Sonogashira reactions of α- and β-1-ethynyl-2-deoxyribosides: synthesis of acetylene-extended C-nucleosides

Article abstract of DOI:10.1016/j.tet.2009.11.030

An improved practical protocol for the synthesis of both anomers of 1-ethynyl-2-deoxiribosides 1 was developed. The Sonogashira coupling of ethynyldeoxyribosides 1 with various aryl- and heteroaryl halides was carried out under various conditions. It was

Full text of DOI:10.1016/j.tet.2009.11.030

Tetrahedron 66 (2010) 530–536
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Sonogashira reactions of
a- and b-1-ethynyl-2-deoxyribosides: synthesis
of acetylene-extended C-nucleosides
a
b,
a,b,
*
*
´ ˇ
Tomas Bobula , Michal Hocek , Martin Kotora
a Department of Organic and Nuclear Chemistry, Faculty of Science, Charles University in Prague, Hlavova 8, 128 43 Praha 2, Czech Republic
b
´
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Flemingovo nam. 2, 166 10 Praha 6, Czech Republic
a r t i c l e i n f o
a b s t r a c t
Article history:
An improved practical protocol for the synthesis of both anomers of 1-ethynyl-2-deoxiribosides 1 was
developed. The Sonogashira coupling of ethynyldeoxyribosides 1 with various aryl- and heteroaryl
halides was carried out under various conditions. It was found that the use of copper-free coupling
protocols could reduce the oxidative dimerisation in favour of arylalkynyldeoxyriboside formation.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 8 May 2009
Received in revised form
20 October 2009
Accepted 5 November 2009
Available online 10 November 2009
Keywords:
Alkynes
C-nucleosides
Aryl halides
Cross-coupling reactions
1. Introduction
promoted reactions such as the Pauson–Khand reaction,5 cyclo-
trimerizations,6,7 and also the Sonogashira coupling reaction.8–12
Since its discovery, the Sonogashira reaction1 has made an
incredible impact on the construction of various molecules and
has become a favourite synthetic tool in organic synthesis.2
Although a great deal of work has been devoted to the explora-
tion and explanation of factors influencing the course of the
Sonogashira reaction, there are a number of interesting issues,
such as reactivity of various alkynyl substrates, that should be
addressed and clarified. One typical example is the reactivity of
1-ethynylsaccharides that are potential candidates for the syn-
thesis of various C-glycoside or C-nucleoside derivatives. Among
For the Sonogashira reaction, the majority of these studies
concerned just the use of specific substrates (usually only -1-
ethynyldeoxyriboside) or the synthesis of specific targets and did
not assess the scope of the reaction.
b
Owing to the different spatial arrangement of the alkynyl moiety
in
a- and b-anomers of 1-ethynyldeoxyriboside derivatives, it is
reasonable to surmise that both anomers might display different
reactivity patterns. Indeed, we observed that during the cyclo-
trimerisation under Rh-catalysis,
tended to dimerise to the corresponding 1,4-bis(deoxyribosyl)but-
1-yn-3-ene as a side reaction. On the other hand, -1-ethyny-
deoxyriboside 1 a was completely devoid of this behaviour under
the same reaction conditions affording the cyclotrimerisation
products.7 In a similar fashion, coupling of 1
a with 3-iodoprope-
a-1-ethynydeoxyriboside 1aa
them
a
- and
b
-anomers of 1-ethynyldeoxyribosides 1 (Fig. 1) are
b
of special interest, because they could serve as starting materials
for the synthesis of various C-20-deoxyribosides that could be
used for the extension of the genetic alphabet,3 or for the con-
struction of acetylene-extended unnatural DNA.4 Despite their
importance, no reliable and efficient synthesis of these crucial
intermediates is available and the current syntheses suffer from
low yields, lack of selectivity, and difficult separation of anomers.
Recently, several groups entered this area and studied the be-
haviour of various 1-ethynyldeoxyribosides 1 in transition-metal
b
a
noic acids was plagued by oxidative dimerisation of the alkyne
to 1,4-bis(deoxyribosyl)buta-1,3-diyne in up to 60% yield.
Interestingly, no such tendency was observed for 1
other hand, oxidative dimerisation of 1 b to the corresponding
diyne (up to 50%) was observed by some9 but not others.8,10,11
b
a.12 On the
b
RO
O
RO
O
1
1
1
a, R = Tol
1 a, R = Tol
b
1 b
, R = Bn
, R = Bn
* Corresponding authors. Tel.: þ420 221 951 334; fax: þ420 221 951 326 (M.K.);
tel.: þ420 220 183 324; fax: þ420 220 183 559 (M.H.).
E-mail addresses: hocek@uochb.cas.cz (M. Hocek), kotora@natur.cuni.cz
(M. Kotora).
c, R = TBDMS
1 c, R = TBDMS
RO
RO
Figure 1. O-Protected 1-ethynyldeoxyribosides 1.
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.11.030

T. Bobula et al. / Tetrahedron 66 (2010) 530–536
531
In view of these observations, we decided to improve the syn-
thesis of 1 and to investigate the Sonogashira reaction of 1 a and
a with various aryl- and heteroaryl halides under several sets of
and essentially the same results were obtained with ethy-
nylmagnesium bromide.
a
1
b
Having both anomers of 1a in sufficient amounts, our attention
turned to the coupling reaction of 1 with organic halides. In order to
find the best reaction conditions for the Sonogashira coupling,
three variants of the reaction were used: (i) condition A (classical
conditions: PdCl2(CH3CN)2, PPh3, CuI, Et3N),1 (ii) copper-free
condition B (PdCl2(CH3CN)2, Cs2CO3, dicyclohexyl-(20,40,60-triiso-
propyl-biphenyl-2-yl)-phosphine),18 and (iii) copper-free condition
C (PdCl2(CH3CN)2, Cs2CO3, 2-dicyclohexylphosphino-20,60-dime-
thoxybiphenyl). All reactions were run until full consumption of
one of the starting materials (monitored by TLC).
reaction conditions.
2. Results and discussion
Prior to the coupling study, we wanted to address the issue of
and -1-ethynydeoxyribosides 1 a and 1 a preparation. It was
reported that these compounds could be easily prepared by the
reaction of the corresponding -halogenose with ethynylmagne-
a-
b
a
b
a
sium bromide in 60–70% isolated yields (along with minor amounts
of the furan derivative).7,13 However, the major product formed was
Initially, the Sonogashira reaction of
a-1-ethynyldeoxyriboside
1aa with various aryl halides was studied. The results are sum-
the a-anomer 1aa and the separation of the anomeric mixture into
individual anomers required the use of preparative HPLC. At the
outset we tried to affect the anomeric ratio in favour of the
marized in Table 2. The coupling with three substituted phenyl
iodides 2a–2c (Entries 1–3) proceeded under both conditions giv-
ing the corresponding products 3aa–3ac in acceptable isolated
yields. Somewhat better yields were obtained under copper-free
conditions (conditions B, 43–53% isolated yields) than under clas-
sical conditions (conditions A, 35–43% isolated yields). Moreover,
under condition A the coupling was plagued by oxidative dimer-
b
-anomer 1ba by carrying out the coupling reaction of ethy-
nylmagnesium bromide with halogenose in the presence of various
transition-metal catalytic systems such as Pd (Entries 1–6), Ni14
(Entry 7), Co15 (Entries 8 and 9), Fe16 (Entries 10 and 11), and Cu17
(Entry 12) salts (Table 1).
