Triphenylphosphine-free approach for one-pot N-alkylation of purine, pyrimidine, and azole derivatives with alcohols using P2O5/KI: A facile and selective route to access carboacyclic nucleosides

Article abstract of DOI:10.1016/j.tet.2019.130499

A facile, selective, and mild synthetic approach for one-pot N-alkylation of nucleobases and other related N-heterocycles via alcohols, using a mixture of P₂O₅ and KI is described. The reaction of structurally diverse purines, pyrimidines, and/or azoles with primary alcohols with the use of P₂O₅/KI and basic mixture of Et₃N/K₂CO₃ in refluxing DMF affords the corresponding N-alkyl derivatives (carboacyclic nucleosides) in good to reasonable yields. The influence of different parameters comprising solvent, base, temperature, and substrate/reagent ratios was assessed on the reaction progress. The secondary and tertiary alcohols were failed to react with nucleobases. The main advantageous of current protocol is formation of water soluble side products in which provides simple work-up and purification processes.

Full text of DOI:10.1016/j.tet.2019.130499

Journal Pre-proof
Triphenylphosphine-free approach for one-pot N-alkylation of purine, pyrimidine, and
azole derivatives with alcohols using P O /KI: A facile and selective route to access
2 5
carboacyclic nucleosides
Somayeh Behrouz, Mohammad Navid Soltani Rad, Samira Ahmadi
PII:
S0040-4020(19)30826-9
https://doi.org/10.1016/j.tet.2019.130499
TET 130499
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 26 May 2019
Revised Date: 30 July 2019
Accepted Date: 1 August 2019
Please cite this article as: Behrouz S, Soltani Rad MN, Ahmadi S, Triphenylphosphine-free approach for
one-pot N-alkylation of purine, pyrimidine, and azole derivatives with alcohols using P O /KI: A facile
2 5
and selective route to access carboacyclic nucleosides, Tetrahedron (2019), doi: https://doi.org/10.1016/
j.tet.2019.130499.
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Graphical Abstract
P2O5/KI/Et3N/K2CO3
DMF, reflux
R OH
N
H
N
R
R = primary alcohols
NH2
O
N
N
N
HN
, ...
,
,
:
N
N
N
N
O
N
H
H
H
H

Triphenylphosphine-free approach for one-pot N-alkylation of purine, pyrimidine, and
azole derivatives with alcohols using P2O5/KI: A facile and selective route to access
carboacyclic nucleosides
Somayeh Behrouz *, Mohammad Navid Soltani Rad *, Samira Ahmadi
Medicinal Chemistry Research Laboratory, Department of Chemistry, Shiraz University of Technology, Shiraz
71555-313, Iran
Tel.: +98-711-7261392; fax: +98-711-7354523; e-mails: behrouz@sutech.ac.ir; soltani@sutech.ac.ir
Abstract: A facile, selective, and mild synthetic approach for one-pot N-alkylation of nucleobases and other related N-
heterocycles via alcohols, using a mixture of P2O5 and KI is described. The reaction of structurally diverse purines,
pyrimidines, and/or azoles with primary alcohols with the use of P2O5/KI and basic mixture of Et3N/K2CO3 in refluxing DMF
affords the corresponding N-alkyl derivatives (carboacyclic nucleosides) in good to reasonable yields. The influence of
different parameters comprising solvent, base, temperature, and substrate/reagent ratios was assessed on the reaction progress.
The secondary and tertiary alcohols were failed to react with nucleobases. The main advantageous of current protocol is
formation of water soluble side products in which provides simple work-up and purification processes.
Keywords: alcohol, N-alkyl nucleobase, nucleoside, P2O5/KI, selective N-alkylation, triphenylphosphine-free
1

