One-pot synthesis of n-alkyl purine, pyrimidine and azole derivatives from alcohols using ph3p/ccl4: A rapid route to carboacyclic nucleoside synthesis

Article abstract of DOI:10.1055/s-0029-1216887

A facile and efficient method for one-pot N-alkylation of nucleobases and azole derivatives from alcohols using triphenylphosphine in carbon tetrachloride is described. In this method, treatment of alcohols with a mixture of triphenylphosphine, carbon tetrachloride, nucleobase or azole derivatives and potassium carbonate in the presence of catalytic amounts of tetra-n- butylammonium iodide (TBAI) in refluxing N,N-dimethylformamide, furnishes the corresponding N-alkyl derivatives in good yields. This methodology is highly efficient for various structurally diverse primary alcohols and also useful for N-alkylation of other N-heterocycles containing an acidic N-H bond.

Full text of DOI:10.1055/s-0029-1216887

PAPER
3067
One-Pot Synthesis of N-Alkyl Purine, Pyrimidine and Azole Derivatives from
Alcohols using Ph3P/CCl4: A Rapid Route to Carboacyclic Nucleoside
Synthesis
A
R
apid Route to Carb
o
oacyclic
N
uc
h
leoside Syn
a
thesis mmad Navid Soltani Rad,*a Ali Khalafi-Nezhad,*b Somayeh Behrouz,b Zeinab Asrari,b Marzieh Behrouz,b
Zohreh Aminia
a
Fax +98(711)7354523; E-mail: soltani@sutech.ac.ir, nsoltanirad@gmail.com
Department of Chemistry, College of Sciences, Shiraz University, Shiraz 71454, Iran
b
Received 21 April 2009; revised 5 May 2009
Since few synthetic methods efficiently provide direct ac-
Abstract: A facile and efficient method for one-pot N-alkylation of
nucleobases and azole derivatives from alcohols using triphe-
nylphosphine in carbon tetrachloride is described. In this method,
treatment of alcohols with a mixture of triphenylphosphine, carbon
cess to the biologically important N-alkyl nucleobases
from alcohols,13 there is still an urgent need to extend and
improve convenient, efficient and selective methods for
tetrachloride, nucleobase or azole derivatives and potassium car- one-pot N-alkylation of nucleobases using alcohols.
bonate in the presence of catalytic amounts of tetra-n-butylammo-
Use of the well-known combination of tertiary phos-
nium iodide (TBAI) in refluxing N,N-dimethylformamide,
phanes with tetrahalomethanes have found increasing ap-
furnishes the corresponding N-alkyl derivatives in good yields. This
plications in preparative chemistry for halogenations,
dehydrations and P–N linking reactions.14 Among these
combinations, triphenylphosphine in carbon tetrachloride
is a famous reagent which can convert an alcohol into the
corresponding alkyl halide15 under mild conditions.
Moreover, the triphenylphosphine in carbon tetrachloride
system has found various important applications includ-
ing: conversion of alcohols into nitriles16 and esters,17
chlorination and chlorodehydration of 1,2-diols,18 cyclo-
dehydration of chiral diols,19 dehydration of aldoximes20a
and amides,20b conversion of carboxylic acids into
amides21a and acid chlorides,21b synthesis of benzox-
azoles,22a [1,3,4]-oxadiazoles,22b b-lactams22c and N-acyl-
indolines.22d However, although triphenylphosphine in
carbon tetrachloride has been widely employed as an effi-
cient and useful reagent for several organic transforma-
tions, there have been no reports on the application of this
combination for the N-alkylation of nucleobases or other
N-heterocycles with alcohols. In a continuation of our in-
terest in the design and synthesis of novel carboacyclic
nucleosides,5a,6a,13,23 in this context, we report triphe-
nylphosphine in carbon tetrachloride as a convenient and
inexpensive reagent combination for the one-pot N-alky-
lation of nucleobases (Scheme 1 and Scheme 2), as well
as azole derivatives (Scheme 3) using alcohols in the pres-
ence of potassium carbonate and a catalytic amount of
tetra-n-butylammonium iodide (TBAI) in anhydrous N,N-
dimethylformamide at reflux for 5–10 hours.
methodology is highly efficient for various structurally diverse pri-
mary alcohols and also useful for N-alkylation of other N-heterocy-
cles containing an acidic N–H bond.
Key words: carboacyclic nucleosides, N-alkylation, nucleobase,
alcohol, triphenylphosphine, carbon tetrachloride, potassium car-
bonate
Carboacyclic nucleosides constitute a special class of nu-
cleoside analogues that have attracted great interest due to
their broad spectrum of antiviral and anticancer activi-
ties.1 The most common route to nucleoside synthesis in-
volves the N-alkylation of nucleobases with alkyl
halides,2 alkyl tosylates3 and mesylates.4 Furthermore, the
N-alkylation of purine and pyrimidine nucleobases with
other carbon electrophiles such as epoxides,5 Michael ac-
ceptors,6 carbonates,7 and allylic esters catalyzed by pal-
ladium(0),8 are well known procedures. Moreover,
acetoxyethyl and acetoxymethyl ethers and their ana-
logues,9 methylthiomethyl ethers10 and cyclic acetals,11 as
active ethers, have also been described for the N-alkyla-
tion of nucleobases.
In view of the wide diversity and availability of alcohols,
lower toxicity and ease of handling with respect to alkyl
halides, the one-pot reaction of nucleobases with alcohols
seems to be a suitable and attractive strategy. Unfortu-
nately, few reports describing conditions that are suitable
for accessing N-alkylatednucleobases from alcohols have
so far been published; the methods that have are mostly
based on Mitsunobu conditions.12 However, the use of
toxic, expensive and explosive reagents such as diethyl
azodicarboxylate (DEAD) and diisopropyl azodicarboxy-
late (DIAD) restricts the applicability of this method.
NH2
NH2
N
N
N
Ph3P, CCl4, K2CO3
N
N
+
R
OH
DMF, TBAI, Δ, 5–10 h
N
H
N
N
R
1a–l
(58–82%)
SYNTHESIS 2009, No. 18, pp 3067–3076
Advanced online publication: 07.07.2009
x
x.
x
x
.
2
0
0
9
Scheme 1
DOI: 10.1055/s-0029-1216887; Art ID: Z07709SS
© Georg Thieme Verlag Stuttgart · New York

3068
M. N. Soltani Rad et al.
PAPER
essential. The explicit interference of moisture was easily
observed by the comparison of results obtained using wet
versus anhydrous N,N-dimethylformamide (Table 1, en-
tries 2 and 3). Using DMSO and HMPA afforded a mod-
erate yield of the corresponding 9-phenethyl-9H-purin-6-
amine (1a).
O
N
O
X
X
HN
Ph3P, CCl4, K2CO3
DMF, TBAI, Δ, 5–10 h
HN
+
R
OH
Z
Z
O
O
N
H
R
X = H, Me, F, Cl, NO2
Z = C, N
2a–l
(52–81%)
Other solvents were inefficient even if the reaction time
was extended for up to 72 hours. The choice of base for
activating the N–H bonds in nucleobases and azoles for
reaction with the alkoxyphosphonium salt intermediate
had a great significance. We therefore evaluated the effect
of various organic and inorganic bases on the reaction
model (Table 2).