isation of
aa (5–15%). To avoid this undesirable side reaction, further
reactions were run only under conditions B or C. The coupling with
2- and 3-iodothiophenes 2d and 2e gave the expected products 3
a-1-ethynyldeoxyriboside to the corresponding diyne
4
Table 1
The reaction of halogenose with ethynylmagnesium bromide
ad
TolO
TolO
O
TolO
O
MgX
and 3ae in mediocre yields of 24% and 25%, respectively. The
O
+
conditions
Cl
TolO
TolO
Table 2
1 a and 1 a
The reaction of 1
a
a with various organyl halides 2
O
TolO
Catalytic systema (mol %)
Solvent
a
/
bb
Yieldc (%)
TolO
O
Entry
O
TolO
conditions
1
Pd(dba)2 (5), PPh3 (50)
Pd(PPh3)4 (10)
Pd(PPh3)4 (5)
Pd(OAc)2 (10), PCy3 (10)
PdCl2(MeCN)2 (10), PPh3 (20)
PdCl2(MeCN)2 (5) PPh3 (10)
Ni(acac)2 (10)
Co(acac)3 (14)
Co(acac)3 (40)
Fe(acac)3 (10)
FeCl3 (5)
THF
THF
THF
2/1
1/1
1/1
2/1
1/1
1/1
2/1
2/1
d
38 (13)
30 (15)
33 (6)
8 (10)
25 (10)
28 (6)
45 (15)
28 (9)
0 (7)
+ Ar
X
+
TolO
3 y
2
TolO
A, B, or C
2
TolO
3d
4
THF/NMPe
2
Ar
1
4
5
THF
THF
THF
THF
TMEDA
THF
TMEDA
THF
6d
7
Entry
1
2, Ar-X
3
3
a
a
y
Cond.a
Yieldb (%)
A (20 h)
B (2 h)
35
53
8
9
10
11
12
13f
a
b
c
MeOOC
NC
I
2/1
2/1
18 (19)
7 (2)
9 (5)
A (0.5 h)
B (2 h)
43
48
2
3
3
3
a
a
I
I
CuCl2 (5)
No added catalyst
THF
2/1
80 (5)
A (1 h)
B (2.5 h)
41
43
a
MeO
Typical reaction conditions: halogenose (1 equiv), ethynylmagnesium bromide
(1.5 equiv), 20 ꢀC unless otherwise noted. (Ethynylmagnesium bromide was added
in one portion).
4
5
3
3
a
a
d
e
B (6 h)
24
25
b
I
Anomeric ratio 1
a
a/1
ba.
S
c
Isolated yield of ethynyldeoxyriboside (anomeric mixture). Isolated yield of the
B (10 h)
furan by-product in parentheses.
S
I
d
Reaction was run at ꢁ20 ꢀC (1.1 equiv of halogenose), and using a slow addition
of ethynylmagnesium bromide (2 equiv).
e
6
3
a
f
B (3 h)
73
1/1 mixture.
f
N
I
Ethynylmagnesium chloride was used instead of bromide.
B (6 h)
33
61
Although the presence of the Pd catalysts led to an increase in
the proportion of the 1ba in a few cases (e.g., Entries 2, 3, 5, and
7
8
3
3
a
a
g
B (18 h)c
N
I
6), the overall yield of both anomers did not surpass 38% (Entry 1).
The highest yield of the desired products (45%) was achieved in
the presence of the Ni-catalyst (Entry 7). Regarding the catalysis
by Fe, Co, or Cu compounds, it proceeded with low efficiency with
respect to the alkynylation selectivity as well as to the combined
Br
h
B (30 h)
41
N
N
B (8 h)
C (5 h)
29
30
9
3
3
a
a
i
j
yields of 1aa and 1ba (Entries 8–12). Although the effort to affect
Br
coupling by transition-metal catalysis failed, we found that by
using ethynylmagnesium chloride, instead of the bromide, the
overall isolated yield of both anomers of 1a could be reproducibly
increased up to 80%, while the amount of the furan derivative was
suppressed to 5% (Entry 13). It should be also added that using of
ethynylmagnesium chloride in the transition-metal catalysed re-
actions did not have any positive effect on the product distribution
I
10
B (5 h)
17
Fe
a
The reaction time is in parentheses.
Isolated yields.
3-Bromopyridine was used.
b
c

532
T. Bobula et al. / Tetrahedron 66 (2010) 530–536
reaction with 2-iodopyridine 2f gave a good 73% yield of 3
prisingly, the reaction with 3-iodopyridine 2g gave rise to the
expected product 3 g in only 33% yield, whereas the use of
3-bromopyridine gave 3 g in 61% yield. The reaction with 3-bro-
mobipyridine 2h proceeded to give 3 h in 41% yield. The coupling
with 1-bromopyrene 2i was carried out under two conditions
(B and C), in both cases the corresponding product 3 i was
a
f. Sur-
iodoferrocene 2j gave the ferrocenyl derivative 3
should be also emphasised that oxidative dimerisation of 1
corresponding diyne like in the case of the
served in any of the cases.
b
j in 20% yield. It
a to the
a-anomer was not ob-
b
a
a
a
Although the isolated yields might seem to be in lower range, in
all cases the starting compounds 1 a and 1 a were fully consumed.
a
b
a
It should be pointed out that each reaction was accompanied by the
formation of tar like material, probably by oligomerisation of the
alkyne. Because it is well known that alkynes can be oligomerised
obtained in comparable yields of 29% and 30%, respectively. Finally,
the coupling with iodoferrocene 2j proceeded to give the ferrocenyl
derivative 3
compound by using an alternative approach based on alkyne-
alkyne metathesis of -1-propyn-1-yldeoxyriboside with propy-
nylferrocene19 did not yield any amount of the expected product.
In the next stage, we studied the coupling with the -anomer
a (Table 3). The reaction with aryl iodides 2a–2b proceeded well
to give the corresponding products 3 a–3 b in good yields of 57
and 47%, respectively. Surprisingly, the coupling with 2c afforded
c a poor yield of 13%. The reactions with 2- and 3-iodothiophenes
2d and 2e gave the expected products 3 d and 3 e in mediocre
yields of 32% and 41%, respectively. Coupling of 2-iodopyridine 2f
gave 3 f in 33% yield. Gratifyingly, the change of the reaction
conditions to C led to the increase in the yield to 70%. The reaction
with 3-iodopyridine 2g gave rise to the expected product 3 g in
50% yield (the use 3-bromopyridine gave 3 g in 43% yield). The
coupling with 3-bromobipyridine 2h proceeded to give 3 h in
a low yield of 19%. The reaction with 1-bromopyrene 2i gave rise to
in 36% under conditions C. Finally, the coupling with
a
j in 17% isolated yield. An attempt to prepare this
in Pd-complex based catalytic systems,20,21
1aa was allowed to
react under conditions B at 80 ꢀC for 4 h. After this period of time
the alkyne disappeared and a small amount diyne 4aa (8%) and
a polymeric material (56%) were isolated from the reaction mixture.
1H NMR spectroscopic analysis clearly showed the presence of the
deoxyribose moiety. This experiment proved that a part of the
starting material is consumed by undesirable oligomerisations.
a
b
1
b
b
b
3
b
3. Conclusion
b
b
We showed that 1-ethynyldeoxyribose derivatives undergo
Sonogashira reaction with various aryl, heteroaryl, and metal-
locenyl derivatives to give the cross-coupling products in reason-
able yields. The data obtained clearly show that the reaction course
could be controlled in individual cases by the conditions employed
(e.g., the change of phosphine, Table 3, Entry 6), as well as the
nature of the aryl halide (e.g., switching from the iodide to the
bromide resulted in higher yield, Table 2, Entry 7). In addition, we
showed that the alkynes are prone to oligomerisation under the
reaction conditions used diminishing the overall yield of the de-
sired cross-coupling products. However, since the oligomeric
products are not chromatographically mobile, the desired products
can be easily isolated. Worth of mention is the different suscepti-
b
b
b
b
3bi
Table 3
The reaction of 1
ba with various organyl halides 2
Ar
O
TolO
O
TolO
conditions
+
Ar
X
bility to oxidative dimerisation of 1aa and 1ba to give the corre-
B or C
1β
2
3βy
sponding diynes.7b The obtained results clearly indicate that
individual approach to each cross-coupling reaction should be
considered in order to achieve the efficient coupling with high
yields of the desired products. The final arylalkynyl derivatives can
be considered as novel acetylene-extended C-nucleosides with
tunable properties.
TolO
TolO
Entry
1
2, Ar-X
3
3
b
y
a
Cond.a
Yieldb (%)
57
b
B (2.5 h)
MeOOC
NC
I
2
3
4
5
3
3
3
3
b
b
b
b
b
B (3 h)
B (15 h)
B (4 h)
B (6 h)
47
13
32
41
I
I
4. Experimental
c
MeO
4.1. General procedure for the coupling of halogenose with
ethynylmagnesium bromide in the presence of transition-
metal catalysts
d
e
I
S
Reactions were performed under a protective atmosphere of
argon in dried 50 mL microwave vials. A 0.5 M THF solution of
ethynylmagnesium chloride (194 mg, 3.0 mL, 1.5 mmol) was added
to a solution of halogenose (388 mg, 1 mmol), catalyst, and ligand
in THF, NMP or TMEDA (8–10 mL) and the reaction mixture was
maintained at 20 ꢀC for 3 h. The reaction mixture was quenched
with 1 M HCl, extracted with EtOAc (3ꢂ10 mL), the combined or-
ganic fractions were washed with water (10 mL), brine (10 mL), and
dried over MgSO4. The volatiles were removed under reduced
pressure and column chromatography of the residue on silica gel
(40/1 toluene/acetone) yielded products (details are given in the
Supplementary data).
