One-pot synthesis of N-alkyl purine and pyrimidine derivatives from alcohols using TsIm: a rapid entry into carboacyclic nucleoside synthesis

Article abstract of DOI:10.1016/j.tet.2007.11.101

A convenient and efficient one-pot N-alkylation of nucleobases from alcohols using N-(p-toluenesulfonyl)imidazole (TsIm) is described. In this method, treatment of alcohols with a mixture of purine or pyrimidine nucleobase, TsIm, K₂CO₃, and triethylamine in refluxing DMF regioselectively furnishes the corresponding N-alkyl nucleobases in good yields. This methodology is highly efficient for various structurally diverse primary alcohols.

Full text of DOI:10.1016/j.tet.2007.11.101

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 1778e1785
www.elsevier.com/locate/tet
One-pot synthesis of N-alkyl purine and pyrimidine derivatives from
alcohols using TsIm: a rapid entry into carboacyclic nucleoside synthesis
b
b
Mohammad Navid Soltani Rad a, , Ali Khalafi-Nezhad , Somayeh Behrouz ,
*
Mohammad Ali Faghihi a, Abdolkarim Zare b, Abolfath Parhami b
a Department of Chemistry, Faculty of Basic Sciences, Shiraz University of Technology, Shiraz 71555-313, Iran
b Department of Chemistry, College of Sciences, Shiraz University, Shiraz 71454, Iran
Received 5 September 2007; received in revised form 7 November 2007; accepted 29 November 2007
Available online 3 December 2007
Abstract
A convenient and efficient one-pot N-alkylation of nucleobases from alcohols using N-(p-toluenesulfonyl)imidazole (TsIm) is described. In
this method, treatment of alcohols with a mixture of purine or pyrimidine nucleobase, TsIm, K2CO3, and triethylamine in refluxing DMF
regioselectively furnishes the corresponding N-alkyl nucleobases in good yields. This methodology is highly efficient for various structurally
diverse primary alcohols.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Nucleobase; Alcohol; N-Alkylation; N-(p-Toluenesulfonyl)imidazole (TsIm); Triethylamine; K2CO3
1. Introduction
diethyl azodicarboxylate (DEAD) and diisopropyl azodicar-
boxylate (DIAD); the presence of unreacted PPh3 and forma-
tion of O]PPh3, which requires a tedious work up and
cumbersome separation process. Recently, we have reported
the N-(p-toluenesulfonyl)imidazole (TsIm) as an efficient,
cheap, and stable reagent for the one-pot conversion of alco-
hols into alkyl azides13 and nitriles.14 In this context, herein;
we report TsIm as an appropriate reagent for the one-pot
N-alkylation of nucleobases using alcohols in the presence
of a K2CO3/triethylamine mixture in anhydrous DMF
(Schemes 1 and 2).
The N-alkylation of nucleobases has great significance
since it is a direct and appealing route into nucleosides syn-
thesis.1 The N-alkylation of purine and pyrimidine nucleo-
bases is usually achieved using different sources of carbon
electrophiles including: alkyl halides,2 alkyl tosylates,3 alkyl
mesylates,4 epoxides,5 Michael acceptors,6 carbonates,7 and
allylic esters catalyzed by Pd(0).8 Furthermore, the N-alkyl-
ation of nucleobases can also be achieved using active ethers
including: acetoxyethyl acetoxymethyl ether and its ana-
logues,9 methylthiomethyl ether,10 and cyclic acetals.11 Due
to the advantageous and attractive strategy of the direct
synthesis of acyclic nucleosides from alcohols, some limited
methods have been developed. Along this line, methods based
on Mitsunobu conditions are widely applied.12 However, this
method is accompanied by several drawbacks including:
utilizing toxic, expensive, and explosive reagents such as
NH2
NH2
N
N
N
TsIm, K2CO3, Et3N
N
N
R
OH
+
DMF, Δ 4-24 h
N
H
N
N
R
1a-k
Scheme 1.
2. Results and discussion
* Corresponding author. Tel.: þ98 711 7261392; fax: þ98 711 7354523.
E-mail addresses: soltani@sutech.ac.ir, nsoltanirad@gmail.com (M.N.
Soltani Rad).
The first step of this synthetic approach consists of finding
out the optimized reaction conditions. The optimization was
0040-4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.11.101

M.N. Soltani Rad et al. / Tetrahedron 64 (2008) 1778e1785
1779
Table 2
Effect of various bases on conversion of 2-phenylethanol into 9-phenethyl-9H-
purin-6-amine in anhydrous DMF
O
O
X
X
TsIm, K2CO3, Et3N
HN
HN
R
OH
+
Z
Z
DMF, Δ 4-10 h
Yielda (%)
O
N
R
O
N
H
Entry
Base
Time (h)
X=H,Me,F,Cl,NO2
Z=C,N
1
2
3
4
5
6
7
8
9
10
a
DBN
DBU
12
12
24
24
24
6
48
54
14
20
16
67
58
18
13
81
2a-k
O
S N
O
DABCO
DMAP
MgO
N
TsIm :
Me
Cs2CO3
K2CO3
Et3N
Scheme 2.
6
24
24
4
begun with studying the effect of various solvents on the
model reaction of adenine, 2-phenylethanol, and freshly pre-
pared TsIm (1.5e2.0 equiv) in the presence of an equimolar
mixture of K2CO3/Et3N. As the data in Table 1 indicates,
through the examined solvents, anhydrous DMF (Table 1,
entry 3) afforded the best result and hence it was solvent of
choice for all reactions. Using DMSO and wet DMF afforded
a moderate yield of the corresponding 9-phenethyl-9H-purin-
6-amine (1a) while other solvents were inefficient even
when the reaction time was prolonged.
The choice of the reaction base for activation of the alcohol
to react with TsIm and nucleobase was of great significance. In
this case, we investigated the effect of miscellaneous organic
and inorganic bases on the reaction model (Table 2). The
results in Table 2 demonstrate that among the employed bases,
an equimolar mixture of K2CO3/Et3N (Table 2, entry 10) was
the most efficient base for the progress of reaction. Further-
more, using K2CO3 (1 equiv) (Table 2, entry 7) or Et3N
(2 equiv) (Table 2, entry 8) alone in reaction is not as efficient
as an equimolar mixture of K2CO3/Et3N. DBN, DBU (Table 2,
entries 1 and 2), and Cs2CO3 (Table 2, entry 6) afforded 1a in
moderate yields while other bases were nearly inefficient.
Interestingly, comparing the results of the base’s role in our
previous research into synthesis of alkyl azides13 and nitriles14
with this recent work, shows that Et3N is more responsible for
activation of alcohol than K2CO3.
NaH
K2CO3/Et3Nb
Isolated yield.
Ratio (1:1).
b
effect in the enhancement of reaction efficiency. This can be
attributed to solubility of nucleobases in comparison with so-
dium azide and cyanide in DMF.
We also examined other TsIm analogues (Table 3). As the
data in Table 3 indicates, higher yield of 9-phenethyl-9H-pu-
rin-6-amine (1a) and short reaction time were obtained with
TsIm (Table 4, entry 3) in comparison with other sulfonyl ana-
logues. Replacing the tolyl in TsIm with methyl, trifluromethyl,
and phenyl gave no improvement in reaction yield (Table 3, en-
tries 1, 2, and 4). Furthermore, changing the imidazole residue to
other azole derivatives did not affect the reaction efficiency (Ta-
ble3, entries5and 6). N-Tosylphthalimide(Table3, entry7)was
inactivefortheconversionof 2-phenylethanoltothecorrespond-
ing 9-phenethyl-9H-purin-6-amine, even after reflux for 48 h.
