A one pot three-step process for the synthesis of an array of arylated benzimidazoribosyl nucleosides

Article abstract of DOI:10.1039/c0ob00866d

A three-step one pot reaction/purification protocol was developed to facilitate rapid access to benzimidazole-based nucleosides, for which benzoylated benzimidazoribosyl nucleosides incorporating boronic esters were key reaction intermediates.

Full text of DOI:10.1039/c0ob00866d

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PAPER
A one pot three-step process for the synthesis of an array of arylated
benzimidazoribosyl nucleosides†
Jolanta Hałuszczak,a Simon J. F. Macdonaldb and Marie E. Migaud*a
Received 12th October 2010, Accepted 5th January 2011
DOI: 10.1039/c0ob00866d
A three-step one pot reaction/purification protocol was developed to facilitate rapid access to
benzimidazole-based nucleosides, for which benzoylated benzimidazoribosyl nucleosides incorporating
boronic esters were key reaction intermediates.
Introduction
Since the discovery of nucleic acids, efforts in accessing natural and
synthetic nucleosides have been continuous in order to supply bi-
ologists and biochemists with useful synthetic materials.1 Much of
the recent work has focused on expanding the pool of nucleoside-
based antivirals2 and on accessing nucleoside analogues with novel
carbohydrate frameworks, such as locked nucleic acids (LNA) and
bicyclic nucleic acids (BNA)3 or nucleoside analogues with fluo-
rescent properties. The latter analogues4 have been employed to
label genes5 and to analyse DNA sequences,6,7 and have also been
used as building blocks in unnatural cofactors to explore enzyme
activities.8,9 Such activities include that of adenosine diphosphate
ribosylcyclase which converts nicotinamide adenine dinucleotide
(NAD) into the second messenger cyclic adenosine diphosphate
ribose (cADPR) (Scheme 1). This cyclase is able to convert a
wide range of substrates (e.g. nicotinamide guanine dinucleotide,
NGD) (Scheme 1) into cyclic analogues (e.g. cyclic guanosine
diphosphate ribose; cGDPR), which have been used to probe the
physiological properties of cADPR and the catalytic properties
of this enzyme.10,11 We are particularly interested in nucleosides
which, once converted to their dinucleotide parents, can be alky-
Scheme 1 Cyclisation of dinucleotides by ADP-ribosylcyclase.
lated through cyclisation by this enzyme, to become fluorescent
the Lewis acid promoted approach developed by Vorbru¨ggen.21
cyclised compounds. We postulated that benzimidazole-based
This method can be particularly effective in accessing a wide range
nucleosides would provide such opportunity.12–14 Surprisingly, this
of nucleoside analogues if the newly introduced nucleic base-mimic
class of modified nucleosides is under-represented in the literature.
can be subsequently functionalised. Therefore, this work reports
Several methods have been developed over the last 90 years for the
on the strategies adopted in the simple preparation of twenty three
synthesis of nucleosides.15 Amongst the most popular methods,
novel benzimidazole and azabenzimidazole nucleoside analogues.
glycosylations employing silver salts,16 chloromercury salts17 and
fusion18 sodium salts19 or phase transfer reaction conditions20 have
been extensively used. However, the most versatile method remains
Results and discussion
As mentioned above, Vorbru¨ggen’s glycosylation is known to be
extremely versatile and usually proceeds in high yields.22,23 Yet, for
the simple introduction of the bromo-substituted benzimidazoles
1 and 2 on the 1-O-acetyl-2,3,5-tri-O-benzoyl-b-D-ribofuranoside
3, the standard reaction conditions only gave poor to moderate
yields. This limitation had to be overcome if a parallel synthetic
program was to be developed from benzimidazole nucleoside
aQueen’s University Belfast, School of Pharmacy, Medical Biology Centre,
97 Lisburn Road, Belfast, U.K. BT9 7BL. E-mail: m.migaud@qub.ac.uk;
Tel: +44 289097 2689
bGlaxoSmithKline, Stevenage Pharmaceuticals R&D facility, Gunnels Wood
Road, Stevenage, Herts, U.K. SG1 2NY
† Electronic supplementary information (ESI) available: Additional infor-
mation on experimental details, more detailed tables and spectroscopic
data for all new compounds. See DOI: 10.1039/c0ob00866d
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Table 1 Comparison of reaction conditions for Vorbru¨ggen coupling
Substrates
Products
Number
Br position n =
Conditionsa
% yield
Compound number
Br position n =
Ratiob
1
1
2
5
5
4
a
b
b
53
97
80
5/6
5/5
4/7
5/6
5/6
4/7
45 : 55
63 : 37
79 : 21
a Reaction conditions a: i) HMDS; TMS-Cl, reflux, 24 h; ii) 1-O-acetyl-2,3,5-tri-O-benzoyl-b-D-ribofuranoside-3, TMSOTf, DCE, reflux, 2 h; b: 1-O-
acetyl-2,3,5-tri-O-benzoyl-b-D-ribofuranoside-3, BSA, TMSOTf, DCE, reflux, 2 h. b Yields ratio of isolated regioisomers.
precursors such as 4, 5, 6 and 7 (Table 1). Screening of several
reaction conditions ranging from solvent choice (e.g. MeCN, 1,2-
dichloroethane (DCE)) to silylation methods (e.g. hexamethyld-
isilazane (HMDS) vs. N,O-bis (trimethylsilyl)acetamide (BSA))
allowed the identification of improved reaction conditions.24,25
At first, 5-bromobenzimidazole 1, which had been dried by co-
evaporation with toluene, was silylated using HMDS as solvent
and TMSCl as catalyst. After 24 h at reflux and removal of
volatile materials, the silylated bromobenzimidazole was used in
Scheme 2 Cross-coupling of bromobenzimidazole nucleoside 6 with aryl
and heteroarylboronic acids.
the TMSOTf-catalysed ribosylation of 3. Extensive purification
of the crude mixture led to the isolation of 5 and 6 in 53%
overall yield (Table 1). When HMDS was replaced with BSA,
the overall yields increased to 97% under similar glycosylation
conditions, with regioisomer 5 obtained in 61% isolated yield
and its regioisomer 6 obtained in 36%. Coupling of riboside
3 with 4-bromobenzimidazole 2 using the optimized conditions
supplied benzimidazolide-ribosides 4 and 7 in 80% overall yields
in a 4 : 1 ratio, respectively (Table 1). Moreover, no a bromoben-
zimidazoleribosides were isolated in any of the reactions. The
four synthesised bromobenzimidazole nucleosides provided the
framework to develop a library of modified nucleosides using the
C–Br bond for further functionalisation.
be noted that the stability of each boronic acid was found to be
similar.
To broaden the scope of suitable reagents, the Stille-coupling
methodology was therefore considered, as this strategy is known
to work well under mild conditions and can be applied to
various types of substrate.30–32 The coupling of the bromoben-
zimidazolide 6 with 2-pyridyl tributylstannane in the presence
of bis(triphenylphosphine)palladium(II) dichloride in dry DMF
yielded product 8 in 46% yield (Scheme 3). While more successful
than the previous method, this methodology was deemed unsuit-
able due to the limited commercial availability of reagents.
Of the many methods available for C–C bond for-
mation on aryl species,
a Suzuki coupling was initially
investigated.26,27 The reaction between starting compound 6
and 3-pyridinylboronic acid was carried out in the presence
of 1,2,3,4,5-pentaphenyl-1¢-(di-tert-butylphosphino)ferrocene (Q-
Phos), tris[dibenzylideneacetone]dipalladium(0) (Pd2(dba)3) and
potassium fluoride under microwave reaction conditions (Scheme
2). These slightly basic conditions are known to allow for the use
of less reactive aromatic halides and alkyl boronic acids in Suzuki
cross-coupling reactions.28,29
As our initial intentions were to perform the coupling while
minimising sugar deprotection reaction, it was hoped that the
potassium fluoride was sufficiently reactive to contribute to the
coupling reaction and non-nucleophilic towards benzoates. Crude
materials were then purified by reversed phase HPLC. Under these
conditions, compound 8 could only be isolated in 2% yield from
6 and pyridylboronic acid, while compound 9 could be obtained
in 69% yield from 6 and phenylboronic acid (Scheme 2). It must
Scheme 3 Stille coupling between bromobenzimidazole nucleoside 6 and
aryl stannane.
Given our desire to develop a versatile methodology which
included the coupling of heteroaromatics to the benzimidazolide,
we then considered inverting the bromo/boronate functionalities
between the substrate and the reagent to facilitate the C–C bond
formation and gain access to a greater range of commercial
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reagents. It was anticipated that, stable boronate esters of protected
benzimidazolides would undergo Pd(0)-catalysed Suzuki coupling
reactions with a broad range of aryl halides. As such we developed
a three-step one pot strategy for which the bromide on benzim-
idazolide 6 was exchanged for a boronic ester to form 10 which
subsequently reacted with a range of aromatic and heteroaromatic
bromides with the concomitant removal of the benzoyl protecting
groups to yield a library of nucleoside analogues.
As proof of principle, 6-bromobenzimidazolide riboside 6
(Scheme 4) was coupled with bis(pinacolato)diboron in the
presence of 2-(dicyclohexylphosphino)-2¢,4¢,6¢-triisopropyl-1,1¢-
biphenyl (X-Phos), Pd2(dba)3 and potassium acetate in anhydrous
dioxane.33,34 Anhydrous conditions and a change of ligands were
important for the formation of the boronic ester 10 and minimi-
sation of side reactions, e.g. protodeboronation.35 After heating,
the aryl halide, potassium phosphate, ligand and palladium were
added to the reaction mixture and heated at 140 ◦C for three
hours. Conditions required for the activation of the boronic
ester in the presence of aqueous base also cause the removal of
the benzoyl protective groups, yielding the deprotected arylated
benzimidazolide nucleoside analogue 11 (Scheme 4, 5). This one-
pot procedure effectively eliminates the need for purification of the
boronic ester 10 and that of the coupled protected product, thus
leading directly to the new nucleoside derivative.
Scheme 5 Accessing different substitution patterns on the benzimidazole
ring.
To show that this simple strategy could be applied to
other benzimidazole-based bromides than 6, 3-bromopyridine
was reacted with the four different benzimidazolide deriva-
tives 4–7 (Scheme 5). Coupling of the four different bromo-
benzimidazolides yielded compounds 11, 12 and 14 in moderate to
reasonable yields while 7-bromobenzimidazolide 7 gave a mixture
of products which included regioisomers 13 and 14. To investigate
the boronylation yields, progress of the reaction was monitored
by LCMS. The collected data suggested that all the substrates
(4–7) were fully consumed with the yields of the boronylations
summarised in Table 2.