1. Introduction
Over the years, natural and synthetic N-heterocyclic derivatives have gained a special attention in different area
of sciences and industries due to their broad spectrum of applications. Purine and pyrimidine nucleobases are
among the most abundant N-heterocycles which mainly found as a component in DNA and RNA structures.
Carboacyclic nucleosides are known as an important class of N-alkylnucleobase derivatives that have received
enormous research interests owing to their abundant applications in medicinal chemistry. In particular, they have
been known for their chemotherapeutic properties against numerous types of cancer, viral, and microbial
diseases [1]. Penciclovir, famciclovir, adefovir, and cidofovir are well-identified carboacyclic nucleoside drugs
having potent anti-viral activity (Figure 1). In addition, nucleosides are used as molecular tools and probes for
studying the biological systems [2].
NH2
NH2
O
N
N
N
N
N
N
N
N
N
HN
H2N
O
O
P
N
O
N
O
P
H2N
N
N
OH
OH
OH
OH
O
O
OH
OH
O
O
HO
O
Penciclovir
Famciclovir
Adefovir
Cidofovir
Figure 1. The structure of some carboacyclic nucleosides as anti-viral drugs
Regarding to the unique therapeutic activity of nucleosides, there has been the massive interests to synthesize
the numerous carboacyclic nucleoside derivatives via N-alkylation of nucleobases using different carbon
electrophiles. To gain the N-alkylated nucleobases, the most common used carbon electrophiles are comprising
alkyl halides [3], alkyl sulfonates [4], epoxides [5], α, β-unsaturated carbonyl compounds [6], and ethers [7].
Despite the fact that these carbon electrophiles are strong alkylating agents; however, most of them were
recognized to be toxic and carcinogenic [8]. Thus, because of toxicity, the applicability of the aforementioned
alkylating agents particularly in scale-up synthesis is restricted. Therefore, there is an enormous interest to apply
the other sources of carbon electrophiles with more safety. To this end, alcohols would be a suitable and
worthwhile candidate regarding to their wide structural diversity, accessibility, lower toxicity, ease of handling
and more safety in comparison with other structurally related alkylating agents. In this context, the first report by
Mitsunobu on use of alcohols as the alkylating agent had initiated a massive upheaval in organic transformations
[9,10]. Particularly, the use of Mitsunobu conditions for the direct synthesis of N-alkylated nucleobases from
alcohols affords the remarkable achievements and provides the N-alkyl nucleobases in good yields [11-16].
However, the application of this reaction is restricted by two main drawbacks; first, the use of diethyl
azodicarboxylate (DEAD), and second, the formation of triphenylphosphine oxide. While the former is an
explosive and expensive reagent, the latter is tediously separated from the reaction mixture. To overcome these
problems, our group has reported N-(p-toluenesulfonyl)imidazole (TsIm) [17] and TsCl/bmim[Br] [18] as efficient,
inexpensive, and safe reagents for one-pot synthesis of N-alkyl nucleobases from alcohols. Up to now, a few TPP-
free protocols for efficient conversion of alcohols into N-alkyl nucleobases have been established, hence there is a
2

great deal of endeavors to discover and improve the simple, convenient and efficient protocols to acquire the N-
alkyl nucleobases from alcohols.
Phosphorus pentoxide is a commercially available, non-toxic, and low-cost reagent which is used in many
organic transformations [19]. In continuation of our ongoing interest on discovering simple, mild, and efficient
process for synthesis of N-alkyl nucleobases from alcohols [17, 18]; hereby, we report the simple and convenient
method for the direct N-alkylation of nucleobases and other related N-heterocycles via alcohols using P2O5/KI in
the presence of Et3N/K2CO3 in DMF at reflux condition (Scheme 1).
P2O5/KI/Et3N/K2CO3
R OH
N
H
N
R
DMF, reflux
R = primary alcohols
NH2
O
N
N
N
HN
, ...
,
,
:
N
H
N
N
H
N
O
N
H
H
Scheme 1. The N-alkylation of nucleobases via alcohols using P2O5/KI
2. Results and discussion
The initial effort for N-alkylation of nucleobases and other N-heterocycles via alcohols was begun by recognizing
the optimized condition. In this connection, the N-alkylation reaction of adenine with 1-octanol using P2O5/KI was
selected as a sample reaction. Afterward, the influence of parameters like solvent, base, temperature, and molar
ratio of ROH/P2O5/KI was investigated on sample reaction.
As the solvent displays an undeniable role in the reaction progress, primarily our attempt was focused on
studying the effect of different solvents on synthesis of 9-octyl-9H-purin-6-amine as a sample product (Table 1).
The results in Table 1 demonstrate that among the different types of examined solvents, anhydrous DMF affords
the best results in terms of reaction rate and yield (entry 5). The progress of sample reaction was also explored in
normal DMF to determine whether the contained moisture in DMF could affect the reaction path (Table 1, entry
4). However, a negligible difference was observed. Thus, the normal DMF was selected as a choose solvent for all
reactions. Among tested solvents, HMPA and DMSO result in 65% and 71% yields of product, respectively (Table
1, entries 2 and 3). Furthermore, using polar protic solvents such as H2O, EtOH, and PEG-400 failed to acquire the
satisfactory result even though the reaction time was prolonged up to 24 h (entries 7-9). Moreover, when
[bmim]Br was employed as a typical room temperature ionic liquid, only 27% of product was obtained after 18 h
(Table 1, entry 10). Other solvents such as MeCN, acetone, toluene and THF provide no further improvement in
the reaction progress (entries 1, 6, 11, and 12).
In the next step, the effect of diverse bases on progress of sample reaction was examined (Table 2). In the
absence of base, no product was gained even after 48 h (Table 2, entry 1). Apparently, the presence of an efficient
base has undeniable role for activation of N-H bond in nucleobases to enhance their nucleophilic power.
Regarding to obtained results in Table 2, the examined heterogeneous inorganic bases lead to less satisfactory
3