Scheme 2
N
N
Ph3P, CCl4, K2CO3
DMF, TBAI, Δ, 5–10 h
+
R
OH
N
R
N
H
3a–d
(66–81%)
Table 2 Effect of Bases on Conversion of 2-Phenylethanol into 9-
Phenethyl-9H-purin-6-amine (1a) in Anhydrous N,N-Dimethylfor-
mamide
Scheme 3
NH2
In order to establish optimized reaction conditions, we
chose the reaction of adenine, 2-phenylethanol and potas-
sium carbonate, in the presence of a mixture of triphe-
nylphosphine in carbon tetrachloride and a catalytic
amount of TBAI, as a reaction model. Initially, the effect
of various aprotic solvents on the model reaction was
studied. The results are depicted in Table 1.
NH2
Ph3P, CCl4
base
N
N
N
N
HO
N
+
DMF, TBAI
reflux
N
N
H
N
1a
Entry
Base
Time (h)
Yield (%)a
15
Table 1 Effect of Solvents on Conversion of 2-Phenylethanol into
9-Phenethyl-9H-purin-6-amine (1a)
1
2
3
4
5
6
7
8
9
DBN
24
12
12
12
72
7
DBU
26
NH2
NH2
DABCO
DMAP
MgO
35
Ph3P, CCl4
solvent
N
N
N
N
HO
N
+
23
K2CO3
TBAI, reflux
N
N
H
N
trace
40
1a
Cs2CO3
K2CO3
Et3N
Entry
Solventa
Time (h)
Yield (%)b
45
5
82
1
2
3
4
5
6
7
8
9
DMSO
DMF
7
24
5
72
72
trace
trace
NRc
82
NaH
DMF
a Isolated yield.
MeCN
HMPA
NMP
18
12
18
12
18
12
NR
37
The results in Table 2 demonstrate that, of the examined
bases, potassium carbonate (Table 2, entry 7) was the
most appropriate base for the reaction. DBU, DABCO,
and cesium carbonate (Table 2, entries 2, 3 and 6) afford-
ed moderate yields of 1a, while other bases were ineffi-
cient.
10
THF
NR
toluene
acetone
NR
NR
We also investigated the role of various phase-transfer
catalysts (PTC) on the reaction model. In this case, tetra-
n-butylammonium halides (TBAX; X = F, Cl, Br and I)
were employed. In the absence of PTC, the reaction oc-
curred in only low yields (<10%). However, the use of
TBAI afforded 1a in higher yield in a short reaction time;
other PTCs were not as effective.
a All solvents except DMF (entry 2) were anhydrous.
b Isolated yield. NR = no reaction.
c No reaction after refluxing for 72 h.
As the data in Table 1 indicates, anhydrous N,N-dimethyl-
formamide (Table 1, entry 3) was found to be the most ef-
ficient solvent and, hence, was the solvent of choice for all
further reactions. In view of the fact that the generated re-
active intermediates in the reaction mixture are very sus-
ceptible to moisture, the use of a well-dried solvent is
In a series of other experiments, we investigated the influ-
ence of several reagents as positive-halogen sources in-
stead of carbon tetrachloride, in combination with
triphenylphosphine (Table 3). According to the results in
Synthesis 2009, No. 18, 3067–3076 © Thieme Stuttgart · New York

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A Rapid Route to Carboacyclic Nucleoside Synthesis
3069
Table 4 One-Pot N-Alkylation of Nucleobases and Other Azoles
via Alcohols Using Ph3P, CCl4, K2CO3, TBAI in Refluxing N,N-
Dimethylformamide
Table 3, the triphenylphosphine in carbon tetrachloride
system was found to be the most suitable and efficient re-
agent for the conversion of 2-phenylethanol into 1a. The
use of N-chlorosuccinimide, N-bromosuccinimide, isocy-
anuric chloride or molecular bromine (Table 3, entries 2–
5) did not afford satisfactory results; DDQ and CHI3 (en-
tries 6 and 7) were also inefficient even after refluxing for
72 hours.
Compd Structurea
Mp
(°C)
Time Yield
(h) (%)b
NH2
N
N
N
1a
1b
180.3
161.4
5
5
82
75
N
N
Table 3 Effect of Various Reagents Giving Positive-Halogens on
the Conversion of 2-Phenylethanol into 1a in Anhydrous N,N-Di-
methylformamide
NH2
NH2
NH2
N
N
HO
+
N
N
N
N
Ph3P, reagent
N
N
K2CO3, DMF
TBAI, reflux
N
N
H
N
OMe
1a
NH2
Entry
Reagent
Time (h)
Yield (%)a
N
N
N
N
N
1c
237.3 10 60
1
2
3
4
5
6
7
Ph3P, CCl4
5
12
12
18
24
72
72
82
N
Ph3P, NCS
35
NH2
Ph3P, NBS
27
N
N
1d
141.1
97.8
6
7
82
58
Ph3P, isocyanuric chloride
Ph3P, Br2
10
N
12
NH2
Ph3P, DDQ
Ph3P, CHI3
trace
trace
N
N
1e
a Isolated yield.
N
NH2
The optimized stoichiometric ratio of Ph3P–CCl4–ROH–
nucleobase–K2CO3 for the conversion of 2-phenylethanol
into 1a was found to be 1.5:2:1.5:1:1.
N
N
1f
N
N
127.0
149.2
7
6
77
80
N
The generality and versatility of this method was demon-
strated by its application to various structurally diverse al-
cohols and nucleobases. As the results in Table 4 indicate,
a range of alcohols reacted with purine 1a–l and pyrimi-
dine 2a–l nucleobases as well as azoles 3a–d to afford the
corresponding N-alkyl derivatives. The results demon-
strate that this method is efficient and suitable for primary
alcohols, including aliphatic, benzylic and allylic alco-
hols, while secondary and tertiary types did not give satis- 1h
factory results. For instance, N-alkylation of adenine with
isopropyl alcohol afforded the corresponding product 1l
only in trace amounts (<10%). In order to demonstrate the
generality of this method, the optimized conditions were
also applied to other azole derivatives including: benzim-
NH2
N
N
1g
N
O
O
HN
Ph
N
N
124.3
159.4
5
8
58
65
N
N
O
N
Me
N
1i
N
idazole, 2-methyl-4-nitro-1H-imidazole and imidazole
3a–d. Interestingly, 1H NMR and 13C NMR studies indi-
cated that good regioselectivity was achieved for the N-
alkylation in nucleobases.24 The N-alkylation of purine
and pyrimidine nucleobases was achieved chiefly on N9
and N1 sites, respectively, while the corresponding N7-
alkyl or N1,N3-dialkyl derivatives were found in trace
amounts (<5–7%).
N
O
Me
Synthesis 2009, No. 18, 3067–3076 © Thieme Stuttgart · New York

