transformation developed in this study represents a significant contribution to the nucleoside field, once it allows for the synthesis of unexplored scaffolds through selective functionalization of triazole nucleosides.

Full text of DOI:10.1021/acs.joc.6b00323

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Article
Functionalization of 2H-1,2,3-Triazole C-
Nucleoside Template via N2 Selective Arylation
Alexandra Basilio Lopes, Patrick Wagner, Rodrigo Octavio Mendonça Alves de Souza, Nadège Lubin
Germain, Jacques Uziel, Jean-Jacques Bourguignon, Martine Schmitt, and Leandro S. M. Miranda
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00323 • Publication Date (Web): 11 May 2016
Downloaded from http://pubs.acs.org on May 12, 2016
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Functionalization of 2Hꢀ1,2,3ꢀTriazole CꢀNucleoside Template via N2 Selective
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Arylation
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Alexandra Basilio Lopes1, Patrick Wagner2, Rodrigo Octavio Mendonça Alves
de Souza1, Nadège Lubin Germain3, Jacques Uziel3, JeanꢀJacques Bourguignon2,
Martine Schmitt2, Leandro S. M. Miranda1*
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1ꢀ Universidade Federal do Rio de Janeiro, Biocatalysis and Organic Syntheis Group; Av Athos
da Silveira Ramos 149, Centro de Tecnologia, Bl A, 21941909, Ilha do Fundão, Rio de Janeiro, Brazil.
2ꢀ Université de Strasbourg, Laboratoire d’Innovation Thérapeutique UMR7200, Faculté de
Pharmacie, , CNRS, 74 route du Rhin, BP60024, Illkirch, France.
3ꢀ Université de CergyꢀPontoise, UMR CNRS 8123, Laboratoire de chimie biologique EA 4505,
Fꢀ95000 CergyꢀPontoise Cedex, France.
leandrosoter@iq.ufrj.br
Keywords: 1,2,3ꢀTriazole , Arylation, Nucleosides
R2
N2 selective arylation
N NH
N
N
O
N
O
Pd-catalyzed C-N coupling
N
TBDPSO
TBDPSO
R1
R1
O
O
R1 = H, CO2Et, 4-OMePh
R2 = EWG-Ph, EDG-Ph, Het
O
O
55ꢀ98% yield
ABSTRACT: Cꢀnucleosides are an under explored and important class of nucleosides
with antiviral and anticancer activity. In addition, triazole heterocycles are well
employed as a strategy to modify nucleobase in nucleoside analogues, although rare
examples were described for triazoyl Cꢀnucleosides. N2ꢀarylꢀ1,2,3ꢀtriazole Cꢀnucleoside
compounds that could be obtained by selective 1,2,3ꢀtriazole heterocycle N2 arylation
in 1ꢀβꢀDꢀribofuranosylꢀ2Hꢀ1,2,3ꢀtriazole substrate were designed in this study. The
optimized condition used AdBrettPhos/[PdCl(allyl)]2 as the catalyst system. This
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transformation was accomplished by aryl halides bearing an electron donor and
withdrawing groups, as well as by heterocyclic halides in good to excellent yields. The
transformation developed in this study represents a significant contribution to the
nucleoside field, once it allows for the synthesis of unexplored scaffolds through
selective functionalization of triazole nucleosides.
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INTRODUCTION
Nucleosides are molecules ubiquitously present in living organisms, where they
play important roles, like their phosphorylated derivatives (i.e. nucleotides), by working
as secondary messengers and enzyme cofactors, besides acting in genetic information
storage, transcription and translation.1 Such nucleotideꢀmediated processes make this
compound class important lead for drug development.2 In fact, many nucleosides and
nucleosideꢀderived compounds are found in clinics to treat cancer and viruses.3 Among
derivatives developed in the early years of nucleoside chemistry, there was the
construction of triazoleꢀderived nucleosides, such as ribavirin, a designed guanosine
analogue bearing a 1,2,4ꢀtriazole.4,2c With the advent of the copperꢀcatalyzed [3+2]
cycloaddition between terminal acetylenes and azides, new interest in triazole
nucleoside chemistry and biology arose.4b Through this methodology, synthesis of 1,4
and 1,4,5 substituted 1,2,3ꢀtriazole nucleosides has been reported (Figure 1).5 Interest
for 1,2,3ꢀtriazole nucleosides was also observed in the Cꢀnucleoside class, which has a
nonꢀhydrolyzable anomeric bond and, consequently, is not susceptible to degradation by
phosphorylases.5,6,7 It was demonstrated that natural and synthetic Cꢀnucleosides could
have anticancer and antiviral properties.7 More recently, the discovery of two synthetic
antiviral Cꢀnucleosides, BCX4430 and GSꢀ6620, could indicate a renewed interest in
this nucleoside class.7 However, the use of such strategy in the 1,2,3ꢀtriazoyl nucleoside
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chemistry has been hampered by the lack of efficient methodology to introduce
acetylene into the anomeric position.8 Recently, two authors (Germain, L. N., and Uziel,
J.) developed a stereoselective indiumꢀmediated alkynylation reaction9 that enabled Cꢀ
triazole nucleosides synthesis.
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(R1 = cꢀpropyl, CO2Me, CF3; R2 = H)4a
(R1 = CONH2 R2 = Br)4c
RO
N
N
O
N
R1
(R1 = ꢀCH2ꢀUracyl, ꢀCH2ꢀAdenosyl, ꢀCH2ꢀTimidinyl; R2 = H)4d
(R1 = CONH2 R2 = ethynyl)4e
R2
RO
OR
R = Bz or H
(R1 = octyl, 4ꢀOCH3Ph, CO2Et; R2 = H)4f
R1
HO
N
N
O
HO
N
O
NH
N
(R1 = CO2Et, H)5
N
R2
HO
This Work
OH
R1
HO
OH
Figure 1: Different 1ꢀβꢀDꢀribofuranosylꢀ1,2,3ꢀtriazole scaffolds
Once synthetic nucleoside analogues development is in continuous and intense
research due to their potential biological activity, search for unreported scaffolds is
highly desirable. With this in mind, and with an appropriate methodology to reach Cꢀ
triazole nucleosides, it was decided in this study to explore scaffolds based on 1,2,3ꢀ
triazole aglycone N2 functionalization (Figure 1). Its introduction into the nucleosides
is unprecedented and would lead to potentially active nucleosides. Very few reports on
selective arylation of 1,2,3ꢀtriazole N2 position are reported.10 Liu and coꢀworkers
described copper catalysis use on this transformation with the use of 4,5ꢀdisubstituted
2Hꢀ1,2,3ꢀtriazoles, which lead to N2ꢀsubstituted 1,2,3ꢀtriazoles.10c More recently, a
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palladiumꢀcatalyzed 2Hꢀ1,2,3ꢀtriazole N2 regioselective arylation was reported by
Buchwald and coꢀworkers.6 However, in both cases, only model compounds were
described. Such lack of background on 2Hꢀ1,2,3ꢀtriazole N2 arylation, embedded in
polyfunctional compounds, makes the synthesis of desired nucleoside skeletons a
challenge. In this paper, achievements on 2Hꢀ1,2,3ꢀtriazole Cꢀnucleosides N2 arylation
reaction are reported.
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RESULTS AND DISCUSSION
1ꢀβꢀDꢀribofuranosylꢀ2Hꢀ1,2,3ꢀtriazole (1) was synthesized according to Scheme
1. For such, DꢀRibose (3) was protected as the corresponding isopropylidene acetal at
the 2,3 positions, followed by the acetylation of the remaining hydroxyls. Indium
mediated alkynylation with 1ꢀiodoꢀ2ꢀ(trimethylsilyl)acetylene9 furnished the desired βꢀ
ribosyl acetylene 5. Acetylene 7 was used in a copperꢀcatalyzed [3+2] cycloaddition
with azidotrimethylsilane, leading to the desired ribosyl triazole 1. For the envisaged
and selective N2 arylation of 1, the catalyst system reported by Buchwald (L1
(Me4tBuXPhos)/Pd2(dba)3)6 was used as starting point. When the reaction was carried
out with the 5’ position protected as an acetate, partial hydrolysis was observed in crude
reaction mixture NMR analysis. Then, the attention in this study was turned to the use
of a more resistant protecting group, such as TBDPS. With this group, the reaction of 1
with bromobenzene led to the isolation of a single product (2a) in 43% yield.
The assignment of this product as the desired N2 arylated nucleoside 2a was
done with the aid of NMR spectroscopy. For such, the 1,4ꢀ (8a) and 1,5ꢀ (8b)
regioisomers were synthesized separately and their NMR data were collected. Then,
data were compared with that of the 2a compound, obtained under Buchwald
conditions.
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Important differences could be observed concerning carbohydrate core chemical
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1
shifts and aromatic signals of the different regioisomers in H NMR spectra, especially
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in protons adjacent to the nitrogenꢀbonded carbon in the aromatic ring. While these
protons are at 7.55ꢀ7.58 and 7.61ꢀ7.63 ppm, respectively, for the 1,4ꢀ (8a) and 1,5ꢀ (8b)
regioisomers, these protons are located at 8.01ꢀ8.04 ppm (Figure 2), in the 2,4ꢀ
regioisomer.