results compare to assessed organic bases (Table 2, entries 2-5 vs 7-10). As depicted, the highest yield of the
product and shortest reaction time were obtained when the combination of Et3N/K2CO3 in a 1:1 molar ratio was
employed (Table 2, entry 6). Also, the separate use of each one of K2CO3 (entry 5) or Et3N (entry 7) were not as
efficient as the combination of Et3N/K2CO3 (1:1 ratio).
Table 1 Effect of different solvents on synthesis of 9-octyl-9H-purin-6-amine a
NH2
N
NH2
N
N
N
P2O5/KI/Et3N/K2CO3
Solvent, reflux
N
N
HO
N
H
5
N
5
Entry
1
Solvent
MeCN
HMPA
DMSO
DMF
Time (h)
Yield d (%)
24
12
10
7
2
65
3
71
4
7
79
5
DMF b
Acetone
H2O
7
80
6
18
24
24
24
18
24
18
20
7
15
8
EtOH
17
9
PEG-400 c
[bmim]Br c
Toluene
THF
27
10
11
12
22
Trace
Trace
a Reaction conditions: adenine (1 mmol), 1-octanol (1 mmol), P2O5 (1.5 mmol), KI (1.5 mmol), Et3N (1 mmol), K2CO3 (1 mmol), Solvent (5
mL). b Anhydrous DMF. c The reaction temperature was raised up to 100 °C. d Isolated yield.
Table 2 Effect of different bases on synthesis of 9-octyl-9H-purin-6-amine a
NH2
N
NH2
N
N
N
P2O5/KI/Base
DMF, reflux
N
N
HO
N
H
5
N
5
Entry
Base
-
Time (h)
Yield c (%)
1
48
36
14
36
12
7
NR d
29
45
21
58
79
65
73
60
63
2
Al2O3
KOH
MgO
3
4
5
K2CO3
b
6
Et3N/K2CO3
Et3N
7
10
9
8
DBU
9
DABCO
DMAP
12
63
10
a Reaction conditions: adenine (1 mmol), 1-octanol (1 mmol), P2O5 (1.5 mmol), KI (1.5 mmol), Base (1 mmol), DMF (5 mL). b 1:1 ratio was
employed. c Isolated yield. d No reaction.
4

In further assessment, we also investigated the effect of temperature variations on the reaction progress. Thus,
the reaction of adenine with 1-octanol was achieved at different temperatures (Table 3). Firstly, it was attempted
to perform the reaction at ambient temperature. Practically, no reaction was carried out even if the reaction time
was prolonged from 24 h up to 36 h (entries 1 and 2). However, increasing the reaction temperature from room
temperature up to reflux condition remarkably increased the reaction efficiency (Table 3, entries 3-9). The best
result was attained when the sample reaction was achieved at reflux condition for 7 h (Table 3, entry 10). Further
increase in reaction time at reflux condition did not result in more satisfactory result (entry 11).
Table 3 Effect of different temperatures on synthesis of 9-octyl-9H-purin-6-amine a
NH2
NH2
N
N
N
P2O5/KI/Et3N/K2CO3
DMF, T (°C)
N
N
HO
N
H
5
N
N
5
Entry
Time (h)
Yield b (%)
Temperature (°C)
1
r.t.
24
36
18
24
12
18
9
NR c
NR
10
15
23
35
45
57
65
79
79
2
r.t.
3
80
4
80
5
100
100
120
120
Reflux
Reflux
Reflux
6
7
8
12
5
9
10
7
11
12
a Reaction conditions: adenine (1 mmol), 1-octanol (1 mmol), P2O5 (1.5 mmol), KI (1.5 mmol), Et3N (1 mmol), K2CO3 (1 mmol), DMF (5 mL). b
Isolated yield. c No reaction.
In another attempt to improve the reaction efficiency, the effect of different molar ratios of ROH/P2O5/KI for
synthesis of 9-octyl-9H-purin-6-amine was examined (Table 4). When the reaction was carried out in the absence
of KI, no desired product was obtained after reflux for 48 h (entry 1). It is also worth mentioning that the
corresponding alkene is generated through the course of reaction in the absence of KI as detected by GC analysis.
Practically, using KI increased the reaction yield and rate. As shown in Table 4, no reaction was conducted in the
absence of P2O5 even though the reaction was prolonged up to 24 h (entry 2). Clearly, this experience confirms
that P2O5 has undeniable role on reaction progress. The optimized molar ratio of ROH/P2O5/KI for conversion of 1-
octanol into 9-octyl-9H-purin-6-amine was found to be 1.0:1.5:1.5 (Table 4, entry 6). Furthermore, raising the
amount of P2O5-KI relative to alcohol has no distinguishable improvement on the reaction efficacy (Table 4,
entries 7-9).
After discovering the optimized reaction conditions, the general applicability, scope and limitations of the
present protocol were assessed by examining varities of structurally diverse alcohols, nucleobases and other N-
5

