A general synthesis of alkylpyridines

Article abstract of DOI:10.1016/S0040-4020(01)00170-3

The hydroboration of alkenes, followed by the coupling of the B-alkyl-9-borabicyclo[3.3.1]nonane derivatives with bromopyridines constitutes an efficient procedure for the attachment of functionalized alkyl chains to the pyridine nucleus.

Full text of DOI:10.1016/S0040-4020(01)00170-3

TETRAHEDRON
Pergamon
Tetrahedron 57 42001) 3125±3130
A general synthesis of alkylpyridines
Beatriz Iglesias, Rosana Alvarez and Angel R. de Lerap
 Â
Departamento de Quõmica Organica, Universidade de Vigo, 36200 Vigo, Spain
Received 11 December 2000; revised 26 January2001; accepted 6 February2001
AbstractÐThe hydroboration of alkenes, followed by the coupling of the B-alkyl-9-borabicyclo[3.3.1]nonane derivatives with bromo-
pyridines constitutes an ef®cient procedure for the attachment offunctionalized alkyl chains to the pyridine nucleus. q 2001 Elsevier Science
Ltd. All rights reserved.
1. Introduction
ef®cientlytransmetalate to palladium was an important
breakthrough in this ®eld. Since alkylboranes are easily
prepared byhydroboration of alkenes, and the Suzuki reac-
tion shows excellent compatibilitywith an arrayof func-
tional groups in both reactants, being the by-products rather
inocuous, the preparative scope of this coupling process is
remarkable.4,5
Besides its presence as partial structures of manypharma-
ceuticals, alkylpyridines constitute a structural motif
commonlyfound in biologicallyactive natural products.
1a
Notably among the latter are 3-alkylpyridines produced by
sponges of the Niphatidae family1b which have been
proposed as biosynthetic precursors of the more complex
manzamine and related alkaloids.2 Given the readyavail-
abilityof halogenated pryidines, their cross-coupling to
alkynylcopper species catalyzed by palladium 4Sonogashira
coupling reaction)3 followed byhdyrogenation of the
alkynyl moiety3a has been the most frequentlyused method
for attachment of the side chain to the pyridine nucleus.
However, a most straightforward approach could be envis-
aged if direct attachment of the alkyl chain using the trans-
metalation to palladium of the corresponding alkyl
organometallic derivative was feasible. The formation of
the Csp3±Csp2 bond has proven to be a dif®cult endeavour.
The discoverybySuzuki that the 9-alkyl-9-BBN derivatives
In connection with a synthetic project aimed at the prepara-
tion of some metabolites with alarm pheromone activity
found in Mediterranean cephalaspideans,6 we directed our
efforts to implement the Suzuki reaction for attachment
of alkyl side chains to the pyridine ring found on these
metabolites. Gratifyingly, the palladium-catalyzed cross-
coupling reaction of the alkylborane generated in situ by
hydroboration of the corresponding alkene 1c, and 3-bromo-
pyridine 2b was veryef®cient, providing in high yield the
alkanol 3c on route to haminol-C 4 4Scheme 1). As an
extension of this work, we have found that the Suzuki
cross-coupling of 9-alkyl-9-BBN derivatives is equally
Scheme 1.
Keywords: pyridines; Suzuki reactions; heterocycles.
Corresponding author. Tel.: 134-86-812316; fax: 134-86-812382; e-mail: qolera@uvigo.es
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020401)00170-3

3126
B. Iglesias et al. / Tetrahedron 57 *2001) 3125±3130
applicable to the entire series of bromopyridines. This ®nd-
ing, together with the limitations encountered using other
heterocyclic halides are reported.
For the coupling of bromopyridine 2b to the alkylborane
obtained from 1c, we also found that an inorganic base
had an essential role, since its absence precluded the reac-
tion. The set of reaction conditions explored involve the use
of bases in both aqueous and polar aprotic solvents.8,9
Although a combination of Pd4PPh3)4 and NaOH in THF/
H2O works well in this coupling 4entry1), best yields and
lower temperatures were achieved when using K2CO3 as
base in the solvent system THF/DMF/H2O 4entry2). With
PdCl24dppf) as catalyst, best yields were obtained with less
basic reagents, such as powdered K3PO4 or Cs2CO3
suspended in a THF/DMF mixture 4entries 4±6), although
the temperatures were in general higher than those required
with Pd4PPh3)4. Previouslyit has been reported that treating
the reaction mixture with water for 30 min after the hydro-
boration step resulted in improved yields of the coupling
product, perhaps as a result of a more ef®cient hydrolysis
of the residual 9-BBN.8 However in our case this modi®-
cation gave low yields of alkylpyridine 3c 450%, entry7).
