Highly efficient protocol for one-pot N-alkylation of nucleobases using alcohols in bmim[Br]: A rapid route to access acyclic nucleosides

Article abstract of DOI:10.1007/s13738-015-0633-9

Highly efficient protocol for one-pot N-alkylation of nucleobases using alcohol in ionic liquid media as a straightforward route to access acyclic nucleoside was described. In this protocol purine, pyrimidine as well as azole derivatives underwent the N-a

Full text of DOI:10.1007/s13738-015-0633-9

J IRAN CHEM SOC
DOI 10.1007/s13738-015-0633-9
ORIGINAL PAPER
Highly efficient protocol for one‑pot N‑alkylation of nucleobases
using alcohols in bmim[Br]: a rapid route to access acyclic
nucleosides
Mohammad Navid Soltani Rad1 · Somayeh Behrouz1 · Elham Zarenezhad2 ·
Narjes Kaviani1
Received: 27 November 2014 / Accepted: 14 March 2015
© Iranian Chemical Society 2015
Abstract Highly efficient protocol for one-pot N-alkyla-
tion of nucleobases using alcohol in ionic liquid media as
a straightforward route to access acyclic nucleoside was
described. In this protocol purine, pyrimidine as well as
azole derivatives underwent the N-alkylation reaction with
primary or secondary alcohols using TsCl/TEA/K2CO3
in bmim[Br] to afford the products in good-to-excellent
yields. The influence of factors in this method including the
type of ionic liquid, base and sulfonating agents was dis-
cussed. The current method showed an appropriate selec-
tivity in reaction with primary alcohols in comparison with
secondary alcohols. This protocol is mild, safe and easy to
apply; moreover, it is quite compatible with eco-friendly
and green chemistry protocols, since the exploitation of
toxic and hazardous materials such as DMF and alkyl hal-
ides has been prevented.
Introduction
The N-alkylation reactions of nucleobases are of great
significance, since these reactions are rapid and straight-
forward route to access the acyclic nucleosides as the
most known and used pharmaceutical agents for viral and
cancer chemotherapy [1–9]. However, the N-alkylation
of nucleobases is a difficult reaction as the nucleobases
including purines and pyrimidines are known as ambi-
dent nucleophiles that traditionally react to produce a
mixture of isometric products [10–13]. This often causes
a complicated mixture of products that mostly led to
cumbersome separation process. Additionally, the nucle-
obases have marginal solubility in normal organic sol-
vents. This lack of solubility usually results in decline in
nucleobase reactivity and hence lowers the yield of prod-
ucts [14, 15].
Keywords Acyclic nucleoside · Alcohol · Ionic liquids ·
Nucleobase · One-pot N-alkylation
For increasing the nucleobases solubility in organic
media, solvents with high dielectric constants, comprising
DMF, NMP and DMSO are normally employed. However,
despite these solvents’ abilities to accelerate the nucleo-
philic displacements [16], the relatively high boiling points,
thermal instability, remarkable odour problems and mis-
cibility with both aqueous and organic phases can make
product isolation tedious and solvent recovery in most
cases is impossible [17].
Electronic supplementary material The online version of this
article (doi:10.1007/s13738-015-0633-9) contains supplementary
material, which is available to authorized users.
* Mohammad Navid Soltani Rad
Therefore, for solvent recovery, high temperature even at
reduced pressure is often required to remove the aforemen-
tioned solvents from the products. Recovery of the solvent
at a high temperature can damage sensitive molecules such
as nucleosides. Furthermore, the use of highly toxic DMF
as a solvent has a serious environmental cost and hence its
application ineluctably should be limited [18, 19].
soltani@sutech.ac.ir
* Somayeh Behrouz
behrouz@sutech.ac.ir
1
Medicinal Chemistry Research Laboratory, Department
of Chemistry, Shiraz University of Technology,
71555-313 Shiraz, Iran
2
Traditionally, the N-alkylation reaction of nucleobases
via alkyl halides is a rapid synthetic route to get access
Department of Chemistry, Islamic Azad University,
Yazd Branch, Yazd, Iran
1 3

J IRAN CHEM SOC
to acyclic nucleosides [20–23]; however, alkyl halides are
known today as harmful reagents with proven carcino-
genic properties [24]. Therefore, employing carbon elec-
trophile with a lower toxic effect is critically essential. To
overcome this problem, the direct N-alkylation of nucle-
obases with alcohols would be a highly advantageous and
attractive strategy, since alcohols are known as versatile
reagents that are less toxic, easily handled and wildly
available in comparison with related alkyl halides [25].