The results indicated that boronylation of sterically hindered
bromobenzimidazoleribosides 4 and 7 occurred with lower yields.
Steric effects have previously been reported to influence boronic
esters’ syntheses and coupling of sterically hindered boronates.36,37
This could explain low yields obtained for compound 14 and the
mixture of products observed for 13.
To expand efficiently on the range of modified benzimidazole
nucleosides and establish the robustness of the strategy, boronic
ester derivative 16 was reacted with a range of aromatic and
heteroaromatic bromides, using a split-vial approach for which
solutions of base (K3PO4) and catalysts (X-phos, Pd2dba3) were
prepared and split equally between the vials containing 16 and
Scheme 4 Three-step one pot synthetic strategy via in situ generation of
the benzimidazoloborono ester nucleoside 10 and synthesis of 11.
Table 2 Comparison of boronylation yields for the first step (i) in Scheme 5a
% HPLC peak area of benzimidazolideriboside by-productb
Reagent
Br position n =
% HPLC peak area of boronylation
4
5
6
7
4
5
6
7
35
76
88
6
18
20
10
82
a Other products remained unidentified. b Protodeboronation product.
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Table 3 Nucleosides from aryl bromides
Table 4 Nucleosides from heteroaromatic bromides
% isolated yield
over 3 steps
Entry
1
Compound number
R
27
31
40
61
2
3
12
28
4
5
29a
30a
11
12
% isolated yield
over 3 steps
Entry
1
Compound number
R
17
45
5
31
12
2
3
4
18
19
20
18
15
23
6
7
32
33
23
32
8
9
34
35
16
20
5
21
22
6
7
8
22
23
24
20
19
48
10
36
No reaction
a 3-bromopyrazole was used in these syntheses (two separate runs).
achieved when partially optimised conditions were applied (e.g. 11,
12). Using this divergent strategy, nineteen novel benzimidazole
nucleosides could be prepared and purified in a timely fashion.
Even the pyridinyl and carboxylic acid derivatives (12, 27 and 28)
and (21–23), respectively, could be accessed under these automated
conditions.
9
25
26
17
31
10
Preliminary investigation of the fluorogenicity of the novel
compounds was examined to establish whether the fluorescence
emission spectra of the synthesised nucleosides would red shift
upon alkylation. As such compound 33 was reacted with methyl
iodide in methanol and excitation-emission spectra of the crude
mixture were collected. The alkylation mixture consisted mainly
of compounds 33 and the methylated parent (37) as measured by
its coupling partner. To ease product isolation and following a
one-fit all reaction protocol, a simple operative procedure was
developed where by the solvents were evaporated and the residue
re-dissolved in a 1 : 1 H2O/MeOH mixture. This mixture was
filtered once through an SPE filter and purified by mass-directed
reverse phase HPLC. While the yields of reactions (Table 3 and 4)
with the aromatic and heteroaromatic bromides range from poor
to average, the variability can be accounted for by a combination
of different reaction rates according to the coupling partner and
the one-fit-all purification protocol. However, good yields were
1
mass spectroscopy and H NMR. For compound 33 excitation
maximum was observed at 290 nm while the emission maximum
was found at 350 nm. As for the mixture of compounds 33 and
the methylated parent (37), a second excitation maximum was
detected at 300 nm and when the solution was excited at 300
nm a red shift to approximately 420 nm was observed (graph
in supplementary material). These preliminary data suggest our
2824 | Org. Biomol. Chem., 2011, 9, 2821–2831
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choice of benzimidazole derivatives could lead to fluorogenic
dinucleotides, suitable substrates for the ADP-ribosylcyclase.
Mass-directed autopreparation was carried out using a Waters
Micromass ZQ platform in one of the following conditions:
Method A: Sunfire C18 column (150 mm ¥ 30 mm i.d. 5 mm
packing diameter) at ambient temperature with a flow rate of
40 ml min-1 and an injection volume of 1 ml. UV detection was in
the range 210–350 nm. The mobile phase consisted of 0.1% formic
acid in water (solvent 1) against 0.1% formic acid in acetonitrile
(solvent 2) with a gradient of 95% solvent 1 for 1 min changing to
70% solvent 1 over 9 min, changing to 99% solvent 2 over 0.5 min
and maintained for 4.5 min.
Method B: Sunfire C18 column (150 mm ¥ 30 mm i.d. 5 mm
packing diameter) at ambient temperature with a flow rate of
40 ml min-1 and an injection volume of 1 ml. UV detection was in
the range 210–350 nm. The mobile phase consisted of 0.1% formic
acid in water (solvent 1) against 0.1% formic acid in acetonitrile
(solvent 2) with a gradient of 95% solvent 1 for 1 min changing
to 70% solvent 1 over 19 min, changing to 99% solvent 2 over 0.5
min and maintained for 4.5 min.
Conclusions
Herein, we have described a methodology which offers far-ranging
opportunities for the synthesis and purification of benzimidazole-
based nucleosides using boronate nucleosides as synthetic interme-
diates. Although some of the yields are low, the range of derivatives
thus prepared demonstrates the breadth of this methodology,
especially considering how under-represented in the literature
this class of nucleoside analogues is. As such, it offers access to
benzimidazole based nucleosides, which is time and cost effective.
Experimental Section
General
Chemicals and solvents were obtained from Aldrich, ALLICHEM
LLC, Chemical block Ltd., ABCR Gelest Ltd. (UK), Priceton Bio,
KairoKem and used without further purification.
A range of LC/MS purification protocols have been developed
for this work:
Method C: XBridge C18 column (100 mm ¥ 30 mm i.d. 5 mm
packing diameter) at ambient temperature with a flow rate of
40 ml min-1 and an injection volume of 1 ml. UV detection was
in the range 210–350 nm. The mobile phase consisted of 10 mm
ammonium bicarbonate in water against acetonitrile (solvent 2)
with a gradient of 95% solvent 1 for 1 min changing to 70%
solvent 1 over 9 min, changing to 99% solvent 2 over 0.5 min
and maintained for 4.5 min.
Method D: XBridge C18 column (100 mm ¥ 30 mm i.d. 5 mm
packing diameter) at ambient temperature with a flow rate of
40 ml min-1 and an injection volume of 1 ml. UV detection was
in the range 210–350 nm. The mobile phase consisted of 10 mm
ammonium bicarbonate in water (solvent 1) against acetonitrile
(solvent 2) with a gradient of 70% solvent 1 for 1 min changing
to 15% solvent 1 over 19 min, changing to 99% solvent 2 over 0.5
min and maintained for 4.5 min.
System I consisted of a Waters ZQ platform with an Agilent/HP
1100 auto sampler. The HPLC analysis was conducted on a Sunfire
C18 column (30 mm ¥ 4.6 mm i.d. 3.5 mm packing diameter) at
30 ◦C with a flow rate of 3 ml min-1 and an injection volume of 5
mL. UV detection was in the range 210–350 nm. The mobile phase
consisted of 0.1% formic acid in water (solvent A) against 0.1%
formic acid in acetonitrile (solvent B) with a gradient of 97% A
for 0.1 min changing to 100% B over 4.2 min, maintained for 0.6
min and then reverting to 97% A over 0.1 min.
System II consisted of a Waters ZQ platform with an Agi-
lent/HP 1100 auto sampler. The HPLC analysis was conducted
on a Sunfire C18 column (30 mm ¥ 4.6 mm i.d. 3.5 mmpacking
diameter) at 30 ◦C with a flow rate of 3 ml min-1 and an injection
volume of 5 mL. UV detection was in the range 210–350 nm.
The mobile phase consisted of 0.1% trifluoroacetic acid in water
(solvent A) against 0.1% trifluoroacetic acid in acetonitrile (solvent
B) with a gradient of 97% solvent 1 for 0.1 min changing to 100%
B over 4.2 min, maintained for 0.6 min and then reverting to 97%
A over 0.1 min. (TFA)
Experimental procedures
5-Bromo-1-(2¢,3¢,5¢-tri-O-benzoyl-b-D-ribofuranosyl)benzimida-
zole (5) and 6-bromo-1-(2¢,3¢,5¢-tri-O-benzoyl-b-D-ribofuranosyl)-
benzimidazole (6). HMDS method. A solution of 5-bromobenzi-
midazole (2 g, 10.1 mmol, 1.15 equiv.) in HMDS (20 ml) with
a catalytic amount of TMS-Cl (100 ml) was refluxed for 24 h.
The excess of solvent was then removed by co-evaporation with
toluene in vacuo. The residue was redissolved in DCE (20 ml) and
combined with a previously prepared solution of 1-O-acetyl-2,3,5-
tri-O-benzoyl-b-D-ribofuranose (4.45 g, 8.82 mmol, 1 equiv.) with
TMSOTf (4.3 g, 19 mmol, 2.2 mmol) in DCE (20 ml). The reaction
mixture was heated to reflux for 2 h and quenched by pouring onto
a saturated potassium carbonate solution (30 ml). The organic
layer was then diluted with DCM and washed with a saturated
potassium carbonate solution (30 ml) and water (3x 30 ml) before
it was dried over MgSO4, filtered and concentrated in vacuo. The
crude mixture was purified by silica column chromatography with
a solvent gradient (5% AcOEt, 30% c-hex, 65% DCM to 10%
AcOEt, 30% c-hex, 60% DCM) to yield 1.38 g (24%) of the 5-
substituted product 5 and 1.63 g (29%) of the 6-substituted product
6.
System III consisted of a Waters ZQ platform with an Agi-
lent/HP 1100 auto sampler. The HPLC analysis was conducted
on an XBridge C18 column (50 mm ¥ 4.6 mm i.d. 3.5 mm packing
diameter) at 30 ◦C with a flow rate of 3 ml min-1 and an injection
volume of 5 mL. UV detection was in the range 210–350 nm.
The mobile phase consisted of 10mM ammonium bicarbonate
in water adjusted to pH 10 with ammonia solution (solvent A)
against acetonitrile (solvent B) with a gradient of 99% A for 0.1
min changing to 97% B over 3.9 min, maintained for 1 min.
For system IV, the UPLC analysis was conducted on an UPLC
BEH C18 column (50 mm ¥ 2.1 mm i.d. 1.7 mmpacking diameter)
◦
at 40 C with a flow rate of 1 ml min-1 and an injection volume
of 5 mL. UV detection was in the range 210–350 nm. The mobile
phase consisted of 0.1% formic acid in water (solvent A) against
0.1% formic acid in acetonitrile (solvent B) with a gradient of 97%
A changing to 100% B over 1.5 min, maintained for 0.4 min and
then reverting to 97% A over 0.1 min.
