One-pot protocol for N-alkylation of purine, pyrimidine and azole derivatives via alcohols using Ph3P/I2: simple route for carboacyclic nucleoside synthesis

Article abstract of DOI:10.1016/j.tet.2016.06.069

A simple and efficient synthetic protocol for the one-pot N-alkylation of nucleobases and their related N-heterocycles via alcohols utilizing the combination of PPh₃and I₂is reported. In this protocol purine, pyrimidine and azole derivatives underwent the N-alkylation reaction with diverse primary alcohols using Ph₃P/I₂in the presence of Et₃N-K₂CO₃in anhydrous DMF to give the N-alkyl adducts (carboacyclic nucleosides) in good yields (up to 90%). The influence of some parameters in this reaction including type of solvent, base, reagents and temperature was discussed. In addition, this protocol has proved the favorable selectivity towards primary hydroxyl versus secondary hydroxyl group in diols.

Full text of DOI:10.1016/j.tet.2016.06.069

Tetrahedron xxx (2016) 1e7
Contents lists available at ScienceDirect
Tetrahedron
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One-pot protocol for N-alkylation of purine, pyrimidine and azole
derivatives via alcohols using Ph3P/I2: simple route for carboacyclic
nucleoside synthesis
*
Mohammad Navid Soltani Rad , Faezeh Soleimani
Medicinal Chemistry Research Laboratory, Department of Chemistry, Shiraz University of Technology, Shiraz 71555-313, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple and efficient synthetic protocol for the one-pot N-alkylation of nucleobases and their related N-
heterocycles via alcohols utilizing the combination of PPh3 and I2 is reported. In this protocol purine,
pyrimidine and azole derivatives underwent the N-alkylation reaction with diverse primary alcohols
using Ph3P/I2 in the presence of Et3N-K2CO3 in anhydrous DMF to give the N-alkyl adducts (carboacyclic
nucleosides) in good yields (up to 90%). The influence of some parameters in this reaction including type
of solvent, base, reagents and temperature was discussed. In addition, this protocol has proved the fa-
vorable selectivity towards primary hydroxyl versus secondary hydroxyl group in diols.
Ó 2016 Elsevier Ltd. All rights reserved.
Received 15 April 2016
Received in revised form 12 June 2016
Accepted 27 June 2016
Available online xxx
Keywords:
Carboacyclic nucleoside
Alcohol
Nucleobase
One-pot N-Alkylation
TPP-I2
1. Introduction
Despite the usefulness of the above carbon-electrophiles in N-
alkylation reactions, the high risk of toxicity has limited their ap-
Since the discovery of acyclovir as a potent antiviral agent, ex-
tensive efforts have been made to develop other new acyclic nu-
cleoside analogues.1 Among acyclic nucleoside analogues,
carboacyclic nucleosides are a prominent type of nucleosides
exhibiting considerable antiviral and anticancer activities.2 In this
connection, the emergence of the well-established antiviral and
anticancer drugs such as (S)-DHPA, EHNA, Penciclovir (PCV) and
Famciclovir (FCV) has widely increased the scientists’ insights into
design and synthesis of new chemotherapeutic agents for over-
coming cancer and viral-caused dispositions (Fig. 1).
plicability in large scale synthesis. Alkyl halides, epoxides and Mi-
chael acceptors are known today as harmful carbon-electrophiles
with incontrovertible carcinogenic properties.12e14 Therefore,
employing a carbon electrophile with a lower toxicity and envi-
ronmental cost is essential. To overcome this problem, the direct N-
alkylation of nucleobases with alcohols would be a highly advan-
tageous and attractive strategy, since alcohols are known as
The most common, rapid and straightforward route to access
carboacyclic nucleosides involves CeN bond formation through the
N-alkylation reaction of nucleobases or other related N-heterocy-
cles with varied types of carbon-electrophiles such as RX (R¼alkyl;
X¼halide,3 OTs4 and OMs5), epoxides,6 Michael acceptors,7 esters,8
carbonates,9 ethers10 and acetals.11
NH2
N
NH2
N
N
N
N
N
N
N
OH
OH
OH
EHNA
(S)-DHPA
O
N
N
N
HN
N
N
N
N
OAc
OAc
OH
OH
H2N
H2N
PCV
FCV
* Corresponding author. Tel.: þ98 71 3735 4500; fax: þ98 71 3735 4520; e-mail
address: soltani@sutech.ac.ir (M.N. Soltani Rad).