In general, the most established procedures developed for
N-alkylation of nucleobases with alcohols are based on
Mitsunobu conditions [26–31]. However, these protocols,
suffer from many disadvantages. For example, the use of
diethyl azodicarboxylate (DEAD) and its related esters
limited the applicability of Mitsunobu reactions in large-
scale synthesis of N-alkylated nucleobase since these
reagents are not only expensive but are also potentially
explosive. In addition, the generated triphenyl phosphine
oxide (O=PPh3) often interferes with other products dur-
ing the purification process. These defects largely annihi-
late the applicability of Mitsunobu conditions in N-alkyla-
tion of nucleobases.
One of the most significant aspects of green chemis-
try is the elimination of hazardous and toxic solvents in
chemical synthesis to avoid the generation of waste. In
this regard, ionic liquids have proved to be an alternative
green reaction media, catalysts, and reagents owing to
their unique properties such as extreme of polarity, non-
flammability, less volatility, high thermal stability, recycla-
bility, negligible vapour pressure and ability to dissolve a
wide range of materials [32–38]. During the past decade,
there has been a dramatic increase in employing the recy-
clable room-temperature ionic liquids (RTILs) as solvent
for organic synthesis [32–35, 39–41]. Up to now, many
ionic liquids have been synthesized and their applica-
tions in several organic transformations and synthesis have
been extensively examined and reviewed [32, 33, 42–44].
Among RTILs, imidazolium ionic liquids are typical, since
they are easily synthesized and their physical and chemi-
cal properties can be tuned by considering the different
alkyl side chains on imidazolium ring and also appropriate
counter ions [45–49].
TsCl/K2CO3/TEA
+ R-OH
N
R
N
H
Br
80°C,4-12 h
N
N
C4H9
R:alkyl, benzyl, alkenyl...
: purines, pyrimidines and azoles
N
H
Scheme 1 One-pot N-alkylation of nucleobases via alcohols using
TsCl/K2CO3/TEA in bmim[Br]
Experimental
General remarks
All chemical reagents were purchased from Fluka or
Merck. Solvents were purified by standard procedures,
and stored over 3 Å molecular sieves. Reactions were fol-
lowed by TLC using SILG/UV 254 silica-gel plates. Col-
umn chromatography was performed on silica gel 60
(0.063–0.200 mm, 70–230 mesh; ASTM). Melting points
were measured using a Büchi-510 melting point appara-
tus in open capillary tubes and they are uncorrected. IR
spectra were obtained using a Shimadzu FT-IR-8300 spec-
trophotometer. H- and 13C-NMR spectra were recorded
1
on a Brüker Avance-DPX-250 spectrometer operating at
250/62.5 MHz, respectively. Chemical shifts are given in δ
relative to tetramethylsilane (TMS) as an internal standard,
coupling constants J are given in Hz. Abbreviations used
1
for H NMR signals are: s = singlet, d = doublet, t = tri-
plet, q = quartet, m = multiplet, b = broad, etc. GC/MS
was performed on a Shimadzu GC/MS-QP 1000-EX appa-
ratus (m/z; rel.%). Elemental analyses were performed on a
Perkin–Elmer 240-B micro-analyzer.
General procedure for the one‑pot N‑alkylation
of nucleobases via alcohols in ionic liquids
In a double-necked round-bottom flask (100 mL) was
added a mixture consisting of nucleobase (0.01 mol),
alcohol (0.012 mol), TsCl (2.86 g, 0.015), TEA (1.01 g,
0.01 mol) and K2CO3 (1.38 g, 0.010 mol) in bmim[Br]
(10 mL). The flask was immersed in an oil bath, kept at
80 °C and stirred for the time when TLC indicated no fur-
ther progress in the conversion (Tables 4, 5, 6). The mixture
was then diluted with water (200 mL) and extracted with
EtOAc (3 × 50 mL). The organic layer was dried (Na2SO4)
and evaporated to afford the crude product which was puri-
fied by traditional column chromatography on silica gel
eluting with proper solvents.