S
I
B (8 h)
C (12 h)
33
70
6
3
bf
N
I
B (6.5 h)
B (8 h)c
50
43
7
8
3
3
b
g
N
I
Br
bh
B (15 h)
19
N
N
B (8 h)
C (5 h)
29
36
9
3
3
b
i
j
Br
4.2. Reaction of halogenose with ethynylmagnesium chloride
I
10
b
B (12 h)
20
Fe
A 0.5 M THF solution of ethynylmagnesium chloride (194 mg,
3.0 mL, 1.5 mmol) was added to a solution of halogenose (388 mg,
1 mmol) and the reaction mixture was maintained at 20 ꢀC for 3 h.
The reaction mixture was quenched with 1 M HCl, extracted with
EtOAc (3ꢂ10 mL), the combined organic fractions were washed
a
The reaction time is in parentheses.
Isolated yields.
3-Bromopyridine was used.
b
c

T. Bobula et al. / Tetrahedron 66 (2010) 530–536
533
with water (10 mL), brine (10 mL), and dried over MgSO4. The
volatiles were removed under reduced pressure and column
chromatography of the residue on silica gel (40/1 toluene/acetone)
7.42–7.48 (m, 2H), 7.91–7.99 (m, 4H); 13C NMR (75 MHz, CDCl3)
21.7 (2C), 39.6, 52.2, 64.3, 68.8, 75.8, 82.4, 84.8, 91.3, 126.8, 126.9,
127.2, 128.2, 129.1 (2C), 129.2 (2C), 129.4 (2C), 129.7 (2C), 129.8 (2C),
131.6 (2C), 143.9, 144.1, 166.1, 166.2, 166.5; IR (neat) 3069, 3022,
d
yielded 302 mg (80%) of 2/1 mixture of the
a
- and
b
-anomer. The
n
spectroscopic characteristics were in agreement with the pre-
2997, 2953, 2920, 1718,1704, 1609, 1402,1268,1170, 1050,1017, 959,
770, 687 cmꢁ1; HRMS (EI) m/z for C31H28O7 calcd 512.1835, found
512.1820. Rf (3/1 hexane/EtOAc)¼0.40.
viously reported data.7a
4.3. General procedure for the classical Sonogashira
reaction (conditions A)
4.5.2. 1,4-Bis[1
yl]butadiyne (4aa). [
CDCl3) d 2.34 (m, 2H), 2.37 (s, 6H), 2.41 (s, 6H), 2.61–2.71 (ddd,
a-1,2-dideoxy-3,5-di-O-(4-toluoyl)-D-ribofuranos-1-
20
a]
þ44 (c 0.3, CHCl3); 1H NMR (300 MHz,
D
Et3N (27 mg, 37
PdCl2(CH3CN)2 (3.4 mg, 13
(5.0 mg, 26 mol), 1 a (50.0 mg, 0.13 mmol), and 2a–2c (0.13 mmol)
mL, 0.26 mmol) was added to a solution of
m
mol), PPh3 (7.0 mg, 26 mol), CuI
m
J¼13.8, 7.8, 6.6 Hz, 2H), 4.46–4.61 (m, 2H), 4.50–4.58 (m, 4H), 5.04
m
a
(dd, J¼8.1, 2.4 Hz, 2H), 5.50–5.53 (m, 2H), 7.19–7.25 (m, 8H), 7.90–
in dry THF (3 mL) and the reaction mixture was maintained at 20 ꢀC
until the starting material disappeared. Then the reaction mixture
was quenched with 1 M HCl, extracted with EtOAc (3ꢂ20 mL),
combined organic fractions were washed with H2O (10 mL), brine
(10 mL), and dried over MgSO4. The volatiles were removed under
reduced pressure and column chromatography of the residue on
silica gel (hexane/EtOAc) gave the desired products.
7.93 (m, 8H); 13C NMR (75 MHz, CDCl3)
d 21.7 (4C), 39.5 (2C), 64.1
(2C), 68.7 (2C), 69.7 (2C), 75.5 (2C), 79.0 (2C), 82.6 (2C), 126.6 (2C),
126.9 (2C), 129.1 (4C), 129.2 (4C), 129.7 (4C), 129.9 (4C), 143.9 (2C),
144.1 (2C),166.1 (2C), 166.2 (2C); IR (neat) n 3063, 3034, 2952, 2923,
2851, 1720, 1613, 1452, 1375, 1309, 1271, 1179, 1106, 1078, 1017, 837,
751, 695 cmꢁ1; HRMS (EI) m/z for C46H42O10 calcd 755.2856, found
755.2844. Rf (3/1 hexane/EtOAc)¼0.72.
4.4. General procedure for the copper/free Sonogashira
reaction (conditions B)
4.5.3. 1
a
-[(4-Cyanophenyl)ethynyl]-1,2-dideoxy-3,5-di-O-(4-tol-
b). Conditions A. 4-Iodobenzonitrile 2b
uoyl)]- -ribofuranose (3a
D
(30 mg, 0.13 mmol), reaction time 0.5 h. Column chromatography
(5/1 hexane/EtOAc) afforded 27 mg (43%) of the title compound as
a yellow solid and 3.0 mg (5%) of 4aa as dark brown oil. Conditions
B. 4-Iodobenzonitrile 2b (30 mg, 0.13 mmol), reaction time 2 h.
Reactions were performed under a protective atmosphere of
argon in dried microwave vials. A solution of PdCl2(CH3CN)2
(3.4 mg, 13
yl)-phosphine (19.0 mg, 40
a or 1 a (50 mg, 0.13 mmol) and 2a–2j (0.13 mmol) in dry ace-
m
mol), dicyclohexyl-(20,40,60-triisopropyl-biphenyl-2-
mmol), Cs2CO3 (112.0 mg, 0.35 mmol),
Column chromatography (5/1 hexane/EtOAc) afforded 30 mg (48%)
20
1
a
b
of the title compound as a yellow solid: mp 111–112 ꢀC; [
a
]
D
þ29 (c
tonitrile (3 mL) was heated to 80 ꢀC for 2–30 h. Then the reaction
mixture was quenched with H2O and the acetonitrile was removed
under reduced pressure. Residue was dissolved in EtOAc (10 mL),
washed with H2O (2ꢂ10 mL), brine (10 mL), and dried over MgSO4.
The volatiles were removed under reduced pressure and column
chromatography of the residue on silica gel (hexane/EtOAc) affor-
ded the desired products.
0.51, CHCl3); 1H NMR (300 MHz, CDCl3)
d 2.40 (s, 3H), 2.41 (s, 3H),
2.45–2.48 (m, 1H), 2.70 (ddd, J¼13.8, 6.6, 6.3 Hz, 1H), 4.50 (dd,
J¼12.0, 4.8 Hz, 1H), 4.55 (dd, J¼12.0, 4.2 Hz, 1H), 4.66–4.71 (m, 1H),
5.21 (dd, J¼7.8, 2.7 Hz, 1H), 5.54–5.60 (m, 1H), 7.10–7.14 (m, 2H),
7.20–7.26 (m, 2H), 7.43–7.48 (m, 2H), 7.55–7.59 (m, 2H), 7.90–7.92
(m, 2H), 7.93–7.95 (m, 2H); 13C NMR (75 MHz, CDCl3)
d 21.7 (2C),
39.5, 64.2, 68.7, 75.8, 82.5, 84.0, 92.9, 111.9, 118.3, 126.8, 126.9, 127.2,
129.1 (2C), 129.2 (2C), 129.7 (2C), 129.8 (2C), 131.9 (2C), 132.2 (2C),
4.5. General procedure for the copper/free Sonogashira
reaction (conditions C)
143.9, 144.2, 166.1, 166.2; IR (neat) n 3719, 3697, 3621, 2957, 2219,
1710, 1611, 1274, 1111, 1083, 752, 690, 668 cmꢁ1; HRMS (EI) m/z for
C30H25NO5 calcd 479.1733, found 479.1733. Rf (5/1 hexane/
EtOAc)¼0.24.