3070
M. N. Soltani Rad et al.
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Table 4 One-Pot N-Alkylation of Nucleobases and Other Azoles
via Alcohols Using Ph3P, CCl4, K2CO3, TBAI in Refluxing N,N-Di-
methylformamide (continued)
Table 4 One-Pot N-Alkylation of Nucleobases and Other Azoles
via Alcohols Using Ph3P, CCl4, K2CO3, TBAI in Refluxing N,N-Di-
methylformamide (continued)
Compd Structurea
Mp
(°C)
Time Yield
(h) (%)b
Compd Structurea
Mp
(°C)
Time Yield
(h) (%)b
O
O
Cl
HN
Me
N
N
1j
103.7
8
66
2f
170.3
6
59
N
O
O
N
O
O
N
Me
HN
HN
O
2g
2h
199.2 10 71
Me
1k
135.2 10 61
N
N
O
O
N
N
O
N
Me
F
NH2
N
101.2
123.0
7
7
52
67
N
O
N
O
N
1l
234.8 10 tracec
N
HN
O
2i
O
N
O
HN
2a
62.4
7
6
70
55
O
N
O
HN
HN
2j
136.8 10 55
HN
N
O
N
O
2b
2c
118.0
O
N
NO2
2k
146.3 10 81
OMe
O
N
O
O
N
HN
149.2
5
74
NO2
O
O
HN
2l
231.6 10 68
O
N
O
N
Cl
HN
N
N
O
2d
263.6
154.4
6
6
78
72
O
3a
3b
223.2
118.1
9
9
66
74
N
N
N
O
NO2
N
N
O
N
HN
O
2e
O
Cl
Synthesis 2009, No. 18, 3067–3076 © Thieme Stuttgart · New York

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A Rapid Route to Carboacyclic Nucleoside Synthesis
3071
Table 4 One-Pot N-Alkylation of Nucleobases and Other Azoles
via Alcohols Using Ph3P, CCl4, K2CO3, TBAI in Refluxing N,N-Di-
methylformamide (continued)
One-Pot N-Alkylation of Nucleobases Using Alcohols: General
Procedure
To a double-necked round-bottom flask (100 mL) equipped with a
condenser was added a mixture of PPh3 (0.015 mol), CCl4 (0.02
mol), alcohol (0.015 mol), nucleobase or other N-heterocycle (0.01
mol), K2CO3 (0.01 mol) and a catalytic amount of TBAI (0.1 g) in
anhydrous DMF (30 mL). The mixture was refluxed for the appro-
priate time until TLC monitoring indicated no further improvement
in the conversion (Table 4). The solvent was evaporated under vac-
uum and the remaining foam was dissolved in CHCl3 or EtOAc
(100 mL) and subsequently washed with H2O (2 × 100 mL). The or-
ganic layer was dried on Na2SO4, filtered and evaporated. The crude
product was purified by short column chromatography on silica gel
eluting with suitable solvents.
Compd Structurea
Mp
(°C)
Time Yield
(h) (%)b
O2N
N
3c
116.2
99.4
7
68
N
N
9-Phenethyl-9H-purin-6-amine (1a)13
Column chromatography (SiO2, EtOAc) afforded the product as
white needle crystals.
N
3d
10 81
O
Yield: 1.96 g (82%); mp 180.3 °C; Rf = 0.23 (EtOAc).
IR (KBr): 3335 (NH2), 3142, 2928 cm–1.
1H NMR (250 MHz, DMSO-d6): d = 3.12 (t, J = 7.2 Hz, 2 H,
PhCH2), 4.37 (t, J = 7.2 Hz, 2 H, NCH2), 7.08–7.28 (m, 7 H, Ph and
NH2), 7.79 [s, 1 H, C(2)-H, adenine], 8.16 [s, 1 H, C(8)-H, adenine].
a All products were characterized by 1H and 13C NMR, IR, CHN, and
MS analysis.
b Isolated yield.
c This compound was produced in a trace amount (<10%).
13C NMR (62.5 MHz, DMSO-d6): d = 35.2, 44.2, 118.5, 126.2,
Furthermore, O-alkylation of the pyrimidine nucleobases
was not observed. When the N-alkylation of adenine and
uracil was classically achieved using alkyl halide, such as
(2-chloroethyl)benzene in the presence of potassium car-
bonate in N,N-dimethylformamide,25 affording 1a and 2c,
respectively, we witnessed that the ratio of N7-alkyl/N9-
alkyl in adenine and/or N1, N3-dialkyl/N1-alkyl in uracil
was remarkable improved with respect to the present
method using 2-phenylethanol. Hence, we presume that
the regioselectivity of nucleobase N-alkylation is more ki-
netically controlled using alkyl halides than using alcohol,
and this leads to higher reactivity of alkyl halides in com-
parison to alcohols.
127.9, 128.1, 138.1, 140.4, 149.4, 152.0, 155.7.
MS (EI): m/z (%) = 239 (35).
Anal. Calcd for C13H13N5: C, 62.25; H, 5.48; N, 29.27. Found: C,
62.29; H, 5.49; N, 29.26.
9-(4-Methoxybenzyl)-9H-purin-6-amine (1b)13
Column chromatography (SiO2, EtOAc) afforded the product as
white needle crystals.
Yield: 1.91 g (75%); mp 161.4 °C; Rf = 0.22 (EtOAc).
IR (KBr): 3315 (NH2), 3155, 2930 cm–1.
1H NMR (250 MHz, DMSO-d6): d = 3.67 (s, 3 H, OMe), 5.37 (s,
2 H, NCH2), 6.86 [d, J = 8.6 Hz, 2 H, C(2,6)-H, aryl], 7.01 [s, 1 H,
C(2)-H, adenine], 7.23 [d, J = 8.6 Hz, 2 H, C(3,5)-HAr], 7.31 (s, 2 H,
NH2, adenine), 8.48 [s, 1 H, C(8)-H, adenine].
In conclusion, a novel and efficient method has been es-
tablished for the one-pot N-alkylation of purines and py-
rimidines as well as other azoles, using alcohols in the
presence of triphenylphosphine, carbon tetrachloride, po-
tassium carbonate and TBAI (cat.) in refluxing N,N-di-
methylformamide. In this method, various primary
alcohols underwent reaction with nucleobases and other
N-heterocycles to afford N-alkyl derivatives in reasonable
to good yields. In addition, this method can be extended to
other N-heterocycles prone to N-alkylation.
13C NMR (62.5 MHz, DMSO-d6): d = 45.8, 54.9, 113.9, 118.6,
121.4, 135.1, 140.5, 149.2, 152.4, 155.8, 158.9.
MS (EI): m/z (%) = 255 (40).
Anal. Calcd for C13H13N5O: C, 61.17; H, 5.13; N, 27.43. Found: C,
61.20; H, 5.12; N, 27.46.
(E)-9-Cinnamyl-9H-purin-6-amine (1c)13
Column chromatography (SiO2, EtOAc) afforded the product as
pale-yellow needle crystals.
Yield: 1.51 g (60%); mp 237.3 °C; Rf = 0.32 (EtOAc).
IR (KBr): 3355 (NH2), 3130, 2950.
All chemicals were purchased from either Fluka or Merck. Solvents
were purified and dried by standard procedures, and stored over 3 Å
molecular sieves. Reactions were followed by TLC using SILG/UV
254 silica-gel plates. Column chromatography was performed on
silica gel 60 (0.063–0.200 mm, 70–230 mesh; ASTM). Melting
points were obtained using a Büchi-510 apparatus in open capillar-
ies and are uncorrected. IR Spectra were obtained using a Shimadzu
FT-IR-8300 spectrophotometer. 1H- and 13C NMR Spectra were ob-
tained using a Bruker Avance-DPX-250 spectrometer operating at
250/62.5 MHz, respectively (d in ppm, J in Hz). GC/MS were per-
formed on a Shimadzu GC/MS-QP 1000-EX apparatus (m/z; rel.
%). Elemental analyses (CHNS) were performed on a Perkin–Elmer
240-B micro-analyzer.
1H NMR (250 MHz, DMSO-d6): d = 4.92 (d, J = 5.1 Hz, 2 H,
NCH2), 6.43 (d, J = 16.4 Hz, 1 H, =CH-Ph), 7.20–7.31 (m, 6 H,
CH2-CH, aryl), 7.35 [s, 1 H, C(2)-H, adenine], 7.40 (s, 2 H, NH2,
exch D2O), 8.15 [s, 1 H, C(8)-H, adenine].