2. Results and discussion
In order to de®ne the scope and limitations of the alkyl
Suzuki coupling reaction,7 the positional isomers of bromo-
pyridine 42a±c) were chosen as the organic electrophile
partner, whereas for convenience the trialkylborane com-
ponent was prepared in situ byhydroboration of commer-
ciallyavailable alkenols 1a±c, 5 4Fig. 1).
The coupling of 3-bromopyridine 2b and the 9-BBN deriva-
tive of 5-hexen-1-ol 1c 4Scheme 1) was selected for optimi-
zation of the reaction conditions, and the results are listed in
Table 1.
Compared to other electrophiles, which couple at about
508C,9 bromopyridine 2b generallyrequires higher tempera-
tures 4.658C). Buchwald recentlyreported the room
temperature Suzuki cross-coupling of aryl boronic acids or
alkylboranes with aryl bromides and the even less-reactive
aryl chlorides using mixtures of palladium acetate and 2-4di-
tert-butylphosphino)biphenyl with low catalyst loadings in
different base/solvent systems.10 In our hands, however, the
modi®cation proved ineffective with KF in THF at 658C
4entry8), but proceeded in moderate iyeld 470%) with
K3PO4 in toluene, requiring however 1008C to go to com-
pletion 4entry9).
The palladium-catalyzed coupling of organic halides or
pseudohalides to organoboranes 4Suzuki reaction) is consid-
ered to share with other organometallic processes 4e.g. the
coupling of organostannanes, organozinc reagents, ¼) a
catalytic cycle involving three basic steps: 41) the oxidative
addition of the electrophilic halide to Pd 40), 42) the trans-
metalation of the carbon substituent from the organometal
to the resulting Pd4II) complex, and 43) the rapid reductive
elimination of the cross-coupling product with the regenera-
tion of the PdL2 catalyst. However, the Suzuki reaction
differs from others in that it requires a base for the coupling
reaction to have an appreciable rate. This suggests the
formation of a tetravalent boron species and a halide-by-
base metathesis capable of effecting boron to palladium
transmetalation, as an additional step of the catalytic
cycle.4b
The combination of catalyst, base and solvent found to be
optimal for the reaction 4see Table 1, entry2, Pd4PPh ) ,
K2CO3 in THF/DMF/H2O) was then used for coupling the
3 4
Figure 1.
Table 1. Suzuki coupling of 3-bromopyridine 2b with the 9-BBN derivative of 5-hexen-1-ol 1c
stEntryCataly Base
Solvent
T 48C)
t 4h)
Yield 4%)
1
2
3
4
5
6
7
8
9
Pd4PPh3)4
Pd4PPh3)4
NaOH
THF/H2O
THF/DMF/H2O
THF/H2O
THF/DMF
THF/DMF
THF/DMF
THF/H2O/DMF
THF
75±80
65±70
65
90
80
90
100
65
3.5
1
20
6
17
24
19.5
15
17
87
93a
60±70
60±70
89
88
50
±
K2CO3
NaOH
K3PO4
Cs2CO3
K2CO3
K2CO3
KF
PdCl24dppf)
PdCl24dppf)
PdCl24dppf)
PdCl24dppf)
PdCl24dppf)
b
Pd4OAc)2
Pd4OAc)2
b
K3PO4
THF/toluene
100
70
a
Ref. 6.
8 mol% 2-4di-tert-butylphosphino)biphenyl was added as ligand.
b

B. Iglesias et al. / Tetrahedron 57 *2001) 3125±3130
3127
Table 2. Generalized synthesis of alkylpyridines by Suzuki reaction
the Sonogashira coupling, followed bythe hydrogenation of
the alkyne.11 However, all our attempts directed at the
coupling of nucleoside 1112 4Fig. 2) with alkylboranes
proved unsuccessful, despite the fact that iodides are in
general more reactive than bromides. In addition, even
simpler heterocycles such as 2-iodothiophene 12 or 4-iodo-
pyrazole 13 4Fig. 2) proved less reactive under the same
reaction conditions that worked ef®cientlyfor the bromo-
pyridine series, including application of the improved Buch-
wald protocol.10 Nevertheless, the latter gave a moderate
yield 455%) for the coupling of 1c to 5-bromopyrimidine
14, a substrate found to be scarcelyreactive under the more
classical Suzuki coupling conditions, for the generation of
the coupling product 15 4Scheme 2).
a
EntryR±Br Alkene Reaction conditions
Product Yield 4%)
1
2
3
4
5
6
7
8
2a
2a
2a
2a
2b
2b
2b
2b
2c
2c
2c
2c
1a
1b
1c
5
1a
1b
1c
5
1a
1b
1c
5
NaOH, 708C, 14.5 h
K2CO3, 708C, 4 h
K2CO3, 708C, 3 h
K2CO3, 708C, 4 h
Cs2CO3, 578C, 2 h
K2CO3, 708C, 4 h
K2CO3, 658C, 1 h
K2CO3, 708C, 2 h
K2CO3, 758C, 3 h
K2CO3, 708C, 4 h
K2CO3, 708C, 2 h
K2CO3, 708C, 2 h
6a
6b
6c
7
75
86
78
78
93
69
93
69
60
94
78
63
3a
3b
3c
8
9
9a
9b
9c
10
10
11
12
a
41) Alkene, 9-BBN, THF, 258C; 42) R±Br, Pd4PPh3)4, base in H2O, DMF,
57±708C.