Recently, we established two different protocols for
one-pot N-alkylation of nucleobases via alcohols [50, 51].
However, in both protocols, DMF ineluctably was used as a
solvent to dissolve all reactants and reagents. As part of our
continual research on one-pot N-alkylation of nucleobases
using alcohols and exploiting the utilities of ionic liquids in
organic transformation, we hereby disclose the first exam-
ple of one-pot N-alkylation of nucleobases via alcohols
using TsCl/K2CO3/TEA in bmim[Br] as RTILs (Scheme 1).
1 3

J IRAN CHEM SOC
Recovery of bmim[Br]
H, C(6)-H, uracil), 11.10 (s, 1 H, NH exchangeable with
D2O) ppm; 13C NMR (100 MHz, DMSO-d6, 25 °C):
δ = 25.4, 26.1, 32.3, 33.4, 38.8, 48.9, 101.7, 147.5, 151.1,
164.2 ppm; IR (KBr) ν cm−1: 3276, 3117, 2921, 2849,
1679, 1716, 1478; MS [m/z (%)]: 222 (25.8); Anal. Calcd
for C12H18N2O2: C, 64.84; H, 8.16; N, 12.60. Found: C,
64.92; H, 8.21; N, 12.67.
The aqueous layer obtained from work-up procedure was
evaporated in vacuo on an oil bath to remain the crude
bmim[Br] in which was diluted and extracted from the dis-
solved salts using anhydrous DCM (30 mL). The solution
was filtered and evaporated to obtain the pure bmim[Br]
which was subsequently used for further reactions.
5-(2-(1H-Benzo[d]imidazol-1-yl)ethyl)-4-methylthiazole
Characterization data of new compounds
(3c)
9-((Tetrahydrofuran-2-yl)methyl)-9H-purin-6-amine (1 g)
Column chromatography purification on silica gel with
MeOH/EtOAc (1:14) afforded bright brown foam (1.60 g,
66 %); Rf (MeOH/EtOAc, 1:7) 0.36; H NMR (400 MHz,
1
Column chromatography purification on silica gel with
MeOH/EtOAc (1:7) afforded pale yellow foam (1.75 g,
CDCl3, 25 °C): δ = 1.97 (s, 3 H, CH3), 3.15 (t, J = 6.4 Hz,
2 H, NCH2CH2), 4.22 (t, J = 6.4 Hz, 2 H, NCH2), 7.17–
7.22 (m, 3 H, aryl) 7.55 (s, 1 H, C(2)-H, benzimidazole),
7.68–7.70 (m, 1 H, aryl), 8.44 (s, 1 H, C(2)-H, thiazole)
ppm; 13C NMR (100 MHz, CDCl3, 25 °C): δ = 15.5, 27.8,
53.0, 108.9, 120.3, 122.5, 123.9, 128.3, 133.9, 144.2,
144.4, 148.0, 151.9 ppm; IR (liquid film) ν cm−1: 3076,
2984, 1698, 1459, 1282; MS [m/z (%)]: 243 (18.4); Anal.
Calcd for C13H13N3S: C, 64.17; H, 5.39; N, 17.27; S, 13.18.
Found: C, 64.25; H, 5.47; N, 17.19; S, 13.32.
1
80 %); Rf (MeOH/EtOAc, 1:7) 0.12; H NMR (400 MHz,
DMSO-d6, 25 °C): δ = 1.30–1.54 (complex, 4 H, 2 CH2),
3.34–3.52 (m, 2 H, NCH2), 3.87–3.99 (m, 3 H, OCH2,
OCH), 7.01 (s, 2 H, NH2, exchangeable with D2O), 7.83 (s,
1 H, C(2)-H, adenine), 7.91 (s, 1 H, C(8)-H, adenine) ppm;
13C NMR (100 MHz, DMSO-d6, 25 °C): δ = 25.1, 29.1,
57.8, 67.9, 80.6, 117.2, 144.7, 149.2, 152.9, 156.6 ppm; IR
(liquid film) ν cm−1: 3417, 3100, 2958, 1649, 1464, 1168;
MS [m/z (%)]: 219 (20.5); Anal. Calcd for C10H13N5O:
C, 54.78; H, 5.98; N, 31.94. Found: C, 54.70; H, 5.87; N,
32.05.