Reactions were performed under a protective atmosphere of
argon in dried microwave vials. A solution of PdCl2(CH3CN)2
(3.4 mg, 13
biphenyl (19.0 mg, 40
a (50 mg, 0.13 mmol) and 2f, 2i (0.13 mmol) in dry acetonitrile
m
mol), 2-dicyclohexylphosphino-20,60-dimethoxy-
4.5.4. 1
a
-[(4-Methoxyphenyl)ethynyl]-1,2-dideoxy-3,5-di-O-(4-tol-
c). Conditions A. 1-Iodo-4-methoxy-ben-
mmol), Cs2CO3 (112.0 mg, 0.35 mmol), 1
a
a or
uoyl)]- -ribofuranose (3a
D
1
b
zene 2c (31 mg, 0.13 mmol), reaction time 1 h. Column
chromatography (5/1 hexane/EtOAc) afforded 26 mg (41%) of the
title compound as a yellowish-brown oil and 5.0 mg (8%) of 4aa as
a dark brown oil. Conditions B. 1-Iodo-4-methoxy-benzene 2c
(31 mg, 0.13 mmol), reaction time 2.5 h. Column chromatography
(3 mL) was heated to 80 ꢀC for 5–12 h. Then the reaction mixture
was quenched with H2O and the acetonitrile was removed under
reduced pressure. Residue was dissolved in EtOAc (10 mL), washed
with H2O (2ꢂ10 mL), brine (10 mL), and dried over MgSO4. The
volatiles were removed under reduced pressure and column
chromatography of the residue on silica gel (hexane/EtOAc) affor-
ded the desired products.
(5/1 hexane/EtOAc) afforded 27 mg (43%) of the title compound as
20
a yellowish-brown oil: [
CDCl3)
a
]
D
þ10 (c 0.48, CHCl3); 1H NMR (400 MHz,
d
2.38–2.40 (m,1H) (overlapped with CH3–Tol signal), 2.40 (s,
3H), 2.41 (s, 3H), 2.68 (ddd, J¼13.7, 8.1, 6.9 Hz, 1H), 3.79 (s, 3H), 4.50
(dd, J¼11.8, 4.9 Hz, 1H), 4.56 (dd, J¼11.8, 4.0 Hz, 1H), 4.66–4.70 (m,
1H), 5.20–5.22 (m, 1H), 5.53–5.56 (m, 1H), 6.80–6.83 (m, 2H), 7.11–
7.15 (m, 2H), 7.20–7.25 (m, 2H), 7.30–7.35 (m, 2H); 7.90–7.92 (m, 2H),
4.5.1. 1
(4-toluoyl)]-
a
-[(4-Methoxycarbonylphenyl)ethynyl]-1,2-dideoxy-3,5-di-O-
D
-ribofuranose (3 a). Conditions A. Methyl 4-iodo-
a
benzoate 2a (35 mg, 0.13 mmol), reaction time 20 h. Column
chromatography (3/1 hexane/EtOAc) afforded 12 mg (35%) of the
title compound as an orange solid and 5 mg (14%) of 4aa as a dark
brown oil. Conditions B. Methyl 4-iodobenzoate 2a (35 mg,
0.13 mmol), reaction time 2 h. Column chromatography (3/1 hex-
ane/EtOAc) afforded 28 mg (53%) of the title compound as an or-
ange solid. Mp 89–91 ꢀC; [
(300 MHz, CDCl3) d 2.38 (s, 3H), 2.39 (s, 3H), 2.46–2.52 (m, 1H), 2.69
7.93–7.97 (m, 2H); 13C NMR (100 MHz, CDCl3)
d 21.7 (2C), 39.8, 64.4,
55.3, 69.0, 75.9, 82.1, 85.6, 86.8, 113.8 (2C), 114.6, 127.0 (2C), 129.1
(2C),129.2 (2C), 129.8 (2C),129.9 (2C), 133.3 (2C), 143.8, 144.0, 159.7,
166.3 (2C); IR (neat) n 3035, 2958, 2923, 2834, 2224,1723,1711,1607,
1511, 1456, 1267, 1179, 1105, 1013, 835, 150 cmꢁ1; MS (FAB) m/z 213
(10), 135 (8), 119 (100), 91 (18). Rf (5/1 hexane/EtOAc)¼0.26.
20
a
]
þ30 (c 0.51, CHCl3); 1H NMR
D
(ddd, J¼8.4, 8.2, 5.1 Hz, 1H), 3.92 (s, 3H), 4.50 (dd, J¼12.0, 4.8 Hz,
1H), 4.56 (dd, J¼12.0, 3.9 Hz, 1H), 4.66–4.70 (m, 1H), 5.22 (dd, J¼7.8,
2.7 Hz, 1H), 5.55–5.59 (m, 1H), 7.10–7.15 (m, 2H), 7.20–7.26 (m, 4H),
4.5.5. 1
ribofuranose (3
0.13 mmol), reaction time 6 h. Column chromatography (3/1
a
-[(2-Thienyl)ethynyl]-1,2-dideoxy-3,5-di-O-(4-toluoyl)]-
D-
ad). Conditions B. 2-Iodothiophene 2d (28 mg, 15 mL,

534
T. Bobula et al. / Tetrahedron 66 (2010) 530–536
hexane/EtOAc) afforded 15 mg (24%) of the title compound as
with 3-bromopyridine. 3-Bromopyridine 2g (21 mg, 14 mL,
0.132 mmol) reaction time 18 h. Column chromatography (3/1
hexane/EtOAc) afforded 37 mg (61%) as a yellow viscous oil.
20
a dark brown viscous oil: [
a
]
þ13 (c 0.3, CHCl3); 1H NMR
D
(300 MHz, CDCl3)
d
2.40 (s, 3H), 2.41 (s, 3H), 2.43–2.46 (m, 1H), 2.67
(ddd, J¼13.9, 8.1, 6.9 Hz, 1H), 4.49 (dd, J¼12.0, 4.8 Hz, 1H), 4.55 (dd,
J¼12.0, 3.9 Hz, 1H), 4.64–4.70 (m, 1H), 5.22 (dd, J¼8.1, 3.0 Hz, 1H),
5.53–5.59 (m, 1H), 6.95 (dd, J¼5.1, 3.6 Hz, 1H), 7.17–7.25 (m, 2H)
(overlapped with CDCl3 and H-m-Tol signal), 7.17–7.29 (m, 4H);
7.90–7.95 (m, 2H), 7.96–8.00 (m, 2H); 13C NMR (75 MHz, CDCl3)
4.5.9. 1
a
-[(2,20-Bipyridyl)ethynyl]-1,2-dideoxy-3,5-di-O-(4-toluoyl)]-
h). Conditions B. 5-Bromo-[2,20]bipyridine 2h22
D-ribofuranose (3
a
(27 mg, 0.13 mmol), reaction time 30 h. Column chromatography
(1/1 hexane/EtOAc) afforded 29 mg (41%) of the title compound as
a yellow viscous oil: [
CDCl3)
20
d
21.7 (2C), 39.6, 64.3, 69.0, 75.8, 78.9, 82.4, 92.0, 122.4, 126.9, 127.0,
127.4 (2C), 129.1 (2C), 129.2 (2C), 129.7 (2C), 129.9 (2C), 132.4, 143.9,
144.0, 166.2, 166.3; IR (neat) 3419, 3104, 3071, 2952, 2855, 2221,
a
]
þ13 (c 0.67, CHCl3); 1H NMR (300 MHz,
D
d
2.37 (s, 3H), 2.41 (s, 3H), 2.50–2.56 (m, 1H), 2.73 (ddd,
n
J¼13.8, 2.4, 2.8 Hz, 1H), 4.52 (dd, J¼12.0, 4.8 Hz, 1H), 4.57 (dd,
J¼12.0, 3.9 Hz, 1H), 4.69–4.73 (m, 1H), 5.26 (dd, J¼8.1, 3.0 Hz, 1H),
5.56–5.59 (m, 1H), 7.13–7.22 (m, 4H), 7.30 (ddd, J¼7.5, 4.8, 0.9 Hz,
1H), 7.76 (dd, J¼8.4, 2.1 Hz, 1H), 7.80–7.85 (m, 1H), 7.90–7.99 (m,
4H), 8.36 (d, J¼8.4 Hz,1H), 8.40 (d, J¼8.1 Hz,1H), 8.67–8.73 (m, 2H);