Various sulfonyl chlorides were examined instead of TsIm
to attain 1a (Table 4). Lower yields of 1a were obtained when
Table 3
Comparison of TsIm reactivity with analogues in reaction of adenine with
2-phenylethanol
Entry
Reagent
Time (h)
Yielda (%)
In other experiments, we have investigated the effect of
various phase transfer catalysts on the model reaction. In
this case, tetra-n-butylammonium halides (TBAX; X¼F, Cl,
Br, and I) were employed. In contrary with azidation13 and
cyanidation14 of alcohols using TsIm, TBAX had a negligible
O
N
N
1
Me
S
O
O
S
N
N
6
54
2
3
4
5
6
F3C
10
10
4
32
81
69
60
51
O
O
S
O
O
S
N
N
Table 1
Effect of various solvents on conversion of 2-phenylethanol into 1a
Entry
Solvent
Time (h)
Yieldb (%)
N
N
1
2
3
4
5
6
7
8
9
10
a
DMSO
DMF
6
6
57
63
O
O
S
O
DMFa
4
81
22
N
N
12
12
MeCN
HMPA
NMP
12
12
48
12
48
12
48
NO2
N
10
O
S
O
NRc
15
N
N
THF
Toluene
Acetone/H2Od
H2O
NR
10
O
O
S
O
NR
7
N
48
NRb
Anhydrous DMF.
O
b
c
d
Isolated yield.
No reaction.
Ratio (1:1).
a
Isolated yield.
No reaction.
b

1780
M.N. Soltani Rad et al. / Tetrahedron 64 (2008) 1778e1785
Table 4
Effect of various sulfonyl chlorides in reaction of adenine with
2-phenylethanol
Table 5
One-pot N-alkylation of purines via alcohols using TsIm/Et3N/K2CO3 in
refluxing DMF
Entry
Sulfonyl chloride
Time (h)
Yielda (%)
Compound
Structure
Mp (ꢀC) Time (h) Yielda (%)
NH2
O
1
Me
S
O
Cl
Cl
12
18
N
N
N
1a
180.1
161.1
4
6
81
72
N
O
S
O
2
3
F3C
12
12
12
10
27
22
NH2
N
O
S
O
N
N
N
Cl
1b
O
OCH3
4
S
Cl
NH2
O
N
a
N
1c
237.3
140.0
10
5
68
83
Isolated yield.
N
N
sulfonyl chlorides were employed for sulfonylation of 2-phe-
nylethanol instead of TsIm. Additionally, the extension of
these reactions to sulfonyl chlorides, uracil, and 2-phenyletha-
nol led to complicated mixtures of side products. This proba-
bly results from the fact that, highly reactive sulfonyl chlorides
have less selectivity for individual reactions with alcohols.
While adenine and uracil are ambident nucleophiles that can
readily react with sulfonyl chlorides at various N-sites to
afford the complicated mixture of products.
NH2
N
N
1d
N
N
NH2
N
N
N
N
1e
98.1
5
61
N
NH2
To evaluate the general applicability and versatility of the
method, the optimized conditions were applied to various
structurally diverse alcohols and nucleobases (Tables 5 and
6). As the results in Tables 5 and 6 indicate, various alcohols
reacted with purine and pyrimidine nucleobases to afford
products 1aek and 2aek, respectively. Depicted data in Ta-
bles 5 and 6 indicate this method is suitable for primary alco-
hols including: aliphatic, benzylic, and allylic while the
secondary and tertiary types rarely react with nucleobases.
For instance, the N-alkylation of adenine with isopropyl alco-
hol afforded 1j in 23% yield. This method is also applicable
for the alkylation of other N-heterocycles. For example, the
N-alkylation of benzimidazole (purine-like scaffold) was
achieved with 2-(2-methyl-4-nitro-1H-imidazol-1-yl) ethanol,
which attained 1k in a good yield. Interestingly, good regiose-
lectivity was observed for the site of N-alkylation in nucleo-
bases.15 In the case of purine nucleobases, the N9 isomers
were almost the dominant products and N7 isomers were
produced in trace amounts (<4e7%). The N-alkylation of py-
rimidines was achieved chiefly from N1 site and N1,N3-dialkyl
derivatives were also produced in trace amounts (<10e12%).
Furthermore, O-alkylation of pyrimidine nucleobases was not
observed.
N
N
1f
127.3
148.7
6
5
75
78
N
NH2
N
N
1g
N
N
O
O
HN
Ph
N
N
1h
1i
124.1
158.6
4
9
58
61
N
N
N
O
N
H3C
O
N
N
CH3
NH2
N
N
1j
234.8
223.7
24
10
23
65
N
N
N
N
1k
N
N
To study the regioselectivity of described method, we com-
pared the TsIm mediated N-alkylation of adenine and uracil
with 1-(2-chloroethyl) benzene using a method applied by Laz-
rek and co-workers.16 The results are summarized in Table 7.
Mechanistically, it is interesting to note, there is a consider-
able tendency for alcohols to react with TsIm in comparison to
the reaction of nucleobases with TsIm. To demonstrate this ex-
perience, we conducted two reactions. In the first experiment,
NO2
a
Isolated yield.
the reaction was achieved in the absence of adenine with all
components including TsIm, Et3N, K2CO3, and 2-phenyletha-
nol. The obtained product was an alkyl tosylate.

M.N. Soltani Rad et al. / Tetrahedron 64 (2008) 1778e1785
1781
Table 6
One-pot N-alkylation of pyrimidines via alcohols using TsIm/Et3N/K2CO3 in
refluxing DMF
Table 7
Comparison of the regioselectivity of N-alkylation for nucleobases
Compound
A.S.a
Nucleobase
Method
Ratiod
Compound
Structure
Mp (ꢀC) Time (h) Yielda (%)
OH
Cl
TsIm/Et3N/K2CO3 95:5b
NH2
O
N
N
1a
HN
2a
61.2
6
63
K2CO3/DMF16
61:39b
N
N
H
O
N
O
OH
Cl
TsIm/Et3N/K2CO3 92:8c
O
HN
HN
2c
O
N
K2CO3/DMF16
58:42c
O
N
H
2b
2c
118.9
150.1
4
5
60
71
a
OCH3
Alkylating source.
b
c
d
N9/N7.
N1-alkyl/N1,N3-dialkyl.
Isomers were separated by column chromatography.
O
N
HN
O
In the second reaction, the same condition was established
but in the presence of adenine and absence of alcohol. Interest-
ingly, no tosylation of nucleobase was achieved even when the
reflux time was prolonged to 48 h. The same result was also
observed when the uracil was used.
O
HN
O
N
O
2d
263.0
6
80
N
O
3. Conclusion
O
N
A convenient method for the one-pot N-alkylation of purines
and pyrimidines using alcohols in the presence of TsIm, Et3N,
and K2CO3 in refluxing DMF has been established. In this
method various primary alcohols including: aliphatic, benzylic,
and allylic underwent reaction with purines and pyrimidines to
afford N-alkyl derivatives in reasonable to good yields. How-
ever, this method was not effective enough for N-alkylation
of nucleobases with secondary and tertiary alcohols. Good
regioselectivities were observed for both purines and pyrimi-
dines in the case of site of N-alkylation using this method.
HN
2e
2f
154.6
169.4
7
6
66
59
O
O
Cl
HN
O
N
O
N
HN
2g
2h
198.1
101.3
10
8
62
54
4. Experimental
O
O
N
4.1. General
F
HN
All chemicals were purchased from Fluka or Merck chem-
ical companies except for TsIm, which was freshly prepared
O
according to, published methods.13 Solvents were purified
O
N
17
˚
and dried due to reported methods and stored over 3 A mo-
HN
lecular sieves.12 The progress of the reactions was followed
with TLC using silica gel SILG/UV 254 plates. Silica gel 60,
0.063e0.200 mm (70e230 mesh ASTM) was used for column
chromatography. IR spectra were run on a Shimadzu FTIR-
2i
2j
123.2
136.4
146.3
6
10
10
58
60
76
O
O
1
8300 spectrophotometer. The H NMR (250 MHz) and 13C
HN
N
NMR (62.5 MHz) were run on a Bru¨ker Avanced DPX-250,
FT-NMR spectrometer; d in parts per million, J in hertz.