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Scheme 1: 1ꢀβꢀDꢀRibofuranosylꢀ2Hꢀ1,2,3ꢀTriazole (1) Preparation and First Condition for
N2 Selective Arylation
Such deshielding has already been observed for N2ꢀbonded aryl groups protons in 1,2,3ꢀ
triazoles.6 Further evidence can be obtained through analysis of their NOESY spectra
(See supporting information). In the case of the 1,4ꢀ regioisomer, correlations can be
observed between triazole ring H5 and protons adjacent to the aryl ring nitrogenꢀbonded
carbon (Figure 2). Concerning the 2,4ꢀ and 1,5ꢀ regioisomers, the previously described
correlation is absent (Figure 2). However, for the 1,5ꢀ regioisomer, correlation between
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ribosyl ring H2' and H3' and protons adjacent to the aryl ring nitrogenꢀbonded carbon
4
5
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13
was observed (Figure 2). Additionally, regarding the regioisomers C NMR spectra,
triazole ring C5 carbon can be used to distinguish between 1,4ꢀ and 1,5ꢀ regioisomers.11
As previously reported in the literature, chemical shift of this carbon is observed in the
119ꢀ123 ppm range for the 1,4ꢀ regioisomer, while this carbon is observed in the 133ꢀ
136 ppm range in the case of 1,5ꢀ regioisomer. In fact, chemical shifts observed for C5
were 120.2 ppm, 132.7 ppm and 134.2 ppm for 1,4ꢀ, 1,5ꢀ and 2,4ꢀ regioisomers,
respectively.
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Figure 2: NOESY correlations and 1H NMR chemical shifts of H2/2'' of 1,4ꢀ, 2,4ꢀ, and 1,5 ꢀ
triazole Cꢀnucleoside regioisomers
With methodology to distinguish between the different regioisomers resulting
from 1 arylation, yield optimization of this reaction proceeded by analyzing the
influence of different reaction conditions. These results are summarized in Table 1.
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Table 1: Screening Reaction Conditions for N2 Selective Arylation of 1
4
5
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7
8
Ph
N
NH
N
N
N
O
O
Ligand, Catalyst
N
TBDPSO
TBDPSO
K3PO4 (2.0 equiv), PhBr (1.2 equiv)
Solvent, 120 °C, Reaction Time
9
O
O
O
O
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(1)
(2a)
Liganda
Catalysta
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Solvent Time (h) Yield (%) c,d
Entry
Me4tBuXPhos
tBuXPhos
toluene
toluene
toluene
toluene
toluene
3
3
43
n.r
1
2
tBuBrettPhos
AdBrettPhos
AdBrettPhos
3
traces
73
3
3
4
5
71(66)c
14
5
AdBrettPhos [PdCl(cinnamyl)]2 toluene
5
6
AdBrettPhos
AdBrettPhos
AdBrettPhos
AdBrettPhosb
[PdCl(allyl)]2
[PdCl(allyl)]2
[PdCl(allyl)]2
toluene
dioxane
MeTHF
toluene
5
89(81)c
83(86)c
89 (87)c
84(82)c
7
5
8
5
9
b
[PdCl(allyl)]2
10
10
a: 5.0 mol% ligand and 2.5 mol% catalyst; b: 3.0 mol% ligand and 1.5 mol% catalyst; c: yields refer
to isolated, chromatographically purified materials; d: yields were determined by H NMR experiments,
using diiodomethane as an internal standard; n.r.: no reaction
1
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2
Me
Me
Me
OMe
OMe
3
4
5
Me
PtBu2
iPr
PtBu2
iPr
MeO
PtBu2
iPr
MeO
PAd2
iPr
iPr
iPr
iPr
iPr
6
7
8
9
iPr
iPr
L2 (tBuXPhos)
iPr
L3 (tBuBrettPhos)
iPr
L1 (Me4tBuXPhos)
L4 (AdBrettPhos)
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O
Cl
Cl
Pd
Pd
Pd
Pd
Pd2
Cl
Cl
3
[PdCl(cinnamyl)]2
[PdCl(allyl)]2
Pd2(dba)3
As depicted in Table 1, the catalyst system previously reported in the literature
(L1/Pd2(dba)3) only provided moderated yield. Other L2ꢀL4 biaryl phosphine ligands
were examined with Pd2(dba)3, in which only L4 increased yield, up to 73% (Entry 4,
Table 1).12 Substitution of palladium catalyst from Pd2(dba)3 to [PdCl(allyl)]2 associated
with L4 gave a further yield increase, up to 89% (Entry 7, Table 1). However,
combination between L4 and [PdCl(cinnamyl)]2 did not lead to good results (Entry 6,
Table 1). Concerning the solvent, only a small yield impact was observed by changing
toluene for dioxane or MeTHF (Table 1, Entries 8 and 9, respectively). The best yields
observed using a more steric demanding ligand, such as AdBrettPhos under reaction
conditions, can be used, as previously proposed,12ꢀ13 in a more favorable reductive
elimination with these complexes.
The optimized conditions developed in Table 1 were subsequently evaluated
according to the aromatic halide structure. As depicted in Table 2, the reaction
conditions developed are effective for aryl and heteroaryl groups crossꢀcoupling, except
for ortho substituted electrophiles and 2ꢀbromopyridine. Only one product was observed
by HPLC analyses in the crude reaction mixture. After isolation and characterization by
NMR, all new products corresponded to N2ꢀarylated products. Both electron donor and
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electron withdrawing groups are well tolerated. Electron poor heteroarenes, such as
pyridine and pyrimidine, gave excellent yields. Some failure reactions were supposed to
be caused by halide reduction. These assumptions were made by crude reaction mixture
HPLC analyses at the end of each reaction. Regarding the entries 4, 8 and 14, it was
observed that the 2Hꢀ1,2,3ꢀtriazole substrate remained in the reaction mixture, but aryl
halides have disappeared. It suggests that oxidative addition occurred, but the aryl
halide was reduced, that is, reductive elimination was inefficient or the catalyst was
decomposed.14 On the other hand, the aryl halide was found at the end of the reaction
with 2Hꢀ1,2,3ꢀtriazole substrate for entry 11, and only 8% of conversion was obtained.
Low reaction rate is a possibility for low conversion.
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Table 2: Scope of N2 Selective Arylation of 1
Ar
N NH
N
N
AdBrettPhos (3.0 mol%)
[PdCl(allyl)]2 (1.5 mol%)
O
N
O
N
TBDPSO
TBDPSO
K3PO4 (2.0 equiv),
ArX (1.2 equiv).
Toluene, 120oC, 10h
O
O
O
O
(1)
(2aꢀo)
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Yield (%)a, b
82
1
2
3
4
Ar
X
Product
2a
Entry
1
Br,
5
6
7
8
9
OTf
Br
2a
2b
55
70
2
3
10
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Br
Br
I
2c
2d
2d
n.r
55
85
4
5
6
I
I
2e
2f
71
n.r
7
8
Br
Br
Br
2g
2h
2i
89
85
9
10
11
n.dc
Br
Br
2j
98
98
12
13
2k
Br
Br
2l
n.r
83
14
15d
2m
Br
2n
76
16
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Br
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Reaction conditions: [PdCl(allyl)]2 (1.5 mol%), AdBrettPhos (3.0 mol%), K3PO4 (2.0 equiv), ArBr (1.2
equiv), toluene, 120°C, 10h (Method A); Pd2(dba)3 (1.5 mol%), AdBrettPhos (3.0 mol%), K3PO4 (2.0
equiv.), ArBr (1.2 equiv.), toluene, 120°C, 10h (Method B). a: yields refer to isolated,
chromatographically purified materials; b: Unpublished products were fully characterized by NMR and
HRMS data; c: 8% conversion was observed in the HPLC, however no product was isolated; d: Method
B; n.r: no reaction, n.d: not determined
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In entries 5 and 6, it was verified that the employed reaction condition gave
better conversion with 4ꢀiodoꢀanisole than with 4ꢀbromoꢀanisole. This result seems
surprising, but it was supposed that it could be associated with AdBrettPhos use in
toluene. Aryl iodides do not afford good yields like aryl bromides and aryl chlorides in
CꢀN cross coupling reaction. There are two factors that contribute for aryl iodide
inefficiency, as follows: formation of unreactive Pd dimers bridged by iodide anions
and iodide salts inhibitory effect.15,16 Use of some biaryl phosphine ligands, like
BrettPhos (for primary amines) and RuPhos (for secondary amines) in aryl and
heteroaryl iodides amination, in nonꢀpolar solvents, such as toluene, gave yields similar
to those obtained with aryl bromides. Both ligands produce monomeric oxidative
addition complexes in solution, allowing for aryl iodides amination to be accomplished.
Nonꢀpolar solvent success is explained by iodide salts poor solubility.
In order to evaluate the possibility of N2ꢀselective arylation being performed by
a SNAr mechanism, some reactions were run with electronꢀpoor substrates, such as 4ꢀ
bromopyridine and 4ꢀbromobenzonitrile, in the absence of palladium. No reaction was
observed.