1930, 1793, 1616, 1509, 1456, 1409, 1376, 1209, 1130, 996, 853, 759,
710, 666 cmꢁ1; HRMS (EI) m/z for C27H24O5S calcd 460.1344, found
460.1331. Rf (3/1 hexane/EtOAc)¼0.56.
4.5.6. 1
ribofuranose (3
a
-[(3-Thienyl)ethynyl]-1,2-dideoxy-3,5-di-O-(4-toluoyl)]-
e). Conditions B. 3-Iodothiophene 2e (28 mg, 13
D
-
13C NMR (75 MHz, CDCl3)
d 21.7 (2C), 39.6, 64.3, 68.8, 75.8, 82.5,
a
mL,
82.6, 92.6, 119.6, 120.3, 121.5, 124.0, 126.8, 126.9, 129.1 (2C), 129.3
(2C), 129.7 (2C), 129.8 (2C), 137.2, 139.6, 143.9, 144.2, 149.0, 151.7,
0.13 mmol), reaction time 10 h. Column chromatography (3/1 hex-
ane/EtOAc) afforded 15 mg (25%) of the title compound as a dark
154.8, 155.2, 166.1, 166.2; IR (neat) n 3419, 3050, 2957, 2855, 1727,
20
brown viscous oil: [
CDCl3)
a
]
þ14 (c 0.5, CHCl3); 1H NMR (300 MHz,
1611, 1587, 1542, 1409, 1281, 1212, 1180, 1112, 1021, 1002, 916, 886,
873, 852, 798, 691, 662 cmꢁ1; HRMS (m/z) for C33H28N2O5 calcd
532.1998, found 532.2010. Rf (1/1 hexane/EtOAc)¼0.73.
D
d
2.39 (s, 3H), 2.41 (s, 3H), 2.42–2.50 (m, 1H), 2.67 (ddd,
J¼13.8, 7.8, 6.9 Hz, 1H), 4.51 (dd, J¼11.7, 4.5 Hz, 1H), 4.55 (dd, J¼11.7,
3.9 Hz,1H), 4.65–4.68 (m,1H), 5.19 (dd, J¼7.8, 3.0 Hz,1H), 5.54–5.58
(m, 1H), 7.06 (dd, J¼5.1, 0.9 Hz, 1H), 7.12–7.17 (m, 2H), 7.20–7.25 (m,
2H), 7.24–7.28 (m, 1H) (overlapped with H-m-Tol signal), 7.39 (dd,
4.5.10. 1
a
-[(1-Pyrenyl)ethynyl]-1,2-dideoxy-3,5-di-O-(4-toluoyl)]-
D-
ribofuranose (3
ai). Conditions B. 1-Bromopyrene 2i (46 mg,
J¼3.0, 0.9 Hz,1H), 7.91–8.00 (m, 4H); 13C NMR (75 MHz, CDCl3)
d
21.7
0.16 mmol), reaction time 8 h. Column chromatography (5/1 hex-
ane/EtOAc) afforded 28 mg (29%) of the title compound as a yellow
viscous oil. Conditions C. 1-Bromopyrene 2i (46 mg, 0.16 mmol),
reaction time 5 h. Column chromatography (5/1 hexane/EtOAc)
(2C), 39.7, 64.4, 69.0, 75.8, 80.8, 82.2, 87.9, 121.6, 125.2 (2C), 126.9,
127.0,129.1 (2C),129.2 (2C),129.7 (2C),129.9 (2C),130.2,143.9,144.0,
166.2,166.3; IR (neat) n 3394, 2928,1726,1707,1612,1454,1275,1179,
1109, 1019, 750 cmꢁ1; HRMS (EI) m/z for C27H24O5S calcd 460.1344,
found 460.1356. Rf (3/1 hexane/EtOAc)¼0.60.
afforded 29 mg (30%) of the title compound as a yellow viscous oil:
20
[a
]
ꢁ84 (c 0.28, CHCl3); 1H NMR (400 MHz, CDCl3)
d 2.15 (s, 3H),
D
2.41 (s, 3H), 2.63–2.72 (m, 1H), 2.84 (ddd, J¼14.8, 8.0, 1.2 Hz, 1H),
4.58 (dd, J¼11.6, 4.8 Hz, 1H), 4.65 (dd, J¼11.6, 4.0 Hz, 1H), 4.80–4.86
(m, 1H), 5.46 (dd, J¼8.0, 2.1 Hz, 1H), 5.62–5.70 (m, 1H), 6.88 (d,
J¼8.0 Hz, 2H), 7.23 (d, J¼8.0 Hz, 2H) (overlapped with CDCl3 signal),
7.90–8.10 (m, 10H), 8.14–8.20 (m, 2H), 8.44–8.47 (d, J¼9.2 Hz, 1H);
4.5.7. 1
a
-[(2-Pyridyl)ethynyl]-1,2-dideoxy-3,5-di-O-(4-toluoyl)]-
D-
ribofuranose (3
af). Conditions B. 2-Iodopyridine 2f (27 mg, 14 mL,
0.13 mmol), reaction time 3 h. Column chromatography (3/1 hex-
ane/EtOAc) afforded 44 mg (73%) of the title compound as a dark
20
brown viscous oil: [
a
]
þ25 (c 0.72, CHCl3); 1H NMR (300 MHz,
13C NMR (100 MHz, CDCl3)
d 21.4, 21.6, 40.1, 64.4, 69.3, 76.0, 82.4,
D
CDCl3)
d
2.37 (s, 3H), 2.41 (s, 3H), 2.51–2.57 (m, 1H), 2.71 (ddd,
84.8, 93.9, 117.0, 124.2, 124.3, 124.4, 125.3, 125.5, 125.6, 126.2, 126.8,
127.0, 127.2, 128.2, 128.3, 128.9 (2C), 129.2 (2C), 129.7 (2C), 129.9
J¼13.8, 8.4, 2.7 Hz, 1H), 4.51 (dd, J¼11.7, 5.4 Hz, 1H), 4.56 (dd,
J¼11.7, 3.6 Hz, 1H), 4.65–4.70 (m, 1H), 5.19 (dd, J¼7.8, 3.0 Hz, 1H),
5.54–5.58 (m, 1H), 7.09–7.13 (m, 2H), 7.20–7.25 (m, 2H), 7.35–7.40
(m, 2H), 7.58–7.62 (m, 1H), 7.90–7.94 (m, 2H), 7.94–8.02 (m, 2H),
(2C), 130.9, 131.1, 131.4, 132.0, 143.9, 144.0, 166.3, 166.4; IR (neat)
n
2956, 2929, 2857, 2845, 1721, 1712, 1610, 1455, 1413, 1270, 1177,
1105, 1021, 848, 752 cmꢁ1; HRMS (EI) m/z for C39H30O5 calcd
579.2171, found 579.2184. Rf (5/1 hexane/EtOAc)¼0.30.
8,62 (br s, 1H); 13C NMR (75 MHz, CDCl3)
d 21.7 (2C), 39.5, 64.3,
68.7, 75.7, 82.5, 82.8, 91.7, 123.2, 126.9, 127.0, 128.2, 129.1 (2C),
129.2 (2C), 129.7 (2C), 129.9 (2C), 136.5, 142.4, 143.9, 144.0, 149.5,
4.5.11. 1
a
-[1-Ferrocenyl]ethynyl-1,2-dideoxy-3,5-di-O-(4-toluoyl)]-
j). Conditions B. 1-Iodoferrocene 2j (34 mg,
166.2 (2C); IR (neat)
n
3419, 3035, 2939, 2588, 2362, 1930, 1732,
D-ribofuranose (3a
1615, 1508, 1409, 1288, 1130, 917, 843, 760, 691 cmꢁ1; HRMS (EI)
m/z for C28H25NO5 calcd 455.1733, found 455.1723. Rf (3/1 hexane/
EtOAc)¼0.18.