5-Bromo-1-(2¢,3¢,5¢-tri-O-benzoyl-b-D-ribofuranosyl)benzimi-
dazole (5) and 6-bromo-1-(2¢,3¢,5¢-tri-O-benzoyl-b-D-ribofura-
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nosyl)benzimidazole (6). BSA method. A solution of 5-bromo-
benzimidazole (3 g, 15.2 mmol, 1.5 equiv.), 1-O-acetyl-2,3,5-tri-O-
benzoyl-b-D-ribofuranose (3; 5.12 g, 10.1 mmol, 1 equiv.) and TM-
SOTf (6.77 g, 30.5 mmol, 3 equiv.) in DCE (100 ml) including BSA
(9.29 g, 45.1 mmol, 4.5 equiv.) was refluxed for 3 h and quenched
by pouring onto a saturated potassium carbonate solution (50 ml).
The organic layer was then diluted with DCM and washed again
with a saturated potassium carbonate solution and then three
times with water. The organic phase was then dried over MgSO4
and concentrated. The crude was purified by silica column chro-
matography with a solvent gradient (5% AcOEt, 30% c-hex, 65%
DCM to 10% AcOEt, 30% c-hex, 60% DCM) to yield 3.98 g (61%)
of the 5-substituted product 5 and 2.33 g (36%) of the 6-substituted
product 6.
consisting of five steps: (1) heating to 110 ◦C, hold time: 15
min, (2) cooling: 5 min, (3) heating to 110 ◦C, hold time: 30
min, (4) cooling: 5 min, (5) heating to 110 ◦C, hold time: 60
min. The reaction progress was checked by LCMS and when
the peak for starting material had disappeared (MW = 639/641),
and new peaks appeared (MW = 606 or 688) additional Pd2dba3
(2.75 mg, 0.003 mmol) and ligand – X-phos (5.72 mg, 0.012 mmol)
were added. Then appropriate aromatic bromide (0.39 mmol,
1.3 equiv.) was dissolved in the suspension and finally K3PO4
(478 mg, 22.5 mmol) dissolved in 0.5 ml of water was added.
Another microwave reaction was carried out 140 ◦C for 3 h
(Biotage Initiator 2.5). After the reaction, solvents were removed,
residues redissolved in 2 ml of MeOH and filtered through
SPE filter. Purification of the final compound was done through
mass-directed autopreparation, splitting the crude mixture into
3 samples of 1 ml each. Solvents were removed through freeze
drying. Compounds were characterised.
4-bromo-1-(2¢,3¢,5¢-tri-O-benzoyl-b-D-ribofuranosyl)benzimida-
zole (4) and 7-bromo-1-(2¢,3¢,5¢-tri-O-benzoyl-b-D-ribofuranosyl)-
benzimidazole (7). BSA method. A solution of 4-bromobenzimi-
dazole (0.5 g, 2.54 mmol, 1.5 equiv.), 1-O-acetyl-2,3,5-tri-O-
benzoyl-b-D-ribofuranose (3; 0.854 g, 1.69 mmol, 1 equiv.) and
TMSOTf (0.83 g, 5.08 mmol, 3 equiv.) in DCE (100 ml) including
BSA (1.57 g, 7.62 mmol, 4.5 equiv.) was refluxed for 3 h and
quenched by pouring onto a saturated potassium carbonate
solution (50 ml). The organic layer was then diluted with DCM and
washed again with the a saturated potassium carbonate solution
and then three times with water. The organic phase was then dried
over MgSO4 and concentrated. The crude was purified by column
chromatography with a solvent gradient (5% AcOEt, 30% c-hex,
65% DCM to 10% AcOEt, 30% c-hex, 60% DCM) to yield 0.689
g (63%) of the 4-substituted product 4 and 185 mg (17%) of the
7-substituted product 7.
In the case of the synthesis of compounds 12 and 17–36 the
reaction of the first step of the coupling was carried out in one
◦
reaction vial containing the material for all 20 reactions (140 C
for 3 h Biotage Initiator 2.5). The reaction mixture was split into 20
vials and appropriate bromides were added. Palladium and ligand
(for all 20 reactions) were mixed in 1 ml of dioxane and split
equally into reactions, the same procedure was used in case of
potassium phosphate. The resulting mixture was reacted at 126 ◦C
for 3 h (Antonpaarsynthos 3000). After the reaction, solvents were
removed, residues redissolved in 3 ml of MeOH/water (50 : 50)
and filtered through SPE filter. Purification of the final compound
was performed through mass-directed autopreparation, splitting
the crude mixture into 3 samples of 1 ml each. Only 1 ml was
purified37 and the yield was calculated by multiplying the mass by
three. Solvents were removed through freeze drying.
General procedure for cross - coupling with aryl boronic
acids. A mixture of 6-bromo-1-(2¢,3¢,5¢-tri-O-benzoyl-b-D-ribo-
furanosyl)benzimidazole (6; 108 mg, 0.17 mmol, 1 equiv.), boronic
acid (0.202 mmol, 1.2 equiv), KF (0.336 mmol, 2 equiv.), Q-
phos (4.8 mg, 6.7 mmol) and Pd2dba3 (1.54 mg, 1.68 mmol) in
dry THF (200 ml) was prepared. The reaction mixture was then
heated in 100 ◦C for one hour (Biotage Initiator 2.5) and puri-
fiedby mass-directed autopreparation (Method C). The reaction
yielded 2 mg (2%) for 6-(3¢-pyridyl)-1-(2¢¢,3¢¢,5¢¢-tri-O-benzoyl-b-
D-ribofuranosyl)benzimidazole (8) and 74 mg (69%) 6-phenyl-1-
(2¢¢,3¢¢,5¢¢-tri-O-benzoyl-b-D-ribofuranosyl)benzimidazole (9).
4-Bromo-1-(2¢,3¢,5¢-tri-O-benzoyl-b-D-ribofuranosyl)benzimida-
zole (4). 1H NMR (400 MHz, CDCl3) d (ppm): 8.23 (s, 1H, H2),
8.13-8.11 (m, 2H, H-Ph), 8.00–7.93 (m, 4H, H-Ph), 7.65–7.38 (m,
11H, H-Ph, H5, H7), 6.97 (t, J = 8.0, 8.0 Hz, 1H, H6), 6.37 (d,
J = 6.1 Hz, 1H, H1¢), 6.05 (t, J = 5.9, 5.9 Hz, 1H, H2¢), 5.98
(dd, J = 4.1, 5.8 Hz, 1H, H3¢), 4.92 (dd, J = 2.6, 12.3 Hz, 1H,
H5¢), 4.88–4.83 (m, 1H, H4¢), 4.77 (dd, J = 3.3, 12.3 Hz, 1H,
H5¢); 13C NMR (100 MHz, CDCl3) d (ppm): 166.1 (C O), 165.3
(C O), 164.9 (C O), 143.0 (C9), 141.2 (C2), 133.9 (C8), 133.9
(C-Ph), 133.7 (C-Ph), 132.9 (C-Ph), 129.9(C-Ph), 129.8 (C-Ph),
129.7 (C-Ph), 129.1 (C-Ph), 128.8 (C-Ph), 128.6 (C-Ph), 128.6 (C-
Ph), 128.2 (C-Ph), 126.2 (C5), 124.6 (C6), 114.2 (C7), 110.2 (C4),
87.7 (C1¢), 80.9 (C4¢), 73.5 (C2¢), 71.0 (C3¢), 63.5 (C5¢); LC/MS
(system II): retention time: 3.60 min; UVmax = 280 nm; M.S. (ES) m
s-1: C33H25BrN2O7: calculated [M+H]+- 641.0923, actual [M+H]+-
641.0944.
Procedure for stannane coupling. 6-(3¢-pyridyl)-1-(2¢¢,3¢¢,5¢¢-tri-
O-benzoyl-b-D-ribofuranosyl)benzimidazole (8). To a mixture of
6-bromo-1-(2¢,3¢,5¢-tri-O-benzoyl-b-D-ribofuranosyl)benzimida-
zole (6) (50 mg, 0.078 mmol, 1 equiv.), 4-pyridyltributanestan-
nane (43 mg, 0.117 mmol, 1.5 equiv) and bis(triphenylphos-
phine)palladium(II) dichloride (8.8 mg, 12.6 mmol, 0.16 equiv.)
DMF (200 ml) was added. Then the reaction was performed at
120 ◦C for half an hour (Biotage Initiator 2.5) and purified by
mass-directed autopreparation (method D). The reaction yielded
23 mg (46%) of purified nucleoside (8).
5-Bromo-1-(2¢,3¢,5¢-tri-O-benzoyl-b-D-ribofuranosyl)benzimida-
zole (5). 1H NMR (600 MHz, CDCl3): 8.16 (s, 1H, H2), 8.12-
8.11 (m, 2H, H-Ph), 7.99–7.94 (m, 5H, H-Ph, H4), 7.65–7.39 (m,
10H, H-Ph, H7), 7.22 (dd, J = 1.7, 8.6 Hz, 1H, H6), 6.35 (d,
J = 5.8 Hz, 1H, H1¢), 6.02 (t, J = 5.8, 5.8 Hz, 1H, H2¢), 5.96 (dd,
J = 5.7, 4.6 Hz, 1H, H3¢), 4.92 (dd, J = 2.7, 12.4 Hz, 1H, H5¢),
General procedure for one pot three-step synthesis. Starting
materials (4, 5, 6 or 7, 192 mg, 0.3 mmol), bis(pinacolato)diboron
(83.8 mg, 0.33 mmol), potassium acetate (71 mg, 0.75 mmol),
Pd2dba3 (2.75 mg, 0.003 mmol) and X-phos (5.72 mg, 0.012 mmol)
were dissolved in dry 1,4-dioxane (1.5 ml). The reaction mixture
was placed in a microwave (Biotage Initiator 2.5) in a cycle
4.86–4.85 (m, 1H, H4¢), 4.76 (dd, J = 3.4, 12.4 Hz, 1H, H5¢); 13
C
NMR (125 MHz, CDCl3) d (ppm): 166.1 (C O), 165.3 (C O),
165.0 (C O), 141.7 (C9), 141.7 (C2), 134.0 (C-Ph), 133.9 (C-
Ph), 133.7 (C-Ph), 129.8 (C-Ph), 129.7 (C-Ph), 129.1 (C8), 128.8
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(C-Ph), 128.6 (C-Ph), 128.6 (C-Ph), 128.6 (C-Ph), 128.2 (C-Ph),
126.8 (C-Ph), 123.7 (C-Ph), 123.6 (C6), 116.2 (C4), 112.0 (C5),
110.0 (C7), 87.6 (C1¢), 80.7 (C4¢), 73.6 (C2¢), 71.0 (C3¢), 63.4 (C5¢);
IR: 3062(w), 2926 (w), 1725 (s), 1602 (w), 1584 (w), 1493 (w), 1452
(m); LC/MS (system II): retention time: 3.41 min; UVmax = 280
nm; M.S. (ES) m s-1:C33H25BrN2O7: calculated [M+H]+- 641.0923,
actual [M+H]+- 641.0936.