In order to further expand the structural diversity of this new nucleosides library,
4,5ꢀdisubstitutedꢀ2Hꢀ1,2,3ꢀtriazole systems Nꢀarylation was also evaluated. The
carboxylic ester derivative 12 was prepared from de ribofuranosyl intermediate 4 via an
alkynylation step with ethyl 3ꢀiodopropiolate mediated by indium. The ribofuranosyl
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propiolate derivative (9) obtained was then submitted to cycloaddition reaction with
azidotrimethylsilane, obtaining ribosylꢀ2Hꢀ1,2,3ꢀtriazole 10. A twoꢀreaction sequence,
Cꢀ5' ribosyl ring hydroxyl group deprotection and protection, provided the desired
carboxylic ester 12 (Scheme 2).
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Scheme 2. Synthesis of Ethyl 5ꢀ(1ꢀβꢀDꢀRibofuranosyl)ꢀ2Hꢀ1,2,3ꢀTriazoleꢀ4ꢀCarboxylate
(12)
O
AcO
1.
O
I
AcO
N
NH
N
AcO
O
TMSN3
OEt
OAc
O
O
OEt
In(0), DCE, 90 ºC, 5h
DMF/EtOH (9:1)
100 °C, 30 min (MW)
53%
O
O
2. TsOH.H2O, acetone
25 °C, 6h, NaHCO3
54%
O
OEt
O
O
O
O
(4)
(10)
(9)
HO
TBDPSO
N
NH
N
N
NH
N
O
O
K2CO3, EtOH
TBDPSCl
imidazole, DMAP,
CH3CN, 25 °C, 1.5 h,
52%
40 °C, 18h
96%
O
O
O
OEt
OEt
O
O
O
(11)
(12)
Preparation of 5ꢀArylꢀ2Hꢀ1,2,3ꢀtriazole 14 was performed via a SuzukiꢀMiyaura
crossꢀcoupling (SMCC) reaction from the readily available brome derivative 13
(Scheme 3). The key to the success of this SMCC reaction was the use of CataCxium
(Ad2nꢀBuP) ligand in combination with Pd(OAc)2. This catalyst system was previously
reported by Tan et al for unprotected haloimidazoles SMCC.17 Nꢀarylation reactions
results are given in Table 3.
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Scheme 3. Synthesis of 4ꢀ(1ꢀβꢀDꢀRibofuranosyl)ꢀ5ꢀ(4ꢀMethoxyphenyl)ꢀ2Hꢀ1,2,3ꢀTriazole
(14)
5
6
7
8
N
NH
N
N
NH
N
O
O
TBDPSO
NBS (1.0 equiv), AcOiPr
TBDPSO
Br
9
25 °C, 45h, 76%
O
O
O
O
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(1)
(13)
NH
N
O
N
4ꢀOMeꢀPhB(OH)2 (1.25 equiv)
TBDPSO
Pd(AcO)2 (6.0 mol%), Ad2nꢀBuP (2.5 mol%),
K3PO4 (3.0 equiv), dioxane/H2O (2:1),
120 °C, 15h, 65%
O
O
OMe
(14)
With ([PdCl(allyl)2], AdBrettPhos, K3PO4) optimal conditions, the 4,5ꢀ
disubstitutedꢀ2Hꢀ1,2,3ꢀtriazole derivatives 12 and 14 can be coupled efficiently to
phenyl and 4ꢀpyridyl bromides, furnishing the desired products in good to excellent
yields.
Table 3: 4,5ꢀDisubstitutedꢀ2Hꢀ1,2,3ꢀTriazole Substrate N2 Selective Arylation
Ar
N NH
N
N
O
N
O
N
TBDPSO
TBDPSO
AdBrettPhos, [PdCl(allyl)]2
R
R
O
O
O
K3PO4 (2.0 equiv),
ArBr (1.2 equiv),
Toluene, 120oC
O
(12, 14)
(15aꢀd)
Ar
Rc
Product
15a
Yield (%)d, e
73
Entry
1a
CO2Et
2a
3b
CO2Et
15b
15c
84
93
4ꢀOMePh
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4b
4ꢀOMePh
15d
88
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9
Reaction conditions: a: [PdCl(allyl)]2 (3.0 mol%), AdBrettPhos (6.0 mol%), K3PO4 (2.0 equiv.), ArBr
(1.2 equiv.), toluene, 120°C, 10 h. b: [PdCl(allyl)]2 (1.5 mol%), AdBrettPhos (3.0 mol%), K3PO4 (2.0
equiv.), ArBr (1.2 equiv.), toluene, 120°C, 23 h. c: R = CO2Et (12), R = 4ꢀOMePh (14); d: yields refer to
isolated, chromatographically purified materials; e: Unpublished products were fully characterized by
NMR and HRMS data.
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In this effort to obtain a fully deprotected 2ꢀarylꢀ1,2,3ꢀtriazoylꢀCꢀnucleoside,
compound 2a deprotection was investigated as an illustrative example. As expected, 2a
deprotection was efficiently performed in a twoꢀstep reaction using TBAF/CsF and
TFA, respectively, providing 17 in quantitative yield (Scheme 4).
Scheme 4. Full Deprotection of 2ꢀArylꢀ1,2,3ꢀTriazoylꢀCꢀNucleoside Derivative 2a
Ph
Ph
Ph
N
N
N
N
N N
O
O
O
N
N
N
TBAF, CsF
TFA, DCM
TBDPSO
HO
HO
THF, 50 °C, 4h,
96%
H2O, 25 °C, 24 h,
100%
O
O
O
O
HO
OH
(17)
(2a)
(16)
In conclusion, new nucleoside scaffold N2ꢀArylꢀ1,2,3ꢀtriazoyl ribonucleosides
were synthesized through development of a catalyst system based on the AdBrettPhos
biaryl phosphine ligand and the [PdCl(allyl)]2 catalyst. Monoꢀ and disubstituted 1,2,3ꢀ
triazoylribofuranoside N2 selective arylation could be carried out with aryl halides
bearing electron donor and withdrawing groups, as well as with heterocyclic halides, in
good to excellent yields.
EXPERIMENTAL SECTION
General information. Chemicals and solvents were purchased from commercial
sources and used without further purification. Thin layer chromatography was
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performed on silica gel plates; spots were detected under UVꢀlight or by
spraying with 5% H2SO4 solution in ethanol. Flash chromatography was
performed with silica gel 60, 40ꢀ63 ꢁm. 1H and 13C NMR spectra were recorded
on 300, 400, and 500 MHz apparatuses. Microwave irradiation was performed in a
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Biotage Initiator EXP. HPLC analyses were performed using a C18 3.5µm, 4.6*50mm
column. High resolution mass spectra were obtained using a TOFꢀMS with ESI source.
1,5ꢀdiꢀOꢀacetylꢀ2,3ꢀOꢀIsopropylideneꢀDꢀribofuranose (4)18. To a suspension of Dꢀ
ribose (5.0 g, 33.30 mmol) in dry acetone (40 mL) were added 2,2ꢀdimethoxypropane
(20 mL, 17.3 g, 166.52 mmol) and pꢀtoluenesulfonic acid monohydrate (127 mg, 2
mol%). After being stirred at room temperature for 30 min, the clear resulting mixture
was neutralized with NaHCO3, filtered through celite and concentrated under reduced
pressure. The residue was purified by flash column chromatography on silica gel
(cyclohexane/AcOEt 9:1 to 7:3) to afford de desired acetal as a colorless oil (3200 mg,
1
51%). (α:β = 1.6:10) H (500MHz, CDCl3): δ ppm 1.30 (s, 3H), 1.46 (s, 3H), 3.68ꢀ3.72
(m, 2H), 4.01 (br s, 1H), 4.37 (s, 1H), 4.55 (d, J = 5.9 Hz, 1H), 4.80 (d, J = 5.9 Hz, 1H),
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5.31 (d, J = 6.2 Hz, 1H), 5.38 (d, J = 6.3 Hz, 1H). C (125MHz, CDCl3): δ ppm 24.8,
26.4, 63.6, 81.8, 86.9, 87.8, 102.9, 112.3. A suspension of the previously prepared
acetal (2,3ꢀisopropylideneꢀDꢀribofuranose (3.2 g, 16.82 mmol) in pyridine (15.0 mL,
14.6 g, 185.08 mmol) at 0 °C was treated with acetic anydride (8.0 mL, 8.6 g, 84.13
mmol). The temperature was raised to 80 °C and the reaction stirred for 6 h. The
reaction mixture was coꢀevaporated with toluene to remove pyridine. The residue was
taken up in ethyl acetate (20 mL), washed with 10% HCl solution (1x10 mL) and water
(2x10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and
evaporated. The oil obtained was purified by flash column chromatography on silica gel
1
(petroleum ether/AcOEt 4:1) to afford 4 as a colorless oil (2900 mg, 63%). H
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(500MHz, CDCl3): δ ppm 1.32 (s, 3H), 1.48 (s, 3H), 2.04 (s, 3H), 2.08 (s, 3H), 4.07ꢀ
4.14 (m, 2H), 4.45 (t, J = 7.0 Hz, 1H), 4.70 (s, 2H), 6.20 (s, 1H). 13C (125MHz, CDCl3):
δ ppm 20.9, 21.3, 25.2, 26.5, 64.2, 81.7, 85.2, 85.4, 102.2, 113.4, 169.4, 170.6.
9
(5)9.