Mass spectra were recorded on a Shimadzu GCeMS-QP
1000 EX apparatus. Microanalyses were performed on a Per-
kineElmer 240-B microanalyzer. Melting points (mp) were
recorded on a Bu¨chi 510 apparatus in open capillary tubes
and are uncorrected.
O
N
O
NO2
HN
2k
O
N
a
Isolated yield.

1782
M.N. Soltani Rad et al. / Tetrahedron 64 (2008) 1778e1785
4.2. General procedure for one-pot N-alkylation of
nucleobases using alcohols
4.2.4. 9-(Hex-5-enyl)-9H-purin-6-amine (1d)
Column chromatography on SiO2, eluted with EtOAc af-
forded white prism crystals (1.80 g, 83%). Mp¼140.0 ꢀC; Rf
(EtOAc)¼0.36; dH (250 MHz, DMSO-d6) 1.34 (2H, m,
CH2), 1.84 (2H, m, CH2), 2.06 (2H, m, CH2), 4.20 (2H, t, J
7.0 Hz, NCH2), 4.93 (2H, dd, J 1.3, 9.2 Hz, ]CH2), 5.78
(1H, m, ]CH), 7.32 (2H, br s, NH2, exchangeable with
D2O), 8.22 (1H, s, C(2)eH, adenine), 8.25 (1H, s, C(8)eH,
adenine); dC (62.5 MHz, DMSO-d6) 25.1, 29.0, 32.4, 42.6,
114.8, 118.6, 138.1, 140.7, 149.4, 152.3, 155.9; IR (KBr) n
cmꢂ1: 3330 (NH2), 3115, 2948; MS [m/z (%)]: 217 (21.0).
Anal. Calcd for C11H15N5: C, 60.81; H, 6.96; N, 32.23%.
Found: C, 60.86; H, 7.00; N, 32.20%.
In a double-necked round bottom flask (100 mL) equipped
with a condenser was added a mixture, consisting of alcohol
(0.01 mol), TsIm (0.012 mol), Et3N (0.02 mol), K2CO3
(0.01 mol), and nucleobase (0.01 mol) in DMF (30 mL). The
mixture was heated at reflux, and in most cases, darkening oc-
curred. Heating was continued until TLC indicated no further
improvement in the conversion (Tables 5 and 6). The solvent
was evaporated under vacuum and the remaining foam was
dissolved in CHCl3 (100 mL) and subsequently washed with
water (2ꢁ100 mL). The organic layer was dried (Na2SO4)
and evaporated. The crude product was purified by column
chromatography on silica gel eluting with proper solvents
described below.
4.2.5. (Z)-9-(Hex-3-enyl)-9H-purin-6-amine (1e)
Column chromatography on SiO2, eluted with EtOAc af-
forded pale yellow prism crystals (1.3 g, 61%). Mp¼98.1 ꢀC;
Rf (EtOAc)¼0.19; dH (250 MHz, DMSO-d6) 0.64 (3H, t, J
7.6 Hz, Me), 1.70 (2H, m, MeCH2), 2.58 (2H, m, NCH2CH2),
4.14 (2H, t, J 6.7 Hz, NCH2), 5.37 (2H, m, 2(]CH)), 7.23 (2H,
br s, NH2, exchangeable with D2O), 8.12 (1H, s, C(2)eH, ad-
enine), 8.19 (1H, s, C(8)eH, adenine); dC (62.5 MHz, DMSO-
d6) 13.6, 19.7, 27.0, 42.5, 118.6, 124.3, 134.2, 140.8, 149.4,
152.2, 155.8; IR (KBr) n cmꢂ1: 3300 (NH2), 3110, 2950; MS
[m/z (%)]: 217 (22.3). Anal. Calcd for C11H15N5: C, 60.81;
H, 6.96; N, 32.23%. Found: C, 60.80; H, 7.01; N, 32.35%.
4.2.1. 9-Phenethyl-9H-purin-6-amine (1a)
Column chromatography on SiO2, eluted with EtOAc af-
forded white needle crystals (1.93 g, 81%). Mp¼180.1 ꢀC; Rf
(EtOAc)¼0.24; dH (250 MHz, DMSO-d6) 3.14 (2H, t, J
7.2 Hz, PhCH2), 4.37 (2H, t, J 7.2 Hz, NCH2), 7.09e7.28 (7H,
m, aryl and NH2), 7.78 (1H, s, C(2)eH, adenine), 8.18 (1H, s,
C(8)eH, adenine); dC (62.5 MHz, DMSO-d6) 35.1, 44.2,
118.7, 126.4, 127.9, 128.3, 137.9, 140.6, 149.4, 152.3, 155.8;
IR (KBr) n cmꢂ1: 3335 (NH2), 3142, 2928; MS [m/z (%)]: 239
(35). Anal. Calcd for C13H13N5: C, 62.25; H, 5.48; N, 29.27%.
Found: C, 62.31; H, 5.45; N, 29.32%.
4.2.6. (E)-9-(Hex-3-enyl)-9H-purin-6-amine (1f)
Column chromatography on SiO2, eluted with EtOAc af-
forded white prism crystals (1.62 g, 75%). Mp¼127.3 ꢀC; Rf
(EtOAc)¼0.27; dH (250 MHz, DMSO-d6) 0.51 (3H, t, J
7.4 Hz, Me), 1.03 (2H, m, MeCH2), 1.64 (2H, m, NCH2CH2),
4.46 (2H, t, J 4.0 Hz, NCH2), 5.37 (2H, m, 2(]CH)), 7.07 (2H,
s, NH2, exchangeable with D2O), 7.83 (1H, s, C(2)eH, ade-
nine), 7.91 (1H, s, C(8)eH, adenine); dC (62.5 MHz, DMSO-
d6) 13.6, 21.4, 33.3, 44.3, 118.6, 124.7, 134.0, 140.3, 149.2,
152.4, 155.9; IR (KBr) n cmꢂ1: 3310 (NH2), 3110, 2950; MS
[m/z (%)]: 217 (21.7). Anal. Calcd for C11H15N5: C, 60.81;
H, 6.96; N, 32.23%. Found: C, 60.81; H, 7.00; N, 32.20%.
4.2.2. 9-(4-Methoxybenzyl)-9H-purin-6-amine (1b)
Column chromatography on SiO2, eluted with EtOAc af-
forded white needle crystals (1.84 g, 72%). Mp¼161.1 ꢀC;
Rf (EtOAc)¼0.22; dH (250 MHz, DMSO-d6) 3.67 (3H, s,
OMe), 5.37 (2H, s, NCH2), 6.87 (2H, d, J 8.6 Hz, C(2,6)eH,
aryl), 7.01 (1H, s, C(2)eH, adenine), 7.22 (2H, d, J 8.6 Hz,
C(3,5)eH, aryl), 7.29 (2H, s, NH2, adenine), 8.48 (1H, s,
C(8)eH, adenine); dC (62.5 MHz, DMSO-d6) 45.6, 54.9,
113.9, 118.6, 121.6, 135.1, 140.5, 149.3, 152.5, 155.9, 158.7;
IR (KBr) n cmꢂ1: 3315 (NH2), 3155, 2930; MS [m/z (%)]: 255
(40). Anal. Calcd for C13H13N5O: C, 61.17; H, 5.13; N,
27.43%. Found: C, 61.22; H, 5.10; N, 27.44%.