87.4 (C1¢¢), 80.9 (C4¢¢), 74.1 (C2¢¢), 71.3 (C3¢¢), 63.7 (C5¢¢); LC/MS
(system I): retention time: 2.82 min; UVmax = 294 nm; M.S. (ES)
m s-1:C38H29N3O7: calculated [M+H]+- 640.2084, actual [M+H]+-
640.2089.
6 - Phenyl - 1 - (2¢¢ , 3¢¢ , 5¢¢ - tri - O - benzoyl - b - D - ribofuranosyl)-
benzimidazole (9). 1H NMR (400 MHz, CDCl3) d (ppm): 8.26 (s,
1 H, H2), 8.08–8.06 (m, 2 H, H-Ph), 8.01–7.96 (s, 4 H, H-Ph), 7.87
(d, J = 6.0 Hz, 1 H, H4), 7.85 (s, 1 H, H7), 7.62–7.29 (m, 15 H,
H-Ph, H2¢-H6¢, H5), 6.47 (d, J = 6.0 Hz, 1 H, H1¢¢), 6.09 (t, J = 5.8,
5.8 Hz, 1 H, H2¢¢), 5.98 (dd, J = 4.0, 5.6 Hz, 1 H, H3¢¢), 4.92–4.88
(m, 2 H, H5¢¢,H4¢¢), 4.80 (dd, J = 4.3, 12.9 Hz, 1 H, H5¢¢);13C NMR
(100 MHz, CDCl3) d (ppm): 166.2 (C O), 165.3 (C O), 164.9
(C O), 143.3 (C8), 141.4 (C1¢), 140.6 (C2), 137.8 (C9), 133.9 (C-
Ph), 133.8 (C-Ph), 133.5 (C-Ph), 133.2 (C-Ph), 129.8 (C-Ph), 129.8
(C-Ph), 129.6 (C-Ph), 129.0 (C-Ph), 128.7 (C-Ph), 128.7 (C-Ph),
128.6 (C-Ph), 128.6 (C-Ph), 128.3 (C-Ph), 127.5 (C-Ph), 127.1 (C-
Ph), 123.2 (C5), 120.7 (C4), 119.6 (C6), 109.1 (C7), 87.4 (C1¢¢),
80.9 (C4¢¢), 74.2 (C2¢¢), 71.4 (C3¢¢), 63.8 (C5¢¢); IR: 3067 (w), 2957
(w), 1721 (s), 1600 (w), 1584 (w), 1476 (w), 1452 (m); LC/MS
(system III): retention time: 3.77 min; UVmax = 274 nm; M.S. (ES)
m s-1:C38H30N2O7: calculated [M+H]+- 639.2131, actual [M+H]+-
639.2142.
6-Bromo-1-(2¢,3¢,5¢-tri-O-benzoyl-b-D-ribofuranosyl)benzimida-
zole (6). 1H NMR (600 MHz, CDCl3): 8.16 (s, 1 H, H2), 8.12-8.14
(m, 2 H, H-Ph), 8.01–7.95 (m, 4 H, H-Ph), 7.84 (d, J = 1.6 Hz, 1 H,
H7), 7.66 (d, J = 8.6 Hz, 1 H, H4), 7.63–7.39 (m, 10 H, H-Ph,H5),
6.35 (d, J = 6.1 Hz, 1 H, H1¢), 6.00 (t, J = 5.9, 5.9 Hz, 1 H, H2¢), 5.97
(dd, J = 3.7, 5.6 Hz, 1 H, H3¢), 4.89 (dd, J = 2.6, 12.2 Hz, 1 H, H5¢),
4.87–4.86 (m, 1 H, H4¢), 4.78 (dd, J = 3.2, 12.2 Hz, 1 H, H5¢); 13
C
NMR (125 MHz, CDCl3) d (ppm): 166.2 (C O), 165.3 (C O),
165.0 (C O), 141.0 (C9), 141.0 (C2), 134.0 (C-Ph), 133.9 (C-Ph),
133.7 (C-Ph), 133.7 (C8), 129.9 (C-Ph), 129.8 (C-Ph), 129.8 (C-
Ph), 129.8 (C-Ph), 129.8 (C-Ph), 129.7 (C-Ph), 129.1 (C-Ph), 128.8
(C-Ph), 128.8 (C-Ph), 128.6 (C-Ph), 128.6 (C-Ph), 128.6 (C-Ph),
128.2 (C-Ph), 126.6 (C-Ph), 126.6 (C-Ph), 122.0 (C5), 117.2 (C4),
113.9 (C6), 110.0 (C7), 87.2 (C1¢), 81.0 (C4¢), 73.9 (C2¢), 71.26
(C3¢), 63.7 (C5¢); IR: 3065 (w), 2924 (w), 1722 (s), 1602 (w), 1583
(w), 1493 (w), 1451 (m); LC/MS (system II): retention time: 3.33
min; UVmax = 278 nm, M.S. (ES) m s-1:C33H25BrN2O7: calculated
[M+H]+- 641.0923, actual [M+H]+- 641.0931.
6-(3¢-Pyridyl)-1-(b-D -ribofuranosyl)benzimidazole (11). 1H
NMR (400 MHz, CD3OD) d (ppm): 8.87 (br. s, 1 H, H2¢), 8.54 (s,
1 H, H2), 8.50 (d, J = 4.5 Hz, 1 H, H6¢), 8.18–8.16 (m, 2 H, H7,
H4¢), 7.79 (d, J = 8.4 Hz, 1 H, H4), 7.61 (dd, J = 1.6, 8.4 Hz, 1 H,
H5), 7.52 (dd, J = 4.9, 7.9 Hz, 1 H, H5¢), 6.06 (d, J = 5.9 Hz, 1 H,
H1¢¢), 4.54 (t, J = 5.7, 5.7 Hz, 1 H, H2¢¢), 4.33 (dd, J = 3.7, 5.2 Hz, 1
H, H3¢¢), 4.19–4.16 (m, 1 H, H4¢¢), 3.91 (dd, J = 2.8, 12.2 Hz, 1 H,
H5¢¢), 3.83 (dd, J = 3.1, 12.2 Hz, 1 H, H5¢¢); 13C NMR (100 MHz,
CD3OD) d (ppm): 148.6 (C2¢), 148.4 (C6¢), 144.6 (C9), 144.2 (C2),
138.9 (C3¢), 136.9 (C4¢), 134,8 (C6), 134.2 (C8), 125.5 (C5¢), 123.4
(C5), 120.9 (C4), 111.6 (C7), 91.1 (C1¢¢), 87.2 (C4¢¢), 75.8 (C2¢¢),
71.8 (C3¢¢), 62.6 (C5¢¢); IR: 3192 (br), 2926 (w), 1579 (m), 1452 (m),
1417 (w); LC/MS (system I): retention time: 0.57 min; M.S. (ES)
m s-1: C17H17N3O4: calculated [M+H]+- 328.1297, actual [M+H]+-
328.1293.
7-Bromo-1-(2¢,3¢,5¢-tri-O-benzoyl-b-D-ribofuranosyl)benzimida-
zole (7). 1H NMR (400 MHz, CDCl3) d (ppm): 8.36 (s, 1 H, H2),
8.16–8.14 (m, 2 H, H-Ph), 8.01–7.93 (m, 4 H, H-Ph), 7.77 (dd, J =
0.7, 8.1 Hz, 1 H, H4), 7.64–7.37 (m, 11 H, H-Ph,H6,H1¢), 7.17
(t, J = 8.0, 8.0 Hz, 1 H, H5), 6.06 (t, J = 5.4, 5.4 Hz, 1 H, H2¢),
5.98 (t, J = 5.1, 5.1 Hz, 1 H, H3¢), 4.89 (dd, J = 2.8, 12.2 Hz, 1
H, H5¢), 4.85–4.83 (m, 1 H, H4¢), 4.74 (dd, J = 3.4, 12.2 Hz, 1
H, H5¢); 13C NMR (100 MHz, CDCl3) d (ppm): 166.2 (C O),
165.2 (C O), 164.9 (C O), 146.1 (C9), 141.1 (C2), 133.9 (C-Ph),
133.8 (C-Ph), 133.7 (C-Ph), 133.6 (C-Ph), 130.9 (C8), 129.9 (C-
Ph), 129.8 (C-Ph), 129.7 (C-Ph), 129.7 (C-Ph), 129.2 (C-Ph), 128.8
(C-Ph), 128.8 (C-Ph), 128.7 (C-Ph), 128.6 (C-Ph), 128.6 (C-Ph),
128.5 (C-Ph), 128.4 (C-Ph), 124.0 (C5), 120.3 (C4), 102.4 (C7),
86.1 (C1¢), 80.0 (C4¢), 75.2 (C2¢), 70.8 (C3¢), 63.5 (C5¢); LC/MS
(system II): retention time: 3.59 min; UVmax = 278 nm; M.S. (ES) m
s-1: C33H25BrN2O7: calculated [M+H]+- 641.0923, actual [M+H]+-
641.0955.
5-(3¢-Pyridyl)-1-(b-D -ribofuranosyl)benzimidazole (12). 1H
NMR (600 MHz, CD3OD) d (ppm): 8.84 (d, J = 2.0 Hz, 1 H, H2¢),
8.51 (dd, J = 1.3, 4.8 Hz, 1 H, H6¢), 8.38 (s, 1 H, H2), 8.15–8.13 (m,
1 H, H4¢), 7.95 (d, J = 1.3 Hz, 1 H, H4), 7.89 (d, J = 8.5 Hz, 1 H,
H7), 7.63 (dd, J = 1.7, 8.5 Hz, 1 H, H6), 7.53 (dd, J = 4.9, 7.8 Hz,
1 H, H5¢), 6.01 (d, J = 5.9 Hz, 1 H, H1¢¢), 4.49 (t, J = 5.6, 5.6 Hz,
1 H, H2¢¢), 4.30 (dd, J = 3.8, 5.3 Hz, 1 H, H3¢¢), 4.15 (q, J = 3.3,
3.3, 3.4 Hz, 1 H, H4¢¢), 3.89 (dd, J = 3.0, 12.1 Hz, 1 H, H5¢¢), 3.81
(dd, J = 3.4, 12.1 Hz, 1 H, H5¢¢); 13C NMR (150 MHz, CD3OD)
d (ppm): 148.6 (C-Ar), 148.4 (C-Ar), 145.2 (C-Ar), 144.1 (C-Ar),
139.0 (C-Ar), 136.8 (C-Ar), 134.4 (C-Ar), 133.9 (C-Ar), 125.5 (C-
Ar), 124.0 (C-Ar), 118.8 (C-Ar), 113.4 (C-Ar), 91.0 (C1¢¢), 87.1
(C4¢¢), 76.0 (C2¢¢), 71.8 (C3¢¢), 62.7 (C5¢¢); LC/MS (system I37):
retention time: 0.47 min; M.S. (ES) m s-1: C17H17N3O4: calculated
[M+H]+- 328.1297, actual [M+H]+- 328.1291.