A
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1ꢀtrimethylsilylethynylꢀ5ꢀOꢀacetylꢀ2,3ꢀOꢀIsopropylideneꢀβꢀDꢀribofuranose
suspension of indium (In0) (0.75 g, 6.56 mmol) in anhydrous 1,2ꢀdichloroethane (10
mL) under argon was stirred during 20 min at room temperature. Further 1ꢀiodoꢀ2ꢀ
trimethylsilylacetylene (1.2 g, 5.47 mmol) and the ribofuranoside 4 (0.75 g, 2.73 mmol)
were added into the reaction tube that was sealed and then evacuated and backfilled
with argon (this process was repeated a total of 3 times). The reaction mixture was
stirred during 6h at 90 °C. The mixture was filtered over celite and evaporated. The
crude residue was taken in anhydrous acetone (4 mL) and treated with pꢀtoluenesulfonic
acid monohydrate (16 mg, 3 mol%). After being stirred at room temperature for 5h, the
mixture was neutralized with NaHCO3, filtered through celite and concentrated under
reduced pressure. The crude residue obtained was purified by flash column
chromatography on silica gel (cyclohexane/AcOEt 3:1) to give 5 as a yellow oil (431
1
mg, 58%). H (400MHz, CDCl3): δ ppm 0.15 (s, 9H), 1.33 (s, 3H), 1.50 (s, 3H), 2.09
(s, 3H), 4.19 (dd, J = 5.1, 9.8 Hz, 1H), 4.23ꢀ4.27 (m, 1H), 4.30 (dd, J = 5.6, 9.8 Hz, 1H),
4.67 (dd, J = 2.2, 6.2 Hz, 2H), 4.80 (dd, J = 2.2, 6.1 Hz, 1H), 13C (100MHz, CDCl3): δ
ppm ꢀ0.26, 20.9, 25.4, 26.9, 63.9, 75.2, 82.9, 83.7, 86.5, 92.8, 102.7, 114.0, 170.7.
1ꢀethynylꢀ2,3ꢀOꢀIsopropylideneꢀβꢀDꢀribofuranose (6). To a solution of 5 (1.2 g, 3.87
mmol) in methanol (12 mL) was added potassium carbonate (0.8 g, 5.81 mmol). The
mixture was stirred at room temperature for 8h. The reaction mixture was concentrated,
the residue was taken in water (5 mL) and acidified with acetic acid to pH 5ꢀ6. The
water phase was extracted with acetyl acetate (2x15mL), dried over anhydrous sodium
sulfate, filtered and concentrated under reduced pressure. Heptane was used to remove
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the excess of acetic acid. The yellow oil obtained was purified by flash column
4
5
6
7
8
chromatography on silica gel (heptane/AcOEt 9:1 to 7:3) to give 6 as a colorless oil
1
(680 mg, 89%). H (400MHz, CDCl3): δ ppm 1.33 (s, 3H), 1.51 (s, 3H), 2.12 (br s, 1H),
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2.60 (d, J = 2.3 Hz, 1H), 3.75ꢀ3.76 (m, 2H), 4.19ꢀ4.22 (m, 1H), 4.68 (t, J = 2.5 Hz, 1H),
4.74 (dd, J = 2.2, 6.3 Hz, 1H), 4.81 (dd, J = 2.7, 6.2 Hz, 1H). 13C (100MHz, CDCl3): δ
ppm 25.3, 27.0, 62.9, 74.8, 75.6, 81.7, 82.3, 86.6, 86.7, 113.9.
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1ꢀethynylꢀ5ꢀOꢀ(tertꢀbutyldiphenylsilyl)ꢀ2,3ꢀOꢀIsopropylideneꢀβꢀDꢀribofuranose (7). To
a solution of 6 (0.68 g, 3.43 mmol) in anhydrous acetonitrile (12 mL) were added
imidazole (0.30 g, 4.46 mmol), 4ꢀ(dimethylamino)ꢀpyridine (0.46 g, 3.77 mmol) and
tertꢀbutyldiphenylchlorosilane (0.94 g, 0.9 mL, 3.43 mmol). The mixture was stirred at
room temperature for 2h and then it was concentrated. The residue was taken in ethyl
acetate (20 mL) and washed with saturated solution of sodium bicarbonate (1x10 mL).
The water phase was extracted with ethyl acetate (1x10 mL). The combined organic
phases were dried over anhydrous sodium sulfate, filtered and evaporated. The crude
residue was purified by flash column chromatography on silica gel (heptane 100% to
1
heptane/AcOEt 9.5:0.5) to give 7 as a colorless oil (1.220 mg, 81%). H (400MHz,
CDCl3): δ ppm 1.08 (s, 9H), 1.34 (s, 3H), 1.53 (s, 3H), 2.42 (d, J = 2.3 Hz, 1H), 3.78ꢀ
3.84 (m, 2H), 4.20ꢀ4.23 (m, 1H), 4.62 (t, J = 2.6 Hz, 1H), 4.76 (dd, J = 2.9, 6.2 Hz, 1H),
4.80 (dd, J = 1.9, 6.2 Hz, 1H), 7.37ꢀ7.45 (m, 6H), 7.67ꢀ7.71 (m, 4H). ). 13C (125MHz,
CDCl3): δ ppm 19.4, 25.5, 27.0, 27.2, 63.7, 74.6, 75.1, 81.7, 82.9, 86.2, 86.4, 113.7,
127.8, 127.9, 129.88, 129.91, 133.3, 133.4, 135.78, 135.84. HRMSꢀESI: m/z [M+Na]+
calcd for C26H32O4SiNa+, 459.1968, found 459.1960.
4ꢀ(5ꢀOꢀ(tertꢀbutyldiphenylsilyl)ꢀ2,3ꢀOꢀIsopropylideneꢀβꢀDꢀribosyl)ꢀ2Hꢀ1,2,3ꢀtriazole
(1). To a solution of compound 7 (0.69 g, 1.58 mmol) in N,Nꢀdimethylformamide (12
mL) and ethanol (1.4 mL) were added copper (I) iodide (0.045g, 0.237 mmol) and
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azidotrimethylsilane (0.36 g, 0.42 mL, 3.16 mmol). The mixture was stirred for 1 min
under vacuum/argon in a sealed tube and placed into a microwave apparatus at 120 °C
for 30 min. The mixture was filtered over celite and concentrated. The residue was
taken in ethanol and purified with activated carbon. After evaporation of the solvent the
residue was purified by flash column chromatography (heptane/AcOEt 9:1 to 8.5:1.5) to
give compounds 1 as colorless oil (566 mg, 75%). Care should be taken because the
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reaction releases gas. H (400MHz, CDCl3): δ ppm 1.03 (s, 9H), 1.38 (s, 3H), 1.61 (s,
3H), 3.78 (d, J = 4.4 Hz, 1H), 4.26 (dd, J = 3.3, 4.3 Hz, 1H), 4.81 (dd, J = 3.2, 6.5 Hz,
1H), 4.89 (dd, J = 4.8, 6.5 Hz, 1H), 5.13 (d, J = 4.6 Hz, 1H), 7.33ꢀ744 (m, 6H), 7.63ꢀ
7.66 (m, 4H), 7.68 (br s, 1H). 13C (100MHz, CDCl3): δ ppm 19.4, 25.6, 26.9, 27.6, 64.1,
79.3, 82.2, 85.26, 85.30, 114.6, 127.88, 127.91, 129.95, 129.98, 133.2, 133.3, 135.8.
HRMSꢀ ESI: m/z [M+H]+ calcd for C26H33N3O4SiH+, 480.2319, found 480.2311.
General Procedure for the N2 arylation of 1ꢀβꢀDꢀribosylꢀ1,2,3ꢀtriazoles (Method A).
To ovenꢀdried tube was added [PdCl(allyl)]2 and AdBrettPhos. The tube was sealed,
toluene (a half of the total volume) was added via syringe and then the tube was
evacuated and backfilled with argon (this process was repeated a total of 3 times). The
resulting brown mixture was stirred at 120 °C for 2 min, at this point the color of the
mixture turned to dark brown. A second ovenꢀdried tube was charged with 1,2,3ꢀtriazole
derivative, K3PO4 (2.0 equiv) and aryl halides (1.2 equiv). The tube was sealed, toluene
(a half of the total volume) was added via syringe, the mixture was evacuated and
backfilled with argon (this process was repeated a total of 3 times). The premixed
catalyst solution was added via syringe to the tube containing 1,2,3ꢀtriazole, aryl halide
and base. The reaction mixture was stirred at 120 °C for 10ꢀ23 h. The reaction was
cooled to room temperature, concentrated under reduced pressure and purified by flash
column chromatography on silica gel (heptane/AcOEt) to afford pure products.
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General Procedure for the N2 arylation of 1ꢀβꢀDꢀribosylꢀ1,2,3ꢀtriazoles (Method B).
To ovenꢀdried tube was added Pd2(dba)3 and AdBrettPhos. The tube was sealed, toluene
(a half of the total volume) was added via syringe and then the tube was evacuated and
backfilled with argon (this process was repeated a total of 3 times). The resulting brown
mixture was stirred at 120 °C for 2 min, at this point the color of the mixture turned to
dark brown. A second ovenꢀdried tube was charged with 1,2,3ꢀtriazole derivative,
K3PO4 (2.0 equiv) and aryl halides (1.2 equiv). The tube was sealed, toluene (a half of
the total volume) was added via syringe, the mixture was evacuated and backfilled with
argon (this process was repeated a total of 3 times). The premixed catalyst solution was
added via syringe to the tube containing 1,2,3ꢀtriazole, aryl halide and base. The
reaction mixture was stirred at 120 °C for 10 h. The reaction was cooled to room
temperature, concentrated under reduced pressure and purified by flash column
chromatography on silica gel (heptane/AcOEt) to afford pure products.