Fig. 1. The structure of some famous carboacyclic nucleoside analogues.
http://dx.doi.org/10.1016/j.tet.2016.06.069
0040-4020/Ó 2016 Elsevier Ltd. All rights reserved.
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2
M.N. Soltani Rad, F. Soleimani / Tetrahedron xxx (2016) 1e7
Table 1
versatile reagents having less toxicity, easily handled and widely
available with respect to related alkyl halides. In general, Mitsu-
nobu approaches15 for N-alkylation of nucleobases with alcohols
are the most established and developed procedures. Nevertheless,
the N-alkylation of nucleobases with alcohols through the Mitsu-
nobu conditions suffers from two main disadvantages comprising
(i) the use of an expensive diethyl azodicarboxylate (DEAD), and (ii)
an explosive nature of DEAD. These drawbacks considerably have
restricted the applicability of Mitsunobu conditions in large scale
synthesis of N-alkylated nucleobases.
The combination of triphenylphosphine (TPP) and iodine is an
interesting reagent used in various organic transformations mainly
in conversion of alcohols into the corresponding alkyl iodides.16 In
addition this combination is involved in the conversion of thiols,17
and enols18 into iodides, reduction of various sulfur derivatives to
sulfides or thiols,17 reduction of epoxides,19 iodohydrins,20 and
vicinal diols21 to alkenes, synthesis of iodohydrins from epoxides,22
esterification of carboxylic acids,23 acetalizations of carbonyl
groups,24 dehydrating agent25 and also upgrading agent for Beck-
mann rearrangement.26
The influence of solvent type on sample reactiona
O
N
O
HN
O
TPP/I2
HN
O
OH
+
K2CO3/TEA,
solvent,reflux
O
N
O
H
2e
Entry
Solvent
Time (h)
Yieldd (%)
1
2
3
4
5
6
7
8
DMF
10
6
49
70
27
14
27
54
36
12
21
58
NRe
NR
DMFb
DMSO
MeCN
HMPA
NMP
15
20
26
9
THF
12
48
36
30
72
72
Toluene
Acetone
bmim[Br]c
PEG 200c
H2O
9
10
11
12
a
Reaction conditions: uracil (1 mmol), alcohol (1 mmol),TPP (1 mmol), I2
(1 mmol), K2CO3 (1 mmol), TEA (1 mmol) and solvent (5 mL).
Apart from a few known combinations of TPP/I2 with some
assisting agents like imidazole27 and other bases,16 the combination
of TPP/I2 with nucleophiles was rarely studied and reported.28 The
TPP/I2/Nucleophile combination is an attractive mixture providing
a straightforward route to establish diverse CeNu bonds through
alcohols.
b
Anhydrous DMF.
c
The reaction was conducted at 100 ꢀC.
d
Isolated yield.
No reaction.
e
In an attempt for converting certain alcohols into the corre-
sponding alkyl iodides using the combination of TPP/I2/imidazole
in anhydrous DMF at elevated temperature (>100 ꢀC), we wit-
nessed that beside the generation of expected alkyl iodides, a few
portions of N-alkyl imidazoles were also obtained. In continuation
of this study, we found the addition of an appropriate base to re-
action mixture extensively improved production of the perquisite
N-alkyl imidazole adducts. Inspired by this experiment, other ex-
amined N-heterocyclic compounds like purine and pyrimidine
nucleobases also were led to their corresponding N-alkyl adducts.
Given our long-standing interest in synthesis of carboacyclic nu-
cleosides through one-pot N-alkylation of nucleobases via alco-
hols,29 we now report the one-pot N-alkylation of nucleobases via
alcohols using the combination of TPP/I2 in refluxing DMF (anhyd)
in the presence of triethylamine (TEA) and K2CO3 as a basic mixture
(Scheme 1).
Table 2
The influence of temperature on sample reactiona
O
O
HN
O
TPP/I2
HN
N
O
OH
+
K2CO3/TEA,
O
DMF, Heat (T° C)
O
N
H
2e
Entry
T ꢀ
C
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
25
25
25
50
50
50
75
75
75
6
NRc
NR
NR
10
12
22
15
21
32
30
48
55
57
61
67
70
70
70
12
18
6
12
18
6
12
18
6
9
10
11
12
13
14
15
16
17
18
100
TPP/I2
+ R-OH
100
100
125
12
18
6
N
H
K2CO3/TEA, DMF,reflux
N
R
125
125
Reflux
Reflux
Reflux
12
18
6
12
18
R:alkyl, benzyl, alkenyl...