In summary, the palladium-catalyzed Suzuki cross-coupling
reaction of B-alkyl-9-borabicyclo[3.3.1]nonane derivatives
and bromopyridines has proved fruitful for the preparation
of functionalized alkylpyridines. The method has the added
bene®t of compatibilitywith additional functional groups in
both reaction components, thus providing a convenient
alternative for the preparation of biologicallyand pharma-
ceutically relevant alkylpyridines.13,14
isomeric bromopyridines 2a±c to the alkylboranes derived
from alkenols 1a±c, 5 depicted in Fig. 1. The results are
collected in Table 2. Alkylpyridines with different substi-
tution pattern and side chain length could be ef®ciently
obtained 4alkylpyridines 6a, 3a and 9a are commercially
available) regardless of the position of the halogen atom
and the length of the side chain. Onlyin two cases 4see
Table 2, entries 1 and 5) did a change in the base 4NaOH
or Cs2CO3 instead of K2CO3) afford better yields than the
generalized reaction conditions.
3. Experimental
3.1. General
Given the success in the use of heteroaromatic halides as
electrophilic partners, we attempted to broaden the appli-
cation of the hydroboration-alkyl Suzuki tandem reaction to
the preparation of additional heterocyclic derivatives of
biological interest. Appealing candidates are pyrimidine
nucleosides, since the ones modi®ed at the C5-position
have been used as antiviral agents, to stabilize DNA-triple
helices and for the incorporation of reporter groups into
oligonucleotides.11 Attachment of alkyl side chains to the
5-position of the pyrimidine nucleoside frequently relies on
Solvents were dried according to published methods and
were distilled before use. All other reagents were commer-
cial compounds of the highest purityavailable. Analytical
thin-layer chromatography 4TLC) was performed using
Merck silica gel 460 F-254) plates 40.25 mm) precoated
with a ¯uorescent indicator. Column chromatographywas
performed using Merck silica gel 60 4particle size 0.040±
0.063 mm). Proton 41H) and carbon 413C) magnetic reson-
ance spectra 4NMR) were recorded on a Bruker AMX-400
Figure 2.
Scheme 2.

3128
B. Iglesias et al. / Tetrahedron 57 *2001) 3125±3130
[400 MHz 4100 MHz for 13C)] Fourier transform spectro-
meter, and chemical shifts are expressed in parts per million
4d) relative to tetramethylsilane 4TMS, 0 ppm) or chloro-
0.50 mmol), 2-bromopyridine 2a 40.10 g, 0.60 mmol),
Pd4PPh3)4 40.06 g, 0.05 mmol) and K2CO3 40.84 mL, 3 M
in H2O, 2.5 mmol), it was obtained 0.07 g 478%) of 6-pyri-
1
form 4CHCl3, 7.24 ppm for H and 77.00 ppm for 13C) as
din-2-yl-hexan-1-ol 6c, after puri®cation bychroma-
tography4SiO , AcOEt). H NMR 4400 MHz, CDCl3) d
internal reference. 13C multiplicities 4s, singlet; d, doublet; t,
triplet; q, quartet) were assigned with the aid of the DEPT
pulse sequence. Infrared spectra 4IR) were obtained on a
MIDAC Prospect Model FT-IR spectrophotometer. Absorp-
tions are recorded in wave numbers 4cm21). Low-resolution
mass spectra were taken on an HP59970 instrument operat-
ing at 70 eV. High-resolution mass spectra were taken on a
VG Autospec M instrument.
1
2
1.40 4m, 4H, 2H312H4), 1.60 4m, 2H, 2H5), 1.70 4m, 2H,
2H2), 1.90 4br s, 1H, OH), 2.79 4t, Jˆ7.7 Hz, 2H, 2H6), 3.63
0
4t, Jˆ6.5 Hz, 2H, 2H1), 7.10 4dd, Jˆ7.6, 4.6 Hz, 1H, H5 ),
0
7.14 4d, Jˆ7.6 Hz, 1H, H3 ), 7.59 4dt, Jˆ7.6, 1.8 Hz, 1H,
H4 ), 8.51 4d, Jˆ4.6 Hz, 1H, H6 ); 13C NMR 4100 MHz,
0
0
CDCl3) d 25.4 4t), 28.8 4t), 29.8 4t), 32.5 4t, C2), 38.1 4t,
0
0
0
C6), 62.7 4t, C1), 120.9 4d, C5 ), 122.7 4d, C3 ), 136.4 4d, C4 ),
0
0
149.0 4d, C6 ), 162.3 4s, C2 ); IR 4NaCl) n 3600±3100 4br,
O±H), 2931 4s, C±H), 2858 4s, C±H), 1594 4m), 1570 4m),
1476 4m), 1436 4m), 1250 4w), 1054 4m), 1001 4w), 844 4m),
759 4m) cm21; MS m/z 4%) 180 4[M11]1, 2), 148 45), 121
444), 120 419), 106 429), 93 4100), 85 418), 83 429); HRMS
calcd for C11H18NO 4[M1H]1) 180.1388, found 180.1391.