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2ꢀ(phenyl)ꢀ4ꢀ(2,3ꢀisopropylideneꢀ5ꢀtertꢀbutyldiphenylsilylꢀβꢀDꢀribosyl)ꢀ1,2,3ꢀtriazole
(2a). Following general procedure for Nꢀarylation of 1ꢀβꢀDꢀribosylꢀ1,2,3ꢀtriazoles
(Method A), a mixture of bromobenzene (6.6 µL, 0.0625 mmol), 1,2,3ꢀtriazole
derivative 1 (25.0 mg, 0.0521 mmol), K3PO4 (22.1 mg, 0.104 mmol), [PdCl(allyl)2]
(0.292 mg, 0.000782 mmol), L4 (1.00 mg, 0.00156 mmol) in toluene (0.38 mL) was
stirred at 120 °C for 10 h. The crude was purified by flash column chromatography on
silica gel (heptane/AcOEt 8.5:1.5) to afford a yellow oil (23.8 mg, 82%). 1H NMR (400
MHz, CDCl3): δ ppm 1.03 (s, 9H), 1.41 (s, 3H), 1.63 (s, 3H), 3.78 (d, J = 4.4 Hz, 2H),
4.28 (dd, J = 3.2, 4.3 Hz, 1H), 4.87 (dd, J = 3.1, 6.5 Hz, 1H), 5.02 (dd, J = 4.6, 6.5 Hz,
1H), 5.16 (d, J = 4.6 Hz, 1H), 7.30ꢀ7.40 (m, 7H), 7.43ꢀ7.47 (m, 2H), 7.63ꢀ7.65 (m, 4H),
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7.77 (s, 1H); 8.01ꢀ8.04 (m, 2H). C NMR (100 MHz, CDCl3): δ ppm 19.4, 25.7, 26.9,
27.6, 64.1, 79.7, 82.4, 85.2, 85.4, 114.5, 119.1, 127.6, 127.8, 127.9, 129.3, 129.88,
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for C32H37N3O4SiH+, 556.2632, found 556.2620.
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2ꢀ(4ꢀtoluil)ꢀ4ꢀ(2,3ꢀisopropylideneꢀ5ꢀtertꢀbutyldiphenylsilylꢀβꢀDꢀribosyl)ꢀ1,2,3ꢀtriazole
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(2b). Following general procedure for Nꢀarylation of 1ꢀβꢀDꢀribosylꢀ1,2,3ꢀtriazoles
(Method A), a mixture of 4ꢀbromotoluene (9.2 µL, 0.0751 mmol), 1,2,3ꢀtriazole
derivative 1 (30.0 mg, 0.0625 mmol), K3PO4 (26.5 mg, 0.125 mmol), [PdCl(allyl)2]
(0.350 mg, 0.000938 mmol), L4 (1.20 mg, 0.00188 mmol) in toluene (0.45 mL) was
stirred at 120 °C for 10 h. The crude was purified by flash column chromatography on
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silica gel (heptane/AcOEt 9:1) to afford a colorless oil (25.0 mg, 70%). H NMR (400
MHz, CDCl3): δ ppm 1.03 (s, 9H), 1.40 (s, 3H), 1.62 (s, 3H), 2.40 (s, 3H), 3.79 (d, J =
4.4 Hz, 2H), 4.27 (dd, J = 3.2, 4.3 Hz, 1H), 4.86 (dd, J = 3.1, 6.5 Hz, 1H), 5.01 (dd, J =
4.6, 6.5 Hz, 1H), 5.15 (d, J = 4.6 Hz, 1H), 7.25 (d, J = 8.6 Hz, 2H), 7.30ꢀ7.42 (m, 6H),
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7.64ꢀ7.66 (m, 4H), 7.74 (s, 1H), 7.90 (dt, J = 2.4, 8.5 Hz, 2H). C NMR (100 MHz,
CDCl3): δ ppm 19.4, 21.2, 25.7, 26.9, 27.6, 64.1, 79.6, 82.4, 85.2, 85.4, 114.5, 119.0,
127.8, 127.9, 129.8, 129.9, 129.9, 133.2, 133.4, 133.9, 135.7, 135.8, 137.5, 137.8,
148.3. HRMSꢀESI: m/z [M+H]+ calcd for C33H39N3O4SiH+, 570.2788, found 570.2785.
2ꢀ(4ꢀmethoxyphenyl)ꢀ4ꢀ(2,3ꢀisopropylideneꢀ5ꢀtertꢀbutyldiphenylsilylꢀβꢀDꢀribosyl)ꢀ1,2,3ꢀ
triazole (2d). Following general procedure for Nꢀarylation of 1ꢀβꢀDꢀribosylꢀ1,2,3ꢀ
triazoles (Method A), a mixture of 4ꢀiodoanisole (17.6 mg, 0.0751 mmol), 1,2,3ꢀtriazole
derivative 1 (30.0 mg, 0.0625 mmol), K3PO4 (26.5 mg, 0.125 mmol), [PdCl(allyl)2]
(0.350 mg, 0.000938 mmol), L4 (1.20 mg, 0.00188 mmol) in toluene (0.45 mL) was
stirred at 120 °C for 10 h. The crude was purified by flash column chromatography on
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silica gel (heptane/AcOEt 9.5:0.5 to 9:1) to afford a colorless oil (31.0 mg, 85%). H
NMR (400 MHz, CDCl3): δ ppm 1.03 (s, 9H), 1.40 (s, 3H), 1.62 (s, 3H), 3.78 (d, J = 4.4
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Hz, 2H), 3.86 (s, 3H), 4.27 (dd, J = 3.2, 4.3 Hz, 1H), 4.85 (dd, J = 3.1, 6.5 Hz, 1H), 5.00
(dd, J = 4.7, 6.5 Hz, 1H), 5.14 (d, J = 4.6 Hz, 1H), 6.96 (dt, J = 3.3, 9.2 Hz, 2H), 7.30ꢀ
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7.42 (m, 6H), 7.63ꢀ7.65 (m, 4H), 7.72 (s, 1H), 7.93 (dt, J = 3.3, 9.2 Hz, 2H). C NMR
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(100 MHz, CDCl3): δ ppm 19.4, 25.7, 26.9, 27.6, 55.7, 64.1, 79.6, 82.4, 85.2, 85.4,
114.4, 114.5, 120.6, 127,8, 127.9, 129.88, 129.92, 133.3, 133.4, 133.7, 133.8, 135.75,
135.77, 148.2, 159.2. HRMSꢀESI: m/z [M+H]+ calcd for C33H39N3O5SiH+, 586.2737,
found 586.2731.
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2ꢀ(3ꢀmethoxyphenyl)ꢀ4ꢀ(2,3ꢀisopropylideneꢀ5ꢀtertꢀbutyldiphenylsilylꢀβꢀDꢀribosyl)ꢀ1,2,3ꢀ
triazole (2e). Following general procedure for Nꢀarylation of 1ꢀβꢀDꢀribosylꢀ1,2,3ꢀ
triazoles (Method A), a mixture of 3ꢀiodoanisole (17.6 mg, 9.0 µL, 0.0751 mmol),
1,2,3ꢀtriazole derivative 1 (30.0 mg, 0.0625 mmol), K3PO4 (26.5 mg, 0.125 mmol),
[PdCl(allyl)2] (0.350 mg, 0.000938 mmol), L4 (1.20 mg, 0.00188 mmol) in toluene
(0.45 mL) was stirred at 120 °C for 10 h. The crude was purified by flash column
chromatography on silica gel (heptane/AcOEt 9.5:0.5 to 9:1) to afford a colorless oil
(26.0 mg, 71%). 1H NMR (400 MHz, CDCl3): δ ppm 1.03 (s, 9H), 1.41 (s, 3H), 1.63 (s,
3H), 3.78 (d, J = 4.4 Hz, 2H), 3.87 (s, 3H), 4.28 (dd, J = 3.3, 4.3 Hz, 1H), 4.86 (dd, J =
3.2, 6.5 Hz, 1H), 5.02 (dd, J = 4.6, 6.5 Hz, 1H), 5.15 (d, J = 4.6 Hz, 1H), 6.89 (ddd, J =
0.8, 2.5, 8.3 Hz, 1H), 7.30ꢀ7.43 (m, 7H), 7.60 (t, J = 2.3 Hz, 1H), 7.62ꢀ7.66 (m, 5H),
7.76 (s, 1H). 13C NMR (100 MHz, CDCl3): δ ppm 19.4, 25.7, 26.9, 27.6, 55.7, 64.1,
79.6, 82.3, 85.2, 85.4, 104.5, 111.4, 113.9, 114.5, 127.8, 127.9, 129.89, 129.92, 130.2,
133.2, 133.4, 134.2, 135.7, 135.8, 140.9, 148.7, 160.5. HRMSꢀESI: m/z [M+H]+ calcd
for C33H39N3O5SiH+, 586.2737, found 586.2731.