13C NMR (62.5 MHz, DMSO-d6): d = 44.4, 118.6, 124.4, 126.6,
127.4, 128.7, 132.3, 135.8, 140.5, 149.1, 152.3, 155.9.
MS (EI): m/z (%) = 251 (29.8).
Anal. Calcd for C14H13N5: C, 66.92; H, 5.21; N, 27.87. Found: C,
66.89; H, 5.25; N, 27.90.
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3072
M. N. Soltani Rad et al.
PAPER
9-(Hex-5-enyl)-9H-purin-6-amine (1d)13
Column chromatography (SiO2, EtOAc) afforded the product as
white prism crystals.
Anal. Calcd for C9H13N5O: C, 52.16; H, 6.32; N, 33.79. Found: C,
52.19; H, 6.29; N, 33.84.
Benzyl-[9-(2-ethoxyethyl)-9H-purin-6-yl]amine (1h)13
Column chromatography (SiO2, EtOAc) afforded the product as
white needle crystals.
Yield: 1.78 g (82%); mp 141.1 °C; Rf = 0.36 (EtOAc).
IR (KBr): 3330 (NH2), 3115, 2948 cm–1.
1H NMR (250 MHz, DMSO-d6): d = 1.33 (m, 2 H, CH2), 1.84 (m,
2 H, CH2), 2.06 (m, 2 H, CH2), 4.19 (t, J = 6.9 Hz, 2 H, NCH2), 4.93
(dd, J = 1.3, 9.2 Hz, 2 H, =CH2), 5.76 (m, 1 H, =CH), 7.34 (br s,
2 H, NH2, exch D2O), 8.22 [s, 1 H, C(2)-H, adenine], 8.25 [s, 1 H,
C(8)-H, adenine].
13C NMR (62.5 MHz, DMSO-d6): d = 25.2, 29.0, 32.4, 42.4, 114.8,
118.6, 138.1, 140.7, 149.4, 152.5, 155.8.
Yield: 1.72 g (58%); mp 124.3 °C; Rf = 0.41 (EtOAc).
IR (KBr): 3300 (NH2), 3130, 2900 cm–1.
1H NMR (250 MHz, DMSO-d6): d = 1.00 (t, J = 6.9 Hz, 3 H, Me),
3.36 (q, J = 6.9 Hz, 2 H, MeCH2), 3.70 (t, J = 5.2 Hz, 2 H, NCH2),
4.27 (t, J = 5.2 Hz, 2 H, OCH2), 4.72 (br s, 2 H, PhCH2), 7.13–7.66
(m, 5 H, HAr), 8.09 [s, 1 H, C(2)-H, adenine], 8.22 [s, 1 H, C(8)-H,
adenine], 8.51 (br s, 1 H, NH, exch D2O).
MS (EI): m/z (%) = 217 (21.0).
13C NMR (62.5 MHz, DMSO-d6): d = 15.3, 40.9, 43.2, 65.8, 68.0,
119.3, 126.9, 127.5, 128.5, 140.5, 141.5, 149.2, 152.7, 154.9.
Anal. Calcd for C11H15N5: C, 60.81; H, 6.96; N, 32.23. Found: C,
60.84; H, 7.01; N, 32.22.
MS (EI): m/z (%) = 297 (20.1).
(Z)-9-(Hex-3-enyl)-9H-purin-6-amine (1e)13
Column chromatography (SiO2, EtOAc) afforded the product as
pale-yellow prism crystals.
Anal. Calcd for C16H19N5O: C, 64.63; H, 6.44; N, 23.55. Found: C,
64.62; H, 6.48; N, 23.57.
7-Benzyl-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione (1i)13
Column chromatography (SiO2, EtOAc–n-hexane, 50:50) afforded
the product as white needle crystals.
Yield: 1.26 g (58%); mp 97.8 °C; Rf = 0.19 (EtOAc).
IR (KBr): 3300 (NH2), 3110, 2950 cm–1.
1H NMR (250 MHz, DMSO-d6): d = 0.66 (t, J = 7.6 Hz, 3 H, Me),
1.70 (m, 2 H, MeCH2), 2.59 (m, 2 H, NCH2CH2), 4.13 (t, J = 6.7
Hz, 2 H, NCH2), 5.39 [m, 2 H, 2(=CH)], 7.31 (br s, 2 H, NH2, exch
D2O), 8.12 [s, 1 H, C(2)-H, adenine], 8.19 [s, 1 H, C(8)-H, adenine].
13C NMR (62.5 MHz, DMSO-d6): d = 13.5, 19.8, 27.1, 42.4, 118.7,
124.2, 134.0, 140.9, 149.7, 152.2, 155.7.
Yield: 1.75 g (65%); mp 159.4 °C; Rf = 0.48 (EtOAc).
IR (KBr): 3100, 2980, 2895, 1720 (C=O), 1705 (C=O) cm–1.
1H NMR (250 MHz, DMSO-d6): d = 3.32 [s, 3 H, N(3)-Me], 3.51
[s, 3 H, N(1)-Me], 5.52 [s, 2 H, N(7)-CH2], 7.12–7.31 (m, 5 H, HAr),
7.62 [s, 1 H, C(8)-H].
13C NMR (62.5 MHz, DMSO-d6): d = 28.1, 29.5, 50.0, 106.5, 127.5,
127.7, 128.6, 135.3, 140.8, 148.7, 151.5, 155.1.
MS (EI): m/z (%) = 217 (22.3).
Anal. Calcd for C11H15N5: C, 60.81; H, 6.96; N, 32.23. Found: C,
60.79; H, 7.02; N, 32.25.
MS (EI): m/z (%) = 270 (31.4).
Anal. Calcd for C14H14N4O2: C, 62.21; H, 5.22; N, 20.73. Found: C,
62.22; H, 5.24; N, 20.71.
(E)-9-(Hex-3-enyl)-9H-purin-6-amine (1f)13
Column chromatography (SiO2, EtOAc) afforded the product as
white prism crystals.
7-Allyl-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione (1j)
Column chromatography (SiO2, EtOAc–n-hexane, 50:50) afforded
the product as white needle crystals.
Yield: 1.67 g (77%); mp 127.0 °C; Rf = 0.27 (EtOAc).
IR (KBr): 3310 (NH2), 3110, 2950 cm–1.
1H NMR (250 MHz, DMSO-d6): d = 0.51 (t, J = 7.2 Hz, 3 H, Me),
1.03 (m, 2 H, MeCH2), 1.65 (m, 2 H, NCH2CH2), 4.46 (t, J = 4.0
Hz, 2 H, NCH2), 5.39 [m, 2 H, 2(=CH)], 7.07 (s, 2 H, NH2, exch
D2O), 7.83 [s, 1 H, C(2)-H, adenine], 7.91 [s, 1 H, C(8)-H, adenine].
Yield: 1.45 g (66%); mp 103.7 °C; Rf = 0.38 (EtOAc).
IR (KBr): 3050, 2987, 2890, 1725 (C=O), 1708 (C=O) cm–1.
1H NMR (250 MHz, DMSO-d6): d = 3.17 [s, 3 H, N(3)-Me], 3.36
[s, 3 H, N(1)-Me], 4.73 (d, J = 5.2 Hz, 2 H, NCH2), 5.00–5.13 (dd,
J = 11.5, 16.4 Hz, 2 H, =CH2), 5.77–5.93 (m, 1 H, =CH), 7.40 [s,
1 H, C(8)-H].
13C NMR (62.5 MHz, DMSO-d6): d = 13.5, 21.4, 33.4, 44.3, 118.6,
124.7, 134.1, 140.3, 149.2, 152.4, 155.8.