heterocycles (Tables 5-7). Thus, several primary and secondary alcohols involving various functionalities
underwent the reaction with purine and pyrimidine nucleobases as well as several bioactive N-heterocycles
including, benzimidazole, imidazole, 2-phenylimidazole, 2-methyl-4(5)-nitroimidazole, and indole.
Table 4 Effect of different molar ratios of ROH/P2O5/KI (X:Y:Z) on synthesis of 9-octyl-9H-purin-6-amine a
NH2
NH2
N
N
N
P2O5/KI/Et3N/K2CO3
DMF, reflux
N
N
HO
N
H
5
N
N
5
Entry
molar ratios of ROH/P2O5/KI
Time (h)
Yield b (%)
NR c
NR c
41
1
2
3
4
5
6
7
8
9
1:1:0
48
24
12
10
9
1:0:1
1:0.5:1
1:1:1
65
1:1.3:1.3
1:1.5:1.5
1:1.7:1.7
1:2:2
73
7
79
7
80
7
80
1:2.5:2.5
7
79
a Reaction conditions: adenine (1 mmol), 1-octanol (X mmol), P2O5 (Y mmol), KI (Z mmol), Et3N (1 mmol), K2CO3 (1 mmol), DMF (5 mL). b
Isolated yield. c No reaction.
Pyrimidine type nucleobases like uracil, thymine, and 6-azauracil were converted to the corresponding N-alkyl
derivatives in good yields (Table 5, entries 1-9). Despite the fact that nucleobases are known for their ambident
behavior for their nucleophilicity; however, the notable regioselectivity was observed for N-alkylation site of
applied pyrimidines. Thus, the N1-alkylated adducts were almost obtained as the major products. Due to GC
analysis, the N1,N3-dialkyl adducts were also identified less than 8% [25]. Furthermore, no O-alkylated adducts of
pyrimidine nucleobases were detected using the present protocol.
Purines like adenine, 6-chloropurine, theophylline and theobromine were also readily N-alkylated with primary
alcohols (Table 6, entries 1-9). Like pyrimidines, purines also exhibited the satisfactory regioselectivity toward the
site of N-alkylation. In the case of adenine and 6-chloropurine, the N9-isomers were mainly produced and the N7-
isomers were obtained in trace amounts (less than 6% based on GC analysis) [26]. The N-alkylation of theophylline
was regioselectively led to synthesize of N7-alkylated adducts.
We also examined the generality of this method for N-alkylation of several N-heterocyclic derivatives. In this
context, benzimidazole, imidazole, 2-phenylimidazole, 2-methyl-4(5)-nitroimidazole, and indole were selected to
undergo the N-alkylation reaction exploiting the current protocol (Table 7, entries 1-6). As can be seen in Table 7,
the related N-alkyl adducts were obtained in good yields; however, the use of 2-phenylimidazole resulted in 70%
yield (entry 4). This lower yield can be attributed to the steric hindrance of the starting N-heterocycle.
6

Table 5 Synthesized N-alkyl pyrimidines using P2O5/KI a
Entry [Ref.]
alcohol
pyrimidine
Product
Time (h)
Yield b
O
O
Cl
HN
HN
1
7
82
Cl
OH
O
N
H
O
O
N
O
O
O
O
N
HN
HN
2 [18]
8
8
80
81
O
N
S
O
OH
O
N
H
O
O
N
O
S
O
O
N
O
O
O
N
3 [20]
HN
HN
OH
O
O
N
H
O
N
O
O
O
OH
4 [18]
5 [21]
6 [21]
7
7
9
9
7
9
9
78
50
53
76
69
66
HN
HN
O
N
H
O
N
O
O
OH
HN
HN
O
N
H
O
N
O
O
HN
HN
OH
O
N
H
O
N
O
O
Cl
HN
HN
O
N
O
O
OH
O
N
H
O
Cl
O
HN
8 [20]
HN
N
N
OH
N
N
O
N
O
O
N
H
O
HN
OH
HN
9 [18]
OH
O
N
O
N
H
5
OH
a Reaction conditions: pyrimidine (1 mmol), alcohol (1 mmol), P2O5 (1.5 mmol), KI (1.5 mmol), Et3N (1 mmol), K2CO3 (1 mmol), DMF (5 mL). b
Isolated yield.
Fortunately, the obtained results demonstrated the selectivity of the present protocol for the primary alcohols
compare to other types of alcohols. Different primary alcohols having a simple aliphatic side chain or aliphatic
side chain bearing different functional groups like allylic, benzylic, aryl, ether, and several heterocyclic cores were
efficiently applied for N-alkylation of purines, pyrimidines, and other related N-heterocycles (Tables 5-7). When 1-
phenylethanol was used as a typical secondary alcohol for N-alkylation of theophylline, only 12% of the
corresponding product was obtained (Table 6, entry 8). Attempts were failed to achieve the N-alkylation reaction
of theophylline via tertiary alcohols like t-butyl alcohol and no product was obtained even in trace amount.
7