2ꢀ(4ꢀchlorophenyl)ꢀ4ꢀ(2,3ꢀisopropylideneꢀ5ꢀtertꢀbutyldiphenylsilylꢀβꢀDꢀribosyl)ꢀ1,2,3ꢀ
triazole (2g). Following general procedure for Nꢀarylation of 1ꢀβꢀDꢀribosylꢀ1,2,3ꢀ
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triazoles (Method A), a mixture of 4ꢀbromochlorobenzene (14.4 mg, 8.7 µL, 0.0751
mmol), 1,2,3ꢀtriazole derivative 1 (30.0 mg, 0.0625 mmol), K3PO4 (26.5 mg, 0.125
mmol), [PdCl(allyl)2] (0.350 mg, 0.000938 mmol), L4 (1.20 mg, 0.00188 mmol) in
toluene (0.45 mL) was stirred at 120 °C for 10 h. The crude was purified by flash
column chromatography on silica gel (heptane/AcOEt 9.5:0.5 to 9:1) to afford a
colorless oil (33.0 mg, 89%). 1H NMR (400 MHz, CDCl3): δ ppm 1.03 (s, 9H), 1.41 (s,
3H), 1.63 (s, 3H), 3.79 (d, J = 4.3 Hz, 2H), 4.28 (dd, J = 3.2, 4.2 Hz, 1H), 4.86 (dd, J =
3.0, 6.5 Hz, 1H), 4.99 (dd, J = 4.7, 6.4 Hz, 1H), 5.14 (d, J = 4.7 Hz, 1H), 7.31ꢀ7.44 (m,
8H), 7.63ꢀ7.65 (m, 4H), 7.76 (s, 1H), 7.98 (dt, J = 2.9, 9.0 Hz, 2H). 13C NMR (100
MHz, CDCl3): δ ppm 19.4, 25.7, 26.9, 27.6, 64.1, 79.6, 82.3, 85.2, 85.4, 114.5, 120.3,
127.8, 127.9, 129.4, 129.90, 129.95, 133.2, 133.3, 134.5, 135.7, 138.4, 149.0. HRMSꢀ
ESI: m/z [M+Na]+ calcd for C32H36ClN3O4SiNa+, 612.2061, found 612.2049.
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2ꢀ(4ꢀcianophenyl)ꢀ4ꢀ(2,3ꢀisopropylideneꢀ5ꢀtertꢀbutyldiphenylsilylꢀβꢀDꢀribosyl)ꢀ1,2,3ꢀ
triazole (2h). Following general procedure for Nꢀarylation of 1ꢀβꢀDꢀribosylꢀ1,2,3ꢀ
triazoles (Method A), a mixture of 4ꢀbromobenzonitrile (13.7 mg, 0.0751 mmol), 1,2,3ꢀ
triazole derivative 1 (30.0 mg, 0.0625 mmol), K3PO4 (26.5 mg, 0.125 mmol),
[PdCl(allyl)2] (0.350 mg, 0.000938 mmol), L4 (1.20 mg, 0.00188 mmol) in toluene
(0.45 mL) was heated to 120 °C for 10 h. The crude was purified by flash column
chromatography on silica gel (heptane/AcOEt 9:1) to afford a colorless oil (31.0 mg
85%). 1H NMR (400 MHz, CDCl3): δ ppm 1.02 (s, 9H), 1.41 (s, 3H), 1.63 (s, 3H), 3.79
(ddd, J = 4.1, 11.4 Hz, 2H), 4.30 (dd, J = 3.2, 3.9 Hz, 1H), 4.86 (dd, J = 2.9, 6.5 Hz,
1H), 4.99 (dd, J = 4.8, 6.4 Hz, 1H), 5.14 (d, J = 4.7 Hz, 1H), 7.31ꢀ7.43 (m, 6H), 7.63
(ddd, J = 1.4, 2.7, 6.6 Hz, 4H), 7.75 (dt, J = 2.1, 9.0 Hz, 2H), 7.82 (s, 1H), 8.16 (dt, J =
2.1, 9.0 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ ppm 19.4, 25.7, 26.9, 27.6, 64.1, 79.7,
82.3, 85.2, 85.5, 111.0, 114.6, 118.4, 119.3, 127.8, 127.9, 129.92, 129.99, 133.19,
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133.22, 133.6, 135.5, 135.7, 142.4, 150.2. HRMSꢀESI: m/z [M+Na]+ calcd for
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C33H36N4O4SiNa+, 603.2404, found 603.2382.
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(2j). Following general procedure for Nꢀarylation of 1ꢀβꢀDꢀribosylꢀ1,2,3ꢀtriazoles
(Method A), a mixture of 4ꢀbromopyridine chloridrate (14.6 mg, 0.0751 mmol), 1,2,3ꢀ
triazole derivative 1 (30.0 mg, 0.0625 mmol), K3PO4 (42.5 mg, 0.200 mmol),
[PdCl(allyl)2] (0.350 mg, 0.000938 mmol), L4 (1.20 mg, 0.00188 mmol) in toluene
(0.45 mL) was stirred at 120 °C for 10 h. The crude was purified by flash column
chromatography on silica gel (heptane/AcOEt 9:1) to afford a yellow oil (34.0 mg,
98%). 1H NMR (400 MHz, CDCl3): δ ppm 1.02 (s, 9H), 1.41 (s, 3H), 1.63 (s, 3H), 3.79
(td, J = 4.1, 11.5 Hz, 2H), 4.30 (dd, J = 3.2, 4.0 Hz, 1H), 4.86 (dd, J = 3.0, 6.4 Hz, 1H),
5.00 (dd, J = 4.7, 6.4 Hz, 1H), 5.15 (d, J = 4.6 Hz, 1H), 7.31ꢀ7.43 (m, 6H), 7.63 (ddd, J
= 1.4, 2.9, 6.5 Hz, 4H), 7.83 (s, 1H), 7.93 (dd, J = 1.6, 4.7 Hz, 2H), 8.69 (dd, J = 1.5, 4.8
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Hz, 2H). C NMR (100 MHz, CDCl3): δ ppm 19.4, 25.7, 26.9, 27.6, 64.1, 79.7, 82.3,
85.2, 85.5, 112.9, 114.6, 127.8, 127.9, 129.93, 129.99, 133.18, 133.23, 135.7, 145.6,
150.4, 151.3. HRMSꢀESI: m/z [M+H]+ calcd for C31H36N4O4SiH+, 557.2584, found
557.2572.
2ꢀ(3ꢀpyridyl)ꢀ4ꢀ(2,3ꢀisopropylideneꢀ5ꢀtertꢀbutyldiphenylsilylꢀβꢀDꢀribosyl)ꢀ1,2,3ꢀtriazole
(2k). Following general procedure for Nꢀarylation of 1ꢀβꢀDꢀribosylꢀ1,2,3ꢀtriazoles
(Method A), a mixture of 3ꢀbromopyridine (11.9 mg, 7.3 µL, 0.0751 mmol), 1,2,3ꢀ
triazole derivative 1 (30.0 mg, 0.0625 mmol), K3PO4 (26.5 mg, 0.125 mmol),
[PdCl(allyl)2] (0.350 mg, 0.000938 mmol), L4 (1.20 mg, 0.00188 mmol) in toluene
(0.45 mL) was stirred at 120 °C for 10 h. The crude was purified by flash column
chromatography on silica gel (heptane/AcOEt 9.5:0.5 to 8.5:1.5) to afford a yellow oil
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(34.0 mg, 98%). 1H NMR (400 MHz, CDCl3): δ ppm 1.02 (s, 9H), 1.41 (s, 3H), 1.63 (s,
3H), 3.79 (d, J = 4.2 Hz, 2H), 4.29 (dd, J = 3.2, 4.1 Hz, 1H), 4.87 (dd, J = 3.0, 6.5 Hz,
1H), 5.01 (dd, J = 4.8, 6.5 Hz, 1H), 5.16 (d, J = 4.7 Hz, 1H), 7.30ꢀ7.42 (m, 7H), 7.64
(ddd, J = 1.6, 3.4, 6.3 Hz, 4H), 7.82 (s, 1H), 8.30 (ddd, J = 1.5, 2.6, 8.3 Hz, 1H), 8.60
(dd, J = 1.4, 4.7 Hz, 1H), 9.33 (d, J = 2.4 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ ppm
19.4, 25.7, 26.9, 27.6, 64.1, 79.6, 82.3, 85.2, 85.5, 114.6, 123.8, 126.2, 127.8, 127.9,
129.91, 129.96, 133.2, 133.3, 135.0, 135.7, 136.3, 140.8, 148.6, 149.6. HRMSꢀESI: m/z
[M+H]+ calcd for C31H36N4O4SiH+, 557.2584, found 557.2579.