: purines, pyrimidines and azoles
N
H
a
Reaction conditions: uracil (1 mmol), alcohol (1 mmol),TPP (1 mmol), I2
(1 mmol), K2CO3 (1 mmol), TEA (1 mmol) and DMF (5 mL).
Scheme 1. One-pot N-alkylation of nucleobases via alcohols using TPP/I2 in the
presence of K2CO3/TEA in DMF.
b
Isolated yield.
c
No reaction.
2. Results and discussion
the use of normal DMF, NMP and bmim[Br] as a room temperature
ionic liquid led to reasonable yields of 2e (Table 1, entries 1, 6, 10)
whereas, the other tested solvents displayed the negligible yield of
the desire product. In addition, protic solvents like water or poly-
ethylene glycol (PEG) failed to expedite the reaction even if the
reactions were prolonged over 72 h.
To optimize the reaction conditions, we examined the reaction
of uracil with (tetrahydro-furan-2-yl)-methanol as a sample re-
action. First, we focused our attention on the choice of an appro-
priate solvent. For this purpose, we investigated the effect of
various traditional solvents. The results are shown in Table 1.
As indicated in Table 1, among the examined solvents, the use of
anhydrous DMF gained the best result and thus anhydrous DMF
was employed for all next studied reactions (Table 1, entry 2). Also,
Next, we explored the influence of different temperatures (Table
2). At rt, the reaction was not progressed even if extended for some
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M.N. Soltani Rad, F. Soleimani / Tetrahedron xxx (2016) 1e7
3
Table 3
Table 4
The influence of various bases on sample reactiona
The comparison of TPP/I2 performance with other similar reagentsa
O
N
O
O
O
HN
HN
O
O
HN
TPP/reagent
TPP/I2
HN
O
O
N
OH
OH
+
+
K2CO3/TEA,
DMF, Heat (T° C)
Base, DMF, reflux
N
O
O
O
O
N
H
H
2e
2e
Yield (%)e
Entry
Base
Time (h)
Yield (%)e
Entry
Reagent
Time (h)
1
2
3
4
5
6
7
8
d
72
8
10
18
11
9
12
15
48
6
12
48
NRf
65
60
51
55
62
62
58
25
70
56
32
1
2
3
4
5
6
7
8
I2
6
70
51
38
41
40
53
56
22
DBU
DBN
DABCO
DMAP
NMMb
TEA
Br2
12
14
10
8
9
18
16
NCSb
NBSc
NISd
DBDMHe
ICCf
NCTSA-Nag
K2CO3
MgO
9
a
Reaction conditions: uracil (1 mmol), alcohol (1 mmol), TPP (1 mmol), reagent
(1 mmol), K2CO3 (1 mmol), TEA (1 mmol) and DMF (5 mL).
10
11
12
K2CO3/TEAc
KOH
b
N-Chlorosuccinimide.
N-Bromosuccinimide.
N-Iodosuccinimide.
1,3-Dibromo-5,5-dimethyl hydantoin.
Isocyanuric chloride.
N-Chloro-p-toluenesulfonamide sodium.
d
Al2O3
c
a
d
Reaction conditions: uracil (1 mmol), alcohol (1 mmol),TPP (1 mmol), I2
(1 mmol), base (1 mmol) and DMF (5 mL).
e
b
f
N-methyl morpholine.
1:1 ratio was used.
c
g
d
Basic alumina.
Isolated yield.
No reaction.
e
f
above protocol. It is noteworthy that the N-alkylations were per-
formed in a regioselective manner. For purine bases as ambident
nucleophiles, the N-alkylation from N7 and N1 sites were achieved
for theophylline and theobromine, respectively; whereas, for ade-
nine or N6-benzyladenine the alkylation was conducted through
N9 sites, dominantly. In addition, the marginal quantities of N7-
alkyl adducts for N6-benzyladenine and adenine were also pro-
duced which are <10% for N6-benzyladenine and <10e20% for
adenine, accordingly.30 These ratios of isomers were allocated by
GC analysis. The alkylation from other nucleophilic sites of used
purines was not detected.
Primary alcohols with a simple aliphatic side chain, aliphatic
side chain bearing various functionalities comprising allylic, ben-
zylic, aryl, ether and also other alcohols with heterocyclic-
conjugate residues were applied for N-alkylation of purine nucle-
obases. Nevertheless, the secondary alcohols seldom react with
nucleobases using the current procedure. As an instance, the re-
action of theophylline with 1-phenyl-ethanol led to a low yield of
1m (z8%) which was determined by GC analysis. In addition, ter-
tiary alcohols like t-butyl alcohol and/or 2-phenyl-propan-2-ol
were not altered.