Table 6 Synthesized N-alkyl purines using P2O5/KI a
Entry [Ref.]
alcohol
purine
Product
Time (h)
Yield b
NH2
NH2
N
N
N
OH
N
N
N
N
1
7
79
5
N
N
N
H
5
NH2
NH2
N
Ph
N
N
2
9
74
OH
Ph
O
N
N
N
H
O
NH2
NH2
N
N
N
N
3 [20]
4 [20]
5 [18]
8
9
9
78
75
72
N
OH
N
N
N
H
NH2
NH2
N
N
N
N
N
N
OH
N
N
N
H
NH2
NH2
OH
N
N
N
N
O
N
H
N
N
O
Cl
N
Cl
N
N
N
N
N
Cl
Cl
N
6
N
H
8
82
90
12
91
OH
O
O
NO2
N
N
O
N
H
N
O2N
O
7 [22]
7
N
OH
N
N
N
N
N
N
O
O
N
O
OH
O
8 [22]
10
7
H
N
N
N
N
N
N
N
O
O
N
O
O
N
O
N
H
N
9 [22]
N
N
N
OH
N
N
O
a
b
Reaction conditions: purine (1 mmol), alcohol (1 mmol), P2O5 (1.5 mmol), KI (1.5 mmol), Et3N (1 mmol), K2CO3 (1 mmol), DMF (5 mL).
Isolated yield.
The selectivity of the present protocol for primary alcohol was confirmed through performing a competitive
reaction between two isomeric alcohols comprising 2-phenylethanol (1 mmol) and 1-phenylethanol (1 mmol) as
the representative for primary and secondary alcohols, respectively. The reaction was carried out using
theophylline and P2O5/KI under optimized reaction conditions (Scheme 2). Based on the GC analysis, product (A)
was exclusively produced from the reaction of theophylline with 2-phenylethanol. Practically, there is no chance
for the reaction of 1-phenylethanol with theophylline against 2-phenylethanol.
8

OH
(1 mmol)
O
N
O
N
O
N
H
N
P2O5 (1 mmol)/KI (1 mmol)
Et3N/K2CO3
N
N
N
N
N
N
N
OH
N
DMF, reflux
O
O
O
B
A
(1 mmol)
(1 mmol)
100%
0%
Scheme 2. Competitive one-pot N-alkylation of theophylline with 2-phenylethanol and 1-phenylethanol using P2O5/KI (yields
based on GC analysis)
Table 7 Synthesized N-alkyl azole derivatives using P2O5/KI a
Entry [Ref.]
alcohol
azole
Product
Time (h)
Yield b
1 [18]
8
86
N
OH
N
S
N
N
H
N
S
N
OH
N
N
O
N
2 [23]
8
89
N
N
N
N
H
O
N
O
N
N
N
N
O
O
N
N
O
3
8
7
90
70
N
OH
N
N
H
N
O
O
N
N
OMe
N
MeO
4
Ph
Ph
N
N
OH
H
O
O
O2N
O2N
OH
N
5 [23]
11
10
83
41
N
N
N
N
H
N
N
6 [24]
OH
N
N
H
a
b
Reaction conditions: azole (1 mmol), alcohol (1 mmol), P2O5 (1.5 mmol), KI (1.5 mmol), Et3N (1 mmol), K2CO3 (1 mmol), DMF (5 mL).
Isolated yield.
The selectivity of the present protocol was evaluated via conducting the reaction between a nucleobase and a
diol consisting both primary and secondary hydroxyl groups, simultaneously. Thus, the reaction of 6-azauracil with
1,2-octandiol was achieved under optimized reaction conditions (Scheme 3). As expected, the result showed the
excellent selectivity between two types of hydroxyl groups. Thus, 6-azauracil reacted readily with primary
hydroxyl group of 1,2-octandiol to afford compound C as the major product. In addition, N,N-dialkyl adduct of 6-
azauracil (E) was obtained in a trace amount. However, no D adduct which may be resulted from the reaction at a
secondary hydroxyl of 1,2-octandiol with 6-azauracil was observed.
9