0.13 mmol), reaction time 5 h. Column chromatography (5/1 hex-
ane/EtOAc) afforded 13 mg (17%) of the title compound as a dark
20
brown viscous oil: [
a
]
þ39 (c 0.35, CHCl3); 1H NMR (300 MHz,
D
CDCl3)
d
2.38–2.45 (m, 1H), 2.41 (s, 3H), 2.42 (s, 3H), 2.68 (ddd,
4.5.8. 1
ribofuranose (3
a
-[(3-Pyridyl)ethynyl]-1,2-dideoxy-3,5-di-O-(4-toluoyl)]-
D
-
J¼13.9, 7.8, 6.8 Hz,1H), 4.17 (s, 5H), 4.17–4.20 (m, 2H), 4.36–4.39 (m,
2H), 4.51 (dd, J¼11.4, 3.9 Hz, 1H), 4.55 (dd, J¼11.4, 3.9 Hz, 1H), 4.63–
4.67 (m, 1H), 5.10 (dd, J¼7.8, 3.3 Hz, 1H), 5.51–5.55 (m, 1H), 7.19–
ag). Conditions B. 3-Iodopyridine 2g (27 mg,
0.13 mmol), reaction time 6 h. Column chromatography (3/1 hex-
ane/EtOAc) afforded 20 mg (33%) of the title compound as a yellow
viscous oil: [
7.26 (m, 4H), 7.90–8.00 (m, 4H); 13C NMR (75 MHz, C6D6)
d 22.0,
20
a]
þ26 (c 0.50, CHCl3); 1H NMR (300 MHz, CDCl3)
22.1, 40.6, 65.3, 66.1, 69.6, 69.9 (2C), 70.9 (5C), 72.5 (2C), 77.1, 83.1,
85.0, 86.5, 129.0, 129.5, 130.0 (2C), 130.1 (2C), 130.8 (2C), 131.0 (2C),
D
d
2.39 (s, 3H), 2.41 (s, 3H), 2.47–2.53 (m, 1H), 2.71 (ddd, J¼13.8, 7.5,
7.2 Hz, 1H), 4.50 (dd, J¼12.0, 4.8 Hz, 1H), 4.56 (dd, J¼12.0, 3.9 Hz,
1H), 4.65–4.70 (m, 1H), 5.23 (dd, J¼8.1, 2.7 Hz, 1H), 5.54–5.58 (m,
1H), 7.13–7.17 (m, 2H), 7.20–7.26 (m, 2H), 7.22–7.31 (m, 1H), 7.71 (d,
J¼7.8 Hz, 1H), 7.90–7.97 (m, 4H), 8.55–8.70 (m, 2H); 13C NMR
144.1, 144.5, 166.7, 166.8; IR (neat) n 3380, 2958, 2918, 2229, 1723,
1612, 1506, 1451, 1375, 1272, 1179, 1019, 829, 752 cmꢁ1; HRMS (EI)
m/z for C33H30FeO5 calcd 562.1443, found 562.1450. Rf (5/1 hexane/
EtOAc)¼0.31.
(75 MHz, CDCl3)
d 21.6, 22.6, 39.5, 64.2, 68.7, 75.8, 81.8, 82.4, 92.4,
120.2, 123.3, 126.8, 126.9, 129.1 (2C), 129.2 (2C), 129.7 (2C), 129.8
(2C), 139.5, 143.9, 144.2, 147.9, 151.4, 166.1, 166.2; IR (neat) 3415,
4.5.12. 1
O-(4-toluoyl)]-
b
-[(4-Methoxycarbonylphenyl)ethynyl]-1,2-dideoxy-3,5-di-
-ribofuranose (3 a). Conditions B. Methyl 4-iodo-
n
D
b
3034, 2925, 2855, 1930, 1793, 1735, 1612, 1509, 1408, 1288, 1125,
997, 841, 758, 706, 691 cmꢁ1; HRMS (EI) m/z for C28H25NO5 calcd
455.1733, found 455.1726. Rf (3/1 hexane/EtOAc)¼0.16. Reaction
benzoate 2a (35 mg, 0.13 mmol), reaction time 2.5 h. Column
chromatography (5/1 hexane/EtOAc) afforded 39 mg (57%) of the
20
title compound as a yellow solid: mp 114–117 ꢀC; [
a
]
ꢁ16
D

T. Bobula et al. / Tetrahedron 66 (2010) 530–536
535
(c 0.77, CHCl3); 1H NMR (400 MHz, CDCl3)
d
2.38 (s, 3H), 2.43
0.13 mmol), reaction time 6 h. Column chromatography (5/1 hex-
(s, 3H), 2.56–2.59 (m, 2H), 3.92 (s, 3H), 4.55 (dd, J¼12.0, 4.0 Hz,
1H), 4.58 (dd, J¼12.0, 4.8 Hz, 1H), 4.62 (ddd, J¼6.4, 4.0, 1.5 Hz,
1H), 5.10–5.15 (m, 1H), 5.58–5.61 (m, 1H), 7.15–7.22 (m, 2H),
7.24–7.29 (m, 2H), 7.40–7.46 (m, 2H), 7.90–7.96 (m, 2H), 7.95–
d 21.7 (2C), 39.9, 52.2,
64.4, 68.8, 76.4, 82.7, 85.1, 89.9, 126.7, 126.9, 127.1, 129.1 (2C),
129.2 (2C), 129.4 (2C), 129.7 (2C), 129.8 (2C), 129.9 (2C), 131.7,
ane/EtOAc) afforded 25 mg (41%) of the title compound as a viscous
20
oil: [
a]
ꢁ35 (c 0.32, CHCl3); 1H NMR (400 MHz, CDCl3)
d 2.39 (s,
D
3H), 2.42 (s, 3H), 2.53–2.57 (m, 2H), 4.44 (ddd, J¼6.8, 4.4, 2.4 Hz,
1H), 4.55 (dd, J¼12.0, 0.8 Hz, 1H), 4.58 (dd, J¼12.0, 1.2 Hz, 1H), 5.07–
5.12 (m,1H), 5.56–5.59 (m,1H), 7.07 (dd, J¼4.8,1.2 Hz,1H), 7.16–7.19
(m, 2H), 7.24–7.27 (m, 1H) (overlapped with CDCl3 and H-m-Tol
signals), 7.24–7.27 (m, 2H), 7.42–7.48 (m,1H), 7.90–7.98 (m, 4H); 13C
8.05 (m, 4H); 13C NMR (100 MHz, CDCl3)
143.8, 144.2, 165.9, 166.3, 166.5; IR (neat)
n
2949, 2920, 2852,
NMR (100 MHz, CDCl3)
86.5, 121.3, 125.2, 126.8, 127.1, 129.1 (2C), 129.2 (2C), 129.4 (2C),
d 21.6, 21.8, 39.9, 64.5, 68.9, 76.5, 81.2, 82.6,
1722, 1613, 1436, 1369, 1272, 1180, 1108, 1016, 839, 755, 692 cmꢁ1
;
HRMS (EI) m/z for C31H28O7 calcd 513.1913, found 513.1893. Rf (5/
1 hexane/EtOAc)¼0.30.
129.7 (2C), 129.8, 129.9, 143.7, 144.2, 165.9, 166.3; IR (neat) n 2965,
2911, 1715, 1608, 1267, 1480, 1105, 1021, 840, 782, 749 cmꢁ1; HRMS
(EI) m/z for C27H24O5S calcd 461.1423, found 461.1408. Rf (5/1
hexane/EtOAc)¼0.36.
4.5.13. 1
b
-[(4-Cyanophenyl)ethynyl]-1,2-dideoxy-3,5-di-O-(4-tol-
b). Conditions B. 4-Iodobenzonitrile 2b
uoyl)]- -ribofuranose (3
D
b
(30 mg, 0.13 mmol), reaction time 3 h. Column chromatography (5/1
4.5.17. 1
b
-[(2-Pyridyl)ethynyl]-1,2-dideoxy-3,5-di-O-(4-toluoyl)]-
D-
hexane/EtOAc) afforded 30 mg (47%) of the title compound as
ribofuranose (3
b
f). Conditions B. 2-Iodopyridine 2f (27 mg, 14 mL,
20
a yellow solid: mp 126–127 ꢀC, [
a
]
D
ꢁ63 (c 0.30, CHCl3); 1H NMR
0.13 mmol), reaction time 8 h. Column chromatography (2/1
hexane/EtOAc) afforded 19 mg (33%) as a grey solid. Conditions C.
(400 MHz, CDCl3)
d
2.39 (s, 3H), 2.43 (s, 3H), 2.57–2.60 (m, 2H), 4.47
(ddd, J¼6.8, 4.4, 2.4 Hz, 1H), 4.53 (dd, J¼12.0, 4.4 Hz, 1H), 4.60 (dd,
J¼12.0, 4.4 Hz, 1H), 5.10–5.15 (m, 1H), 5.59–5.61 (m, 1H), 7.15–7.23
(m, 2H), 7.24–7.29 (m, 2H), 7.42–7.45 (m, 2H), 7.53–7.58 (m, 2H),
2-Iodopyridine 2f (27 mg, 14
mL, 0.13 mmol), reaction time 12 h.