3.2. General procedure for the hydroboration-Suzuki
tandem reaction
To a cooled 408C) solution of alkenol 41.50 mmol) in THF
43 mL) was slowlyadded 9-BBN 40.5 M in THF,
4.50 mmol). The mixture was slowlywarmed up to 25 8C
and then stirred for 2±6 h to give a solution of the B-alkyl-9-
BBN derivative. Procedure A. The solution of B-alkyl-9-
BBN in THF was transferred into a separate ¯ask containing
the heterocyclic halide, the palladium catalyst [Pd4PPh3)4 or
PdCl2dppf] and the base 4K2CO3, NaOH, Cs2CO3 or K3PO4)
in DMF. The mixture was stirred at the appropriate tempera-
ture until TLC monitoring showed complete disappearance
of the starting material. It was then diluted with AcOEt and
poured into H2O. The aqueous layer was extracted with
AcOEt 43£). The combined organic layers were washed
with brine, dried 4Na2SO4) and evaporated. Procedure B
Water 43 mL) was added to the solution of B-alkyl-9-BBN
in THF and the mixture was stirred at 258C for 90 min. It
was then transferred into a separate ¯ask containing the
heterocyclic halide, Pd4OAc)2, K3PO4 and 2-4di-tert-butyl-
phosphino)biphenyl in toluene. The ®nal mixture was
stirred at 1008C until complete disappearance of the starting
material. It was then worked up as in procedure A.
3.2.3. rac-1-Pyridin-2-yl-pentan-3-ol ,7). According to the
general procedure described above 4procedure A, Table 2,
708C, 4 h), the reaction of rac-1-penten-3-ol 5 40.10 g,
1.16 mmol), 2-bromopyridine 2a 40.22 g, 1.39 mmol),
Pd4PPh3)4 40.13 g, 0.12 mmol) and K2CO3 41.6 mL, 3 M
in H2O, 4.65 mmol), afforded, after puri®cation bychroma-
tography4SiO , AcOEt), 0.15 g 478%) of rac-1-pyridin-2-
2
1
yl-pentan-3-ol 7. H NMR 4400 MHz, CDCl3) d 0.89 4t,
Jˆ7.4 Hz, 3H, 3H5), 1.40 4m, 2H, 2H4), 1.70 4m, 1H, H2),
1.90 4m, 1H, H2), 2.90 4m, 2H, 2H1), 3.50 4m, 1H, H3), 7.06
0
0
4dd, Jˆ7.5, 5.1 Hz, 1H, H5 ), 7.12 4d, Jˆ7.5 Hz, 1H, H3 ),
0
7.55 4dt, Jˆ7.5, 1.7 Hz, 1H, H4 ), 8.42 4d, Jˆ5.1 Hz, 1H,
H6 ); 13C NMR 4100 MHz, CDCl3) d 10.1 4q, C5), 30.3 4t,
0
0
C4), 34.6 4t, C2), 35.9 4t, C1), 72.4 4d, C3), 121.0 4d, C5 ),
0
0
0
0
123.1 4d, C3 ), 136.7 4d, C4 ), 148.5 4d, C6 ), 161.8 4s, C2 ); IR
4NaCl) n 3600±3100 4br, O±H), 2960 4s, C±H), 2927 4s, C±
H), 2875 4s, C±H), 1596 4s), 1570 4m), 1477 4m), 1436 4s),
1340 4m), 1121 4m), 992 4m), 753 4m) cm21; MS m/z 4%)
166 4[M11]1, 1), 165 4M1, 0.5), 164 4[M ± 1]1, 2), 148
410), 136 450), 118 414), 107 417), 106 449), 93 4100), 92
411), 85 435), 83 454); HRMS calcd for C10H14NO
4[M±H]1) 164.1075, found 164.1077.