In the same way as purines, pyrimidines as well as azoles were
N-alkylated with different primary alcohols (Table 5). Uracil, 5-
nitrouracil, thymine and 6-azauracil showed the considerable
regioselectivity for alkylation from N1-site; nevertheless, a few
N1,N3-dialkyl adducts were also produced in trace amount
(10e15%) which was assigned by GC analysis.31
We also established a competitive reaction between a mixture
consist of primary verses secondary alcohols under optimized
condition to realize the selectivity of this protocol. To this end,
a mixture of two isomeric alcohols comprising 1-phenylethanol
(1 equiv) and 2-phenylethanol (1 equiv) was used to react with
theophylline (1 equiv) in the presence of TPP (1 equiv) and I2
(1 equiv). Due to Scheme 2, in the presence of primary alcohol, the
secondary alcohol has no chance to react with theophylline. Thus,
compound 1l was the single product which was assigned by GC-
analysis.
period of times. However, as expected, by the gradual increment in
temperature, the yields were improved and in this regard, the best
result was obtained at reflux (Table 2, entry 16).
Since the weak nucleophilic nature of nucleobases and related
analogues, the use of an efficient base for enhancing the nucleo-
philicity power of these compounds is crucial. In this context, we
evaluated the effect of some inorganic and organic bases (Table 3).
As Table 3 indicates, in the absence of the base, the reaction did not
occur (Table 3, entry 1). The best result was observed when an
equimolar ratio of K2CO3/TEA was used. The combination of K2CO3/
TEA (Table 3, entry 10) was previously experienced by our research
group to be an appropriate basic mixture for N-alkylation of
nucleobases in DMF.29a,c It is worth mentioning that the used of
each of these bases in a single form yielded 2e in a lower quantity
and longer reaction time. Other bases yielded the desired product
in low to moderate yields.
To find out the performance of TPP/I2 against the other combi-
nations of TPP with halogens or positive-halogen containing re-
agents, we studied the effect of TPP in combination with Br2, NBS,
NCS, NIS, 1,3-Dibromo-5,5-dimethyl hydantoin (DBDMH), iso-
cyanuric chloride (ICC) and N-chloro-p-toluenesulfonamide so-
dium (NCTSA-Na) salt (Table 4, entries 2e8) on a model reaction. As
shown in Table 4, the employment of TPP/Br2 combination in
a sealed tube yielded in a moderate amount (Table 4, entry 2). In
addition, the combination of TPP with some electrophilic-halogen
containing imides like NCS, NBS, NIS, DBDMH, ICC and NCTSA-Na
salt (Table 4, entries 3e8) have progressed the sample reaction in
variable yields and times (Table 4, entries 3e8).
With the optimal reaction conditions in hand, we screened the
versatility and the scope of this protocol. In this regard, three im-
portant types of N-heterocyclic cores comprising purines, pyrimi-
dines and azole derivatives were examined since they generally
exhibit the strong tendency to interact with biomolecules in the
cells. Thereupon, these N-heterocycles were effectively N-alkylated
using the new protocol with a set of structurally diverse alcohols
bearing various functionalities (Table 5).
We also achieved the reaction of thymine with 3-phenoxy-
propane-1,2-diol using current protocol to understand the re-
activity trend between two different types of hydroxyl moieties in
a molecule (Scheme 3).