Column chromatography (2/1 hexane/EtOAc) afforded 42 mg
20
(70%) of the title compound as a grey solid: mp 105–107 ꢀC; [
a]
D
7.90–7.97 (m, 4H); 13C NMR (100 MHz, CDCl3)
d
21.6, 21.7, 39.8, 64.3,
ꢁ42 (c 0.4, CHCl3); 1H NMR (400 MHz, C6D6)
d 1.94 (s, 3H), 2.00
68.6, 76.3, 82.8, 84.2, 91.4, 111.9, 118.3, 126.7, 127.0, 127.2, 129.1 (2C),
129.2 (2C), 129.7 (2C), 129.8 (2C), 131.9 (2C), 132.3 (2C), 143.8, 144.3,
(s, 3H), 2.05–2.34 (m, 1H), 2.26–2.36 (m, 1H), 4.23–4.26 (m, 1H),
4.43 (dd, J¼10.4, 4.8 Hz, 1H), 4.47 (dd, J¼10.4, 5.2 Hz, 1H), 4.87
(dd, J¼8.6, 5.6 Hz, 1H), 5.35–5.37 (m, 1H), 6.45–6.48 (m, 1H),
6.80–6.82 (s, 1H), 6.85–6.88 (m, 2H), 6.90–6.94 (m, 2H), 7.02–
7.04 (m, 1H), 8.00–8.02 (m, 2H), 8.17–8.21 (m, 2H), 8.34–8.37 (m,
165.9,166.2; IR (neat) n 2933, 2851, 2221,1711,1610,1502,1448,1283,
1264, 1176, 1122, 840, 751, 669 cmꢁ1; HRMS (EI) m/z for C30H25NO5
calcd 480.1811, found 480.1796. Rf (5/1 hexane/EtOAc)¼0.22.
1H); 13C NMR (100 MHz, C6D6)
d 22.0, 22.1, 40.4, 65.4, 69.6, 77.6,
4.5.14. 1
b
-[(4-Methoxyphenyl)ethynyl]-1,2-dideoxy-3,5-di-O-(4-tol-
c). Conditions B. 1-Iodo-4-methoxy-ben-
83.8, 86.6, 88.3, 115.3, 123.4, 127.9 (2C), 130.0 (4C), 130.8 (2C),
130.9 (2C), 136.2, 144.0, 144.2, 144.6, 150.9, 166.3, 166.8; IR (neat)
uoyl)]- -ribofuranose (3
D
b
zene 2c (31 mg, 0.13 mmol), reaction time 15 h. Column
n 3040, 2950, 2917, 1721, 1610, 1584, 1464, 1428, 1407, 1368, 1269,
chromatography (5/1 hexane/EtOAc) afforded 8.5 mg (13%) of the
1183, 1105, 1021, 989, 779, 755, 692 cmꢁ1; HRMS (EI) m/z for
C28H25NO5 calcd 456.1811, found 456.1826. Rf (1/1 hexane/
EtOAc)¼0.61.
20
title compound as a yellow viscous oil: [
NMR (400 MHz, CDCl3)
a]
ꢁ26 (c 0.35 CHCl3); 1H
D
d
2.39 (s, 3H), 2.42 (s, 3H), 2.53–2.57 (m,
2H), 3.81 (s, 3H), 4.43 (ddd, J¼9.2, 6.8, 4.4 Hz, 1H), 4.52 (dd, J¼11.8,
1.6 Hz, 1H), 4.58 (dd, J¼11.8, 1.6 Hz, 1H), 5.08–5.13 (m, 1H), 5.56–
5.58 (m, 1H), 6.80–6.84 (m, 2H), 7.15–7.20 (m, 2H), 7.22–7.27 (m,
2H), 7.30–7.35 (m, 2H), 7.89–7.95 (m, 2H), 7.93–7.98 (m, 2H); 13C
4.5.18. 1
b
-[(3-Pyridyl)ethynyl]-1,2-dideoxy-3,5-di-O-(4-toluoyl)]-
D-
ribofuranose (3
b
g). Conditions B. 3-Iodopyridine 2g (27 mg,
0.13 mmol), reaction time 6.5 h. Column chromatography (1/1
NMR (75 MHz, CDCl3)
86.8, 113.8 (2C), 127.0 (2C), 129.0 (2C), 129.1 (2C), 129.0 (2C), 129.1
(2C), 129.7 (2C), 133.3 (2C), 143.8, 143.9, 166.3 (2C); IR (neat) 2959,
d
21.7 (2C), 39.5, 55.3, 64.4, 69.0, 75.9, 82.1,
hexane/EtOAc) afforded 30 mg (50%) of the title compound as
20
a yellow viscous oil: [
a]
ꢁ26 (c 0.27, CHCl3); 1H NMR (400 MHz,
D
n
CDCl3) d 2.38 (s, 3H), 2.42 (s, 3H), 2.57–2.60 (m, 2H), 4.47 (ddd,
2923, 2852,1719,1608, 1506, 1458, 1413,1374,1261,1177, 1102, 1021,
797, 752, 669 cmꢁ1; HRMS (EI) m/z for C30H28O6 calcd 485.1964,
found 485.1976. Rf (5/1 hexane/EtOAc)¼0.26.
J¼6.4, 4.4, 2.4 Hz, 1H), 4.54 (dd, J¼11.6, 4.4 Hz, 1H), 4.58 (dd, J¼11.6,
4.4 Hz, 1H), 5.10–5.13 (m, 1H), 5.59–5.61 (m, 1H), 6.99 (s, 1H), 7.17–
7.21 (m, 2H), 7.23–7.27 (m, 2H), 7.70 (d, J¼7.6 Hz, 1H), 7.90–7.94 (m,
2H), 7.95–7.99 (m, 2H), 8.59 (br s, 1H), 8.64 (br s, 1H); 13C NMR
4.5.15. 1
ribofuranose (3
15 L, 0.13 mmol), reaction time 4 h. Column chromatography (3/
b
-[(2-Thienyl)ethynyl]-1,2-dideoxy-3,5-di-O-(4-toluoyl)]-
D
-
(100 MHz, CDCl3)
120.2, 126.7, 127.0, 129.1 (2C), 129.2 (2C), 129.6 (2C), 129.7 (2C),
d 21.6, 21.7, 39.9, 64.3, 68.6, 76.4, 82.3, 82.8, 90.8,
b
d). Conditions B. 2-Iodothiophene 2d (28 mg,
m
139.3, 143.8, 144.3, 145.8, 148.3, 151.7, 165.9, 166.3; IR (neat) n 2965,
1 hexane/EtOAc) afforded 20 mg (32%) of the title compound as
2911, 1715, 1608, 1267, 1480, 1105, 1021, 840, 782, 749 cmꢁ1; HRMS
(ESI) m/z for C28H25NO5 calcd 456.1811, found 456.1826. Rf (1/1
hexane/EtOAc)¼0.68. Reaction with 3-bromopyridine. 3-Bromopyr-
20
a dark brown solid: mp 95–96 ꢀC; [
NMR (400 MHz, CDCl3)
a
]
ꢁ55 (c 0.32, CHCl3); 1H
D
d
2.39 (s, 3H), 2.42 (s, 3H), 2.54–2.57 (m,
2H), 4.44 (ddd, J¼6.8, 4.4, 2.0 Hz, 1H), 4.52 (dd, J¼11.6, 4.4 Hz, 1H),
4.57 (dd, J¼11.6, 4.4 Hz, 1H), 5.10–5.15 (m, 1H), 5.56–5.58 (m, 1H),
6.95 (dd, J¼5.2, 3.6 Hz, 1H), 7.19 (dd, J¼6.0, 4.8 Hz, 1H), 7.19–7.23
(m, 2H), 7.24–7.27 (m, 1H) (overlapped with CDCl3 and H-m-Tol
signals), 7.24–7.27 (m, 2H), 7.90–7.98 (m, 4H); 13C NMR (100 MHz,
idine 2g (21 mg, 14 mL, 0.132 mmol) reaction time 8 h. Column
chromatography (3/1 hexane/EtOAc) afforded 26 mg (43%) as
a yellow viscous oil.