3.2.1. 5-Pyridin-2-yl-pentan-1-ol ,6b). Following the
general procedure 4procedure A, Table 2, 708C, 4 h), the
reaction of 4-penten-1-ol 1b 40.10 g, 1.16 mmol), 2-bromo-
pyridine 2a 40.22 g, 1.40 mmol), Pd4PPh3)4 40.13 g,
0.12 mmol) and K2CO3 41.60 mL, 3 M in H2O,
4.65 mmol) in DMF 48 mL) afforded, after puri®cation by
chromatography4SiO 2, AcOEt), 0.16 g 486%) of 5-pyridyn-
2-yl-pentan-1-ol 6b. 1H NMR 4400 MHz, CDCl3) d 1.40 4m,
2H, 2H3), 1.60 4m, 2H, 2H4), 1.70 4m, 2H, 2H2), 1.80 4br s,
1H, OH), 2.74 4t, Jˆ7.7 Hz, 2H, 2H5), 3.59 4t, Jˆ6.5 Hz,
3.2.4. 5-Pyridin-3-yl-pentan-1-ol ,3b). Following the
general procedure described above 4procedure A, Table 2,
708C, 4 h), starting from 4-penten-1-ol 1b 40.10 g,
1.16 mmol), 3-bromopyridine 2b 40.22 g, 1.39 mmol),
Pd4PPh3)4 40.13 g, 0.12 mmol) and K2CO3 41.6 mL, 3 M
in H2O, 4.65 mmol), it was obtained 0.13 g 469%) of
5-pyridin-3-yl-pentan-1-ol 3b, after puri®cation bychroma-
tography4SiO , AcOEt). H NMR 4400 MHz, CDCl3) d
0
2H, 2H1), 7.03 4dd, Jˆ7.6, 4.8 Hz, 1H, H5 ), 7.08 4d,
1
0
0
Jˆ7.6 Hz, 1H, H3 ), 7.52 4dt, Jˆ7.6, 1.2 Hz, 1H, H4 ),
2
8.44 4dd, Jˆ4.8, 1.2 Hz, 1H, H6 ); 13C NMR 4100 MHz,
1.40 4m, 2H, 2H3), 1.60 4m, 4H, 2H212H4), 2.63 4t,
Jˆ7.7 Hz, 2H, 2H5), 3.65 4t, Jˆ6.5 Hz, 2H, 2H1), 7.21
0
CDCl3) d 25.3 4t), 29.4 4t), 32.4 4t), 37.9 4t, C5), 62.0 4t,
0
0
4dd, Jˆ7.7, 4.8 Hz, 1H, H5 ), 7.50 4d, Jˆ7.7 Hz, 1H, H4 ),
0
C1), 120.8 4d, C5 ), 122.7 4d, C3 ), 136.3 4d, C4 ), 148.7 4d,
0
0
8.44 4d, Jˆ4.8 Hz, 1H, H6 ), 8.44 4s, 1H, H2 ); 13C NMR
0
0
0
0
C6 ), 161.9 4s, C2 ); IR 4NaCl) n 3600±3100 4br, O±H), 2929
4s, C±H), 2859 4s, C±H), 1596 4s), 1570 4w), 1477 4m),
1437 4m), 1369 4w), 1353 4w), 1055 4m), 1006 4m), 959
4w), 764 4m) cm21; MS m/z 4%) 166 4[M11]1, 43), 120
421), 106 426), 93 4100), 85 417), 83 426); HRMS calcd
for C10H15NO 165.1154, found 165.1150.
4100 MHz, CDCl3) d 25.3 4t), 30.9 4t), 32.5 4t), 32.9 4t, C5),
0
62.6 4t, C1), 123.3 4d, C5 ), 135.8 4d, C4 ), 137.7 4s, C3 ),
0
0
0
0
147.2 4d, C6 ), 149.8 4d, C2 ); IR 4NaCl) n 3600±3100 4br,
O±H), 2928 4s, C±H), 2858 4s, C±H), 1447 4s), 1352 4m),
1217 4m), 1063 4m), 1009 4s), 958 4m), 754 4m), 714 4m)
cm21; MS m/z 4%) 166 4[M11]1, 5), 165 4M1, 32), 164 4[M
± 1]1, 14), 148 45), 118 426), 106 4100), 105 452), 93 443),
92 438); HRMS calcd for C10H15NO 165.1154, found
165.1148.