Results and discussion
1-(2-(1,1-Dioxido-3-oxobenzo[d]isothiazol-2(3H)-yl)ethyl)
pyrimidine-2,4 (1H,3H)-dione (2c)
To optimize the reaction condition, we examined the reac-
tion of uracil with 2-hydroxyethyl saccharine as a sample
reaction. First, we focused our attention on the choice of an
appropriate ionic liquid as a reaction media. For this pur-
pose, we investigated some representative examples among
the main classes of ILs that have been established so far.
The results are shown in Table 1.
Column chromatography purification on silica gel with
n-hexane/EtOAc (1:3) afforded yellow foam (2.57 g, 80 %);
1
Rf (EtOAc) 0.19; H NMR (400 MHz, DMSO-d6, 25 °C):
δ = 3.67 (t, J = 7.6 Hz, 2 H, NCH2), 3.73 (t, J = 7.6 Hz, 2
H, NCH2), 5.22 (d, J = 7.9 Hz, 1 H, C(5)-H, uracil), 6.97–
7.31 (m, 4 H, aryl) 7.54 (d, J = 7.9 Hz, 1 H, C(6)-H, ura-
cil), 11.08 (s, 1 H, NH, exchangeable with D2O) ppm; 13C
NMR (100 MHz, DMSO-d6, 25 °C): δ = 40.1, 56.1, 102.5,
122.2, 123.3, 128.6, 135.8, 137.8, 140.8, 146.9, 150.8,
163.9, 171.4 ppm; IR (liquid film) ν cm−1: 3420, 3110,
2958, 1732, 1615, 1459, 1164; MS [m/z (%)]: 321 (26.2);
Anal. Calcd for C13H11N3O5S: C, 48.59; H, 3.45; N, 13.08;
S, 9.98. Found: C, 48.50; H, 3.54; N, 13.17; S, 10.03.
As can be seen in Table 1, the influence of certain ionic
liquids including 1-alkyl-3-methylimidazolium (Cnmim)
and tetrabutyl ammonium ILs was examined on a sample
reaction. In general, among the examined ILs, 1-alkyl-
3-methyl-imidazolium ILs (Table 1, entries 1–12) demon-
strated to be more appropriate media for conducting the
experiment in comparison with tetrabutyl ammonium ILs
(Table 1, entries 13–15). Concerning the ionic liquids, we
found that the nature of the cation played the predominant
role. From 1-alkyl-3-methyl-imidazolium [Cnmim] ILs,
it is well demonstrated that the length of alkyl side chains
on imidazolium core evidently affects the progress of reac-
tion [45–49] and in this context the best result was obtained
when C4mim salts, in particular [bmim][Br] were used.
Interestingly, increasing the length of 1-alkyl residue
from ethyl to butyl enhanced the progress of reaction,
whereas more increase in alkyl length from butyl up to
octyl resulted in lower yields for 2c (Table 1, entries 1–7).
1-(2-Cyclohexylethyl) pyrimidine-2, 4(1H, 3H)-dione (2d)
Column chromatography purification on silica gel with
MeOH/EtOAc (1:7) afforded creamy solid (1.73 g, 78 %);
mp = 153–154 °C; Rf (MeOH/EtOAc, 1:7) 0.31; 1H NMR
(400 MHz, DMSO-d6, 25 °C): δ = 0.88–1.12 (complex, 5
H, 2 CH2, CH), 1.63–1.70 (m, 6 H, 3 CH2), 2.39–2.40 (m,
2 H, NCH2CH2), 4.15 (t, J = 6.8 Hz, 2 H, NCH2) 5.45 (d,
J = 7.2 Hz, 1 H, C(5)-H, uracil), 8.14 (d, J = 7.2 Hz, 1
1 3

J IRAN CHEM SOC
Table 1 The influence of ILs type on one-pot N-alkylation of nucle-
obases via alcohol
It was well reviewed that the physicochemical properties of
ionic liquids can be altered by choosing the different alkyl
residues and anions [45–49]. In this regard, the effects of
various anion conjugates with [bmim] cation were tested
(Table 1, entries 3, 8–12). Changing the bromide anion to
chloride and also iodide had a marginal effect in promot-
ing the sample reaction. In the same circumstances, the
use of [bmim] ILs bearing the fluorine anions including
bmim[BF4], bmim[PF6] and bmim[OTf] (Table 1, entries
10–12) showed undistinguishable effects in rise of −reac-
H
O
O
O
S
N
O
O
O
O
N
HN
S
N
+
N
TsCl
OH
O
N
H
K2CO3/TEA, IL, 80°C
O
2c
O
Entry
IL
Time (h)
Yield (%)a
1
emim[Br]
C3mim[Br]
bmim[Br]
C5mim[Br]
C6mim[Br]
C7mim[Br]
omim[Br]
bmim[Cl]
bmim[I]
11
9
51
55
80
73
73
68
48
76
78
77
77
79
34
46
52
2
−
tion compare to bmim[Br]. Although PF6 and BF4 are
3
7
the two anion types that were utilized majorly in most of
IL applications [39–44]; nevertheless, they are suffering