4.2.7. 9-(2-Ethoxyethyl)-9H-purin-6-amine (1g)
Column chromatography on SiO2, eluted with EtOAc af-
forded white needle crystals (1.6 g, 78%). Mp¼148.7 ꢀC; Rf
(EtOAc)¼0.12; dH (250 MHz, DMSO-d6) 0.98 (3H, t, J
6.9 Hz, Me), 3.36 (2H, q, J 6.9 Hz, MeCH2), 3.69 (2H, t, J
5.2 Hz, NCH2), 4.27 (2H, t, J 5.2 Hz, OCH2), 7.24 (2H, s,
NH2, exchangeable with D2O), 8.06 (1H, s, C(2)eH, adenine),
8.48 (1H, s, C(8)eH, adenine); dC (62.5 MHz, DMSO-d6)
14.8, 65.2, 67.5, 67.6, 118.5, 141.1, 149.4, 152.3, 155.8; IR
(KBr) n cmꢂ1: 3310 (NH2), 3160, 2985; MS [m/z (%)]: 207
(23). Anal. Calcd for C9H13N5O: C, 52.16; H, 6.32; N,
33.79%. Found: C, 52.21; H, 6.27; N, 33.83%.
4.2.3. (E)-9-Cinnamyl-9H-purin-6-amine (1c)
Column chromatography on SiO2, eluted with EtOAc
afforded pale yellow needle crystals (1.71 g, 68%). Mp¼
237.3 ꢀC; Rf (EtOAc)¼0.32; dH (250 MHz, DMSO-d6) 4.93
(2H, d, J 5.0 Hz, NCH2), 6.43 (1H, d, J 16.4 Hz, ]CHe
Ph), 7.21e7.31 (6H, complex, CH2eCH, aryl), 7.37 (1H, s,
C(2)eH, adenine), 7.40 (2H, s, NH2, exchangeable with
D2O), 8.15 (1H, s, C(8)eH, adenine); dC (62.5 MHz,
DMSO-d6) 44.5, 118.6, 124.5, 126.3, 127.8, 128.5, 132.3,
135.8, 140.5, 149.3, 152.4, 155.9; IR (KBr) n cmꢂ1: 3355
(NH2), 3130, 2950; MS [m/z (%)]: 251 (29.8). Anal. Calcd
for C14H13N5: C, 66.92; H, 5.21; N, 27.87%. Found: C,
66.88; H, 5.25; N, 27.91%.
4.2.8. Benzyl-[9-(2-ethoxyethyl)-9H-purin-6-yl]-amine (1h)
Column chromatography on SiO2, eluted with EtOAc af-
forded white needle crystals (1.72 g, 58%). Mp¼124.1 ꢀC;
Rf (EtOAc)¼0.41; dH (250 MHz, DMSO-d6) 1.00 (3H, t, J

M.N. Soltani Rad et al. / Tetrahedron 64 (2008) 1778e1785
1783
6.9 Hz, Me), 3.36 (2H, q, J 6.9 Hz, MeCH2), 3.69 (2H, t, J
5.2 Hz, NCH2), 4.28 (2H, t, J 5.2 Hz, OCH2), 4.72 (2H, br
s, PhCH2), 7.13e7.66 (5H, m, aryl), 8.09 (1H, s, C(2)eH, ad-
enine), 8.21 (1H, s, C(8)eH, adenine) 8.51 (1H, br s, NH); dC
(62.5 MHz, DMSO-d6) 15.3, 40.9, 43.2, 65.8, 68.0, 119.4,
126.9, 127.5, 128.5, 140.6, 141.5, 149.3, 152.7, 154.8; IR
(KBr) n cmꢂ1: 3300 (NH2), 3130, 2900; MS [m/z (%)]: 297
(20.1). Anal. Calcd for C16H19N5O: C, 64.63; H, 6.44; N,
23.55%. Found: C, 64.68; H, 6.46; N, 23.60%.
with D2O); dC (62.5 MHz, CDCl3) 14.0, 22.5, 26.9, 29.0, 29.1,
31.7, 40.5, 48.8, 102.0, 144.5, 151.0, 164.4; IR (KBr) n cmꢂ1
3200 (NH), 3100, 2895, 1735 (C]O), 1710 (C]O); MS
[m/z (%)]: 224 (34.9). Anal. Calcd for C12H20N2O2: C, 64.26;
H, 8.99; N, 12.49%. Found: C, 64.20; H, 9.03; N, 12.44%.
:
4.2.13. 1-(4-Methoxybenzyl)pyrimidine-2,4(1H,3H)-dione
(2b)
Column chromatography on SiO2, eluted with EtOAc/n-
hexane (50:50) afforded white cube crystals (1.4 g, 60%).
Mp¼118.9 ꢀC; Rf (EtOAc)¼0.38; dH (250 MHz, DMSO-d6)
3.70 (3H, s, OMe), 3.73 (2H, s, NCH2), 5.58 (1H, d, J 7.8 Hz,
C(5)eH uracil), 6.84 (2H, d, J 8.6 Hz, C(2,6)eH, aryl), 6.90
(2H, d, J 8.6 Hz, C(3,5)eH, aryl), 7.72 (1H, d, J 7.8 Hz,
C(6)eH uracil), 11.17 (1H, s, N3eH, exchangeable with
D2O); dC (62.5 MHz, DMSO-d6) 49.6, 54.9, 101.1, 113.5,
4.2.9. 7-Benzyl-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione
(1i)
Column chromatography on SiO2, eluted with EtOAc/n-
hexane (50:50) afforded white needle crystals (1.65 g, 61%).
Mp¼158.6 ꢀC; Rf (EtOAc)¼0.48; dH (250 MHz, CDCl3)
3.31 (3H, s, N(3)eMe), 3.49 (3H, s, N(1)eMe), 5.53 (2H, s,
N(7)eCH2), 7.12e7.31 (5H, m, aryl), 7.62 (1H, s, C(8)eH);
dC (62.5 MHz, CDCl3) 27.9, 29.6, 50.1, 106.8, 127.3, 127.8,
128.6, 129.1, 145.3, 150.9, 158.7, 163.6; IR (KBr) n cmꢂ1
:
3250 (NH), 3100, 2895, 1728 (C]O), 1715 (C]O); MS
[m/z (%)]: 232 (55.4). Anal. Calcd for C12H12N2O3: C, 62.06;
H, 5.21; N, 12.06%. Found: C, 62.00; H, 5.25; N, 12.04%.
128.6, 135.3, 140.8, 148.7, 151.5, 155.1; IR (KBr) n cmꢂ1
:
3100, 2980, 2895, 1720 (C]O), 1705 (C]O); MS [m/z (%)]:
270 (31.4). Anal. Calcd for C14H14N4O2: C, 62.21; H, 5.22; N,
20.73%. Found: C, 62.26; H, 5.26; N, 20.70%.
4.2.14. 1-Phenethylpyrimidine-2,4(1H,3H)-dione (2c)
Column chromatography on SiO2, eluted with EtOAc/n-hex-
ane (50:50) afforded white cube crystals (1.53 g, 71%). Mp¼
150.1 ꢀC; Rf (EtOAc)¼0.29; dH (250 MHz, DMSO-d6) 2.83
(2H, t, J 7.2 Hz, PhCH2), 3.89 (2H, t, J 7.2 Hz, NCH2), 5.45
(1H, d, J 7.8 Hz, C(5)eH uracil), 7.16e7.30 (5H, m, aryl), 7.50
(1H, d, J 7.8 Hz, C(6)eH uracil), 11.23 (1H, s, N3eH, exchange-
able with D2O); dC (62.5 MHz, DMSO-d6) 34.1, 48.7, 100.4,
126.2, 128.3, 128.5, 137.7, 145.5, 150.7, 163.6; IR (KBr) n
cmꢂ1: 3250 (NH), 3110, 2895, 1730 (C]O), 1720 (C]O);
MS [m/z (%)]: 216 (27). Anal. Calcd for C12H12N2O2: C,
66.65; H, 5.59; N, 12.96%. Found: C, 66.70; H, 5.63; N, 12.90%.