Purines like adenine, N6-benzyladenine, theophylline and
theobromine were efficiently N-alkylated with alcohols using the
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4
M.N. Soltani Rad, F. Soleimani / Tetrahedron xxx (2016) 1e7
Table 5
a
One-pot N-alkylation of nucleobases via alcohol using TPP/I2
Table 5 (continued)
Yield (%)b
68
Entry
Product
Time (h)
Yield (%)b
Entry
1
Product
Time (h)
NH2
N
N
N
N
1a
15
O
O
N
14
18
63
N
N
O
N
NH2
N
1n
O
N
N
2
3
12
11
75
72
1b
N
O
N
O
HN
NH2
N
2a
15
16
20
8
66
75
O
N
N
N
1c
O
OCH3
HN
2b
NH2
N
O
N
N
N
1d
4
5
11
10
76
69
N
O
NH2
HN
2c
N
N
N
O
N
17e
O
8
72
1e
N
N
O
S
O
NH2
N
N
O
6
7
15
9
78
71
1f
N
N
HN
O
18f
19
10
6
76
70
O
N
N
HN
Ph
2d
N
O
N
1g
N
N
O
O
N
HN
N
S
O
O
2e
N
8
12
14
80
84
O
N
1h
O
N
N
O
O
N
O
N
HN
9c
20
21
13
10
74
82
2f
N
N
O
O
1i
O
N
N
O
N
NO2
2g
HN
O
O
O
O
N
N
10
8
86
90
Cl
O
1j
N
N
O
N
Me
NO2
HN
O
N
11d
12
O
2h
22
18
80
N
N
N
1k
O
O
N
N
OH
O
O
N
N
12
13
6
89
8
HN
N
2i
23
24
9
67
78
O
N
1l
O
N
N
O
N
N
3a
48
N
N
O
14
O
N
N
1m
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M.N. Soltani Rad, F. Soleimani / Tetrahedron xxx (2016) 1e7
5
Table 5 (continued )
I2
Base
I
Ph3P
[Ph3P-I] I
Entry
Product
Time (h)
Yield (%)b
(I)
RCH2OH
N
H
Base
O2N
N
25g
12
83
RCH2OH
Base
N
Ph3P OCH2R
I
Ph3P
(II)
N
N
3b
N
(III)
N
O
N
N
26h
27
16
14
86
73
N
N
H
O
N
3c
N
N
RCH2I
Ph3P=O
CH2R
Base
N
N
3d
Scheme 4. A plausible mechanism for one-pot N-alkylation reaction of nucleobases
via alcohols using TPP/I2 combination.
S
N
a
Reaction conditions: uracil (1 mmol), alcohol (1 mmol), TPP (1 mmol), I2
(1 mmol), K2CO3 (1 mmol), TEA (1 mmol) and DMF (5 mL).
imidazole is mainly to facilitate the conversion, through the gen-
eration of imidazolium triphenylphosphonium iodide in-
termediate. Similarly with imidazole, we believe that purines,
pyrimidines and azoles achieve the PeN bond to gain the in-
termediate (II). In continuation, (II) reacts further with alcohols to
produce the intermediate (III). The intermediate (III) also can be
obtained directly from iodotriphenylphosphonium iodide (I) which
eventually converts to alkyl iodide. The in situ produced alkyl io-
dide reacts with the base activated nucleobase to yield the corre-
sponding N-alkyl nucleobase adduct. To verify the possibility of
such a mechanism, both GC and TLC analysis have confirmed the
production of the corresponding alkyl iodide especially in the early
reaction times.
b
Isolated yields for shown structures.
From reaction of 2-(4-hydroxy-butyl)-isoindole-1,3-dione with theophylline.
From reaction of 2-(2-methyl-4-nitro-imidazol-1-yl)-ethanol with theophy-
c
d
lline.
e
From reaction of 2-(2-hydroxy-ethyl)-1,1-dioxo-1,2-dihydro-1l6-benzo[d] iso-
thiazol-3-one with uracil.
f
From reaction of 2-(6-hydroxy-hexyl)-isoindole-1,3-dione with uracil.
From reaction of 2-(1H-benzo[d]imidazol-1-yl)ethanol with 2-methyl-4-nitro-
g
imidazole.
h
From reaction of 7-(2-hydroxy-ethyl)-1,3-dimethyl-3,7-dihydro-purine-2,6-
dione with benzimidazole.
O
3. Conclusion
OH
(1 equiv.)
N
N
N
(100%)
O
N
O
N
In conclusion, we have developed a facile, simple and highly
convenient protocol for one-pot N-alkylation of nucleobases via
alcohols using the combination of TPP/I2 in the presence of a basic
mixture of K2CO3/TEA. The influence of various parameters effec-
tive in this current protocol including solvent, base, temperature
and reagent has been discussed. Using this protocol, the nucleo-
bases like purines, pyrimidines and azoles were regioselectively N-
alkylated in good to excellent yields. This synthetic methodology
found to be a suitable route for N-alkylation reaction via primary
alcohols, whereas the secondary and tertiary alcohols were failed to
react with nucleobases.
H
N
1l
K CO /TEA
N
I2
+
TPP
+
+
+
DMF, reflux, 24 h
OH
N
O
O
(1 equiv.)
(1 equiv.)
N
N
(1 equiv.)
(0%)
(1 equiv.)