from several defects: these two anions may decompose
when heated in the presence of water and liberate HF [52,
53]. Furthermore, they are too expensive to be employed
in a large-scale organic synthesis. In addition, bmim[PF6]
is water immiscible and extremely hydrophobic which
causes a technical problem through the workup proce-
dure. Tetrabutylammonium halides including tetrabutyl-
ammonium bromide (TBAB), tetrabutylammonium chlo-
ride (TBAC) and tetrabutylammonium fluoride (TBAF)
were proved to be mediocre ILs media for conducting the
N-alkylation of uracil using the current procedure (Table 1,
entries 13–15). The insufficiencies of tetrabutylammonium
halides in the current protocol are attributed to side reac-
tions like Hoffmann elimination and N-butylation reaction
of nucleobases that normally happened through the course
of reaction. The N-butylation was often observed when the
reaction was prolonged and remained at high temperature.
Therefore, TBAB was proved to have the weakest perfor-
mance and N-butyl uracil adducts are considerably pro-
duced when TBAB was employed.
4
9
5
9
6
10
12
8
7
8
9
8
10
11
12
13
14
15
bmim[BF4]
bmim[PF6]
bmim [OTf]
TBABb
9
9
8
12
10
10
TBAC
TBAF
a
Isolated yield, b The reaction was conducted at 100 °C
Table 2 The influence of various bases on one-pot N-alkylation of
nucleobases via alcohol
H
O
O
O
S
N
O
O
O
O
N
HN
S
TsCl
N
+
N
OH
O
N
H
base, bmim[br], 80°C
O
2c
O
The nucleobases and alcohols are weak nucleophiles. To
activate the nucleobase and alcohol, the use of an appropri-
ate base is critically essential for progress of the reaction.
To this end, some organic and inorganic bases were applied
to evaluate their impacts in progress of sample reaction
(Table 2).
As can be seen in Table 2, in the absence of base, the
reaction was not achieved at all even if the reaction time
was prolonged up to 72 h. The best result was obtained
when an equimolar ratio of K2CO3/TEA was applied. The
combination of K2CO3/TEA (Table 2, entry 10) was pre-
viously experienced by our research group and found to
be an appropriate basic mixture for one-pot N-akylation
of nucleobases in DMF [50]. Similarly, this basic mixture
also works well in an ionic liquid media and it was used for
one-pot N-akylation of nucleobases in the current method.
It is worth mentioning that when K2CO3 or TEA was used
alone, moderate yield of product was obtained. The use
of heterocyclic bases including, DBU, DBN, DABCO,
DMAP, and NMM resulted in average-to-good yields of
Entry
Base
Time (h)
Yield (%)d
1
–
72
9
0
2
DBU
DBN
DABCO
DMAP
NMMa
K2CO3
MgO
TEA
69
60
58
53
60
62
32
57
80
42
36
20
3
10
14
12
9
4
5
6
7
9
8
24
10
7
9
10
11
12
13
K2CO3/TEAb
KOH
8
NaOH
Al2Oc3
8
24
All bases were tested at 80 °C
a
b
c
N-Methyl morpholine,
1:1 ratio was used,
basic alumina,
d isolated yield
1 3

J IRAN CHEM SOC
Table 3 The influence of various sulfonating agents on one-pot
N-alkylation of nucleobases via alcohol
Simple aliphatic, aliphatic bearing various functionalities,
allylic and benzylic alcohols were used for N-alkylation
of purine nucleobases. Using the current protocol, good
regioselectivity was also observed for purine nucleobases
as ambident nucleophiles. While theophylline and theo-
bromine were merely N-alkylated from N7 and N1 sites,
respectively; nevertheless, N6-benzyladenine and adenine
majorly afforded the N9-alkyl adducts. To assess the scope
of this protocol, three significant classes of N-heterocyclic
compounds that often display the remarkable propensity
to interact with biomolecules, encompass purines, pyrimi-
dines and azoles were applied for this purpose. In this con-
text, the purines, pyrimidines as well as azoles were suc-
cessfully N-alkylated using the current protocol with a set
of structurally diverse alcohols (Tables 4, 5, 6).