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2ꢀ(5ꢀpyrimidinyl)ꢀ4ꢀ(2,3ꢀisopropylideneꢀ5ꢀtertꢀbutyldiphenylsilylꢀβꢀDꢀribosyl)ꢀ1,2,3ꢀ
triazole (2m). Following general procedure for Nꢀarylation of 1ꢀβꢀDꢀribosylꢀ1,2,3ꢀ
triazoles (Method B), a mixture of 5ꢀbromopyrimidine (11.9 mg, 0.0751 mmol), 1,2,3ꢀ
triazole derivative 1 (30.0 mg, 0.0625 mmol), K3PO4 (26.5 mg, 0.125 mmol), Pd2(dba)3
(0.859 mg, 0.000938 mmol), L4 (1.20 mg, 0.00188 mmol) in toluene (0.45 mL) was
stirred at 120 °C for 10 h. The crude was purified by flash column chromatography on
silica gel (heptane 100% to heptane/AcOEt 8.5:1.5) to afford a colorless oil (28.8 mg,
83%). 1H NMR (400 MHz, CDCl3): δ ppm 1.02 (s, 9H), 1.41 (s, 3H), 1.63 (s, 3H), 3.79
(d, J = 4.0 Hz, 2H), 4.31 (dd, J = 3.1, 3.9 Hz, 1H), 4.87 (dd, J = 3.0, 6.5 Hz, 1H), 5.00
(dd, J = 4.8, 6.4 Hz, 1H), 5.16 (d, J = 4.8 Hz, 1H), 7.31ꢀ7.43 (m, 6H), 7.61ꢀ7.65 (m,
4H), 7.87 (s, 1H), 9.20 (s, 1H), 9.39 (s, 2H). 13C NMR (100 MHz, CDCl3): δ ppm 19.4,
25.7, 26.9, 27.6, 64.1, 79.6, 82.3, 85.2, 85.5, 114.7, 127.8, 127.9, 129.9, 130.0, 133.1,
133.2, 134.4, 135.70, 135.72, 135.9, 147.1, 150.6, 157.2. HRMSꢀESI: m/z [M+H]+ calcd
for C30H35N5O4SiH+, 558.2537, found 558.2532.
2ꢀ(NꢀBocꢀ5ꢀindolyl)ꢀ4ꢀ(2,3ꢀisopropylideneꢀ5ꢀtertꢀbutyldiphenylsilylꢀβꢀDꢀribosyl)ꢀ1,2,3ꢀ
triazole (2n). Following general procedure for Nꢀarylation of 1ꢀβꢀDꢀribosylꢀ1,2,3ꢀ
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triazoles (Method A), a mixture of NꢀBocꢀ5ꢀbromoindole (22.2 mg, 0.0751 mmol),
1,2,3ꢀtriazole derivative 1 (30.0 mg, 0.0625 mmol), K3PO4 (26.5 mg, 0.125 mmol),
[PdCl(allyl)2] (0.350 mg, 0.000938 mmol), L4 (1.20 mg, 0.00188 mmol) in toluene
(0.45 mL) was stirred at 120 °C for 10 h. The crude was purified by flash column
chromatography on silica gel (heptane 100% to heptane/AcOEt 9:1) to afford a colorless
oil (33.0 mg, 76%). 1H NMR (400 MHz, CDCl3): δ ppm 1.04 (s, 9H), 1.41 (s, 3H), 1.63
(s, 3H), 1.69 (s, 9H), 3.80 (d, J = 4.4 Hz, 2H), 4.29 (dd, J = 3.2, 4.3 Hz, 1H), 4.88 (dd, J
= 3.1, 6.5 Hz, 1H), 5.05 (dd, J = 4.7, 6.5 Hz, 1H), 5.17 (d, J = 4.6 Hz, 1H), 6.62 (d, J =
3.7 Hz, 1H), 7.30ꢀ7.42 (m, 6H), 7.64ꢀ7.67 (m, 5H), 7.77 (s, 1H), 8.02 (dd, J = 2.1, 9.0
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Hz, 1H), 8.21 (d, J = 2.2 Hz, 1H), 8.23 (br s, 1H). C NMR (100 MHz, CDCl3): δ ppm
19.4, 25.7, 26.9, 27.6, 28.3, 64.1, 79.7, 82.4, 84.2, 85.3, 85.4, 107.7, 111.5, 114.5,
115.7, 115.9, 127.5, 127.8, 127.9, 129.88, 129.91, 131.0, 133.2, 133.4, 133.9, 134.5,
135.69, 135.74, 135.8, 148.3, 149.6. HRMSꢀESI: m/z [M+Na]+ calcd for
C39H46N4O6SiNa+, 717.3084, found 717.3078.
2ꢀ(3ꢀquinolyl)ꢀ4ꢀ(2,3ꢀisopropylideneꢀ5ꢀtertꢀbutyldiphenylsilylꢀβꢀDꢀribosyl)ꢀ1,2,3ꢀ
triazole (2o). Following general procedure for Nꢀarylation of 1ꢀβꢀDꢀribosylꢀ1,2,3ꢀ
triazoles (Method A), a mixture of 3ꢀbromoquinoline (15.6 mg, 10 ꢀL, 0.0751 mmol),
1,2,3ꢀtriazole derivative 1 (30.0 mg, 0.0625 mmol), K3PO4 (26.5 mg, 0.125 mmol),
[PdCl(allyl)2] (0.350 mg, 0.000938 mmol), L4 (1.20 mg, 0.00188 mmol) in toluene
(0.45 mL) was stirred at 120 °C for 10 h. The crude was purified by flash column
chromatography on silica gel (heptane 100% to heptane/AcOEt 9:1) to afford a colorless
oil (26.6 mg, 70%). 1H NMR (400 MHz, CDCl3): δ ppm 1.03 (s, 9H), 1.43 (s, 3H), 1.65
(s, 3H), 3.81 (d, J = 4.1 Hz, 2H), 4.32 (dd, J = 3.3, 4.0 Hz, 1H), 4.89 (dd, J = 3.0, 6.5
Hz, 1H), 5.05 (dd, J = 4.8, 6.4 Hz, 1H), 5.20 (d, J = 4.7 Hz, 1H), 7.30ꢀ7.42 (m, 6H),
7.60ꢀ7.66 (m, 5H), 7.75 (ddd, J = 1.4, 6.9, 8.4 Hz, 1H), 7.87 (s, 1H), 7.90 (dd, J = 1.3,
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8.2 Hz, 1H), 8.17 (d, J = 8.5 Hz, 1H), 8.72 (d, J = 2.4 Hz, 1H), 9.67 (d, J = 2.5 Hz, 1H).
13C NMR (100 MHz, CDCl3): δ ppm 19.4, 25.7, 26.9, 27.6, 64.1, 79.7, 82.3, 85.2, 85.4,
114.6, 123.9, 127.6, 127.84, 127.89, 127.96, 128.3, 129.6, 129.86, 129.92, 129.97,
133.13, 133.23, 135.0, 135.7, 142.6, 147.2, 149.7. HRMSꢀESI: m/z [M+H]+ calcd for
C35H38N4O4SiH+, 607.2741, found 607.2737.
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1ꢀ(phenyl)ꢀ4ꢀ(2,3ꢀisopropylideneꢀ5ꢀtertꢀbutyldiphenylsilylꢀβꢀDꢀribosyl)ꢀ1,2,3ꢀtriazole
(8a). To a solution of compound 7 (0.1 g, 0.229 mmol) in N,Nꢀdimethylformamide (1.8
mL) and ethanol (0.2 mL) were added copper (I) iodide (0.0022 g, 0.0114 mmol) and
phenyl azide (0.054 g, 0.458 mmol). The mixture was stirred for 1 min under
vacuum/argon in a sealed tube and placed into a microwave apparatus at 100 °C for 30
min. The mixture was filtered over celite and concentrated. The residue was taken in
ethanol and purified by activated carbon. After evaporation of the solvent the residue
was purified by flash column chromatography (heptane/AcOEt 7:3) to give compound
8a as a yellow oil (98.0 mg, 77%). Care should be taken because the reaction releases
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gas. H NMR (400 MHz, CDCl3): δ ppm 1.03 (s, 9H), 1.40 (s, 3H), 1.62 (s, 3H), 3.81
(qd, J = 4.6, 11.1 Hz, 2H), 4.28 (dd, J = 3.5, 4.5 Hz, 1H), 4.85 (dd, J = 3.4, 6.4 Hz, 1H),
5.10 (dd, J = 4.2, 6.4 Hz, 1H), 5.23 (d, J = 4.1 Hz, 1H), 7.29ꢀ7.43 (m, 7H), 7.44ꢀ7.49
(m, 2H), 7.55ꢀ7.58 (m, 2H), 7.63ꢀ7.65 (m, 4H); 7.87 (s, 1H). 13C NMR (100 MHz,
CDCl3): δ ppm 19.4, 25.6, 26.9, 27.6, 64.3, 79.6, 82.2, 85.2, 85.5, 114.3, 120.2, 120.7,
127.8, 127.9, 128.8, 129.81, 129.89, 129.94, 133.3, 133.4, 135.66, 135.71, 137.1,
148.0. HRMSꢀESI: m/z [M+H]+ calcd for C32H37N3O4SiH+, 556.2632, found 556.2625.
1ꢀ(phenyl)ꢀ5ꢀ(2,3ꢀisopropylideneꢀ5ꢀtertꢀbutyldiphenylsilylꢀβꢀDꢀribosyl)ꢀ1,2,3ꢀtriazole
(8b). To a solution of compound 7 (0.10 g, 0.229 mmol) in N,Nꢀdimethylformamide
(1.8 mL) and ethanol (0.2 mL) was added phenyl azide (0.054 g, 0.458 mmol). The
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mixture was stirred at 100 °C for 24 h. After cooled, the mixture was concentrated and
the residue was purified by flash column chromatography (heptane/AcOEt 2:1), to
afford two products: 1,4ꢀregioisomer (71.0 mg, 56%) and 1,5ꢀregioisomer (26.0 mg,
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20%) as yellow oils. Care should be taken because the reaction releases gas. H NMR
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(400 MHz, CDCl3): δ ppm 1.08 (s, 9H), 1.35 (s, 3H), 1.47 (s, 3H), 3.77ꢀ3.84 (m, 2H),
4.14 (dd, J = 3.3, 3.7 Hz, 1H), 4.76ꢀ4.78 (m, 1H), 4.81ꢀ4.84 (m, 2H), 7.34ꢀ7.45 (m, 6H),
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7.50ꢀ7.52 (m, 3H), 7.61ꢀ7.63 (m, 2H), 7.64ꢀ7.68 (m, 4H); 7.77 (s, 1H). C NMR (100
MHz, CDCl3): δ ppm 19.4, 25.6, 26.9, 27.5, 63.8, 76.2, 81.9, 84.9, 85.2, 115.0, 125.7,
127.9, 129.4, 129.8, 130.0, 132.7, 133.0, 133.1, 135.7, 136.1, 136.2. HRMSꢀESI: m/z
[M+H]+ calcd for C32H37N3O4SiH+, 556.2632, found 556.2627.