N
1m
O
N
Scheme 2. The competitive reaction between primary vs. secondary alcohols using
TPP/I2/K2CO3/TEA in DMF. The conversion yields were assigned by GC-analysis.
O
N
OPh
O
N
OH
O
PhO
OH
N
HN
HN
OH
+
O
OPh
+
TPP,I /K CO ,TEA
DMF,reflux, 24h
O
+
O
N
4. Experimental
O
OH
OPh
PhO
2h
OH
(11%)
OH
HN
4.1. General
(89%)
(0%)
O
N
H
All materials were purchased from either Fluka or Merck. Sol-
vents were purified by standard procedures, and stored over 3 A
Scheme 3. The difference in reactivity between primary vs. secondary hydroxyl groups
in N-alkylation of thymine via 3-phenoxy-propane-1,2-diol.
ꢀ
molecular sieves. Reactions were followed by TLC using SILG/UV
254 silica-gel plates. Column chromatography was performed on
silica gel 60 (0.063e0.200 mm, 70e230 mesh; ASTM). Melting
points were measured using Electrothermal IA 9000 melting point
apparatus in open capillary tubes. IR spectra were obtained using
a Shimadzu FTIR-8300 spectrophotometer. 1H and 13C NMR spectra
As shown in Scheme 3, thymine is majorly N1-alkylated through
replacing with primary hydroxyl moiety to afford adduct 2h;
whereas, the generation of the other one possible isomer (in which
could be obtained by the secondary hydroxyl moiety replacement)
was not observed. In addition to adduct 2h, the N1, N3-dialkyl
adduct of thymine was also obtained in a trace amount.
€
were recorded on a Bruker Avance-DPX-250 spectrometer operat-
ing at 250/62.5 MHz, respectively. Chemical shifts are given in
In terms of reaction mechanism, we believe that the reaction is
conducted by the primary nucleophilic attack of TPP to iodine
giving iodotriphenylphosphonium iodide (I) as a reactive in-
termediate (Scheme 4). In the synthesis of alkyl iodide from alcohol
using the combination of TPP/I2/imidazole, Garegg and co-
workers32 have proved by 31P NMR studies that the role of
d relative to tetramethylsilane (TMS) as an internal standard, cou-
pling constants J are given in Hz. Abbreviations used for 1H NMR
signals are s¼singlet, d¼doublet, t¼triplet, q¼quartet,
m¼multiplet, b¼broad, etc. GC/MS was performed on a Shimadzu
GC/MS-QP 1000-EX apparatus (m/z; rel%). Elemental analyses were
performed on a PerkineElmer 240-B microanalyzer.
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6
M.N. Soltani Rad, F. Soleimani / Tetrahedron xxx (2016) 1e7
4.2. General procedure for one-pot N-alkylation of nucleo-
bases via alcohols using TPP/I2
cmꢂ1: 3281, 3050, 2937, 1728, 1712, 1570, 1452; MS [m/z (%)]: 196
(9.8); Anal. Calcd for C9H12N2O3: C, 55.09; H, 6.16; N, 14.28. Found:
C, 55.17; H, 6.28; N, 14.19.
In a double-necked round bottom flask (100 mL) equipped with
a condenser was added a mixture, consisting of alcohol (1 mmol),
TPP (1 mmol), I2 (1 mmol) Et3N (1 mmol), K2CO3 (1 mmol), and the
desire nucleobase (1 mmol) in anhydrous DMF (5 mL).33 The mix-
ture was heated at reflux. Heating was continued until TLC in-
dicated no further improvement in the conversion (Table 5). 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 short column chromatography
on silica gel eluting with proper solvents.
4.3.5. 1-(3-Phenylpropyl)pyrimidine-2,4(1H,3H)-dione (2f). Column
chromatography purification on silica gel with n-hexane/EtOAc
(2:1) afforded white solid (1.70 g, 74%); mp¼107e108 ꢀC; Rf (EtOAc)
0.42; 1H NMR (DMSO-d6, 250 MHz) dppm: 1.88e1.91 (m, 2H,
PhCH2CH2), 2.55 (t, 2H, J¼7.0 Hz, PhCH2), 3.67 (t, 2H, J¼7.0 Hz,
NCH2), 5.52 (d, 1H, J¼7.3 Hz, C(5)eH, uracil), 7.25 (d, 1H, J¼7.3 Hz,
C(6)eH, uracil), 7.59e7.65 (m, 5H, aryl), 11.23 (s, 1H, NH, ex-
changeable with D2O); 13C NMR (DMSO-d6, 62.5 MHz) dppm: 27.3,
33.7, 47.3, 103.1, 126.9, 128.2, 128.9, 137.9, 142.3, 151.8, 164.0; IR
(KBR)