4.5.19. 1
uoyl)]-D-ribofuranose (3b
h). Conditions B. 5-Bromo-[2,20]bipyr-
b
-[(2,20-Bipyridyl)ethynyl]-1,2-dideoxy-3,5-di-O-(4-tol-
CDCl3)
126.8, 126.9, 127.0, 127.6, 129.1 (2C), 129.2 (2C), 129.7 (2C), 129.8
(2C), 132.7, 143.7, 144.2, 165.9, 166.3; IR (neat) 2958, 2923, 2851,
1717, 1613, 1454, 1372, 1268, 1179, 1100, 1021, 840, 751, 666 cmꢁ1
d
21.6, 21.7, 39.8, 64.5, 68.9, 76.5, 79.3, 82.6, 90.6, 122.2,
idinyl 2h22 (31 mg, 0.13 mmol), reaction time 15 h. Column
n
chromatography (1/1 hexane/EtOAc) afforded 13 mg (19%) of the
20
;
title compound as a white solid: mp 43–45 ꢀC; [
a
]
ꢁ40 (c 0.68,
D
HRMS (EI) m/z for C27H24O5S calcd 461.1423, found. 461.1442. Rf
(5/1 hexane/EtOAc)¼0.36.
CHCl3); 1H NMR (400 MHz, CDCl3)
d 2.37 (s, 3H), 2.43 (s, 3H), 2.59–
2.62 (m, 2H), 4.47–4.50 (m, 1H), 4.56 (dd, J¼11.6, 4.4 Hz, 1H), 4.61
(dd, J¼11.6, 4.4 Hz, 1H), 5.12–5.16 (m, 1H), 5.59–5.62 (m, 1H), 7.16–
7.19 (m, 2H), 7.23–7.27 (m, 2H), 7.31–7.38 (m, 1H), 7.78–7.84 (m,
2H), 7.95–8.00 (m, 4H), 8.36–8.39 (m, 2H), 8.66–8.71 (m, 2H); 13C
4.5.16. 1
b
-[(3-Thienyl)ethynyl]-1,2-dideoxy-3,5-di-O-(4-toluoyl)]-
D-
ribofuranose (3
be). Conditions B. 3-Iodothiophene 2e (28 mg, 13 mL,

536
T. Bobula et al. / Tetrahedron 66 (2010) 530–536
NMR (100 MHz, CDCl3)
91.2, 120.1, 120.3, 121.5, 124.1, 125.3, 126.7, 127.0, 129.1 (2C), 129.2
(2C), 129.7 (2C), 129.8 (2C), 137.3, 139.7, 143.9, 144.3, 148.9, 151.8,
d
21.6, 21.7, 39.9, 64.3, 68.8, 76.4, 82.8, 82.9,
all are broad signals and correspond to characteristic signals of the
protected deoxyribose moiety.
155.0, 166.0, 166.3; IR (neat)
n 2956, 2923, 2852, 1721, 1614, 1455,
Acknowledgements
1380, 1267, 1177, 1102, 1021, 800, 749, 672 cmꢁ1; HRMS (EI) m/z for
C33H28N2O5 calcd 533.2076, found 533.2085. Rf (1/1 hexane/
EtOAc)¼0.68.
This work is a part of the Research Projects Z40550506 and
MSM0021620857, and was supported by the Centre for New Anti-
virals and Antineoplastics (1M0508) of the Ministry of Education,
Youth, and Sports of the Czech Republic and by the Grant Agency of
the ASCR (IAA400550902).
4.5.20. 1
b
-[(1-Pyrenyl)ethynyl]-1,2-dideoxy-3,5-di-O-(4-toluoyl)]-
D-
ribofuranose (3
b
i). Conditions B. 1-Bromopyrene 2i (28 mg,
0.13 mmol), reaction time 8 h. Column chromatography (5/1 hex-
ane/EtOAc) afforded 22 mg (29%) of the title compound as a yellow
viscous oil. Conditions C. 1-Bromopyrene 2i (28 mg, 0.13 mmol),
reaction time 5 h. Column chromatography (5/1 hexane/EtOAc)
Supplementary data
Copies of 1H and 13C NMR spectra of all new compounds and
some experimental details can be found in the online version.
Supplementary data associated with this article can be found in
online version, at doi:10.1016/j.tet.2009.11.030.
afforded 28 mg (36%) of the title compound as a yellow viscous oil.
20
[
a]
ꢁ84 (c 0.28, CHCl3); 1H NMR (400 MHz, CDCl3)
d 2.24 (s, 3H),
D
2.43 (s, 3H), 2.69–2.81 (m, 2H), 4.54 (m, 1H), 4.63 (dd, J¼12.0,
4.4 Hz,1H), 4.67 (dd, J¼12.0, 4.4 Hz,1H), 5.34 (dd, J¼9.2, 6.4 Hz,1H),
5.68–5.70 (m, 1H), 7.06 (d, J¼8.0 Hz, 2H), 7.25 (d, J¼8.0 Hz, 2H)
(overlapped with CDCl3 signal), 7.96–8.10 (m, 10H), 8.16–8.21 (m,
References and notes
2H), 8.46–8.49 (d, J¼8.4 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 21.5,
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21.7, 40.4, 64.5, 69.2, 76.6, 82.8, 85.0, 92.5, 116.7, 124.2, 124.3, 125.3,
125.6, 125.7, 126.2, 126.8, 127.1, 127.2, 128.3, 128.4, 129.0 (2C), 129.2
(2C), 129.7 (2C), 129.8 (2C), 130.9, 131.2, 131.4, 132.1, 143.6, 144.2,
166.0, 166.4; IR (neat)
n 3036, 2950, 2223, 1718, 1613, 1508, 1296,
1176, 1105, 1018, 911, 848, 749, 716, 687 cmꢁ1; HRMS (FAB) m/z for
C39H30O5 calcd 579.2172, found 579.2178. Rf (5/1 hexane/
EtOAc)¼0.32.
4.5.21. 1
b-[(1-Ferrocenyl)ethynyl]-1,2-dideoxy-3,5-di-O-(4-toluoyl)]-
D
-ribofuranose (3
b
j). Conditions B. Iodoferrocene 2j (41 mg,
0.13 mmol), reaction time 12 h. Column chromatography (5/1
hexane/EtOAc) afforded 15 mg (20%) of the title compound as
20
a dark red viscous oil: [
(400 MHz, C6D6)
a
]
ꢁ25 (c 0.2, CHCl3); 1H NMR
D
4. Doi, Y.; Chiba, J.; Morikawa, T.; Inouye, M. J. Am. Chem. Soc. 2008, 130,
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1.96 (s, 3H), 2.00 (s, 3H), 2.15 (ddd, J¼14.0, 6.1,
1.6 Hz, 1H), 2.30 (ddd, J¼14.0, 9.6, 6.0 Hz, 1H), 3.86–3.90 (m, 1H),
4.05 (s, 5H), 4.24–4.27 (m, 2H), 4.34–4.37 (m, 2H), 4.47 (dd,
J¼11.6, 5.2 Hz, 1H), 4.51 (dd, J¼11.6, 5.2 Hz, 1H), 4.93 (dd, J¼9.6,
5.6 Hz, 1H), 5.40–5.44 (m, 1H), 6.86–6.90 (m, 2H), 6.91–6.95 (m,
2H), 8.00–8.04 (m, 2H), 8.16–8.20 (m, 2H); 13C NMR (100 MHz,
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n 2959, 2923, 2851, 1914, 1715, 1506,
1455, 1270, 1174, 1105, 1018, 821, 752, 687, 669 cmꢁ1; HRMS (EI)
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4.6. Polymerization of 1aa (conditions B)
A solution of PdCl2(CH3CN)2 (3.4 mg, 13
(20,40,60-triisopropyl-biphenyl-2-yl)-phosphine (19.0 mg, 40
Cs2CO3 (112.0 mg, 0.35 mmol), 1 a (50 mg, 0.13 mmol) in dry ace-
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silica gel (3/1 hexane/EtOAc) gave 5 mg (8%) of 4, further elution
with neat EtOAc yielded 28 mg (56%) of a brown viscous liquid: 1H
ˇ
´
´
´
ˇ
´
ˇ
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d
2.0–2.4, 4.2–4.7, 5.0–5.6, 6.7–7.2, 7.5–8.0,
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