4.2.10. 9-Isopropyl-9H-purin-6-amine (1j)
Column chromatography on SiO2, eluted with EtOAc afforded
white cube crystals (0.41 g, 23%). Mp¼234.8 ꢀC; Rf
(EtOAc)¼0.26; dH (250 MHz, DMSO-d6) 1.46 (6H, d, J 6.6 Hz,
2Me), 4.66 (1H, m, CH), 7.16 (2H, br s, NH2, exchangeable
with D2O), 8.08 (1H, s, C(2)eH, adenine): 8.17 (1H, s, C(8)e
H, adenine); dC (62.5 MHz, DMSO-d6) 22.0, 46.3, 119.0, 138.7,
148.9, 152.0, 155.8; IR (KBr) n cmꢂ1: 3310 (NH2), 3160, 2985,
2850; MS [m/z (%)]: 177 (31.9). Anal. Calcd for C8H11N5: C,
54.22; H, 6.26; N, 39.52%. Found: C, 54.20; H, 6.30; N, 39.48%.
4.2.11. 1-(2-(2-Methyl-4-nitro-1H-imidazol-1-yl)ethyl)-1H-
benzo[d]imidazole (1k)
4.2.15. 2-(2-(2,4-Dioxo-3,4-dihydropyrimidin-1(2H)-yl)-
ethyl)isoindoline-1,3-dione (2d)
Column chromatography on SiO2, eluted with EtOAc af-
forded pale yellow cube crystals (1.76 g, 65%). Mp¼223.7 ꢀC;
Rf (MeOH/EtOAc) (1:10)¼0.30; dH (250 MHz, DMSO-d6)
1.82 (3H, s, Me), 4.43 (2H, t, J 6.2 Hz, NCH2), 4.68 (2H, t,
J 6.2 Hz, NCH2), 7.19 (m, 2H, aryl), 7.20 (1H, d, J 7.5 Hz,
aryl), 7.65 (1H, d, J 7.5 Hz, aryl), 8.01 (1H, s, C(5)eH, imid-
azole), 8.16 (1H, s, C(2)eH, benzimidazole); dC (62.5 MHz,
DMSO-d6) 12.0, 44.0, 46.1, 109.8, 119.4, 121.7, 122.1,
Column chromatography on SiO2, eluted with EtOAc/
n-hexane (60:40) afforded white cube crystals (2.28 g, 80%).
Mp¼263.0 ꢀC; Rf (EtOAc)¼0.29; dH (250 MHz, DMSO-d6)
3.83e3.87 (4H, m, 2NCH2), 5.45 (1H, d, J 7.8 Hz, C(5)eH
uracil), 7.52 (1H, d, J 7.8 Hz, C(6)eH uracil), 7.78e7.86
(4H, m, aryl), 11.15 (1H, s, N3eH, exchangeable with
D2O); dC (62.5 MHz, DMSO-d6) 36.4, 46.4, 101.0, 123.0,
131.4, 134.3, 145.4, 151.1, 163.6, 167.6; IR (KBr) n cmꢂ1
:
122.5, 133.5, 143.1, 143.8, 145.0, 145.4; IR (KBr) n cmꢂ1
:
3200 (NH), 3210, 2895, 1730e1710 (C]O); MS [m/z (%)]:
285 (40). Anal. Calcd for C14H11N3O4: C, 58.96; H, 3.89;
N, 14.73%. Found: C, 59.00; H, 3.91; N, 14.75%.
3210, 3100, 2980, 2895; MS [m/z (%)]: 271 (33.2). Anal.
Calcd for C13H13N5O2: C, 57.56; H, 4.83; N, 25.82%. Found:
C, 57.51; H, 4.89; N, 25.83%.
4.2.16. 1-(Prop-2-ynyl)pyrimidine-2,4(1H,3H)-dione (2e)16
Column chromatography on SiO2, eluted with EtOAc/
n-hexane (70:30) afforded white cube crystals (1.0 g, 66%).
Mp¼154.6 ꢀC, Lit.16 (154e166 ꢀC); Rf (EtOAc)¼0.28; dH
(250 MHz, DMSO-d6) 3.13 (1H, s, ^CH), 4.28 (2H, s,
NCH2), 5.41 (1H, d, J 7.8 Hz, C(5)eH uracil), 7.64 (1H, d,
J 7.8 Hz, C(6)eH uracil), 11.13 (1H, s, N3eH, exchangeable
with D2O); dC (62.5 MHz, DMSO-d6) 36.5, 75.6, 78.3, 101.6,
144.4, 150.3, 163.5; IR (KBr) n cmꢂ1: 3290 (^CH), 3200
4.2.12. 1-Octylpyrimidine-2,4(1H,3H)-dione (2a)
Column chromatography on SiO2, eluted with EtOAc/
n-hexane (50:50) afforded pale yellow needle crystals (1.4 g,
63%). Mp¼61.2 ꢀC; Rf (EtOAc)¼0.55; dH (250 MHz,
CDCl3) 0.87 (3H, t, J 6.2 Hz, Me), 1.26e1.31 (10H, m,
5CH2), 1.49e1.52 (2H, m, CH2), 3.73 (2H, t, J 7.2 Hz,
NCH2), 5.74 (1H, d, J 7.8 Hz, C(5)eH uracil), 7.20 (1H, d,
J 7.8 Hz, C(6)eH uracil), 10.48 (1H, s, N3eH, exchangeable

1784
M.N. Soltani Rad et al. / Tetrahedron 64 (2008) 1778e1785
(NH), 3100, 2895, 2145 (C^C), 1740 (C]O), 1715 (C]O);
MS [m/z (%)]: 150 (55.7). Anal. Calcd for C7H6N2O2: C,
56.00; H, 4.03; N, 18.66%. Found: C, 56.05; H, 3.99; N,
18.60%.
3200 (NH), 3100, 2980, 1734 (C]O), 1720 (C]O); MS
[m/z (%)]: 166 (43.2). Anal. Calcd for C8H10N2O2: C, 57.82;
H, 6.07; N, 16.86%. Found: C, 57.86; H, 6.00; N, 16.91%.
4.2.21. 2-Butyl-1,2,4-triazine-3,5(2H, 4H)-dione (2j)
4.2.17. 5-Chloro-1-(prop-2-ynyl) pyrimidine-2,4(1H,3H)-
dione (2f)16
Column chromatography on SiO2 eluted with EtOAc/
n-hexane (40:60) afforded white needle crystals (1.02 g,
60%). Mp 136.4 ꢀC; Rf (EtOAc:n-hexane) (4:1) 0.77; dH
(250 MHz, DMSO-d6) 0.63 (3H, t, J 6.2 Hz, CH3), 1.01 (2H,
m, CH2CH3), 1.26 (2H, m, NCH2CH2), 3.48 (2H, t, J 6.5 Hz,
NCH2), 7.20 (1H, s, C(5)eH azauracil), 12.29 (1H, s, N3eH
exchangeable with D2O); dC (62.5 MHz, DMSO-d6) 13.4,
19.4, 28.6, 38.3, 134.5, 148.9, 156.1; IR (KBr) n cmꢂ1: 3200
(NH), 3210, 2985, 2895, 1725e1715 (C]O); MS [m/z (%)]:
169 (35). Anal. Calcd for C7H11N3O2: C, 49.70; H, 6.55; N,
24.84%. Found: C, 49.76; H, 6.51; N, 24.87%.
Column chromatography on SiO2, eluted with EtOAc/
n-hexane (70:30) afforded white cube crystals (1.1 g, 59%).