6-(3¢-Pyridyl)-1-(2¢¢,3¢¢,5¢¢-tri-O-benzoyl-b-D-ribofuranosyl)-
benzimidazole (8). 1H NMR (600 MHz, CDCl3) d (ppm): 8.85
(s, 1 H, H2¢), 8.57 (d, J = 3.9 Hz, 1 H, H6¢), 8.26 (s, 1 H, H2),
8.07–7.96 (m, 6 H, H-Ph), 7.90 (d, J = 8.4 Hz, 1 H, H4), 7.87 (d,
J = 0.8 Hz, 1 H, H7), 7.81 (td, J = 1.8, 1.8, 7.7 Hz, 1 H, H4¢),
7.61–7.37 (m, 10 H, H-Ph, H5), 7.30–7.27 (m, 1 H, H5¢), 6.47 (d,
J = 5.8 Hz, 1 H, H1¢¢), 6.08 (t, J = 5.7, 5.7 Hz, 1 H, H2¢¢), 5.96 (t,
J = 4.9, 4.9 Hz, 1 H, H3¢¢), 4.93–4.90 (m, 2 H, H5¢¢,H4¢¢), 4.80 (dd,
J = 3.8, 12.6 Hz, 1 H, H5¢¢);13C NMR (150 MHz, CDCl3) d (ppm):
166.1 (C O), 165.3 (C O), 165 (C O), 148.6 (C2¢), 148.6 (C6¢),
148.3 (C9), 141.1 (C2), 134.7 (C3¢), 134.0 (C-Ph), 133.9 (C-Ph),
133.6 (C-Ph), 129.9 (C4¢), 129.8 (C6), 129.8 (C-Ph), 129.6 (C-Ph),
129 (C8), 129.0 (C-Ph), 128.7 (C-Ph), 128.7 (C-Ph), 128.7 (C-Ph),
128.6 (C-Ph), 128.6 (C-Ph), 128.6 (C-Ph), 128.6 (C-Ph), 128.3 (C-
Ph), 128.3(C-Ph), 123.5 (C5¢), 122.9 (C5), 121.3 (C4), 109.3 (C7),
7-(3¢-Pyridyl)-1-(b-D-ribofuranosyl)benzimidazole (13) in a mix-
ture. 1H NMR (600 MHz, CD3OD) and 13C NMR (125 MHz,
CD3OD) are shown in the Support Information; LC/MS (system
I): retention time: 0.76 min; UVmax = 264 nm; M.S. (ES) m
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s-1:C17H17N3O4: calculated [M+H]+- 328.1297, actual [M+H]+-
328.1288.
13C NMR (150 MHz, CD3OD) d (ppm): 144.9 (C-Ar), 143.6
(C-Ar), 142.7 (C-Ar), 139.6 (C-Ar), 139.6 (C-Ar), 138.2 (C-Ar),
133.6 (C-Ar), 129.8 (C-Ar), 129.0 (C-Ar), 128.7 (C-Ar), 125.4
(C-Ar), 124.3 (C-Ar), 118.3 (C-Ar), 112.7 (C-Ar), 91.0 (C1¢¢), 87.0
(C4¢¢), 75.9 (C2¢¢), 71.7 (C3¢¢), 62.7 (C5¢¢), 21.6 (CH3); LC/MS
(system I): retention time: 1.68 min; UVmax = 298 nm; M.S. (ES)
m s-1: C19H20N2O4: calculated [M+H]+- 341.1501, actual [M+H]+-
341.1497.
4-(3¢-Pyridyl)-1-(b-D -ribofuranosyl)benzimidazole (14). 1H
NMR (400 MHz, CD3OD) d (ppm): 9.03 (d, J = 1.2 Hz, 1 H, H2¢),
8.54 (d, J = 3.9 Hz, 1 H, H6¢), 8.34 (td, J = 1.5, 1.5, 9.9 Hz, 1 H,
H4¢), 8.26 (s, 1 H, H2), 7.81 (dd, J = 2.1, 7.0 Hz, 1 H, H7), 7.56
(dd, J = 4.9, 7.9 Hz, 1 H, H5¢), 7.47–7.42 (m, 1 H, H5 and H6),
6.02 (d, J = 5.7 Hz, 1 H, H1¢¢), 4.49 (t, J = 5.5, 5.5 Hz, 1 H, H2¢¢),
4.30 (dd, J = 4.0, 5.2 Hz, 1 H, H3¢¢), 4.15 (q, J = 3.3, 3.3, 3.3 Hz,
1 H, H4¢¢), 3.89 (dd, J = 3.0, 12.1 Hz, 1 H, H5¢¢), 3.80 (dd, J =
3.4, 12.2 Hz, 1 H, H5¢¢); 13C NMR (100 MHz, CD3OD) d (ppm):
150.1 (C-Ar), 148.6 (C-Ar), 143.6 (C-Ar), 142.3 (C-Ar), 138.7 (C-
Ar), 135.2 (C-Ar), 129.8 (C-Ar), 125.2 (C-Ar), 125.0 (C-Ar), 123.6
(C-Ar), 121.0 (C-Ar), 112.8 (C-Ar), 90.9 (C1¢¢), 87.0 (C4¢¢), 76.1
(C2¢¢), 71.7 (C3¢¢), 62.6 (C5¢¢); LC/MS (system I): retention time:
0.90 min; UVmax = 314 nm; M.S. (ES) m s-1: C17H17N3O4: calculated
[M+H]+- 328.1297, actual [M+H]+- 328.1284.
5-(4¢-Methylphenyl)-1-(b-D-ribofuranosyl)benzimidazole (19).
1H NMR (600 MHz, CD3OD) d (ppm): 8.50 (s, 1 H, H2), 7.85
(d, J = 0.8 Hz, 1 H, H4), 7.78 (d, J = 8.5 Hz, 1 H, H7), 7.58 (d,
J = 8.5 Hz, 1 H, H6), 7.53 (d, J = 8.0 Hz, 2 H, H2¢, H6¢), 7.25
(d, J = 7.9 Hz, 2 H, H3¢, H5¢), 5.99 (d, J = 5.8 Hz, 1 H, H1¢¢),
4.48 (t, J = 5.6, 5.6 Hz, 1 H, H2¢¢), 4.29 (dd, J = 4.1, 5.2 Hz, 1 H,
H3¢¢), 4.14 (ddd, J = 3.5, 3.5, 3.5 Hz, 1 H, H4¢¢), 3.88 (dd, J = 3.1,
12.1 Hz, 1 H, H5¢¢), 3.81 (dd, J = 3.5, 12.1 Hz, 1 H, H5¢¢); 13C
NMR (150 MHz, CD3OD) d (ppm): 143.6 (C-Ar), 139.9 (C-Ar),
138.0 (C-Ar), 137.9 (C-Ar), 133.5 (C-Ar), 130.5 (C-Ar), 130.5
(C-Ar), 128.1 (C-Ar), 128.1 (C-Ar), 124.1 (C-Ar), 118.1 (C-Ar),
112.7 (C-Ar), 111.4 (C-Ar), 91.0 (C1¢¢), 87.0 (C4¢¢), 75.9 (C2¢¢),
71.7 (C3¢¢), 62.7 (C5¢¢), 21.1 (CH3); LC/MS (system I): retention
time: 1.65 min; UVmax = 288 nm; M.S. (ES) m s-1: C19H20N2O4:
calculated [M+H]+- 341.1501, actual [M+H]+- 341.1504.
5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2¢,3¢,5¢-tri-
O-benzoyl-b-D-ribofuranosyl)benzimidazole (16). 1H NMR
(400 MHz, CDCl3) d (ppm): 8.28 (s, 1 H, H4), 8.22 (s, 1 H, H2),
8.13–8.11 (m, 2 H, H-Ph), 7.99–7.93 (m, 4 H, H-Ph), 7.68–7.37
(m, 11 H, H-Ph, H6, H7), 6.42 (d, J = 6.0 Hz, 1 H, H1¢), 6.04 (t,
J = 5.9, 5.9 Hz, 1 H, H2¢), 5.98 (dd, J = 4.1, 5.7 Hz, 1 H, H3¢),
4.91–4.83 (m, 2 H, H5¢, H4¢), 4.77 (dd, J = 3.3, 12.0 Hz, 1 H, H5¢),
1.36 (s, 12 H, CH3); 13C NMR (100 MHz, CDCl3) d (ppm): 166.2
(C O), 165.3 (C O), 164.9 (C O), 143.7 (C9), 140.7 (C2),
134.8 (C8), 133.9 (C-Ph), 133.8 (C-7), 133.6 (C-Ph), 130.0 (C-Ph),
129.9 (C-Ph), 129.8 (C-Ph), 129.7 (C-Ph), 129.1 (C-Ph), 128.8
(C-Ph), 128.6 (C-Ph), 128.6 (C-Ph), 128.3 (C-Ph), 127.8 (C4),
119.6 (C5), 109.9 (C6), 87.2 (C1¢), 83.8 (C(CH3)2), 80.8 (C4¢), 73.9
(C2¢), 71.2 (C3¢), 63.7 (C5¢), 24.9 (CH3); IR: 2978 (w), 1728 (s),
1602 (w), 1493 (w), 1452 (w); LC/MS (system I): retention time:
3.78 min; M.S. (ES) m s-1: C39H37BN2O9: calculated [M+H]+-
689.2670, actual [M+H]+- 689.2689.