ethylꢀ3ꢀ((5ꢀOꢀacetyl)ꢀ2,3ꢀOꢀIsopropylideneꢀβꢀDꢀribosyl)ꢀpropiolate (9)5. A suspension
of indium (In0) (0.75 g, 6.56 mmol) in anhydrous 1,2ꢀdichloroethane (10 mL) under
argon was stirred during 20 min at room temperature. Further ethyl 3ꢀiodoꢀpropiolate19
(1.2 g, 5.47 mmol) and the ribofuranoside 4 (0.75 g, 2.74 mmol) were added into the
reaction tube that was then sealed. The reaction mixture was stirred for 6h under argon
at 90 °C. The mixture was filtered over celite and evaporated. The crude residue was
taken in anhydrous acetone (4 mL) and treated with pꢀtoluenesulfonic acid monohydrate
(16 mg, 3 mol%). After being stirred at room temperature for 5h, the mixture was
neutralized with NaHCO3, filtered through celite and concentrated under reduced
pressure. The crude residue obtained was purified by flash column chromatography on
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silica gel (cyclohexane/AcOEt 2:1) to give 9 as a yellow oil (464 mg, 54%). H
(400MHz, CDCl3): δ ppm 1.29 (t, J = 7.2 Hz, 3H), 1.33 (s, 3H), 1.51 (s, 3H), 2.10 (s,
3H), 4.18 (dd, J = 5.5, 11.8 Hz, 1H), 4.22 (q, J = 7.2 Hz, 2H), 4.25 (dd, J = 5.2, 11.8
Hz, 1H), 4.34 (dt, J = 2.2, 5.3 Hz, 1H), 4.72 (dd, J = 2.1, 6.2 Hz, 1H), 4.80 (d, J = 2.5
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Hz, 1H), 4.89 (dd, J = 2.4, 6.1 Hz, 1H). C (100MHz, CDCl3): δ ppm 14.1, 20.9, 25.4,
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carboxylate (10). To a solution of compound 9 (0.65 g, 2.08 mmol) in N,Nꢀ
dimethylformamide (16 mL) and ethanol (1.8 mL) was added azidotrimethylsilane (0.48
g, 0.55 mL, 4.16 mmol). The mixture was stirred for 1 min under vacuum/argon in a
sealed tube and placed into a microwave apparatus at 100 °C for 30 min. The mixture
was filtered over celite and concentrated. The residue was taken in ethanol and purified
with activated carbon. After evaporation of the solvent the residue was purified by flash
column chromatography (heptane/AcOEt 9:1 to 7:3) to give compounds 10 as a yellow
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oil (392 mg, 53%). Care should be taken because the reaction releases gas. H
(400MHz, CDCl3): δ ppm 1.37 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H), 1.61 (s, 3H), 2.09 (s,
3H), 4.24 (dd, J = 4.1, 11.6 Hz, 1H), 4.30ꢀ4.48 (m, 4H), 4.68 (dd, J = 4.0, 5.8 Hz, 1H),
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4.99 (dd, J = 2.6, 6.0 Hz, 1H), 5.67 (d, J = 3.0 Hz, 1H). C (100MHz, CDCl3): δ ppm
14.4, 21.0, 25.7, 27.5, 61.8, 64.7, 78.9, 82.2, 83.9, 85.5, 114.7, 160.9, 171.7. HRMSꢀ
ESI: m/z [M+H]+ calcd for C15H21N3O7H+, 356.1458, found 356.1453.
ethyl 4ꢀ(2,3ꢀOꢀIsopropylideneꢀβꢀDꢀribosyl)ꢀ2Hꢀ1,2,3ꢀtriazoleꢀ5ꢀcarboxylate (11). To a
solution of 10 (0.64 g, 1.80 mmol) in ethanol (9.5 mL) was added potassium carbonate
(0.5 g, 3.60 mmol). The mixture was stirred at 40 °C for 18 h. The reaction mixture was
concentrated, the residue was taken in water (5 mL) and acidified with acetic acid to pH
5ꢀ6. The water phase was extracted with acetyl acetate (2x15mL), dried over anhydrous
sodium sulfate, filtered and concentrated under reduced pressure. Heptane was used to
remove the excess of acetic acid. The compound 11 was obtained as a yellow oil (540
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mg, 96%). H (400MHz, CDCl3): δ ppm 1.35 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H), 1.61 (s,
3H), 3.81 (dd, J = 3.2, 12.2 Hz, 1H), 4.04 (dd, J = 2.5, 12.2 Hz, 1H), 4.36 (dd, J = 2.9,
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3.0 Hz, 1H), 4.40ꢀ4.48 (m, 2H), 4.77 (dd, J = 3.1, 6.1 Hz, 1H), 4.91 (dd. J = 3.5, 6.1 Hz,
1H), 5.74 (d, J = 3.1 Hz, 1H). 13C (100MHz, CDCl3): δ ppm 14.3, 25.6, 27.6, 61.7, 62.4,
79.1, 81.3, 86.2, 86.5, 114.2, 134.8, 146.3, 161.6. HRMSꢀESI: m/z [M+H]+ calcd for
C13H19N3O6H+, 314.1352, found 314.1340.
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ethyl
4ꢀ((5ꢀOꢀ(tertꢀbutyldiphenylsilyl)ꢀ2,3ꢀOꢀIsopropylideneꢀβꢀDꢀribosyl)ꢀ2Hꢀ1,2,3ꢀ
triazoleꢀ5ꢀcarboxylate (12). To a solution of 11 (0.54 g, 1.72 mmol) in anhydrous
acetonitrile (6.4 mL) were added imidazole (0.15 g, 2.24 mmol), 4ꢀ(dimethylamino)ꢀ
pyridine (0.23 g, 1.90 mmol) and tertꢀbutyldiphenylchlorosilane (0.47 g, 0.45 mL, 1.72
mmol). The mixture was stirred at room temperature for 1.5 h and then it was
concentrated. The residue was taken in ethyl acetate (10 mL) and washed with saturated
solution of sodium bicarbonate (1x5 mL). The water phase was extracted with ethyl
acetate (1x10 mL). The combined organic phases were dried over anhydrous sodium
sulfate, filtered and evaporated. The crude residue was purified by flash column
chromatography on silica gel (heptane/AcOEt 9:1 to 7:3) to give 12 as a colorless oil
(494 mg, 52%). 1H (400MHz, CDCl3): δ ppm 1.12 (s, 9H), 1.34 (s, 3H), 1.41 (t, J = 7.3
Hz, 3H), 1.60 (s, 3H), 3.62 (dd, J = 6.7, 11.7 Hz, 1H), 3.89 (dd, J = 3.8, 11.8 Hz, 1H),
4.28ꢀ4.32 (m, 1H), 4.38ꢀ4.50 (m, 2H), 4.60 (br s, 1H), 4.89 (br s, 1H), 5.67 (d, J = 2.5
Hz, 1H), 7.37ꢀ7.49 (m, 6H), 7.63ꢀ7.67 (m, 2H), 7.69ꢀ7.72 (m, 2H). 13C (100MHz,
CDCl3): δ ppm 14.2, 19.2, 25.4, 26.9, 27.2, 61.5, 63.8, 79.1, 81.5, 85.4, 85.8, 113.9,
127.9, 128.0, 130.2, 135.5, 135.6, 160.9. HRMSꢀESI: m/z [M+H]+ calcd for
C29H37N3O6SiH+, 552,2530, found 552.2524.
5ꢀbromoꢀ4ꢀ(5ꢀOꢀ(tertꢀbutyldiphenylsilyl)ꢀ2,3ꢀOꢀIsopropylideneꢀβꢀDꢀribosyl)ꢀ2Hꢀ1,2,3ꢀ
triazole (13). To a solution of derivative 1 (0.083 g, 0.173 mmol) in isopropyl acetate
(0.65 mL) was added NꢀBromosuccinimide (0.031 g, 0.173 mmol). The mixture was
stirred at 25 °C for 45 h. The solvent was evaporated and the residue was purified by
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