Mp¼169.4 ꢀC, lit.16 (168e170 ꢀC); Rf (EtOAc)¼0.29; dH
(250 MHz, DMSO-d6) 3.18 (1H, s, ^CH), 4.26 (2H, s,
NCH2), 8.23 (1H, s, C(6)eH uracil), 11.56 (1H, s, N3eH, ex-
changeable with D2O); dC (62.5 MHz, DMSO-d6) 36.3, 75.4,
78.6, 102.7, 145.4, 150.8, 163.2; IR (KBr) n cmꢂ1: 3310
(^CH), 3250 (NH), 3100, 2890, 2150 (C^C), 1735
(C]O), 1715 (C]O); MS [m/z (%)]: 184 (51.8). Anal. Calcd
for C7H5ClN2O2: C, 45.55; H, 2.73; Cl, 19.21; N, 15.18%.
Found: C, 45.62; H, 2.78; Cl, 19.17; N, 15.17%.
4.2.22. 1-Butyl-5-nitropyrimidine-2,4(1H,3H)-dione (2k)
Column chromatography on SiO2 eluted with EtOAc/n-hex-
ane (60:40) afforded pale yellow needle crystals (1.43 g, 76%).
Mp 146.3 ꢀC; Rf (EtOAc:n-hexane) (4:1) 0.68; dH (250 MHz,
DMSO-d6) 0.83 (3H, t, J 6.7 Hz, CH3), 1.26 (2H, m,
CH2CH3), 1.59 (2H, m, NCH2CH2), 3.81 (2H, t, J 6.5 Hz,
NCH2), 9.23 (1H, s, C(6)eH uracil), 11.96 (1H, s, N3eH uracil
exchangeable with D2O); dC (62.5 MHz, DMSO-d6) 18.6, 24.1,
35.6, 54.1, 129.7, 154.4, 155.8, 160.1; IR (KBr) n cmꢂ1: 3250
(NH), 3210, 2985, 2890, 1730e1715 (C]O); MS [m/z (%)]:
213 (25). Anal. Calcd for C8H11N3O4: C, 45.07; H, 5.20; N,
19.71%. Found: C, 45.03; H, 5.21; N, 19.73%.
4.2.18. (E)-1-Cinnamylpyrimidine-2,4(1H,3H)-dione (2g)
Column chromatography on SiO2, eluted with EtOAc/
n-hexane (50:50) afforded white cube crystals (1.42 g, 62%).
Mp¼198.1 ꢀC; Rf (EtOAc)¼0.65; dH (250 MHz, DMSO-d6)
4.51 (2H, d, J 5.6 Hz, NCH2), 5.67 (1H, d, J 7.8 Hz, C(5)eH ura-
cil), 6.36 (1H, m, CH2eCH), 6.64 (1H, d, J 16.0 Hz, ]CHePh),
7.26e7.68 (5H, m, aryl), 7.71 (1H, d, J 7.8 Hz, C(6)eH uracil),
11.36 (1H, s, N3eH, exchangeable with D2O); dC (62.5 MHz,
DMSO-d6) 48.6, 101.2, 124.2, 126.3, 127.8, 128.5, 132.4,
135.8, 145.2, 150.7, 163.7; IR (KBr) n cmꢂ1: 3250 (NH),
3050, 2895, 1730 (C]O), 1710 (C]O); MS [m/z (%)]: 228
(31.4). Anal. Calcd for C13H12N2O2: C, 68.41; H, 5.30; N,
12.27%. Found: C, 68.38; H, 5.26; N, 12.30%.
Acknowledgements
We wish to thank the Shiraz University of Technology and
Shiraz University Research Councils for partial support of this
work.
4.2.19. 1-Allyl-5-fluoropyrimidine-2,4(1H,3H)-dione
(2h)8a,b,18
Column chromatography on SiO2, eluted with EtOAc/
n-hexane (70:30) afforded white needle crystals (0.92 g,
54%). Mp¼101.3 ꢀC, lit.8b (101 ꢀC); Rf (EtOAc)¼0.27; dH
(250 MHz, CDCl3) 4.33 (2H, d, J 5.8 Hz, NCH2), 5.35 (2H,
dd, J 11.0, 16.3 Hz, ]CH2), 5.80 (1H, m, CH), 7.27 (1H, d,
3JHF 5.4 Hz, C(6)eH uracil), 9.65 (1H, s, N3eH, exchangeable
with D2O); dC (62.5 MHz, CDCl3) 51.4, 121.4, 128.2, 131.0,
141.0, 150.9, 158.8; IR (KBr) n cmꢂ1: 3220 (NH), 3050,
2895, 1725 (C]O), 1715 (C]O); MS [m/z (%)]: 170 (38.0).
Anal. Calcd for C7H7FN2O2: C, 49.41; H, 4.15; F, 11.17; N,
16.46%. Found: C, 49.46; H, 4.10; F, 11.14; N, 16.52%.
References and notes
1. (a) De Clercq, E. Advances in Antiviral Drug Design; Johnsson, N. G.,
Ed.; JAI: Greenwich, 1993; Vol. 1, pp 88e164; (b) Chu, C. K.; Cutler,
S. J. J. Heterocycl. Chem. 1986, 23, 289e319; (c) Agrofoglio, L. A.;
Challand, S. R. Acyclic, Carbocyclic and L-Nucleosides; Kluwer: Dor-
drecht, 1998; (d) Naesens, L.; Snoeck, R.; Andrei, G.; Balzarini, J.; Neyts,
J.; De Clercq, E. Antiviral. Chem. Chemother 1997, 8, 1e23; (e) Pathak, T.
Chem. Rev. 2002, 102, 1623e1667; (f) Ichikawa, E.; Kato, K. Synthesis
2002, 1e28; (g) Agrofoglio, L. A.; Gillaizeau, I.; Saito, Y. Chem. Rev.
2003, 103, 1875e1916; (h) Huryn, D. M.; Okabe, M. Chem. Rev. 1992,
92, 1745e1768; (i) Yokoyamma, M.; Momotake, A. Synthesis 1999,
1541e1554; (j) Yokoyamma, M. Synthesis 2000, 1637e1655; (k) Gao,
H.; Mitra, A. K. Synthesis 2000, 329e351.
4.2.20. 1-Allyl-5-methylpyrimidine-2,4(1H,3H)-dione
(2i)8a,b,19
2. (a) Khalafi-Nezhad, A.; Soltani Rad, M. N.; Moosavi-Movahedi, A. A.;
Kosari, M. Helv. Chim. Acta 2007, 90, 730e737; (b) Montgomery, J. A.;
Hewson, K., Jr.; Temple, C. J. Med. Pharm. Chem. 1962, 5, 15e24; (c)
Harnden, M. R.; Jarvest, R. L. Tetrahedron Lett. 1985, 26, 4265e
4268; (d) Biamonte, M. A.; Shi, J.; Hong, K.; Hurst, D. C.; Zhang,
L.; Fan, J.; Busch, D. J.; Karjian, P. L.; Maldonado, A. A.; Sensintaffar,
J. L.; Yang, Y.-C.; Kamal, A.; Lough, R. E.; Lundgren, K.; Burrows,
F. J.; Timony, G. A.; Boehm, M. F.; Kasibhatla, S. R. J. Med. Chem. 2006,
49, 817e828; (e) Schaeffer, H. J.; Gurwara, S.; Vince, R.; Bittner, S.