13C NMR (62.5 MHz, CDCl3): d = 27.80, 29.61, 48.83, 106.71,
119.18, 132.06, 140.71, 148.64, 151.50, 154.95.
MS (EI): m/z (%) = 217 (21.7).
Anal. Calcd for C11H15N5: C, 60.81; H, 6.96; N, 32.23. Found: C,
60.84; H, 6.98; N, 32.19.
MS (EI): m/z (%) = 220.09 (25.4).
Anal. Calcd for C10H12N4O2: C, 54.54; H, 5.49; N, 25.44. Found: C,
54.61; H, 5.53; N, 25.40.
9-(2-Ethoxyethyl)-9H-purin-6-amine (1g)13
Column chromatography (SiO2, EtOAc) afforded the product as
white needle crystals.
3,7-Dimethyl-1-[3-(naphthalen-2-yloxy)propyl]-1H-purine-
2,6(3H,7H)-dione (1k)
Column chromatography (SiO2, EtOAc–n-hexane, 50:50) afforded
Yield: 1.65 g (80%); mp 149.2 °C; Rf = 0.12 (EtOAc).
IR (KBr): 3310 (NH2), 3160, 2985 cm–1.
the product as pale-yellow prism crystals.
1H NMR (250 MHz, DMSO-d6): d = 1.00 (t, J = 6.8 Hz, 3 H, Me),
3.36 (q, J = 6.8 Hz, 2 H, MeCH2), 3.69 (t, J = 5.2 Hz, 2 H, NCH2),
4.27 (t, J = 5.2 Hz, 2 H, OCH2), 7.24 (s, 2 H, NH2, exch D2O), 8.06
[s, 1 H, C(2)-H, adenine], 8.48 [s, 1 H, C(8)-H, adenine].
13C NMR (62.5 MHz, DMSO-d6): d = 14.9, 65.1, 67.5, 67.6, 118.5,
141.0, 149.6, 152.0, 156.0.
Yield: 2.22 g (61%); mp 135.2 °C; Rf = 0.33 (EtOAc).
IR (KBr): 3115, 2973, 2885, 1720 (C=O), 1710 (C=O) cm–1.
1H NMR (250 MHz, DMSO-d6): d = 2.17–2.22 (m, 2 H, CH2), 3.50
[s, 3 H, N(3)-Me], 3.79 [s, 3 H, N(7)-Me], 4.12 (t, J = 5.8 Hz, 2 H,
NCH2), 4.20 (t, J = 5.8 Hz, 2 H, OCH2), 6.96–7.04 (m, 2 H, HAr),
7.23–7.39 (m, 3 H, HAr), 7.61 [s, 1 H, C(8)-H], 7.64–7.69 (m, 2 H,
HAr).
MS (EI): m/z (%) = 207 (23).
Synthesis 2009, No. 18, 3067–3076 © Thieme Stuttgart · New York

PAPER
A Rapid Route to Carboacyclic Nucleoside Synthesis
3073
13C NMR (62.5 MHz, DMSO-d6): d = 27.37, 29.12, 32.89, 38.48,
65.65, 106.03, 107.07, 118.25, 122.93, 125.69, 126.16, 127.00,
128.31, 128.61, 133.97, 140.86, 148.18, 150.95, 154.69, 156.26.
1H NMR (250 MHz, DMSO-d6): d = 2.83 (t, J = 7.2 Hz, 2 H,
PhCH2), 3.91 (t, J = 7.2 Hz, 2 H, NCH2), 5.45 [d, J = 7.8 Hz, 1 H,
C(5)-H uracil], 7.15–7.29 (m, 5 H, HAr), 7.50 [d, J = 7.8 Hz, 1 H,
C(6)-H uracil], 11.24 (s, 1 H, N3-H, exch D2O).
13C NMR (62.5 MHz, DMSO-d6): d = 34.2, 48.7, 100.4, 126.2,
128.3, 128.6, 137.7, 145.6, 150.7, 163.7.
MS (EI): m/z (%) = 364.15 (22.3).
Anal. Calcd for C20H20N4O3: C, 65.92; H, 5.53; N, 15.38. Found: C,
65.86; H, 5.49; N, 15.45.
MS (EI): m/z (%) = 216 (27).
9-Isopropyl-9H-purin-6-amine (1l)13
Column chromatography (SiO2, EtOAc) afforded the product as
white cube crystals.
Anal. Calcd for C12H12N2O2: C, 66.65; H, 5.59; N, 12.96. Found: C,
66.66; H, 5.64; N, 12.91.
Yield: 0.14 g (8%); mp 234.8 °C; Rf = 0.26 (EtOAc).
IR (KBr): 3310 (NH2), 3160, 2985, 2850 cm–1.
1H NMR (250 MHz, DMSO-d6): d = 1.45 (d, J = 6.5 Hz, 6 H, 2 ×
Me), 4.66 (m, 1 H, CH), 7.16 (br s, 2 H, NH2, exch D2O), 8.09 [s,
1 H, C(2)-H, adenine], 8.17 [s, 1 H, C(8)-H, adenine].
2-{2-[2,4-Dioxo-3,4-dihydropyrimidin-1(2H)-yl]ethyl}isoindo-
line-1,3-dione (2d)13
Column chromatography (SiO2, EtOAc–n-hexane, 60:40) afforded
the product as white cube crystals.
Yield: 2.22 g (80%); mp 263.6 °C; Rf = 0.29 (EtOAc).
IR (KBr): 3200 (NH), 3210, 2895, 1730–1710 (C=O) cm–1.
1H NMR (250 MHz, DMSO-d6): d = 3.83–3.87 (m, 4 H, 2NCH2),
5.46 [d, J = 7.8 Hz, 1 H, C(5)-H uracil], 7.52 [d, J = 7.8 Hz, 1 H,
C(6)-H uracil], 7.79–7.87 (m, 4 H, aryl), 11.15 (s, 1 H, N3-H, exch
D2O).
13C NMR (62.5 MHz, DMSO-d6): d = 22.0, 46.4, 119.0, 138.7,
148.9, 152.0, 155.6.
MS (EI): m/z (%) = 177 (31.9).
Anal. Calcd for C8H11N5: C, 54.22; H, 6.26; N, 39.52. Found: C,
54.19; H, 6.31; N, 39.50.
13C NMR (62.5 MHz, DMSO-d6): d = 36.2, 46.3, 101.2, 123.0,
131.4, 134.3, 145.4, 151.1, 163.7, 167.6.
1-Octylpyrimidine-2,4(1H,3H)-dione (2a)13
Column chromatography (SiO2, EtOAc–n-hexane, 50:50) afforded
the product as pale-yellow needle crystals.
MS (EI): m/z (%) = 285 (40).
Anal. Calcd for C14H11N3O4: C, 58.96; H, 3.89; N, 14.73. Found: C,
59.98; H, 3.91; N, 14.75.
Yield: 1.57 g (70%); mp 61.4 °C; Rf = 0.55 (EtOAc).
IR (KBr): 3200 (NH), 3100, 2895, 1735 (C=O), 1710 (C=O) cm–1.
1-(Prop-2-ynyl)pyrimidine-2,4(1H,3H)-dione (2e)13,25
Column chromatography (SiO2, EtOAc–n-hexane, 70:30) afforded
the product as white cube crystals.
1H NMR (250 MHz, CDCl3): d = 0.87 (t, J = 6.2 Hz, 3 H, Me),
1.26–1.31 (m, 10 H, 5 × CH2), 1.48–1.53 (m, 2 H, CH2), 3.73 (t,
J = 7.2 Hz, 2 H, NCH2), 5.74 [d, J = 7.8 Hz, 1 H, C(5)-H uracil],
7.20 [d, J = 7.8 Hz, 1 H, C(6)-H uracil], 10.48 (s, 1 H, N3-H, exch
D2O).