For purine nucleobases (Table 4), adenine, N6-benzylad-
enine, theophylline and theobromine were regioselectively
alkylated with primary and secondary alcohols, whereas
tertiary alcohols were ineffectual in this protocol. Simple
aliphatic, aliphatic bearing various functionalities, allylic
and benzylic alcohols was used for N-alkylation of purine
nucleobases. Using the current protocol, good regioselec-
tivity was also observed for purine nucleobases as ambi-
dent nucleophiles. While theophylline and theobromine,
were merely N-alkylated from N7 and N1 sites, respec-
tively; nevertheless, N6-benzyladenine and adenine majorly
afforded the N9-alkyl adducts.
H
N
O
O
O
S
O
O
O
O
N
HN
S
N
N
+
RSO2Cl
OH
O
N
H
K2CO3/TEA, bmim[br], 80°C
2c
O
O
Entry
RSO2Cl
Time (h)
Yield (%) a
O
H3
C
S
O
O
S
Cl
1
2
9
6
59
79
F3
C
Cl
O
O
S
O
Cl
3
4
5
6
7
10
7
64
80
74
61
73
O
S
O
H3
C
Cl
O
S
O
MeO
Cl
Cl
7
O
S
O
Cl
10
10
O
S
O
Br
Cl
CH3
O
S
O
8
9
14
12
38
54
H3
C
Cl
CH3
O
Cl
S
O
All experiments were achieved at 80 °C
a
Isolated yield
product; whereas, the use of strong bases such as KOH and
NaOH unexpectedly led to faint yields of product as these
bases expedite the decomposition of bmim[Br] through the
Hoffmann-like elimination.
A marginal amount of N7-alkyl adducts for N6-benzy-
ladenine and adenine were also produced which are <8 %
for N6-benzyladenine and <10–15 % for adenine, accord-
ingly. These ratios of isomers were assigned by GC analy-
sis. Alkylation from other nucleophilic sites of used purines
was not detected.
In another experiment, the influence of some sulfonyl
chloride derivatives was surveyed (Table 3). As can be
seen in Table 3, in addition to TsCl, TfCl also showed a
satisfactory result; however, because of its expensiveness,
TsCl was preferred. Other sulfonating agents also under-
went the reaction to display the moderate-to-good yields
of 2c which vary in range of 54–74 %, while 2,4,6-tri-
methybenzene-sulfonyl chloride (Table 3, entry 8) was
reluctant to react efficiently and afforded a low yield of
2c (38 %).
To assess the scope of this protocol, three significant
classes of N-heterocyclic compounds that often display
the remarkable propensity to interact with biomolecules,
encompass purines, pyrimidines and azoles were applied
for this purpose. In this context, the purines, pyrimidines
as well as azoles were successfully N-alkylated using the
current protocol with a set of structurally diverse alcohols
(Tables 4, 5, 6).
Likewise purines, pyrimidines and also azole analogues
were N-alkylated with different types of alcohols (Tables 5,
6). In spite of the ready N-alkylation of pyrimidine and
azoles with primary and secondary alcohols; these nucle-
obases failed to couple with tertiary alcohols using this
method. Uracil and 6-azauracil showed considerable regi-
oselectivity for alkylation from N1-site; nevertheless, a few
N1,N3-dialkyl derivatives were still produced in negligible
yields (10–15 %) which were assigned by GC analysis.
To understand the selectivity of this protocol for type
of alcohol, we performed a competitive reaction between
a mixture consisting of primary and secondary alcohols
under optimized condition. To this end, a mixture of two
isomeric alcohols including 1-phenylethanol (1 equiv.) and
2-phenylethanol (1 equiv.) was introduced to react with the-
ophylline (1 equiv.) in the presence of TsCl (1 equiv.). As
can be seen in Scheme 2, a good selectivity for the reaction
with primary alcohol in comparison with secondary alcohol
was observed in which 1j was mainly obtained, whereas 1p
was generated in a trace amount.