J. Med. Chem. 1971, 14, 367e369; (f) Jones, B. C. N. M.;
Column chromatography on SiO2, eluted with EtOAc/
n-hexane (60:40) afforded white cube crystals (0.96 g,
58%). Mp¼123.2 ꢀC, lit.8b (122 ꢀC); Rf (EtOAc)¼0.25; dH
(250 MHz, CDCl3) 1.89 (3H, s, Me), 4.31 (2H, d, J 5.5 Hz,
NCH2), 5.24 (2H, dd, J 10.8, 16.1 Hz, ]CH2), 5.82 (1H, m,
]CH), 6.96 (1H, s, C(6)eH uracil), 10.23 (1H, br s, N3eH,
exchangeable with D2O); dC (62.5 MHz, CDCl3) 13.8, 51.8,
112.3, 121.4, 133.2, 141.6, 152.2, 166.9; IR (KBr) n cmꢂ1
:

M.N. Soltani Rad et al. / Tetrahedron 64 (2008) 1778e1785
7. Xu, Z.-Q.; Joshi, R. V.; Zemlicka, J. Tetrahedron 1995, 51, 67e76.
1785
Silverton, J. V.; Simons, C.; Megati, S.; Nishimura, H.; Maeda, Y.;
Mitsuya, H.; Zemlicka, J. J. Med. Chem. 1995, 38, 1397e1405; (g)
Verheggen, I.; Aerschot, A. V.; Toppet, S.; Snoeck, R.; Janssen, G.;
Balzarini, J.; De Clercq, E.; Herdewijn, P. J. Med. Chem. 1993, 36,
2033e2040; (h) Hasan, A.; Srivastava, P. C. J. Med. Chem. 1992, 35,
1435e1439; (i) Tanaka, H.; Takashima, H.; Ubasawa, M.; Sekiya, K.;
Nitta, I.; Baba, M.; Shigeta, S.; Walker, R. T.; De Clercq, E.; Miyasaka,
T. J. Med. Chem. 1992, 35, 4713e4719; (j) Gupta, P. K.; Daunert, S.;
Nassiri, M. R.; Wotring, L. L.; Drach, J. C.; Townsend, L. B. J. Med.
Chem. 1989, 32, 402e408; (k) Gupta, P. K.; Nassiri, M. R.; Coleman,
L. A.; Wotring, L. L.; Drach, J. C.; Townsend, L. B. J. Med. Chem.
1989, 32, 1420e1425; (l) Kelley, J. L.; Krochmal, M. P.; Schaeffer,
H. J. J. Med. Chem. 1981, 24, 472e474; (m) Pudlo, J. S.; Saxena,
N. K.; Nassiri, M. R.; Turk, S. R.; Drach, J. C.; Townsend, L. B. J. Med.
Chem. 1988, 31, 2086e2092; (n) Phadtare, S.; Kessel, D.; Corbett,
T. H.; Renis, H. E.; Court, B. A.; Zemlicka, J. J. Med. Chem. 1991, 34,
421e429; (o) Kelley, J. L.; Krochmal, M. P.; Schaeffer, H. J. J. Med.
Chem. 1981, 24, 1528e1531; (p) Kim, C. U.; Luh, B. Y.; Misco, P. F.;
Bronson, J. J.; Hitchcock, M. J. M.; Ghazzouli, I.; Martin, J. C. J. Med.
Chem. 1990, 33, 1207e1213; (q) Girgis, N. S.; Michael, M. A.; Smee,
D. F.; Alaghamandan, H. A.; Robins, R. K.; Cottam, H. B. J. Med.
Chem. 1990, 33, 2750e2755; (r) Hua, M.; Korkowski, P. M.; Vince, R.
J. Med. Chem. 1987, 30, 198e200; (s) Manikowski, A.; Verri, A.; Lossani,
A.; Gebhardt, B. M.; Gambino, J.; Focher, F.; Spadari, S.; Wright, G. E.
J. Med. Chem. 2005, 48, 3919e3929.
8. (a)Amblard, F.;Nolan, S.P.;Gillaizeau,I.;Agrofoglio, L. A.Tetrahedron Lett.
2003, 44, 9177e9180; (b) Amblard, F.; Nolan, S. P.; Schinazi, R. F.; Agrofo-
glio, L. A. Tetrahedron 2005, 61, 537e544; (c) Goux, C.; Sigismondi, S.;
´
Sinou, D.; Perez, M.; Moreno-Manas, M.; Peixats, R.; Villaroya, M. Tetra-
hedron 1996, 52, 9521e9534;(d)Freer,R.;Geen, G. R.;Ramsay, T. W.;Share,
A. C.; Slater, G. R.; Smith, N. M. Tetrahedron 2000, 56, 4589e4595; (e)
Gundersen, L.-L.; Benneche, T.; Undheim, K. Tetrahedron Lett. 1992, 33,
1085e1088; (f) Gundersen, L.-L.; Benneche, T.; Rise, F.; Gogoll, A.;
Undheim, K. Acta Chem. Scand. 1992, 46, 761e771; (g) Crimmins, M. T.;
King, B. W. J. Org. Chem. 1996, 61, 4192e4193; (h) Crimmins, M. T.;
King, B. W.; Zuercher, W. J.; Choy, A. L. J. Org. Chem. 2000, 65, 8499e8509.
9. (a) Singh, D.; Wani, M. J.; Kumar, A. J. Org. Chem. 1999, 64, 4665e4668;
(b) Alahiane, A.; Rochdi, A.; Taourirte, M.; Redwane, N.; Sebti, S.; Lazrek,
H. B. Tetrahedron Lett. 2001, 42, 3579e3581; (c) Geen, G. R.; Kincey,
P. M.; Spoors, P. G. Tetrahedron Lett. 2001, 42, 1781e1784; (d) Rosowsky,
A.; Kim, S.-H.; Wick, M. J. Med. Chem. 1981, 24, 1177e1181; (e) Jahne,
G.; Kroha, H.; Muller, A.; Helsberg, M.; Winkler, I.; Gross, G.; Scholl, T.
¨
Angew. Chem., Int. Ed. Engl. 1994, 33, 562e563; (f) Azymah, M.; Chavis,
C.; Lucas, M.; Imbach, J.-L. Tetrahedron Lett. 1989, 30, 6165e6168; (g)
´
´
Boto, A.; Hernandez, R.; Suarez, E. Tetrahedron Lett. 2001, 42, 9167e
9170; (h) Martinez, A.; Esteban, A. I.; Castro, A.; Gil, C.; Conde, S.; Andrei,
G.; Snoeck, R.; Balzarini, J.; De Clercq, E. J. Med. Chem. 1999, 42, 1145e
1150; (i) Perigaud, C.; Gosselin, G.; Imbach, J.-L. J. Chem. Soc., Perkin
Trans 1 1992, 1943e1952; (j) Bravo, P.; Resnati, G.; Viani, F. Tetrahedron
1993, 49, 713e720; (k) Ashton, W. T.; Canning, L. F.; Reynolds, G. F.; Tol-
man, R. L.; Karkas, J. D.; Liou, R.; Davies, M.-E. M.; DeWitt, C. M.; Perry,
H. C.; Field, A. K. J. Med. Chem. 1985, 28, 926e933.
ˇ
ˇ
ˇ
´
´
´
3. (a) Kasnar, B.; Skaric, V.; Klaic, B.; Zinic, M. Tetrahedron Lett. 1993, 34,
4997e5000; (b) Lewis, M.; McMurry, T. B. H.; De Clercq, E. J. Chem.
Soc., Perkin Trans. 1 1993, 2107e2110; (c) Bennett, S. M.; Nghe, N. B.;
Ogilvie,K. K. J. Med. Chem. 1990, 33, 2162e2173; (d)Holy, A.;Dvorakova,
H.; Jindrich, J.; Masojidkova, M.; Budesinsky, M.; Balzarini, J.; Andrei, G.;
De Clercq, E. J. Med. Chem. 1996, 39, 4073e4088; (e) Sekiyama, T.;
Hatsuya, S.; Tanaka, Y.; Uchiyama, M.; Ono, N.; Iwayama, S.; Oikawa,
M.; Suzuki, K.; Okunishi, M.; Tsuji, T. J. Med. Chem. 1998, 41, 1284e1298.
4. (a) Vandendriessche, F.; Snoeck, R.; Janssen, G.; Hoogmartens, J.;
Aerschot, A. V.; De Clercq, E.; Herdewijn, P. J. Med. Chem. 1992, 35,
1458e1465; (b) Franchetti, P.; Abu Sheikha, G.; Cappellacci, L.; Grifan-
tini, M.; De Montis, A.; Piras, G.; Lei, A. G.; La Collat, P. J. Med.