13C NMR (62.5 MHz, CDCl3): d = 14.0, 22.4, 26.9, 29.0, 29.1, 31.7,
40.5, 48.7, 102.0, 144.5, 151.0, 164.5.
Yield: 1.08 g (72%); mp 154.4 °C; Rf = 0.28 (EtOAc).
IR (KBr): 3290 (≡CH), 3200 (NH), 3100, 2895, 2145 (C≡C), 1740
(C=O), 1715 (C=O) cm–1.
1H NMR (250 MHz, DMSO-d6): d = 3.13 (s, 1 H, ≡CH), 4.26 (s,
2 H, NCH2), 5.44 [d, J = 7.8 Hz, 1 H, C(5)-H uracil], 7.65 [d,
J = 7.8 Hz, 1 H, C(6)-H uracil], 11.11 (s, 1 H, N3-H, exch D2O).
13C NMR (62.5 MHz, DMSO-d6): d = 36.6, 75.6, 78.3, 101.4, 144.6,
150.2, 163.5.
MS (EI): m/z (%) = 224 (34.9).
Anal. Calcd for C12H20N2O2: C, 64.26; H, 8.99; N, 12.49. Found: C,
64.28; H, 9.00; N, 12.43.
1-(4-Methoxybenzyl)pyrimidine-2,4(1H,3H)-dione (2b)13
Column chromatography (SiO2, EtOAc–n-hexane, 50:50) afforded
the product as white cube crystals.
MS (EI): m/z (%) = 150 (55.7).
Anal. Calcd for C7H6N2O2: C, 56.00; H, 4.03; N, 18.66. Found: C,
55.98; H, 4.08; N, 18.60.
Yield: 1.28 g (55%); mp 118.0 °C; Rf = 0.38 (EtOAc).
IR (KBr): 3250 (NH), 3100, 2895, 1728 (C=O), 1715 (C=O) cm–1.
1H NMR (250 MHz, DMSO-d6): d = 3.70 (s, 3 H, OMe), 3.75 (s,
2 H, NCH2), 5.58 [d, J = 7.8 Hz, 1 H, C(5)-H uracil], 6.84 [d, J =
8.5 Hz, 2 H, C(2,6)-HAr], 6.90 [d, J = 8.5 Hz, 2 H, C(3,5)-HAr], 7.72
[d, J = 7.8 Hz, 1 H, C(6)-H uracil], 11.17 (s, 1 H, N3-H, exch D2O).
5-Chloro-1-(prop-2-ynyl)pyrimidine-2,4(1H,3H)-dione (2f)13,25
Column chromatography (SiO2, EtOAc–n-hexane, 70:30) afforded
the product as white cube crystals.
Yield: 1.09 g (59%); mp 170.3 °C; Rf = 0.29 (EtOAc).
IR (KBr): 3310 (≡CH), 3250 (NH), 3100, 2890, 2150 (C≡C), 1735
(C=O), 1715 (C=O) cm–1.
13C NMR (62.5 MHz, DMSO-d6): d = 49.6, 55.1, 101.2, 113.5,
128.6, 129.1, 145.3, 150.7, 158.7, 163.4.
1H NMR (250 MHz, DMSO-d6): d = 3.18 (s, 1 H, ≡CH), 4.26 (s,
2 H, NCH2), 8.23 [s, 1 H, C(6)-H uracil], 11.56 (s, 1 H, N3-H, exch
D2O).
13C NMR (62.5 MHz, DMSO-d6): d = 36.3, 75.4, 78.6, 102.7, 145.4,
150.8, 163.2.
MS (EI): m/z (%) = 232 (55.4).
Anal. Calcd for C12H12N2O3: C, 62.06; H, 5.21; N, 12.06. Found: C,
62.00; H, 5.19; N, 12.00.
1-Phenethylpyrimidine-2,4(1H,3H)-dione (2c)13
Column chromatography (SiO2, EtOAc–n-hexane, 50:50) afforded
the product as white cube crystals.
MS (EI): 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.
Yield: 1.60 g (74%); mp 149.2 °C; Rf = 0.29 (EtOAc).
IR (KBr): 3250 (NH), 3110, 2895, 1730 (C=O), 1720 (C=O) cm–1.
(E)-1-Cinnamylpyrimidine-2,4(1H,3H)-dione (2g)13
Column chromatography (SiO2, EtOAc–n-hexane, 50:50) afforded
the product as white cube crystals.
Synthesis 2009, No. 18, 3067–3076 © Thieme Stuttgart · New York

3074
M. N. Soltani Rad et al.
PAPER
Yield: 1.62 g (71%); mp 199.2 °C; Rf = 0.65 (EtOAc).
1-Butyl-5-nitropyrimidine-2,4(1H,3H)-dione (2k)13
Column chromatography (SiO2, EtOAc–n-hexane, 60:40) afforded
the product as pale-yellow needle crystals.
IR (KBr): 3250 (NH), 3050, 2895, 1730 (C=O), 1710 (C=O) cm–1.
1H NMR (250 MHz, DMSO-d6): d = 4.51 (d, J = 5.6 Hz, 2 H,
NCH2), 5.67 [d, J = 7.8 Hz, 1 H, C(5)-H uracil], 6.36 (m, 1 H, CH2-
CH), 6.64 (d, J = 16.0 Hz, 1 H, =CH-Ph), 7.26–7.68 (m, 5 H, HAr),
7.71 [d, J = 7.8 Hz, 1 H, C(6)-H uracil], 11.36 (s, 1 H, N3-H, exch
D2O).
13C NMR (62.5 MHz, DMSO-d6): d = 48.4, 101.2, 124.2, 126.3,
127.8, 128.5, 132.5, 135.8, 145.2, 150.7, 163.7.
Yield: 1.73 g (81%); mp 146.3 °C; Rf = 0.68 (EtOAc–n-hexane,
4:1).
IR (KBr): 3250 (NH), 3210, 2985 2890, 1730–1715 (C=O) cm–1.
1H NMR (250 MHz, DMSO-d6): d = 0.83 (t, J = 6.7 Hz, 3 H, CH3),
1.26 (m, 2 H, CH2CH3), 1.59 (m, 2 H, NCH2CH2), 3.81 (t, J = 6.5
Hz, 2 H, NCH2), 9.23 [s, 1 H, C(6)-H uracil], 11.96 (s, 1 H, N3-H
uracil exch D2O).
13C NMR (62.5 MHz, DMSO-d6): d = 18.6, 24.1, 35.6, 54.1, 129.7,
154.4, 155.8, 160.1.
MS (EI): m/z (%) = 228 (31.4).
Anal. Calcd for C13H12N2O2: C, 68.41; H, 5.30; N, 12.27. Found: C,
68.42; H, 5.29; N, 12.31.
MS (EI): m/z (%) = 213 (25).
1-Allyl-5-fluoropyrimidine-2,4(1H,3H)-dione (2h)8a,b,13,26
Column chromatography (SiO2, EtOAc–n-hexane, 70:30) afforded
the product as white needle crystals.
Anal. Calcd for C8H11N3O4: C, 45.07; H, 5.20; N, 19.71. Found: C,
45.03; H, 5.21; N, 19.73.
Yield: 0.88 g (52%); mp 101.2 °C; Rf = 0.27 (EtOAc).