For purine nucleobases (Table 4), adenine, N6-ben-
zyladenine, theophylline and theobromine were regiose-
lectively alkylated with primary and secondary alcohols;
whereas, tertiary alcohols were ineffectual in this protocol.
1 3

J IRAN CHEM SOC
Table 4 One-pot N-alkylation of purines via alcohols
Compound
1
Alcohol
Nucleobase
Product
Time (h)
7
Yield (%) a
84
NH2
NH2
N
N
N
N
N
OH
1a
N
H
N
N
NH2
NH2
N
N
N
2
6
11
6
79
74
85
79
N
N
1b
H3CO
N
OH
N
H
N
N
OCH3
NH2
NH2
N
N
N
3
4
5
OH
1c
N
H
N
N
N
NH2
NH2
N
N
N
N
N
N
1d
OH
OH
N
H
N
N
NH2
NH2
N
N
N
N
N
N
1e
8
N
H
N
NH2
NH2
N
N
N
N
O
1f
N
H
OH
OH
N
N
6
7
8
9
7
81
80
36
64
O
NH2
NH2
N
N
N
N
N
O
1g
N
H
N
N
8
O
NH2
NH2
N
N
OH
N
N
N
1h
N
H
N
12
7
N
HN
Ph
N
O
HN
Ph
N
OH
OH
N
N
N
H
1i
N
N
N
O
O
H
Me
O
O
N
N
N
Me
O
N
N
10
11
12
13
14
4
8
6
7
8
91
88
83
81
88
N
Me
1j
N
N
Me
O
O
O
O
H
N
Me
O
Me
OH
OH
O
N
N
N
1k
N
N
Me
N
O
N
Me
CN
O
O
H
Me
N
N
N
Me
O
N
N
N
NC
1l
O
N
Me
N
Me
O
O
Cl
O
Me
O
N
H
N
N
Me
O
1m
N
OH
N
N
Me
N
N
Me
Cl
N
N
O
O
H
Me
N
N
OH
Me
N
N
N
N
N
1n
O
N
Me
N
O
N
Me
To assess the selectivity of nucleobase in reaction with
different types of hydroxyl groups in a diol, we extended
the optimized reaction condition to reaction of 6-azauracil
with 1,2-octandiol (Scheme 3). As shown in Scheme 3,
in the presence of secondary hydroxyl moiety, the pri-
mary hydroxyl group was exclusively replaced and no
1 3

J IRAN CHEM SOC
Table 4 continued
Compound
Alcohol
Nucleobase
Product
Time (h)
6
Yield (%) a
90
N
NO2
O
H
Me
OH
O2N
N
Me
N
N
N
N
15
16
O
N
N
Me
Me
O
O
N
N
N
N
1o
Me
N
OH
O
H
N
Me
Me
O
11
12
61
68
O
N
Me
O
N
N
N
1p
Me
N
N
Me
O
Me
N
O
HN
N
N
17
O
1q
N
O
N
O
OH
N
O
N
Me
a
Isolated yield
Table 5 One-pot N-alkylation of pyrimidines via alcohols
Compound
Alcohol
Nucleobase
Product
Time (h)
8
Yield (%) a
73
O
O
HN
HN
OH
2a
1
O
N
O
O
N
H
O
N
O
O
HN
OH
2b
HN
2
3
7
7
81
80
O
N
O
O
N
H
N
O
O
O
HN
O
O
S
2c
OH
HN
O
N
O
N
O
N
H
N
S
O
O
O
O
O
HN
HN
2d
OH
O
N
4
5
6
7
6
8
78
75
71
65
O
N
H
O
O
HN
HN
2e
OH
O
N
O
N
H
O
O
NO2
2f
NO2
HN
11
9
HN
Cl
O
N
O
N
H
O
OH
O
O
Cl
O
HN
2g
OH
HN
N
O
N
N
O
N
H
O
O
HN
OH
2h
8
12
60
HN
N
OH
O
N
N
C6H13
O
N
H
C6H13
OH
a
Isolated yield
1 3

J IRAN CHEM SOC
Table 6 One-pot N-alkylation of azole derivatives via alcohols
Compound
1
Alcohol
Nucleobase
Product
Time (h)
7
Yield (%) a
76
N
Cl
N
3a
N
N
H
O
OH
O
N
N
Cl
O2N
3b
N
OH
N
N
N
2
3
4
10
10
7
67
66
71
79
N
H
N
NO2
N
N
3c
N
N
S
OH
OH
N
H
S
N
O2N
N
O2N
3d
N
N
N
H
N
3e
N
N
O
5
6
OH
O
N
H
a
Isolated yield
OH
(1 equiv.)