5-(2¢,6¢-Dimethylphenyl)-1-(b-D-ribofuranosyl)benzimidazole
(20). 1H NMR (400 MHz, CD3OD) d (ppm): 8.53 (s, 1 H, H2),
7.83 (d, J = 8.3 Hz, 1 H, H7), 7.40 (d, J = 0.5 Hz, 1 H, H4), 7.15–
7.07 (s, 4 H, H6, H3¢, H4¢, H5¢), 6.02 (d, J = 5.9 Hz, 1 H, H1¢¢), 4.53
(t, J = 5.6, 5.6 Hz, 1 H, H2¢¢), 4.31 (dd, J = 3.8, 5.3 Hz, 1 H, H3¢¢),
4.15 (ddd, J = 3.4, 3.4, 3.4 Hz, 1 H, H4¢¢), 3.89 (dd, J = 3.1, 12.2 Hz,
1 H, H5¢¢), 3.82 (dd, J = 3.6, 12.2 Hz, 1 H, H5¢¢), 1.98 (s, 1 H, CH3,
CH3); 13C NMR (150 MHz, CD3OD) d (ppm): 144.7 (C-Ar),
143.1 (C-Ar), 139.9 (C-Ar), 137.5 (C-Ar), 137.2 (C-Ar), 137.2 (C-
Ar), 133.1 (C-Ar), 128.4 (C-Ar), 128.2 (C-Ar), 126.0 (C-Ar), 120.4
(C-Ar), 112.8 (C-Ar), 111.4 (C-Ar), 91.0 (C1¢¢), 87.1 (C4¢¢), 75.8
(C2¢¢), 71.8 (C3¢¢), 62.7 (C5¢¢), 21.1 (CH3), 21.1 (CH3); LC/MS
(system I): retention time: 1.75 min; UVmax = 276 nm; M.S. (ES)
m s-1: C20H22N2O4: calculated [M+H]+- 355.1658, actual [M+H]+-
355.1649.
5-(2¢-Methylphenyl)-1-(b-D-ribofuranosyl)benzimidazole (17).
1H NMR (400 MHz, CD3OD) d (ppm): 8.52 (s, 1 H, H2), 7.79 (d,
J = 8.4 Hz, 1 H, H7), 7.57 (d, J = 0.9 Hz, 1 H, H4), 7.28-7.21 (m,
5 H, H6, H3¢, H4¢, H5¢, H6¢), 6.01 (d, J = 5.8 Hz, 1 H, H1¢¢), 4.50
(t, J = 5.6, 5.6 Hz, 1 H, H2¢¢), 4.30 (dd, J = 3.8, 5.3 Hz, 1 H, H3¢¢),
4.14 (dd, J = 3.4, 6.9 Hz, 1 H, H4¢¢), 3.89 (dd, J = 3.1, 12.2 Hz, 1
H, H5¢¢), 3.81 (dd, J = 3.5, 12.2 Hz, 1 H, H5¢¢), 2.24 (s, 3 H, CH3);
13C NMR (100 MHz, CD3OD) d (ppm):143.6 (C1¢), 138.8 (C9),
136.7 (C2), 131.5, 131.2, 130.8, 129.5, 128.5, 127.0, 126.4 (C-Ph,
C5, C8), 121.2 (C7), 120.7 (C6), 112.3 (C4), 91.1 (C1¢¢), 87.2
(C4¢¢), 76.1 (C2¢¢), 72.0 (C3¢¢), 62.9 (C5¢¢), 20.9 (CH3); LC/MS
(system I37): retention time: 1.62 min; UVmax = 282 nm; M.S. (ES)
m s-1: C19H20N2O4: calculated [M+H]+- 341.1501, actual [M+H]+-
341.1493.
5-(2¢-Carboxyphenyl)-1-(b-D-ribofuranosyl)benzimidazole (21).
1H NMR (600 MHz, CD3OD) d (ppm): 8.85 (s, 1H, H2), 7.77–
7.73 (m, 2 H, H7, H3¢), 7.68 (d, J = 1.0 Hz, 1 H, H4), 7.51 (dt,
J = 1.3, 7.6, 7.6 Hz, 1 H, H5¢), 7.45–7.39 (m, 2 H, H4¢, H6¢), 7.37
(dd, J = 1.5, 8.4 Hz, 1 H, H6), 5.99 (d, J = 5.7 Hz, 1 H, H1¢¢),
4.48 (t, J = 5.5, 5.5 Hz, 1 H, H2¢¢), 4.29 (dd, J = 4.1, 5.3 Hz, 1
H, H3¢¢), 4.13 (ddd, J = 3.4, 3.4, 3.4 Hz, 1 H, H4¢¢), 3.88 (dd, J =
3.1, 12.1 Hz, 1 H, H5¢¢), 3.80 (dd, J = 3.5, 12.1 Hz, 1 H, H5¢¢);
13C NMR (150 MHz, CD3OD) d (ppm): 169.8 (C O), 148.0 (C-
Ar), 145.1 (C-Ar), 143.6 (C-Ar), 139.9 (C-Ar), 138.0 (C-Ar), 137.9
(C-Ar), 133.5 (C-Ar), 130.5 (C-Ar), 128.1 (C-Ar), 124.1 (C-Ar),
118.1 (C-Ar), 112.7 (C-Ar), 111.4 (C-Ar), 91.0 (C1¢¢), 87.0 (C4¢¢),
75.9 (C2¢¢), 71.7 (C3¢¢), 62.7 (C5¢¢); LC/MS (system I): retention
time: 1.21 min; UVmax = 286 nm; M.S. (ES) m s-1: C19H18N2O6:
calculated [M+H]+- 371.1243, actual [M+H]+- 371.1229.
5-(3¢-Methylphenyl)-1-(b-D-ribofuranosyl)benzimidazole (18).
1H NMR (600 MHz, CD3OD) d (ppm): 8.51 (s, 1 H, H2), 7.86
(d, J = 1.1 Hz, 1 H, H4), 7.79 (d, J = 8.5 Hz, 1 H, H7), 7.58
(dd, J = 1.5, 8.5 Hz, 1 H, H6), 7.46 (s, 1 H, H2¢), 7.42 (d, J =
7.7 Hz, 1 H, H6¢), 7.31 (t, J = 7.6, 7.6 Hz, 1 H, H5¢), 7.14 (d, J =
7.5 Hz, 1 H, H4¢), 5.99 (d, J = 5.8 Hz, 1 H, H1¢¢), 4.49 (t, J = 5.6,
5.6 Hz, 1 H, H2¢¢), 4.30 (dd, J = 4.0, 5.2 Hz, 1 H, H3¢¢), 4.14 (ddd,
J = 3.5, 3.5, 3.5 Hz, 1 H, H4¢¢), 3.89 (dd, J = 3.1, 12.1 Hz, 1 H,
H5¢¢), 3.81 (dd, J = 3.5, 12.2 Hz, 1 H, H5¢¢), 2.41 (s, 3 H, CH3);
5-(3¢-Carboxyphenyl)-1-(b-D-ribofuranosyl)benzimidazole (22).
1H NMR (600 MHz, CD3OD) d (ppm): 8.53 (s, 1 H, H2), 8.30 (t,
J = 1.6, 1.6 Hz, 1 H, H2¢), 7.99 (dt, J = 1.1, 1.2, 7.8 Hz, 1 H, H4¢),
7.94 (d, J = 1.2 Hz, 1 H, H4), 7.88 (ddd, J = 1.1, 1.6, 7.7 Hz, 1 H,
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H6¢), 7.85 (d, J = 8.5 Hz, 1 H, H7), 7.64 (dd, J = 1.6, 8.5 Hz, 1 H,
H6), 7.55 (t, J = 7.7, 7.7 Hz, 1 H, H5¢), 6.01 (d, J = 5.8 Hz, 1 H,
H1¢¢), 4.49 (t, J = 5.6, 5.6 Hz, 1 H, H2¢¢), 4.30 (dd, J = 4.0, 5.3 Hz,
1 H, H3¢¢), 4.15 (ddd, J = 3.4, 3.4, 3.4 Hz, 1 H, H4¢¢), 3.89 (dd,
J = 3.1, 12.2 Hz, 1 HH5¢¢), 3.81 (dd, J = 3.5, 12.1 Hz, 1 H, H5¢¢);
13C NMR (150 MHz, CD3OD) d (ppm): 170.54 (C O), 145.09
(C-Ar), 143.85 (C-Ar), 143.00 (C-Ar), 137.10 (C-Ar), 133.96 (C-
Ar), 133.58 (C-Ar), 132.44 (C-Ar), 130.04 (C-Ar), 129.39 (C-Ar),
129.23 (C-Ar), 124.14 (C-Ar), 118.53 (C-Ar), 113.04 (C-Ar), 91.01
(C1¢¢), 87.03 (C4¢¢), 75.97 (C2¢¢), 71.77 (C3¢¢), 62.69 (C5¢¢); LC/MS
(system I): retention time: 1.32 min; UVmax = 286 nm; M.S. (ES)
m s-1: C19H18N2O6: calculated [M+H]+- 371.1243, actual [M+H]+-
371.1242.
(C5¢¢), 55.8 (OCH3); LC/MS (system I): retention time: 1.56 min;
UVmax = 303 nm; M.S. (ES) m s-1: C19H20N2O5: calculated [M+H]+-
357.1450, actual [M+H]+- 357.1459.
5-(4¢-Methoxyphenyl)-1-(b-D-ribofuranosyl)benzimidazole (26).
1H NMR (600 MHz, CD3OD) d (ppm): 8.48 (s, 1 H, H2), 7.82
(d, J = 1.2 Hz, 1 H, H4), 7.76 (d, J = 8.5 Hz, 1 H, H7), 7.58–7.54
(m, 3 H, H6, H2¢, H6¢), 7.00 (d, J = 8.8 Hz, 2 H, H3¢, H5¢), 5.98
(d, J = 5.8 Hz, 1 H, H1¢¢), 4.48 (t, J = 5.6, 5.6 Hz, 1 H, H2¢¢),
4.29 (dd, J = 4.0, 5.3 Hz, 1 H, H3¢¢), 4.13 (ddd, J = 3.5, 3.5,
3.5 Hz, 1 H, H4¢¢), 3.88 (dd, J = 3.1, 12.1 Hz, 1 H, H5¢¢), 3.83
(s, 3 H, OCH3), 3.80 (dd, J = 3.5, 12.1 Hz, 1 H, H5¢¢); 13C NMR
(150 MHz, CD3OD) d (ppm): 160.6 (C2¢), 145.0 (C-Ar), 143.5 (C-
Ar), 137.8 (C-Ar), 135.2 (C-Ar), 133.2 (C-Ar), 129.3 (C-Ar), 129.3
(C-Ar), 123.9 (C-Ar), 117.8 (C-Ar), 115.3 (C-Ar), 115.3 (C-Ar),
112.6 (C-Ar), 90.9 (C1¢¢), 86.9(C4¢¢), 75.9 (C2¢¢), 71.7 (C3¢¢), 62.7
(C5¢¢), 55.8 (OCH3); LC/MS (system I): retention time: 1.49 min;
UVmax = 310 nm; M.S. (ES) m s-1: C19H20N2O5: calculated [M+H]+-
357.1450, actual [M+H]+- 357.1442.
5-(4¢-Carboxyphenyl)-1-(b-D-ribofuranosyl)benzimidazole (23).