O
O
N
O
N
O
N
OH
5
HO
HN
P2O5/KI/Et3N/K2CO3
DMF, reflux
HN
HN
N
HO
N
N
N
N
O
N
H
O
O
O
5
HO
5
5
5
OH
OH
C
D
E
93%
0%
7%
Scheme 3. Competitive reaction between primary and secondary hydroxyl groups of 1,2-octandiol with 6-azauracil (yields
based on GC analysis)
A plausible mechanism for one-pot N-alkylation of nucleobases and other N-heterocycles via alcohols in the
presence of P2O5/KI is suggested (Scheme 4). We proposed that mechanism should be progressed through the
synthesis of alkyl iodide II as the main reactive intermediate via the reaction of adduct (I) with KI. As matter of
fact, the formation of alkyl iodide (II) was confirmed by TLC monitoring and GC analysis at the early stage of the
reaction. Afterward, the activated nucleobase (III) by Et3N/K2CO3 reacts with in situ generated alkyl iodide (II) to
afford the desired N-alkyl adduct (IV).
It is worth mentioning that the use of triphenylphosphine for N-alkylation of nucleobases with alcohols leads to
synthesize of triphenylphosphine oxide (TPPO) as the main by-product. Practically, TPPO separation from the
desired N-alkyl nucleobases is cumbersome which is a main problem in most cases. However, the use of P2O5/KI
results in phosphorus oxoacid as a main side-product which is readily soluble in water and can be easily discarded
by a simple washing. Therefore, the work-up and purification processes are much easier and cleaner compare to
other TPP-based protocols.
O
P
O
P
O
P
K
I
R OH
R I
R
O
O
O
O
O
I
II
Et3N/K2CO3
N
H
N
III
R
I
N
N
R
IV
II
III
Scheme 4. A tentative mechanism for one-pot N-alkylation of nucleobases with alcohols using P2O5/KI
3. Conclusions
In summary, we have developed a mild, selective, and one-pot procedure for N-alkylation of nucleobases and its
derivatives using alcohols. In this protocol, treatment of primary alcohols with P2O5/KI in the presence of
Et3N/K2CO3 in refluxing DMF, regioselectively affords the corresponding N-alkyl nucleobases in good yields. The
influence of different parameters on the progress of reaction was investigated. Using this method, primary
10

alcohols were selectively underwent the reaction with nucleobases while secondary and tertiary alcohols were
inactive towards nucleobases. Furthermore, this protocol is TPP-free and the main by-product is readily soluble in
water which provides the simple work-up and purification processes.
4. Experimental
4.1. General
All chemicals were purchased from Merck. Solvents were purified using standard procedures and stored over 3Å
molecular sieves. Reactions were monitored by TLC using SILG/UV 254 silica-gel plates. Column chromatography
1
was performed on silica gel 60 (0.063–0.200 mm, 70–230 mesh; ASTM). H- and 13C-NMR spectra were recorded
on Brüker Avance-DPX-250 and Brüker Avance-DPX-400 spectrometers operating at 250/62.5, 300/75 and
400/100 MHz, respectively. Chemical shifts are given in δ relative to tetramethylsilane (TMS) as an internal
1
standard, coupling constants J are given in Hz. Abbreviations used for H NMR signals are s singlet, d doublet, t
triplet, q quartet, m multiplet, b broad, dd doublet of doublet. GC/MS was performed on a Shimadzu GC/MS-QP
1000-EX apparatus (m/z; rel.%). Elemental analyses were performed on a Perkin–Elmer 240-B microanalyzer. IR
spectra were obtained using a Shimadzu FT-IR-8300 spectrophotometer. Melting points were measured using
Electrothermal IA 9000 melting point apparatus in open capillary tubes and are uncorrected.
4.2. General procedure for synthesis of N-alkyl nucleobases via alcohols using P2O5/KI
To a double-necked round bottom flask (100 mL), equipped with a condenser, it was added a mixture of KI (1.5
mmol), P2O5 (1.5 mmol) and the desired alcohol (1 mmol) in DMF (5 mL). The reaction mixture was stirred at r.t.
for 30 min. Next, the considered nucleobase (1 mmol), K2CO3 (1 mmol) and Et3N (1 mmol) were added and the
reaction mixture was heated to reflux for a further 6.5-10.5 h (until TLC indicated no further progress in reaction,
Table 5). The solvent was then evaporated at reduced pressure, and the remaining foam was dissolved in
chloroform (150 mL) and washed with water (2 × 150 mL). The organic layer was dried on Na2SO4 (1 g) and
evaporated. The product was purified using short column chromatography on silica gel eluting with proper
solvents.
4.3. Data for new compounds
4.3.1. 1-(2-(4-chlorophenoxy)ethyl)pyrimidine-2,4(1H,3H)-dione (Table 5, entry 1)
Column Chromatography on silica gel eluted with hexane/EtOAc (1:1) afforded pure product as white solid (218
mg, 82%); m.p. 216-217 °C. IR (KBr): 3200, 3041, 2949, 1725, 1712, 1492, 1039 cm-1. 1H NMR (DMSO-d6, 250 MHz)
δppm = 4.08 (t, J = 4.8 Hz, 2H, NCH2), 4.20 (t, J = 4.8 Hz, 2H, OCH2), 5.57 (d, J = 7.8 Hz, 1H, C(5)-H of uracil), 6.96 (d, J
= 8.9 Hz, 2H, aryl), 7.32 (d, J = 8.9 Hz, 2H, aryl), 7.71 (d, J = 7.8 Hz, 1H, C(6)-H of uracil), 11.34 (s, 1H, NH). 13C NMR
(DMSO-d6, 62.5 MHz) δppm = 46.8, 65.5, 100.6, 116.2, 124.6, 129.2, 146.2, 150.9, 156.8, 163.7. MS (EI): m/z (%) =
266 (27.2) [M+]. Anal. Calc. for C12H11ClN2O3: C, 54.05; H, 4.16; N, 10.50; found: C, 53.84; H, 4.28; N, 10.31.
11