O
O
O
N
Me
O
H
N
Me
O
N
N
O
S Cl
O
Me
O
N
N
+
K2CO3/TEA
bmim[Br],80°C,5h
N
1j +
1p
+
Me
N
N
N
Me
N
Me
OH
N
Me
(1 equiv.)
(12%)
(88%)
(1 equiv.)
(1 equiv.)
Scheme 2 The competitive one-pot N-alkylation reaction of theophylline via primary vs. secondary alcohols using TsCl/K2CO3/TEA in
bmim[Br]
O
O
HO
C6H13
O
N
O
N
HN
2h
HN
OH
N
HN
N
O
N
K2CO3/TEA, TsCl
bmim[Br],80°C,12h
O
N
OH
N
+
+
N
O
C6H13
+
C6H13
O
N
H
C6H13
OH
C6H13
OH
OH
(92%)
(8%)
(0%)
Scheme 3 The selectivity between primary vs. secondary hydroxyl groups in a one-pot N-alkylation reaction of 6-azauracil via using TsCl/
K2CO3/TEA in bmim[Br]
1 3

J IRAN CHEM SOC
O
S Cl
O
O
RCH2O S
O
Et3N
(i)
RCH OH
+
2
-Et3NHCl
CO32-
K2CO3
N
N
N
N
C4H9
C4H9
(ii)
+
2KBr
+
2
Me
Me
Br
2
CO32-
+
CO2 + H2O
N
N
C4H9
+
N
N
(iii) 2
(iv)
C4H9
2
Me
Me
N
N
N
2
H
O
OTs
+
N
N
RCH2O S
O
C4H9
+
N
N
C4H9
Me
Me
N
R
Scheme 4 A plausible mechanism for one-pot N-alkylation of nucleobases via alcohol in bmim[Br] using TSCl/TEA/K2CO3
N-alkylation was observed at site of secondary hydroxyl
group.
to afford the products in good-to-excellent yields. The
influence of factors on this method including ionic liquid,
base and sulfonating agent types was studied. The current
method showed an appropriate selectivity to react with
primary alcohols in comparison with secondary alcohols,
while tertiary alcohols were inert. Good versatility was
observed from the reaction of structurally diverse alcohols
and nucleobases using the current protocol. This method
is mild, safe and environmentally compatible, since the
exploitation of toxic and hazardous materials such as DMF
and alkyl halides has been prevented. Bmim[Br] as a green
solvent is highly sustainable in that it can be recycled and
reused for multiple reaction runs.
A plausible mechanism for one-pot N-alkylation of
nucleobases via alcohols in bmim[Br] using TsCl and
K2CO3/TEA is suggested (Scheme 4). In this mechanism,
TEA as a homogeneous base, first scavenges a proton from
alcohol, and then activated alcohol (alkoxide ion) attacks
TsCl to attain the corresponding alkyltosylate. To endorse
this, the generation of alkyltosylate was readily observed
during the early stage of reaction process and the in situ
generation of alkyltosylate was confirmed by comparing
the reaction contaminants with authentic samples using
GC analysis. Bmim[Br] as a highly polar reaction media
assists the solvation of heterogeneous K2CO3 through cat-
ion–anion exchange reaction which results in formation of
butyl methyl imidazolium carbonate [Bmim]2[CO3] [54].
[Bmim]2[CO3] scavenges a proton from the correspond-
ing nucleobase through acid–base reaction and generates
butyl methyl imidazolium-nucleobase ion-pair. Afterward,
the nucleobase anion attacks the electrophilic carbon at
produced alkyltosylate to afford the corresponding N-alkyl
nucleobase.
Acknowledgments We are grateful to Shiraz University of Technol-
ogy Research Council for partial support of this work.
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