1H NMR (600 MHz, CD3OD) d (ppm): 8.53 (s, 1 H, H2¢), 8.09
(d, J = 8.4 Hz, 1 H, H3¢, H5¢), 7.96 (d, J = 1.3 Hz, 1 H, H4), 7.84
(d, J = 8.5 Hz, 1 H, H7), 7.75 (d, J = 8.4 Hz, 1 H, H2¢, H6¢), 7.67
(dd, J = 1.6, 8.5 Hz, 1 H, H6), 6.00 (d, J = 5.8 Hz, 1 H, H1¢¢),
4.49 (t, J = 5.6, 5.6 Hz, 1 H, H2¢¢), 4.30 (dd, J = 3.9, 5.3 Hz, 1
H, H3¢¢), 4.15 (ddd, J = 3.4, 3.4, 3.4 Hz, 1 H, H4¢¢), 3.89 (dd, J =
3.1, 12.1 Hz, 1 H, H5¢¢), 3.81 (dd, J = 3.5, 12.1 Hz, 1 H, H5¢¢);
13C NMR (150 MHz, CD3OD) d (ppm): 171.1 (C O), 146.6 (C-
Ar), 145.1 (C-Ar), 143.9 (C-Ar), 136.9 (C-Ar), 134.2 (C-Ar), 132.2
(C-Ar), 131.3 (C-Ar), 131.3 (C-Ar), 128.1 (C-Ar), 128.1 (C-Ar),
124.2 (C-Ar), 118.7 (C-Ar), 113.0 (C-Ar), 91.0 (C1¢¢), 87.1 (C4¢¢),
76.0 (C2¢¢), 71.8 (C3¢¢), 62.7 (C5¢¢); LC/MS (system I): retention
time: 1.25 min; UVmax = 298 nm; M.S. (ES) m s-1: C19H18N2O6:
calculated [M+H]+- 371.1243, actual [M+H]+- 371.1242.
5-(2¢-Pyridyl)-1-(b-D-ribofuranosyl)benzimidazole
(27). 1H
NMR (600 MHz, CD3OD) d (ppm): 8.61 (td, J = 1.2, 1.2, 4.9 Hz,
1 H, H6¢), 8.51–8.50 (m, 2 H, H2+H4¢), 8.26 (d, J = 1.4 Hz, 1 H,
H4), 7.95 (dd, J = 1.6, 8.5 Hz, 1 H, H6), 7.91–7.90 (m, 1 H, H3¢),
7.86 (d, J = 8.5 Hz, 1 H, H7), 7.35 (dd, J = 4.5, 8.9 Hz, 1 H, H5¢),
6.01 (d, J = 5.8 Hz, 1 H, H1¢¢), 4.49 (t, J = 5.5, 5.5 Hz, 1 H, H2¢¢),
4.30 (dd, J = 3.8, 5.3 Hz, 1 H, H3¢¢), 4.15 (q, J = 3.4, 3.4, 3.4 Hz,
1 H, H4¢¢), 3.89 (dd, J = 3.1, 12.1 Hz, 1 H, H5¢¢), 3.81 (dd, J =
3.3, 12.1 Hz, 1 H, H5¢¢); 13C NMR (150 MHz, CD3OD) d (ppm):
158.7 (C-Ar), 149.7 (C-Ar), 142.4 (C-Ar), 143.6 (C-Ar), 138.4
(C-Ar), 135.3 (C-Ar), 134.4 (C-Ar), 123.4 (C-Ar), 122.8 (C-Ar),
122.1 (C-Ar), 118.5 (C-Ar), 112.3 (C-Ar), 90.4 (C1¢¢), 86.5 (C4¢¢),
75.4 (C2¢¢), 71.2 (C3¢¢), 62.1 (C5¢¢); LC/MS (system I): retention
time: 0.87 min; UVmax = 316 nm; M.S. (ES) m s-1: C17H17N3O4:
calculated [M+H]+- 328.1297, actual [M+H]+- 328.1302.
5-(2¢-Methoxyphenyl)-1-(b-D-ribofuranosyl)benzimidazole (24).
1H NMR (600 MHz, CD3OD) d (ppm): 8.48 (s, 1 H, H2), 7.77
(d, J = 1.0 Hz, 1 H, H4), 7.73 (d, J = 8.4 Hz, 1 H, H7), 7.45 (dd,
J = 1.5, 8.4 Hz, 1 H, H6), 7.32–7.30 (m, 2 H, H4¢, H6¢), 7.07 (dd,
J = 0.8, 8.8 Hz, 1 H, H3¢), 7.02 (dt, J = 1.0, 7.4, 7.4 Hz, 1 H,
H5¢), 5.99 (d, J = 5.7 Hz, 1 H, H1¢¢), 4.48 (t, J = 5.5, 5.5 Hz, 1
H, H2¢¢), 4.29 (dd, J = 4.1, 5.2 Hz, 1 H, H3¢¢), 4.14 (ddd, J = 3.5,
3.5, 3.5 Hz, 1 H, H4¢¢), 3.89 (dd, J = 3.1, 12.2 Hz, 1 H, H5¢¢), 3.81
(dd, J = 3.2, 12.5 Hz, 1 H, H5¢¢), 3.78 (s, 3 H, OCH3); 13C NMR
(150 MHz, CD3OD) d (ppm): 158.0 (C2¢), 144.3 (C-Ar), 143.2 (C-
Ar), 135.3 (C-Ar), 133.1 (C-Ar), 132.2 (C-Ar), 132.0 (C-Ar), 129.7
(C-Ar), 126.6 (C-Ar), 122.0 (C-Ar), 121.0 (C-Ar), 112.7 (C-Ar),
111.7 (C-Ar), 91.0 (C1¢¢), 86.9 (C4¢¢), 75.9 (C2¢¢), 71.7 (C3¢¢), 62.7
(C5¢¢), 56.1 (OCH3); LC/MS (system I): retention time: 1.49 min;
UVmax = 298 nm; M.S. (ES) m s-1: C19H20N2O5: calculated [M+H]+-
357.1450, actual [M+H]+- 357.1451.
5-(4¢-Pyridyl)-1-(b-D-ribofuranosyl)benzimidazole
(28). 1H
NMR (600 MHz, CD3OD) d (ppm): 8.57 (d, J = 5.9 Hz, 2 H,
H2¢, H6¢), 8.42 (s, 1 H, H2), 8.07 (d, J = 1.2 Hz, 1 H, H4), 7.90 (d,
J = 8.5 Hz, 1 H, H7), 7.77 (dd, J = 1.5, 4.7 Hz, 2 H, H3¢, H5¢),
7.74 (dd, J = 1.6, 8.5 Hz, 1 H, H6), 6.01 (d, J = 5.9 Hz, 1 H, H1¢¢),
4.49 (t, J = 5.6, 5.6 Hz, 1 H, H2¢¢), 4.30 (dd, J = 3.8, 5.2 Hz, 1 H,
H3¢¢), 4.15 (ddd, J = 3.3, 3.3, 3.3 Hz, 1 H, H4¢¢), 3.89 (dd, J = 3.0,
12.1 Hz, 1 H, H5¢¢), 3.81 (dd, J = 3.4, 12.2 Hz, 1 H, H5¢¢); 13C
NMR (150 MHz, CD3OD) d (ppm): 151.1 (C-Ar), 150.5 (C-Ar),
150.5 (C-Ar), 145.1 (C-Ar), 144.4 (C-Ar), 135.1 (C-Ar), 134.0
(C-Ar), 123.8 (C-Ar), 123.3 (C-Ar), 123.3 (C-Ar), 118.9 (C-Ar),
113.5 (C-Ar), 91.0 (C1¢¢), 87.2 (C4¢¢), 76.1 (C2¢¢), 71.8 (C3¢¢), 62.7
(C5¢¢); LC/MS (system I): retention time: 0.43 min; UVmax = 312
nm; M.S. (ES) m s-1: C17H17N3O4: calculated [M+H]+- 328.1297,
actual [M+H]+- 328.1287.
5-(3¢-Methoxyphenyl)-1-(b-D-ribofuranosyl)benzimidazole (25).
1H NMR (600 MHz, CD3OD) d (ppm): 8.51 (s, 1 H, H2), 7.88 (d,
J = 1.2 Hz, 1 H, H4), 7.80 (d, J = 8.5 Hz, 1 H, H7), 7.59 (dd, J =
1.6, 8.5 Hz, 1 H, H6), 7.35 (t, J = 7.9, 7.9 Hz, 1 H, H5¢), 7.22–7.21
(m, 1 H, H6¢), 7.17 (s, 1 H, H2¢), 6.90 (ddd, J = 0.6, 2.5, 8.2 Hz, 1
H, H4¢), 5.99 (d, J = 5.8 Hz, 1 H, H1¢¢), 4.48 (t, J = 5.6, 5.6 Hz, 1
H, H2¢¢), 4.29 (dd, J = 3.9, 5.3 Hz, 1 H, H3¢¢), 4.14 (ddd, J = 3.4,
3.4, 3.4 Hz, 1 H, H4¢¢), 3.88 (dd, J = 3.1, 12.1 Hz, 1 H, H5¢¢), 3.85
(s, 3 H, OCH3), 3.81 (dd, J = 3.5, 12.1 Hz, 1 H, H5¢¢); 13C NMR
(150 MHz, CD3OD) d (ppm): 161.6 (C2¢), 145.0 (C-Ar), 144.2 (C-
Ar), 143.6 (C-Ar), 138.0 (C-Ar), 133.8 (C-Ar), 130.9 (C-Ar), 124.2
(C-Ar), 120.8 (C-Ar), 118.4 (C-Ar), 114.0 (C-Ar), 113.4 (C-Ar),
112.7 (C-Ar), 91.0 (C1¢¢), 87.0 (C4¢¢), 76.0 (C2¢¢), 71.8 (C3¢¢), 62.7
5-(1¢-Pyrazolyl)-1-(b-D-ribofuranosyl)benzimidazole (29). 1H
NMR (600 MHz, CD3OD) d (ppm): 8.43 (s, 1 H, H2), 7.89 (s,
1 H, H3¢), 7.82 (d, J = 1.0 Hz, 1 H, H5¢), 7.73 (d, J = 8.5 Hz,
1 H, H7), 7.55–7.53(m, 2 H, H6 and H4), 6.83 (dd, J = 0.8,
1.7 Hz, 1 H, H4¢), 5.96 (d, J = 5.8 Hz, 1 H, H1¢¢), 4.47 (t, J =
5.6, 5.6 Hz, 1 H, H2¢¢), 4.28 (dd, J = 4.0, 5.3 Hz, 1 H, H3¢¢), 4.13
(q, J = 3.4, 3.4, 3.4 Hz, 1 H, H4¢¢), 3.87 (dd, J = 3.1, 12.2 Hz, 1H,
H5¢¢), 3.80 (dd, J = 3.5, 12.1 Hz, 1 H, H5¢¢); 13C NMR (150 MHz,
CD3OD) d (ppm): 145.0 (C-Ar), 143.4 (C-Ar), 139.7 (C-Ar), 133.3
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(C-Ar), 129.3 (C-Ar), 128.0 (C-Ar), 123.0 (C-Ar), 117.0 (C-Ar),
112.8 (C-Ar), 109.9 (C-Ar), 90.9 (C1¢¢), 87.0 (C4¢¢), 75.9 (C2¢¢),
71.7 (C3¢¢), 62.7 (C5¢¢); LC/MS (system I): retention time: 0.99
min; UVmax = 292 nm; M.S. (ES) m s-1: C15H16N4O4: calculated
[M+H]+- 317.1250, actual [M+H]+- 317.1253.