IR (KBr): 3220 (NH), 3050, 2895, 1725 (C=O), 1715 (C=O) cm–1.
1H NMR (250 MHz, CDCl3): d = 4.34 (d, J = 5.8 Hz, 2 H, NCH2),
5.35 (dd, J = 11.0, 16.3 Hz, 2 H, =CH2), 5.82 (m, 1 H, CH), 7.29 [d,
3JHF = 5.4 Hz, 1 H, C(6)-H uracil], 9.66 (s, 1 H, N3-H, exch D2O).
1-[3-(4-Chlorophenoxy)propyl]-5-nitropyrimidine-2,4(1H,3H)-
dione (2l)
Column chromatography (SiO2, EtOAc–n-hexane, 60:40) afforded
the product as yellow cube crystals.
Yield: 2.21 g (68%); mp 231.6 °C; Rf = 0.68 (EtOAc).
IR (KBr): 3200 (NH), 3100, 2980, 2895, 1730 (C=O), 1715 (C=O)
cm–1.
1H NMR (250 MHz, DMSO-d6): d = 2.07–2.09 (m, 2 H, CH2),
4.02–4.04 (m, 4 H, NCH2, OCH2), 6.85 (d, J = 8.1 Hz, 2 H, HAr),
7.25 (d, J = 8.1 Hz, 2 H, HAr), 9.25 [s, 1 H, C(6)-H, uracil], 11.99 (s,
1 H, N3-H uracil, exch D2O).
13C NMR (62.5 MHz, CDCl3): d = 51.4, 121.5, 128.2, 131.1, 141.0,
150.8, 158.8.
MS (EI): m/z (%) = 170 (38.0).
Anal. Calcd for C7H7FN2O2: C, 49.41; H, 4.15; F, 11.17; N, 16.46.
Found: C, 49.43; H, 4.10; F, 11.19; N, 16.51.
13C NMR (62.5 MHz, DMSO-d6): d = 27.58, 47.11, 65.47, 116.01,
1-Allyl-5-methylpyrimidine-2,4(1H,3H)-dione (2i)8a,b,13,27
Column chromatography (SiO2, EtOAc–n-hexane, 60:40) afforded
the product as white cube crystals.
124.27, 124.79, 129.11, 149.34, 150.83, 154.96, 157.03.
MS (EI): m/z (%) = 325.04 (35).
Yield: 1.11 g (67%); mp 123.2 °C; Rf = 0.25 (EtOAc).
IR (KBr): 3200 (NH), 3100, 2980, 1734 (C=O), 1720 (C=O) cm–1.
Anal. Calcd for C13H12ClN3O5: C, 47.94; H, 3.71; Cl, 10.89; N,
12.90. Found: C, 47.89; H, 3.77; Cl, 10.83; N, 12.97.
1H NMR (250 MHz, CDCl3): d = 1.89 (s, 3 H, Me), 4.33 (d, J = 5.5
Hz, 2 H, NCH2), 5.21 (dd, J = 10.8, 16.1 Hz, 2 H, =CH2), 5.82 (m,
1 H, =CH), 6.96 [s, 1 H, C(6)-H uracil], 10.25 (br s, 1 H, N3-H,
exch D2O).
13C NMR (62.5 MHz, CDCl3): d = 13.5, 51.8, 112.3, 121.4, 133.2,
141.4, 152.2, 167.1.
1-[2-(2-Methyl-4-nitro-1H-imidazol-1-yl)ethyl]-1H-ben-
zo[d]imidazole (3a)13
Column chromatography (SiO2, EtOAc) afforded the product as
pale-yellow cube crystals.
Yield: 1.79 g (66%); mp 223.2 °C; Rf = 0.30 (MeOH–EtOAc, 1:10).
IR (KBr): 3210, 3100, 2980, 2895 cm–1.
1H NMR (250 MHz, CDCl3): d = 1.84 (s, 3 H, Me), 4.45 (t, J = 6.2
Hz, 2 H, NCH2), 4.70 (t, J = 6.2 Hz, 2 H, NCH2), 7.17 (m, 2 H, HAr),
7.21 (d, J = 7.5 Hz, 1 H, HAr), 7.65 (d, J = 7.5 Hz, 1 H, HAr), 8.01 [s,
1 H, C(5)-H, imidazole], 8.16 [s, 1 H, C(2)-H, benzimidazole].
MS (EI): 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.
2-Butyl-1,2,4-triazine-3,5(2H,4H)-dione (2j)13
Column chromatography (SiO2, EtOAc–n-hexane, 40:60) afforded
the product as white needle crystals.
13C NMR (62.5 MHz, CDCl3): d = 12.0, 44.3, 46.1, 109.7, 119.4,
121.7, 122.1, 122.5, 133.3, 143.1, 143.8, 145.0, 145.4.
MS (EI): m/z (%) = 271 (33.2).
Yield: 0.93 g (55%); mp 136.8 °C; Rf = 0.77 (EtOAc–n-hexane,
4:1).
Anal. Calcd for C13H13N5O2: C, 57.56; H, 4.83; N, 25.82. Found: C,
57.50; H, 4.90; N, 25.84.
IR (KBr): 3200 (NH), 3210, 2985 2895, 1725–1715 (C=O) cm–1.
1H NMR (250 MHz, DMSO-d6): d = 0.63 (t, J = 6.2 Hz, 3 H, CH3),
1.01 (m, 2 H, CH2CH3), 1.25 (m, 2 H, NCH2CH2), 3.46 (t, J = 6.5
Hz, 2 H, NCH2), 7.20 [s, 1 H, C(5)-H azauracil], 12.32 (s, 1 H, N3-
H exch D2O).
13C NMR (62.5 MHz, DMSO-d6): d = 13.4, 19.4, 28.6, 38.3, 134.5,
148.9, 156.1.
1-[3-(4-Chlorophenoxy)propyl]-1H-benzo[d]imidazole (3b)
Column chromatography (SiO2, EtOAc) afforded the product as
pale-yellow cube crystals.
Yield: 2.12 g (74%); mp 118.1 °C; Rf = 0.4 (EtOAc).
IR (KBr): 3160, 3100, 2985, 2890 cm–1.
1H NMR (250 MHz, CDCl3): d = 2.25–2.28 (m, 2 H, CH2), 3.79 (t,
J = 6.1 Hz, 2 H, NCH2), 4.35 (t, J = 6.1 Hz, 2 H, OCH2), 6.73 (d,
J = 7.7 Hz, 2 H, HAr), 7.20 (d, J = 7.7 Hz, 2 H, HAr), 7.25–7.35 (m,
4 H, aryl), 7.81 [s, 1 H, C(2)-H, benzimidazole].
MS: m/z (%) = 169 (35).
Anal. Calcd for C7H11N3O2: C, 49.70; H, 6.55; N, 24.84. Found: C,
49.65; H, 6.51; N, 24.80.
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A Rapid Route to Carboacyclic Nucleoside Synthesis
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13C NMR (62.5 MHz, CDCl3): d = 29.33, 41.35, 64.10, 109.53,
115.68, 120.43, 122.16, 122.99, 125.97, 129.42, 133.70, 143.16,
143.88, 156.97.
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,
817. (d) Manikowski, A.; Verri, A.; Lossani, A.; Gebhardt,
B. M.; Gambino, J.; Focher, F.; Spadari, S.; Wright, G. E.
J. Med. Chem. 2005, 48, 3919.
MS (EI): m/z (%) = 286.09 (28.1).
Anal. Calcd for C16H15ClN2O: C, 67.02; H, 5.27; Cl, 12.36; N, 9.77.