4.3.2. 1-(3-(4-chlorophenoxy)propyl)-5-methylpyrimidine-2,4(1H,3H)-dione (Table 5, entry 7)
Column Chromatography on silica gel eluted with hexane/EtOAc (1:1) afforded pure product as white solid (223
mg, 76%); m.p. 169-170 °C. IR (KBr): 3151, 3075, 2867, 1730, 1718, 1456, 1052 cm-1. 1H NMR (DMSO-d6, 250 MHz)
δppm = 1.73 (s, 3H, CH3), 2.03-2.10 (m, 2H, OCH2CH2), 3.82 (t, J = 6.7 Hz, 2H, NCH2), 4.00 (t, J = 5.8 Hz, 2H, OCH2),
13
6.94 (d, J = 8.9 Hz, 2H, aryl), 7.33 (d, J = 8.9 Hz, 2H, aryl), 7.62 (s, 1H, C(6)-H of thymine), 11.24 (s, 1H, NH). C
NMR (DMSO-d6, 62.5 MHz) δppm = 11.8, 27.8, 44.9, 65.4, 108.3, 116.0, 124.2, 129.1, 141.5, 150.9, 157.1, 164.3. MS
(EI): m/z (%) = 294 (29.4) [M+]. Anal. Calc. for C14H15ClN2O3: C, 57.05; H, 5.13; N, 9.50; found: C, 57.18; H, 5.29; N,
9.71.
4.3.3. 9-octyl-9H-purin-6-amine (Table 6, entry 1)
Column Chromatography on silica gel eluted with hexane/EtOAc (1:10) afforded pure product as yellow solid (195
mg, 79%); m.p. 233-234 °C. IR (KBr): 3320, 3100, 2943, 1640, 1453 cm-1. 1H NMR (DMSO-d6, 250 MHz) δppm = 0.81
(s, 3H, CH3), 1.19 (br s, 10H, 5CH2), 1.78 (br s, 2H, NCH2CH2), 4.10 (t, J = 5.2 Hz, 2H, NCH2), 7.16 (s, 2H, NH2), 8.13-
13
8.14 (complex, 2H, C(2)-H , C(8)-H of adenine); C NMR (DMSO-d6, 62.5 MHz) δppm = 14.6, 23.3, 29.3, 30.5, 31.3,
33.4, 56.8, 120.9, 141.7, 150.6, 153.7, 158.3. MS (EI): m/z (%) = 247 (17.2) [M+]. Anal. Calc. for C13H21N5: C, 63.13;
H, 8.56; N, 28.31; found: C, 63.25; H, 8.39; N, 28.45.
4.3.4. 9-(2-(4-benzylphenoxy)ethyl)-9H-purin-6-amine (Table 6, entry 2)
Column Chromatography on silica gel eluted with EtOAc afforded pure product as yellow solid (255 mg, 74%);
1
m.p. 201-202 °C. IR (KBr): 3332, 3076, 2929, 1595, 1487, 1045 cm-1. H NMR (DMSO-d6, 250 MHz) δppm = 3.81 (s,
2H, NH2), 4.29 (t, J = 4.9 Hz, 2H, NCH2), 4.49 (t, J = 4.9 Hz, 2H, OCH2), 6.82 (s, 2H, PhCH2), 7.05-7.25 (complex, 10 H,
13
aryl, C(2)-H of adenine), 8.14 (s, 1H, C(8)-H of adenine). C NMR (DMSO-d6, 62.5 MHz) δppm = 40.1, 42.5, 65.6,
114.4, 118.6, 125.8, 128.3, 128.5, 129.6, 133.7, 141.1, 141.6, 149.5, 152.4, 155.9, 156.2. MS (EI): m/z (%) = 345
(15.3) [M+]. Anal. Calc. for C20H19N5O: C, 69.55; H, 5.54; N, 20.28; found: C, 69.38; H, 5.70; N, 20.07.
4.3.5. 6-chloro-9-(4-(4-chlorophenoxy)butyl)-9H-purine (Table 6, entry 6)
Column Chromatography on silica gel eluted with hexane/EtOAc (2:1) afforded pure product as white solid (276
mg, 82%); m.p. 110-111 °C. IR (KBr): 3095, 2947, 1591, 1473, 1045 cm-1. 1H NMR (DMSO-d6, 250 MHz) δppm = 1.61-
1.72 (m, 2H, NCH2CH2), 1.94-2.05 (m, 2H, OCH2CH2), 3.91 (t, J = 6.3 Hz, 2H, NCH2), 4.34 (t, J = 7.0 Hz, 2H, OCH2),
13
6.83-6.89 (complex, 3H, aryl, C(2)-H of purine), 7.21-7.27 (m, 2H, aryl), 8.69 (s, 1H, C(8)-H of purine). C NMR
(DMSO-d6, 62.5 MHz) δppm = 25.6, 25.8, 43.5, 67.1, 116.0, 124.1, 129.1, 130.8, 147.4, 148.9, 151.3, 151.9, 157.2.
MS (EI): m/z (%) = 336 (30.8) [M+]. Anal. Calc. for C15H14Cl2N4O: C, 53.43; H, 4.18; N, 16.62; found: C, 53.28; H,
4.34; N, 16.53.
4.3.6. 2-(5-(1H-imidazol-1-yl)pentyl)isoindoline-1,3-dione (Table 7, entry 3)
Column Chromatography on silica gel eluted with hexane/EtOAc (1:10) afforded pure product as creamy foam
1
(254 mg, 90%). IR (liquid film): 3100, 2952, 1701, 1590, 1532, 1448 cm-1. H NMR (CDCl3, 250 MHz) δppm = 1.19-
12