3.2.2. 6-Pyridin-2-yl-hexan-1-ol ,6c). Following the
general procedure described above 4procedure A, Table 2,
708C, 3 h), starting from 5-hexen-1-ol 1c 40.05 g,

B. Iglesias et al. / Tetrahedron 57 *2001) 3125±3130
3129
3.2.5. rac-1-Pyridin-3-yl-pentan-3-ol ,8). According to the
general procedure described above 4procedure A, Table 2,
708C, 2 h), starting from rac-1-penten-3-ol 5 40.10 g,
1.16 mmol), 3-bromopyridine 2b 40.22 g, 1.39 mmol),
Pd4PPh3)4 40.13 g, 0.12 mmol) and K2CO3 41.6 mL, 3 M
in H2O, 4.65 mmol), it was obtained 0.13 g 469%) of rac-
3.2.8. rac-1-Pyridin-4-yl-pentan-3-ol ,10). According to
the general procedure described above 4procedure A,
Table 2, 708C, 2 h), starting from rac-1-penten-3-ol 5
40.07 g, 0.87 mmol), 4-bromopyridine hydrochloride 2c´HCl
40.20 g, 1.05 mmol), Pd4PPh3)4 40.10 g, 0.09 mmol) and
K2CO3 41.45 mL, 3 M in H2O, 4.36 mmol), it was obtained
0.09 g 463%) of rac-1-pyridin-4-yl-pentan-3-ol 10, after
1-pyridin-3-yl-pentan-3-ol 8, after puri®cation bychroma-
tography4SiO , AcOEt). H NMR 4400 MHz, CDCl3) d
1
1
puri®cation bychromatography4SiO 2, AcOEt). H NMR
4400 MHz, CDCl3) d 0.96 4t, Jˆ7.4 Hz, 3H, 3H5), 1.4±1.8
2
0.88 4t, Jˆ7.4 Hz, 3H, 3H5), 1.40 4m, 2H, 2H4), 1.70 4m,
3H, 2H21OH), 2.60 4m, 1H, H1), 2.70 4m, 1H, H1), 3.50 4m,
0
4m, 5H, 2H412H21OH), 2.70 4m, 1H, H1), 2.80 4m, 1H,
0 0
H1), 3.50 4m, 1H, H3), 7.15 4m, 2H, H3 1H5 ), 8.49 4m, 2H,
1H, H3), 7.15 4dd, Jˆ7.7, 4.8 Hz, 1H, H5 ), 7.46 4d,
Jˆ7.7 Hz, 1H, H4 ), 8.40 4m, 2H, H2 1H6 ); 13C NMR
H2 1H6 ); 13C NMR 4100 MHz, CDCl3) d 9.8 4q, C5), 30.3
0
0
0
0
0
0
4t), 31.3 4t), 37.2 4t, C1), 71.8 4d, C3), 124.0 4d, C3 1C5 ),
0
4100 MHz, CDCl3) d 9.8 4q, C5), 29.1 4t), 30.3 4t), 38.1 4t,
0
0
C1), 71.8 4d, C3), 123.3 4d, C5 ), 136.0 4d, C4 ), 137.7 4s, C3 ),
0
0
0
0
149.1 4d, C2 1C6 ), 151.9 4s, C4 ); IR 4NaCl) n 3600±3100
4br, O±H), 2927 4s, C±H), 2875 4s, C±H), 1606 4s), 1560
4w), 1419 4s), 1341 4m), 1220 4m), 1121 4m), 1002 4m), 755
4s) cm21; MS m/z 4%) 166 4[M11]1, 11), 165 4M1, 4), 147
441), 136 435), 118 448), 107 430), 106 495), 105 430), 93
4100), 92 459), 80 428), 65 425); HRMS calcd for C10H15NO
165.1154, found 165.1156.
0
0
146.9 4d, C6 ), 149.6 4d, C2 ); IR 4NaCl) n 3600±3100 4br,
O±H), 2960 4s, C±H), 2926 4s, C±H), 2874 4s, C±H), 1579
4w), 1425 4m), 1342 4m), 1121 4m), 1030 4m), 713 4m)
cm21; MS m/z 4%) 166 4[M11]1, 5), 165 4M1, 1), 164
4[M21]1, 3), 149 49), 148 412), 147 497), 136 437), 118
454), 107 415), 106 462), 105 467), 93 437), 92 4100), 85
420), 83 432), 79 415), 62 425); HRMS calcd for
C10H16NO 4[M1H]1) 166.1232, found 166.1231.
3.2.9. 5-Iodo-30,50-O-,tetraisopropyldisiloxane-1,3-diyl)-
20-deoxyuridine ,11). To a solution of 5-iodo-20-deoxy-
uridine 40.05 g, 0.14 mmol) and imidazole 40.02 g,
0.31 mmol) in DMF 40.5 mL) was slowlyadded 1,3-dichloro-
1,1,3,3-tetraisopropyldisiloxane 40.05 mL, 0.15 mmol). After
12 h stirring, excess silylating agent was decomposed by
the addition of MeOH 41 mL), followed byAcOEt
41 mL). The solution was poured into a saturated aqueous
NaCl solution and it was then extracted with AcOEt 43£).