n
cmꢂ1: 3300, 3080, 2961, 1425, 1710, 1542, 1449; MS [m/z
(%)]: 230 (12.5); Anal. Calcd for C13H14N2O2: C, 67.81; H, 6.13; N,
12.17. Found: C, 67.94; H, 6.02; N, 12.25.
4.3. Data for new compounds
4.3.1. 1,3-Dimethyl-7-(2-(4-methylthiazol-5-yl)ethyl)-1H-purine-
2,6(3H,7H)-dione (1h). Column chromatography purification on
silica gel with n-hexane/EtOAc (1:1) afforded creamy solid (2.44 g,
80%); mp¼185e186 ꢀC; Rf (EtOAc) 0.31; 1H NMR (DMSO-d6,
250 MHz) dppm: 2.28 (s, 3H, C]CCH3), 3.29 (s, 3H, N(3)eCH3), 3.33
(t, 2H, J¼7.0 Hz, C]CCH2), 3.46 (s, 3H, N(1)eCH3), 4.42 (t, 2H,
J¼7.0 Hz, NCH2), 7.96 (s, 1H, C(8)eH, theophylline), 8.87 (s, 1H,
C(2)eH, thiazole); 13C NMR (DMSO-d6, 62.5 MHz) dppm: 16.5, 27.4,
30.8, 33.6, 52.7, 108.4, 130.5, 145.1, 149.7, 151.1, 152.0, 152.9, 155.7; IR
4.3.6. 1-(2-(2-Methyl-4-nitro-1H-imidazol-1-yl) ethyl)-1H-benzo [d]
imidazole (3b). Column chromatography purification on silica gel
with EtOAc afforded pale yellow solid (2.25 g, 83%); mp
223e224 ꢀC; Rf (MeOH/EtOAc, 1:10) 0.30; 1H NMR (DMSO-d6,
250 MHz) dppm: 1.82 (s, 3H, CH3), 4.43 (t, 2H, J¼6.2 Hz, NCH2), 4.68
(t, 2H, J¼6.2 Hz, NCH2), 7.17e7.20 (m, 2H, aryl), 7.49 (d, 1H, J¼7.5 Hz,
aryl), 7.65 (d,1H, J¼7.5 Hz, aryl), 8.01 (s,1H, C(5)eH, imidazole), 8.16
(s, 1H, C(2)eH, benzimidazole); 13C NMR (DMSO-d6, 62.5 MHz)
dppm: 12.0, 44.0, 46.1, 109.8, 119.4, 121.9, 122.1, 122.5, 133.5, 143.1,
(KBr)
n
cmꢂ1: 3070, 2965, 1715, 1703, 1571, 1450; MS [m/z (%)]: 305
143.8, 145.0, 145.4; IR (KBr) n
cmꢂ1: 3210, 3100, 2980, 2895, 1532,
(14.2); Anal. Calcd for C13H15N5O2S: C, 51.13; H, 4.95; N, 22.94; S,
10.50. Found: C, 51.21; H, 5.07; N, 22.85; S, 10.56.
1472, 1357; 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.