1.29 (m, 2H, CH2), 1.55-1.66 (m, 2H, CH2), 1.71-1.79 (m, 2H, CH2), 3.55 (t, J = 6.0 Hz, 2H, NCH2), 3.81 (t, J = 6.0 Hz,
2H, NCH2), 6.81 (s, 1H, C(5)-H of imidazole), 6.92 (s, 1H, C(4)-H of imidazole), 7.36 (s, 1H, C(2)-H of imidazole),
13
7.60-7.63 (m, 2H, aryl), 7.71-7.74 (m, 2H, aryl). C NMR (CDCl3, 62.5 MHz) δppm = 25.1, 28.6, 31.4, 42.4, 54.6,
121.2, 127.4, 128.4, 132.9, 133.4, 137.6, 169.1. MS (EI): m/z (%) = 283 (19.8) [M+]. Anal. Calc. for C16H17N3O2: C,
67.83; H, 6.05; N, 14.83; found: C, 67.70; H, 5.91; N, 14.92.
4.3.7. 1-(4-(4-methoxyphenoxy)butyl)-2-phenyl-1H-imidazole (Table 7, entry 4)
Column Chromatography on silica gel eluted with hexane/EtOAc (2:1) afforded pure product as colorless foam
(225 mg, 70%). IR (liquid film): 3065, 2949, 1594, 1471, 1038 cm-1. 1H NMR (CDCl3, 300 MHz) δppm = 1.63-1.70 (m,
2H, NCH2CH2), 1.85-1.95 (m, 2H, OCH2CH2), 3.72 (s, 3H, CH3), 3.76 (t, J = 6.0 Hz, 2H, NCH2), 4.02 (t, J = 7.2 Hz, 2H,
OCH2), 6.70-6.80 (m, 4H, aryl), 7.02 (s, 1H, C(5)-H of imidazole), 7.12 (s, 1H, C(4)-H of imidazole), 7.37-7.39 (m, 3H,
13
aryl), 7.53-7.56 (m, 2H, aryl). C NMR (CDCl3, 75 MHz) δppm = 28.1, 29.1, 46.6, 55.9, 69.3, 115.3, 116.2, 121.5,
127.7, 128.4, 128.9, 129.3, 131.0, 150.4, 154.0, 155.7. MS (EI): m/z (%) = 322 (16.5) [M+]. Anal. Calc. for
C20H22N2O2: C, 74.51; H, 6.88; N, 8.69; found: C, 74.67; H, 6.96; N, 8.58.
Acknowledgments
The authors wish to thank Shiraz University of Technology research council for partial support of this work.
Conflicts of interest
The authors declare that they have no conflict of interest.
A. Supplementary data
Supplementary data associated with this article can be found, in the online version, at https://doi.org/
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Highlights in this current research:
ꢀ
ꢀ
ꢀ
The use of non-toxic and cheap reagents
A triphenylphosphine-free and hence triphenylphosphine oxide-free protocol
The formation of water soluble by-product which in turn makes the reaction work-up and
purification processes more simple and easy
ꢀ
ꢀ
Excellent selectivity towards primary alcohols
Good regioselectivity for both purines and pyrimidines in the case of site of N-alkylation