113.3 (C-Ar), 90.9 (C1¢¢), 87.1 (C4¢¢), 76.0 (C2¢¢), 71.8 (C3¢¢), 62.7
(C5¢¢); LC/MS (system I): retention time: 1.41 min; UVmax = 308
nm; M.S. (ES) m s-1: C16H16N2O4S: calculated [M+H]+- 333.0909,
actual [M+H]+- 333.0911.
5-(2¢-Furanyl)-1-(b-D-ribofuranosyl)benzimidazole
(34). 1H
5-(3¢Pyrazolyl)-1-(b-D-ribofuranosyl)benzimidazole (30). 1H
NMR (500 MHz, CD3OD) d (ppm): 8.56 (s, 1H, H2), 8.50 (s,
1H, H1¢), 8.10 (s, 1H, H4), 7.85–7.80 (m, 2H, H6 and H7), 7.70
(d, J = 1.9, 1H, H5¢), 6.73 (d, J = 2.2, 1H, H4¢), 6.03 (d, J = 5.7,
1H, H1¢¢), 4.52 (t, J = 5.6, 1H, H2¢¢), 4.33 (dd, J = 4.0, 5.0, 1H,
H3¢¢), 4.19–4.17 (m, 1H, H4¢¢), 3.93 (dd, J = 2.8, 12.3, 1H. H5¢¢),
3.84 (dd, J = 12.1, 3.4, 1H, H5¢¢); 13C NMR (125 MHz, CD3OD)
d (ppm): 143.9 (C-Ar), 142.7 (C-Ar), 134.8 (C-Ar), 133.0 (C-Ar),
126.3 (C-Ar), 121.9 (C-Ar), 116.3 (C-Ar), 112.9 (C-Ar), 102.3
(C-Ar), 102.3 (C-Ar), 89.9 (C1¢¢), 86.0 (C4¢¢), 74.9 (C2¢¢), 70.7
(C3¢¢), 61.6 (C5¢¢); LC/MS (system IV): retention time: 0.39 min;
UVmax = 299 nm; M.S. (ES) m s-1:C15H16N4O4: calculated [M+H]+-
317.1250, actual [M+H]+- 317.1241.
NMR (600 MHz, CD3OD) d (ppm): 8.47 (s, 1 H, H2), 7.97 (d,
J = 0.9 Hz, 1 H, H4), 7.76 (d, J = 8.5 Hz, 1 H, H7), 7.69 (dd, J =
1.5, 8.5 Hz, 1 H, H6), 7.55 (d, J = 1.2 Hz, 1 H, H5¢), 6.75 (d, J =
3.3 Hz, 1 H, H3¢), 6.51 (dd, J = 1.8, 3.3 Hz, 1 H, H4¢), 5.97 (d, J =
5.8 Hz, 1 H, H1¢¢), 4.46 (t, J = 5.6, 5.6 Hz, 1 H, H2¢¢), 4.28 (dd, J =
3.9, 5.3 Hz, 1 H, H3¢¢), 4.13 (ddd, J = 3.4, 3.4, 3.4 Hz, 1 H, H4¢¢),
3.87 (dd, J = 3.1, 12.2 Hz, 1 H, H5¢¢), 3.80 (dd, J = 3.5, 12.1 Hz, 1
H, H5¢¢); 13C NMR (150 MHz, CD3OD) d (ppm): 155.5 (C-Ar),
144.8 (C-Ar), 143.8 (C-Ar), 143.2 (C-Ar), 133.6 (C-Ar), 128.0
(C-Ar), 121.1 (C-Ar), 115.1 (C-Ar), 112.9 (C-Ar), 112.7 (C-Ar),
105.5 (C-Ar), 90.9 (C1¢¢), 87.0 (C4¢¢), 75.9 (C2¢¢), 71.7 (C3¢¢), 62.7
(C5¢¢); LC/MS (system I): retention time: 1.32 min; UVmax = 316
nm; M.S. (ES) m s-1: C16H16N2O5: calculated [M+H]+- 317.1137,
actual [M+H]+- 317.1147.
5-(4¢-Isothiazolyl)-1-(b-D-ribofuranosyl)benzimidazole
(31).
5-(3¢-Furanyl)-1-(b-D-ribofuranosyl)benzimidazole
(35). 1H
1H NMR (400 MHz, CD3OD) d (ppm): 9.10 (s, 1 H, H5¢), 8.92 (s,
1 H, H3¢), 8.54 (s, 1 H, H2), 8.01 (d, J = 1.1 Hz, 1 H, H4), 7.84 (d,
J = 8.5 Hz, 1 H, H7), 7.70 (dd, J = 1.6, 8.5 Hz, 1 H, H6), 5.99 (d,
J = 5.9 Hz, 1 H, H1¢¢), 4.48 (t, J = 5.6, 5.6 Hz, 1 H, H2¢¢), 4.29 (dd,
J = 3.8, 5.3 Hz, 1 H, H3¢¢), 4.14 (dd, J = 3.4, 6.8 Hz, 1 H, H4¢¢),
3.88 (dd, J = 3.0, 12.2 Hz, 1 H, H5¢¢), 3.80 (dd, J = 3.4, 12.2 Hz, 1
H, H5¢¢); 13C NMR (150 MHz, CD3OD) d (ppm): 157.6 (C-Ar),
145.2 (C-Ar), 144.2 (C-Ar), 144.1 (C-Ar), 141.7 (C-Ar), 134.2
(C-Ar), 129.3 (C-Ar), 129.3(C-Ar), 124.1 (C-Ar), 118.5 (C-Ar),
113.4 (C-Ar), 91.1 (C1¢¢), 87.3 (C4¢¢), 76.1 (C2¢¢), 71.9 (C3¢¢), 62.8
(C5¢¢); LC/MS (system I): retention time: 1.15 min; UVmax = 290
nm; M.S. (ES) m s-1: C15H15N3O4S: calculated [M+H]+- 334.0862,
actual [M+H]+- 334.0858.
NMR (600 MHz, CD3OD) d (ppm): 8.48 (s, 1 H, H2), 7.92 (d,
J = 1.0 Hz, 1 H, H4), 7.75 (d, J = 8.5 Hz, 1 H, H7), 7.65 (dd,
J = 1.6, 8.5 Hz, 1 H, H6), 7.60 (dd, J = 1.7, 2.6 Hz, 1 H, H4¢),
7.49–7.47 (m, 2 H, H2¢, H5¢), 5.97 (d, J = 5.8 Hz, 1 H), 4.47 (t, J =
5.6, 5.6 Hz, 1 H), 4.29 (dd, J = 4.0, 5.3 Hz, 1 H), 4.13 (ddd, J =
3.4, 3.4, 3.4 Hz, 1 H), 3.88 (dd, J = 3.1, 12.2 Hz, 1 H), 3.80 (dd,
J = 3.5, 12.1 Hz, 1 H); 13C NMR (150 MHz, CD3OD) d (ppm):
144.9 (C-Ar), 143.7 (C-Ar), 143.6 (C-Ar), 133.4 (C-Ar), 132.8
(C-Ar), 127.4 (C-Ar), 127.3 (C-Ar), 123.6 (C-Ar), 120.8 (C-Ar),
117.6 (C-Ar), 112.8 (C-Ar), 90.9 (C1¢¢), 87.0 (C4¢¢), 75.9 (C2¢¢),
71.7 (C3¢¢), 62.7 (C5¢¢); LC/MS (system I): retention time: 1.24
min; UVmax = 298 nm; M.S. (ES) m s-1: C16H16N2O5: calculated
[M+H]+- 317.1137, actual [M+H]+- 317.1141.
5-(2¢-Thiophenyl)-1-(b-D-ribofuranosyl)benzimidazole (32). 1H
NMR (600 MHz, CD3OD) d (ppm): 8.50 (s, 1 H, H2), 7.90 (d,
J = 1.3 Hz, 1 H, H4), 7.76 (d, J = 8.5 Hz, 1 H, H7), 7.63 (dd,
J = 1.7, 8.5 Hz, 1 H, H6), 7.38 (dd, J = 1.1, 3.6 Hz, 1 H, H3¢),
7.34 (dd, J = 1.1, 5.1 Hz, 1 H, H5¢), 7.08 (dd, J = 3.6, 5.1 Hz, 1
H, H4¢), 5.97 (d, J = 5.8 Hz, 1 H, H1¢¢), 4.47 (t, J = 5.6, 5.6 Hz,
1 H, H2¢¢), 4.29 (dd, J = 3.9, 5.3 Hz, 1 H, H3¢¢), 4.14 (ddd, J =
3.4, 3.4, 3.4 Hz, 1 H, H4¢¢), 3.88 (dd, J = 3.1, 12.1 Hz, 1 H,
H5¢¢), 3.80 (dd, J = 3.5, 12.1 Hz, 1 H, H5¢¢);13C NMR (150 MHz,
CD3OD) d (ppm): 145.8 (C-Ar), 144.9 (C-Ar), 143.9 (C-Ar), 133.7
(C-Ar), 131.4 (C-Ar), 129.1 (C-Ar), 125.5 (C-Ar), 124.0 (C-Ar),
123.2 (C-Ar), 117.1 (C-Ar), 113.0 (C-Ar), 90.9 (C1¢¢), 87.0 (C4¢¢),
75.9 (C2¢¢), 71.7 (C3¢¢), 62.7 (C5¢¢); LC/MS (system I): retention
time: 1.48 min; UVmax = 325 nm; M.S. (ES) m s-1: C16H16N2O4S:
calculated [M+H]+- 333.0909, actual [M+H]+- 333.0906.
3-(Methyl)-5-(3¢-thiophenyl)-1-(b-D-ribofuranosyl)benzimida-
zole (37) in a mixture. 1H NMR (300 MHz, CD3OD) is shown
in the Supporting Information; UVmax = 300 nm; M.S. (ES) m
s-1:C17H19N2O4S: calculated [M+H]+- 347.1066, actual [M+H]+-
347.0965.
Acknowledgements
This research was supported by GSK and an FP6 EST-Marie
Curie Scholarship (MEST-CT-2005-020351).
Notes and references
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