The combined organic layers were washed with brine, dried
4MgSO4) and evaporated. Puri®cation bycolumn chroma-
tography4SiO 2, 75:25 hexane/AcOEt) afforded 0.08 g
497%) of protected nucleoside 11 as a white solid 4mp
1828C; Et2O/hexane). 1H NMR 4400 MHz, CDCl3) d
3.2.6. 5-Pyridin-4-yl-pentan-1-ol ,9b). According to the
general procedure described above 4procedure A, Table 2,
708C, 4 h), the reaction of 4-penten-1-ol 1b 40.10 g,
1.16 mmol), 4-bromopyridine hydrochloride 2c´HCl 40.27 g,
1.40 mmol), Pd4PPh3)4 40.13 g, 0.12 mmol) and K2CO3
43.2 mL, 3 M in H2O, 9.30 mmol), afforded, after puri®cation
bychromatography4SiO , AcOEt), 0.18 g 494%) of 5-pyridin-
2
1
4-yl-pentan-1-ol 9b. H NMR 4400 MHz, CDCl3) d 1.4±1.7
4m, 7H, 2H212H312H41OH), 2.63 4t, Jˆ7.7 Hz, 2H, 2H5),
3.65 4t, Jˆ6.5 Hz, 2H, 2H1), 7.11 4d, Jˆ5.8 Hz, 2H,
H3 1H5 ), 8.48 4d, Jˆ5.8 Hz, 2H, H2 1H6 ); 13C NMR
4100 MHz, CDCl3) d 25.2 4t), 29.8 4t), 32.3 4t), 34.9 4t,
0
0
0
0
0
1.0±1.1 4m, 28H, 4£i-Pr), 2.2±2.3 4m, 1H, H2 ), 2.4±2.5
0
C5), 61.8 4t, C1), 123.8 4d, C3 1C5 ), 149.0 4d, C2 1C6 ),
0
151.7 4s, C4 ); IR 4NaCl) n 3600±3100 4br, O±H), 2928
4s, C±H), 2859 4s, C±H), 1608 4m), 1446 4m), 1064 4m),
1006 4s), 752 4m) cm21; MS m/z 4%) 166 4[M11]1, 4), 165
4M1, 20), 164 4[M ± 1]1, 11), 147 413), 119 413), 118 425),
106 4100), 105 470), 93 456), 92 417), 65 413); HRMS calcd
for C10H15NO 165.1154, found 165.1153.
0
0
0
0
0
4m, 1H, H2 ), 3.7±3.8 4m, 1H, H3 ), 4.01 4dd, Jˆ13.2,
0
0
2.9 Hz, 1H, H5 ), 4.13 4dd, Jˆ13.2, 2.2 Hz, 1H, H5 ),
0
0
4.4±4.5 4m, 1H, H4 ), 6.00 4dd, Jˆ7.2, 1.7 Hz, 1H, H1 ),
8.01 4s, 1H, H6), 9.18 4br s, 1H, N±H); 13C NMR
4100 MHz, CDCl3) d 12.4 4d), 12.8 4d), 13.0 4d), 13.5 4d),
16.8 4q), 16.9 4q), 17.0 4q), 17.1 4q), 17.2 4q), 17.4 4q), 17.6
0
0
4q), 17.7 4q), 39.9 4t, C2 ), 59.9 4t, C5 ), 67.1 4d), 68.0 4s, C5),
84.7 4d), 85.3 4d), 144.0 4d, C6), 149.8 4s), 160.1 4s); IR
4NaCl) n 3200±3100 4br), 3100±3000 4br), 2945 4m,
C±H), 2867 4m, C±H), 2360 4m), 1698 4s, CO), 1605 4w),
1461 4m), 1270 4m), 1119 4m), 1038 4s), 887 4m), 773 4m),
698 4m), 612 4w) cm21; MS m/z 4%) 597 4[M11]1, 7), 553
48), 481 411), 455 444), 359 415), 329 410), 315 422), 287
468), 261 4100), 239 426), 217 413), 189 417), 175 432), 135
457), 119 471); HRMS calcd for C21H37N2IO6Si2 4[M1H]1)
597.1313, found 597.1306.