Found: C, 67.05; H, 5.26; Cl, 12.35; N, 9.72.
(3) (a) Kašnar, B.; Škarić, V.; Klaić, B.; Žinić, M. Tetrahedron
Lett. 1993, 34, 4997. (b) Lewis, M.; McMurry, T. B. H.;
De Clercq, E. J. Chem. Soc., Perkin Trans. 1 1993, 2107.
(c) Holy, A.; Dvorakova, H.; Jindrich, J.; Masojidkova, M.;
Budesinsky, M.; Balzarini, J.; Andrei, G.; De Clercq, E.
J. Med. Chem. 1996, 39, 4073.
(4) (a) Vandendriessche, F.; Snoeck, R.; Janssen, G.;
Hoogmartens, J.; Aerschot, A. V.; De Clercq, E.; Herdewijn,
P. J. Med. Chem. 1992, 35, 1458. (b) 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, 2864. (c) Chen, W.; Flavin, M. T.;
Filler, R.; Xu, Z.-Q. J. Chem. Soc., Perkin Trans. 1 1998,
3979.
2-Methyl-4-nitro-1-phenethyl-1H-imidazole (3c)
Column chromatography (SiO2, EtOAc) afforded the product as
white cube crystals.
Yield: 1.57 g (68%); mp 116.2 °C; Rf = 0.62 (EtOAc).
IR (KBr): 3135, 2950, 2878 cm–1.
1H NMR (250 MHz, CDCl3): d = 2.05 (s, 3 H, CH3), 2.99 (t, J = 6.0
Hz, 2 H, PhCH2), 4.10 (t, J = 6.0 Hz, 2 H, NCH2), 6.96–6.98 (m,
2 H, HAr), 7.20–7.25 (m, 3 H, HAr), 7.52 [s, 1 H, C(5)-H, imidazole].
13C NMR (62.5 MHz, CDCl3): d = 12.64, 36.88, 48.66, 119.71,
127.39, 128.62, 128.98, 136.29, 145.01, 146.23.
MS (EI): m/z (%) = 231.1 (12.4).
(5) (a) Khalafi-Nezhad, A.; Soltani Rad, M. N.; Khoshnood, A.
Synthesis 2004, 583. (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, 1245. (c) Guan, H.-P.; Ksebati, M.
B.; Kern, E. R.; Zemlicka, J. J. Org. Chem. 2000, 65, 5177.
(d) Brodfuehrer, P. R.; Howell, H. G.; Sapino, C.;
Vemishetti, P. Tetrahedron Lett. 1994, 35, 3243.
(6) (a) Khalafi-Nezhad, A.; Zarea, A.; Soltani Rad, M. N.;
Mokhtari, B.; Parhami, A. Synthesis 2005, 419.
Anal. Calcd for C12H13N3O2: C, 62.33; H, 5.67; N, 18.17. Found: C,
62.37; H, 5.71; N, 18.15.
1-[3-(Naphthalen-2-yloxy)propyl]-1H-imidazole (3d)
Column chromatography (SiO2, EtOAc) afforded the product as
white cube crystals.
Yield: 1.57 g (68%); mp 99.4 °C; Rf = 0.19 (EtOAc).
IR (KBr): 3150, 2948, 2887 cm–1.
1H NMR (250 MHz, CDCl3): d = 2.15–2.25 (m, 2 H, CH2), 3.93 (t,
J = 5.6 Hz, 2 H, NCH2), 4.11 (t, J = 5.6 Hz, 2 H, OCH2), 6.89 [s,
1 H, C(5)-H, imidazole], 7.06 [s, 1 H, C(4)-H, imidazole], 7.12–
7.15 (m, 2 H, HAr), 7.30–7.40 (m, 2 H, HAr), 7.46 [s, 1 H, C(2)-H,
imidazole], 7.68 (s, 1 H, HAr), 7.72–7.76 (m, 2 H, HAr).
13C NMR (62.5 MHz, CDCl3): d = 30.71, 43.45, 63.74, 106.74,
118.59, 119.02, 123.84, 126.51, 126.77, 127.66, 129.10, 129.57,
129.63, 134.46, 137.31, 156.37.
(b) Guillarme, S.; Legoupy, S.; Aubertin, A.-M.; Olicard, C.;
Bourgougnon, N.; Huet, F. Tetrahedron 2003, 59, 2177.
(c) Scheiner, P.; Geer, A.; Bucknor, A.-M.; Imbach, J.-L.;
Schinazi, R. F. J. Med. Chem. 1989, 32, 73.
(7) Xu, Z.-Q.; Joshi, R. V.; Zemlicka, J. Tetrahedron 1995, 51,
67.
(8) (a) Amblard, F.; Nolan, S. P.; Gillaizeau, I.; Agrofoglio, L.
A. Tetrahedron Lett. 2003, 44, 9177. (b) Amblard, F.;
Nolan, S. P.; Schinazi, R. F.; Agrofoglio, L. A. Tetrahedron
2005, 61, 537. (c) Freer, R.; Geen, G. R.; Ramsay, T. W.;
Share, A. C.; Slater, G. R.; Smith, N. M. Tetrahedron 2000,
56, 4589. (d) G undersen, L.-L.; Benneche, T.; Undheim, K.
Tetrahedron Lett. 1992, 33, 1085. (e) Crimmins, M. T.;
King, B. W.; Zuercher, W. J.; Choy, A. L. J. Org. Chem.
2000, 65, 8499.
(9) (a) Singh, D.; Wani, M. J.; Kumar, A. J. Org. Chem. 1999,
64, 4665. (b) Alahiane, A.; Rochdi, A.; Taourirte, M.;
Redwane, N.; Sebti, S.; Lazrek, H. B. Tetrahedron Lett.
2001, 42, 3579. (c) Jahne, G.; Kroha, H.; Müller, A.;
Helsberg, M.; Winkler, I.; Gross, G.; Scholl, T. Angew.
Chem., Int. Ed. Engl. 1994, 33, 562. (d) Boto, A.;
Hernández, R.; Suárez, E. Tetrahedron Lett. 2001, 42, 9167.
(e) Bravo, P.; Resnati, G.; Viani, F. Tetrahedron 1993, 49,
713.
(10) Obika, S.; Takashima, Y.; Matsumoto, Y.; Kuromaru, K.;
Imanishi, T. Tetrahedron Lett. 1995, 36, 8617.
(11) Han, Y.-K.; Paquette, L. A. J. Org. Chem. 1979, 44, 3733.
(12) Mitsunobu, O. Synthesis 1981, 1.
(13) Soltani Rad, M. N.; Khalafi-Nezhad, A.; Behrouz, S.;
Faghihi, M. A.; Zare, A.; Parhami, A. Tetrahedron 2008, 64,
1778.
(14) (a) Larock, R. C. Comprehensive Organic Transformations,
2nd ed.; Wiley: New York, 1999. (b) Rabinowitz, R.;
Marcus, R. J. Am. Chem. Soc. 1962, 84, 1312. (c) Ramirez,
F.; Desai, N. B.; Mckelvie, N. J. Am. Chem. Soc. 1962, 84,
1745. (d) Fieser, L. F.; Fieser, M. In Reagents for Organic
MS (EI): m/z (%) = 252.12 (38.0).
Anal. Calcd for C16H16N2O: C, 76.16; H, 6.39; N, 11.10. Found: C,
76.11; H, 6.45; N, 11.13.
Acknowledgment
We wish to thank the Shiraz University of Technology and Shiraz
University Research Councils for partial support of this work
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Synthesis 2009, No. 18, 3067–3076 © Thieme Stuttgart · New York