4.3.2. 7-(4-(1,3-Dioxoisoindolin-2-yl)butyl)-1,3-dimethyl-1H-pu-
rine-2,6(3H,7H)-dione (1i). Column chromatography purification
on silica gel with n-hexane/EtOAc (1:1) afforded white solid
(3.20 g, 84%); mp¼234e235 ꢀC; Rf (EtOAc) 0.43; 1H NMR (DMSO-
d6, 250 MHz) dppm: 1.47e1.53 (m, 2H, CH2), 1.77e1.82 (m, 2H, CH2),
3.18 (s, 3H, N(3)eCH3), 3.36 (s, 3H, N(1)eCH3), 3.51 (t, 2H, J¼6.6 Hz,
NCH2), 4.19 (t, 2H, J¼6.6 Hz, NCH2), 7.65e7.72 (m, 4H, aryl), 8.03 (s,
4.3.7. 7-(2-(1H-Benzo[d]imidazole-1-yl)ethyl)-1,3-dimethyl-1H-pu-
rine-2,6(3H,7H)-dione (3c). Column chromatography purification
on silica gel with MeOH/EtOAc (1:14) afforded pale yellow solid
(2.78 g, 86%); mp¼244e245 ꢀC; Rf (MeOH/EtOAc,1:5) 0.24; 1H NMR
(CDCl3, 250 MHz) dppm: 3.44 (s, 3H, N(3)eCH3), 3.54 (s, 3H, N(1)e
CH3), 4.67e4.71 (m, 4H, NCH2CH2N), 6.98 (s, 1H, C(2)eH, benz-
imidazole), 7.28e7.42 (m, 4H, aryl), 7.59 (s, 1H, C(8)eH, theophyl-
line); 13C NMR (CDCl3, 62.5 MHz) dppm: 29.4, 31.4, 50.3, 56.2, 105.9,
115.1, 117.1, 124.3, 126.2, 133.0, 136.1, 142.6, 146.1, 149.6, 152.0, 155.7;
1H, C(8)eH, theophylline); 13C NMR (DMSO-d6, 62.5 MHz) dppm
:
27.1, 29.4, 30.4, 32.2, 41.1, 49.5, 107.3, 127.1, 132.0, 132.7, 145.6,
150.5, 151.4, 154.9, 170.1; IR (KBr)
cmꢂ1: 3100, 2947, 1718, 1706,
1590, 1532, 1448; MS [m/z (%)]: 381 (18.7); Anal. Calcd for
19H19N5O4: C, 59.84; H, 5.02; N, 18.36. Found: C, 59.93; H, 5.16; N,
n
IR (KBr) n
cmꢂ1: 3094, 2952, 1718, 1702, 1479; MS [m/z (%)]: 324
(20.4); Anal. Calcd for C16H16N6O2: C, 59.25; H, 4.97; N, 25.91.
Found: C, 59.37; H, 5.06; N, 25.98.
C
18.25.
Acknowledgements
4.3.3. 2-(6-(2,4-Dioxo-3,4-dihydropyrimidin-1(2H)-yl)hexyl)isoi-
ndoline-1,3-dione (2d). Column chromatography purification on
silica gel with n-hexane/EtOAc (1:2) afforded white solid (2.59 g,
76%); mp¼150e151 ꢀC; Rf (EtOAc) 0.59; 1H NMR (DMSO-d6,
250 MHz) dppm: 1.23e1.36 (m, 4H, 2CH2), 1.63e1.66 (m, 4H, 2CH2),
3.60e3.74 (m, 4H, 2NCH2), 5.59 (d, 1H, J¼7.8 Hz, C(5)eH, uracil),
7.70 (d, 1H, J¼7.8 Hz, C(6)eH, uracil), 7.88e7.96 (m, 4H, aryl), 11.29
(s, 1H, NH, exchangeable with D2O); 13C NMR (DMSO-d6,
62.5 MHz) dppm: 25.9, 26.3, 27.3, 28.0, 41.2, 47.9, 101.9, 127.2, 132.1,
We wish to thank the Shiraz University of Technology Research
Councils for partial support of this work.
Supplementary data
Supplementary data including characterization data and copies
of NMR spectra (1H and 13C NMR) for all compounds associated
with this article can be found in the online version, at http://
dx.doi.org/10.1016/j.tet.2016.06.069. These data include MOL files
and InChiKeys of the most important compounds described in this
article.
133.0, 141.6, 151.4, 163.4, 169.5; IR (KBR)
1730, 1710, 1590, 1472; MS [m/z (%)]: 341 (18.9); Anal. Calcd for
18H19N3O4: C, 63.33; H, 5.61; N, 12.31. Found: C, 63.40; H, 5.73; N,
n
cmꢂ1: 3240, 3035, 2968,
C
12.19.
References and notes
4.3.4. 1-((Tetrahydrofuran-2-yl)methyl)pyrimidine-2,4(1H,3H)-dione
(2e). Column chromatography purification on silica gel with n-
hexane/EtOAc (1:1) afforded yellow oil (1.37 g, 70%); Rf (EtOAc)
0.48; 1H NMR (DMSO-d6, 250 MHz) dppm: 1.85e1.93 (m, 4H,
CH2CH2), 3.65e3.82 (m, 5H, NCH2CH, OCH2), 5.70 (d, 1H, J¼7.9 Hz,
C(5)eH, uracil), 7.63 (d, 1H, J¼7.9 Hz, C(6)eH, uracil), 12.10 (s, 1H,
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Please cite this article in press as: Soltani Rad, M. N.; Soleimani, F., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.06.069