3.2.7. 6-Pyridin-4-yl-hexan-1-ol ,9c). Following the general
procedure described above 4procedure A, Table 2, 708C, 2 h),
starting from 5-hexen-1-ol 1c 40.05 g, 0.5 mmol), 4-bromo-
pyridine hydrochloride 2c´HCl 40.12 g, 0.6 mmol), Pd4PPh3)4
40.06 g, 0.05 mmol) and K2CO3 40.84 mL, 3 M in H2O,
2.5 mmol), it was obtained 0.07 g 478%) of 6-pyridin-4-yl-
hexan-1-ol 9c, after puri®cation bychromatography4SiO
,
2
1
AcOEt). H NMR 4400 MHz, CDCl3) d 1.3±1.7 4m, 8H,
2H212H312H412H5), 2.61 4t, Jˆ7.7 Hz, 2H, 2H6), 3.65 4t,
0
0
3.2.10. 6-Pyrimidin-5-yl-hexan-1-ol ,15). According to the
general procedure described above 4procedure B, 1008C,
19.5 h), the reaction of 5-hexen-1-ol 1c 40.08 g, 0.75 mmol),
5-bromopyrimidine 14 40.08 g, 0.50 mmol), Pd4OAc)2
40.005 g, 0.02 mmol), K3PO4 40.21 g, 1.00 mmol) and 2-
4di-tert-butylphosphino)biphenyl 40.01 g, 0.04 mmol) in
toluene 41.5 mL), afforded, after puri®cation bychroma-
tography4SiO 2, 97:3 CH2Cl2/MeOH), 0.05 g 455%) of
6-pyrimidin-5-yl-hexan-1-ol 15. 1H NMR 4400 MHz,
CDCl3) d 1.3±1.7 4m, 8H, 2H212H312H412H5), 2.62 4t,
Jˆ6.5 Hz, 2H, 2H1), 7.10 4d, Jˆ5.5 Hz, 2H, H3 1H5 ), 8.48
4d, Jˆ5.5 Hz, 2H, H2 1H6 ); 13C NMR 4100 MHz, CDCl3) d
0
0
25.5 4t), 28.8 4t), 30.1 4t), 32.5 4t, C2), 35.0 4t, C6), 62.4 4t, C1),
0
0
0
0
0
123.9 4d, C3 1C5 ), 149.3 4d, C2 1C6 ), 151.7 4s, C4 ); IR
4NaCl) n 3600±3100 4br, O±H), 2931 4s, C±H), 2858 4s,
C±H), 1606 4s), 1558 4w), 1418 4m), 1057 4m), 1003 4m),
724 4w) cm21; MS m/z 4%) 179 4M1, 9), 178 4[M 2 1]1, 9),
120 412), 118 410), 107 411), 106 4100), 105 421), 93 484), 92
415), 85 439), 83 461), 65 412); HRMS calcd for C11H17NO
179.1310, found 179.1305.

3130
B. Iglesias et al. / Tetrahedron 57 *2001) 3125±3130
7. 2-Bromopyridine had been reported to couple to organo-
boranes under carbonylative conditions to give the corre-
sponding ketones. See Ref. 5d.
Jˆ7.7 Hz, 2H, 2H6), 3.60 4br s, 2H, 2H1), 8.58 4s, 2H,
H4 1H6 ), 9.07 4s, 1H, H2 ); 13C NMR 4100 MHz, CDCl3)
d 25.4 4t), 28.7 4t), 30.1 4t), 30.5 4t), 32.4 4t, C6), 62.3 4t, C1),
0
0
0
0
0
0
0
8. Kondo, K.; Sodeoka, M.; Shibasaki, M. Tetrahedron:
Asymmetry 1995, 6, 2453±2464.
135.3 4s, C5 ), 156.3 4d, C2 ), 156.5 4d, C4 1C6 ); IR 4NaCl) n
3600±3100 4br, O±H), 2931 4s, C±H), 2858 4s, C±H), 1562
4s), 1411 4s), 1055 4m), 728 4m), 637 4m) cm21; MS m/z 4%)
181 4[M11]1, 3), 180 4M1, 12), 179 4[M21]1, 7), 149 411),
135 420), 121 412), 108 413), 107 4100), 106 430), 96 417), 94
449), 93 418), 66 414); HRMS calcd for C10H16N2O
180.1263, found 180.1269.
9. 4a) Suzuki, A. J. Organomet. Chem. 1999, 576, 147±168.
4b) Hostetler, E. D.; Fallis, S.; McCarthy, T. J.; Welch, M. J.;
Katzenellenbogen, J. A. J. Org. Chem. 1998, 63, 1348±1351.
4c) Johns, B. A.; Pan, Y. T.; Elbein, A. D.; Johnson, C. R.
J. Am. Chem. Soc. 1997, 119, 4856±4865. 4d) Su, D.-S.;
Meng, D.; Bertinato, P.; Balog, A.; Sorensen, E. J.;
Danishefsky, S. J.; Zheng, Y.-H.; Chou, T.-C.; He, L.;
Horwitz, S. B. Angew. Chem. Int. Ed. Engl. 1997, 36, 757±
759. 4e) FuÈrstner, A.; Konetzki, I. Tetrahedron 1996, 52,
15071±15078. 4f) Kojima, A.; Takemoto, T.; Sodeoka, M.;
Shibasaki, M. J. Org. Chem. 1996, 61, 4876±4877.
4g) Ohba, M.; Kawase, N.; Fujii, T. J. Am. Chem. Soc. 1996,
118, 8250±8257. 4h) Kondo, K.; Sodeoka, M.; Shibasaki, M.
J. Org. Chem. 1995, 60, 4322±4323. 4i) Johnson, C. R.; Braun,
M. P. J. Am. Chem. Soc. 1993, 115, 11014±11015.
Acknowledgements
We thank MEC 4grant SAF98-0143) and Xunta de Galicia
4grant PGIDT99PX30105B) for ®nancial support, and
CACTI 4Universidade de Vigo) for NMR and mass spectra.
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Â
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