Chem. 1995, 38, 4007e4013; (c) Kelley, J. L.; McLean, E. W.; Crouch,
R. C.; Averett, D. R.; Tuttle, J. V. J. Med. Chem. 1995, 38, 1005e1014;
(d) Yu, K.-L.; Bronson, J. J.; Yang, H.; Patick, A.; Alam, M.; Brankovan,
V.; Datema, R.; Hitchcock, M. J. M.; Martin, J. C. J. Med. Chem. 1992, 35,
2958e2969; (e) Yu, K.-L.; Bronson, J. J.; Yang, H.; Patick, A.; Alam, M.;
Brankovan, V.; Datema, R.; Hitchcock, M. J. M.; Martin, J. C. J. Med.
Chem. 1993, 36, 2726e2738; (f) Kim, H. S.; Barak, D.; Harden, T. K.;
Boyer, J. L.; Jacobson, K. A. J. Med. Chem. 2001, 44, 3092e3108; (g)
Choi, J.-R.; Cho, D.-G.; Roh, K. Y.; Hwang, J.-T.; Ahn, S.; Jang, H. S.;
Cho, W.-Y.; Kim, K. W.; Cho, Y.-G.; Kim, J.; Kim, Y.-Z. J. Med. Chem.
2004, 47, 2864e2869; (h) Chen, W.; Flavin, M. T.; Filler, R.; Xu, Z.-Q.
J. Chem. Soc., Perkin Trans. 1 1998, 3979e3988.
10. Obika, S.; Takashima, Y.; Matsumoto, Y.; Kuromaru, K.; Imanishi, T.
Tetrahedron Lett. 1995, 36, 8617e8620.
11. Han, Y.-K.; Paquette, L. A. J. Org. Chem. 1979, 44, 3733e3734.
12. (a) Mitsunobu, O. Synthesis 1981, 1e28; (b) Martin, S. F.; Dodge, J. A.
Tetrahedron Lett. 1991, 32, 3017e3020; (c) Hughes, D. L. Org. Prep.
Proced. Int. 1996, 28, 127e164; (d) Toyota, A.; Katagiri, N.; Kaneko, C.
Heterocycles 1993, 36, 1625e1630; (e) Kozai, S.; Takaoka, S.; Maruyama,
T. Tetrahedron Lett. 2002, 43, 2633e2636; (f) Bombrun, A.; Casi, G.
Tetrahedron Lett. 2002, 43, 2187e2190; (g) Hubert, C.; Alexandre, C.;
Aubertin, A.-M.; Huet, F. Tetrahedron 2002, 58, 3775e3778; (h) Hubert,
C.; Alexandre, C.; Aubertin, A.-M.; Huet, F. Tetrahedron 2003, 59,
3127e3130; (i) Llauger, L.; He, H.; Chiosis, G. Tetrahedron Lett. 2004,
45, 9549e9552; (j) Kim, E. J.; Ko, S. Y.; Dziadulewicz, E. K. Tetrahedron
Lett. 2005, 46, 631e633; (k) Kim, K. R.; Moon, H. R.; Park, A.-Y.; Chun,
M. W.; Jeong, L. S. Bioorg. Med. Chem. 2007, 15, 227e234; (l) Yin, X.-Q.;
Li, W. K.; Schneller, S. W. Tetrahedron Lett. 2006, 47, 9187e9189; (m)
Yang, M.; Zhou, J.; Schneller, S. W. Tetrahedron 2006, 62, 1295e1300;
(n) Danappe, S.; Pal, A.; Alexandre, C.; Aubertin, A.-M.; Bourgougnon,
´
N.; Huet, F. Tetrahedron 2005, 61, 5782e5787; (o) Veliz, E. A.; Beal,
P. A. Tetrahedron Lett. 2006, 47, 3153e3156; (p) Petersen, A. B.; Petersen,
M. A.; Henriksen, U.; Hammerum, S.; Dahl, O. Org. Biomol. Chem. 2003,
1, 3293e3296; (q) Pragnacharyulu, P. V. P.; Varkhedkar, V.; Curtis, M. A.;
Chang, I. F.; Abushanab, E. J. Med. Chem. 2000, 43, 4694e4700.
13. Soltani Rad, M. N.; Behrouz, S.; Khalafi-Nezhad, A. Tetrahedron Lett.
2007, 48, 3445e3449.
5. (a) Khalafi-Nezhad, A.; Soltani Rad, M. N.; Khoshnood, A. Synthesis
2004, 583e589; (b) Boesen, T.; Madsen, C.; Pedersen, D. S.; Nielsen,
B. M.; Petersen, A. B.; Petersen, M. A.; Munck, M.; Henriksen, U.;
Nielsen, C.; Dahl, O. Org. Biomol. Chem. 2004, 2, 1245e1254; (c)
Guan, H.-P.; Ksebati, M. B.; Kern, E. R.; Zemlicka, J. J. Org. Chem.
2000, 65, 5177e5184; (d) Dimenna, W. S.; Piantadosi, C.; Lamb, R. G.
J. Med. Chem. 1978, 21, 1073e1076; (e) Branalt, J.; Kvarnstrom, I.;
Classon, B.; Samuelsson, B. J. Org. Chem. 1996, 61, 3599e3603; (f)
Brodfuehrer, P. R.; Howell, H. G.; Sapino, C.; Vemishetti, P. Tetrahedron
Lett. 1994, 35, 3243e3246; (g) Pedersen, D. S.; Boesen, T.; Eldrup, A. B.;
Kiær, B.; Madsen, C.; Henriksen, U.; Dahl, O. J. Chem. Soc., Perkin
Trans. 1 2001, 1656e1661; (h) Martin, J. C.; Smee, D. F.; Verheyden,
J. P. H. J. Org. Chem. 1985, 50, 755e759; (i) Suwiski, J.; Walczak, K.
Synthesis 2001, 225e228.
14. Soltani Rad, M. N.; Khalafi-Nezhad, A.; Behrouz, S.; Faghihi, M. A.
Tetrahedron Lett. 2007, 48, 6779e6784.
15. (a) Estep, K. G.; Josef, K. A.; Bacon, E. R.; Carabateas, P. M.; Rumney,
S.; Pilling, G. M.; Krafte, D. S.; Volberg, W. A.; Dillon, K.; Dugrenier, N.;
Briggs, G. M.; Canniff, P. C.; Gorczyca, W. P.; Stankus, G. P.; Ezrin,
A. M. J. Med. Chem. 1995, 38, 2582e2595; (b) Ogilvie, K. K.; Cheriyan,
U. O.; Radatus, B. K.; Smith, K. O.; Galloway, K. S.; Kennell, W. L. Can.
J. Chem. 1982, 60, 3005e3010.
16. Lazrek, H. B.; Taourirte, M.; Oulih, T.; Barascut, J. L.; Imbach, J. L.;
Pannecouque, C.; Witrouw, M.; De Clercq, E. Nucleosides Nucleotides
Nucleic Acids 2001, 20, 1949e1960.
17. Vogel, A. I. Practical Organic Chemistry; Longmans, Green: London,
England, 1954; Chapter 2, pp 161e176.
6. (a) Khalafi-Nezhad, A.; Zarea, A.; Soltani Rad, M. N.; Mokhtari, B.;
Parhami, A. Synthesis 2005, 419e424; (b) Guillarme, S.; Legoupy, S.;
Aubertin, A.-M.; Olicard, C.; Bourgougnon, N.; Huet, F. Tetrahedron
2003, 59, 2177e2184; (c) Scheiner, P.; Geer, A.; Bucknor, A.-M.; Imbach,
J.-L.; Schinazi, R. F. J. Med. Chem. 1989, 32, 73e76.
18. Kundu, N. G.; Schmitz, S. A. J. Pharm. Sci. 1982, 71, 935e938.
19. Thibon, J.; Latxague, L.; Deleris, G. J. Org. Chem. 1997, 14, 4635e4642.