HMDS/KI a simple, a cheap and efficient catalyst for the one-pot synthesis of N-functionalized pyrimidines

Article abstract of DOI:10.1080/00397911.2019.1602655

The syntheses of N-Alkylpyrimidine derivatives by reacting pyrimidin-2,4-diones with appropriate alkyl halide under microwave irradiation at 400 W were compared to the conventional synthesis route. These methodologies are regioselective and compatible with numerous substrates and furnish the corresponding N-alkylpyrimidines in good yields using a cheap catalyst HMDS/KI in MeCN. A comparison study between these two different modes of heating was investigated.

Full text of DOI:10.1080/00397911.2019.1602655

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
HMDS/KI a simple, a cheap and efficient catalyst
for the one-pot synthesis of N-functionalized
pyrimidines
Az-Eddine El Mansouri, Mohamed Zahouily & Hassan B. Lazrek
To cite this article: Az-Eddine El Mansouri, Mohamed Zahouily & Hassan B. Lazrek (2019):
HMDS/KI a simple, a cheap and efficient catalyst for the one-pot synthesis of N-functionalized
pyrimidines, Synthetic Communications, DOI: 10.1080/00397911.2019.1602655
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https://doi.org/10.1080/00397911.2019.1602655
HMDS/KI a simple, a cheap and efficient catalyst for the
one-pot synthesis of N-functionalized pyrimidines
a,b
a
b
ꢀ
Az-Eddine El Mansouri , Mohamed Zahouily , and Hassan B. Lazrek
a
Laboratoire de Mat ꢀe riaux, Catalyse & Valorisation des Ressources Naturelles, URAC 24, Facult ꢀe des
Sciences et Techniques, Universit ꢀe Hassan II, Casablanca, Morocco; Laboratory of Biomolecular and
b
Medicinal Chemistry, Department of Chemistry, Faculty of Science Semlalia, Marrakech, Morocco
ABSTRACT
ARTICLE HISTORY
The syntheses of N-Alkylpyrimidine derivatives by reacting pyrimidin-
Received 21 January 2019
2
,4-diones with appropriate alkyl halide under microwave irradiation
KEYWORDS
at 400W were compared to the conventional synthesis route. These
methodologies are regioselective and compatible with numerous
substrates and furnish the corresponding N-alkylpyrimidines in good
yields using a cheap catalyst HMDS/KI in MeCN. A comparison study
between these two different modes of heating was investigated.
Hilbert–Johnson reaction;
microwave irradiation;
N-alkylation; pyrimidin-
2
,4-diones
GRAPHICAL ABSTRACT
Introduction
Numerous biologically important small molecules containing pyrimidines (e.g., Uracil,
Thymine, Cytosine, etc.) possess the ability to inhibit vital enzymes responsible for
DNA biosynthesis, such as thymidylate synthase, thymidine phosphorylase, and reverse
transcriptase. Most of the antiviral compounds that are currently used in the treatment
of the herpes simplex virus (HSV), human immunodeficiency virus (HIV), hepatitis B
CONTACT Mohamed Zahouily
mzahouily@gmail.com;
Laboratoire de Mat ꢀe riaux, Catalyse & Valorisation des
Ressources Naturelles, URAC 24, Facult ꢀe des Sciences et Techniques, Universit ꢀe Hassan II, Casablanca, 20650, Morocco
BP146; Hassan B. Lazrek
hblazrek50@gmail.com
Department of Chemistry, Faculty of Science Semlalia,
Marrakech, Morocco.
ꢀ
Present address: MAScIR Foundation, Nanotechnologie, VARENA Center, Rabat Design, Rue Mohamed El Jazouli,
Madinat El Irfane, 10100 Rabat, Morocco.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental data for this article is available online at on the publisher’s website.
ß 2019 Taylor & Francis Group, LLC

2
A.-E. EL MANSOURI ET AL.
Scheme 1. Usual classical heating conditions of Hilbert–Johnson reaction.
virus (HBV), varicella zoster virus (VZV), and cytomegalovirus (CMV) infections can
[
1]
be described as acyclic nucleoside or nucleotide analogs.
The reported synthesis methods of acyclic nucleoside analogs involve alkylation of
purine or pyrimidine bases with various alkylating agents. The most frequently used
[
2]
[3]
alkylating agents are halogenated compounds. Some alkylating agents are mesylate
[
4]
or tosylate. The coupling reaction at one of the nitrogen atoms in the pyrimidine is
the most effective method for introducing certain substituent with desired functional-
ities into the heterocyclic base. Furthermore, Peptide Nucleic Acids (PNAs) are
oligonucleotide analogs in which the sugar-phosphate backbone is replaced by a N-(2-
amino-ethyl) glycine unit leading to polyamide oligomers, PNA has attracted wide
attention in medicinal chemistry for the development of gene therapy drugs or molecu-
lar probes. N -alkylation of nucleobases affords the important building blocks for PNAs,
1
[
5]
which have been widely described in the literature. For this purpose, several bases,
such as potassium fluoride
[
5b]
[6]
potassium carbonate, in DMF, Et N/DMF
or in
3
[
7]
DMSO have been used. These methods using basic medium are often associated with
one or more of the following drawbacks: (i) the use of DMF or DMSO as solvent with
cumbersome workup of the reaction mixture (ii) low yields and (iii) harsh conditions of
work up. The other promising method for the synthesis of N-alkyl pyrimidine under
milder conditions is the use of Hilbert–Johnson-type reaction (Scheme 1). Moreover,
The improved silyl-Hilbert–Johnson reaction, the most widely used synthetic method,
involves the coupling of per-silylated heterocyclic bases with per-acylated sugars or alky-
[
8]
lating agents in the presence of Friedel-Crafts catalysts (e.g., SnCl , TMSOTf and
4
[
9]
(
CH ) SiI) (Scheme 1).
3 3
[
10]
Microwave Assisted Organic Synthesis (MAOS)
has been widely applied in hetero-
[
11]
cyclic chemistry especially in the synthesis of nucleosides and acyclonucleosides . The
combination of microwave irradiation with the use of catalysts provides chemical proc-
esses with special attributes, such as enhanced reaction rates, higher yields, better activ-
[
12]
ity, and improved ease of manipulation.
This reaction has been the dominant
method for the preparation of pyrimidine, purine and other heterocyclic nucleoside ana-
logs. On the other hand, potassium iodide (KI) as abundant, green, and inexpensive
alkali metal halide is a better choice due to the leaving ability of halide anion
–
–
–
＋
þ
þ
(
I > Br > Cl ) and alkali metal cation (K > Na > Li ), which is dominant for the
[
13]
catalytic activity.
reaction such as O-alkylation
For these reasons potassium iodide has been used in the alkylation
[
14]
[15,16]
and N-alkylation.
We present here a new application of the HMDS/KI for the catalysis of the synthesis of
N-alkylpyrimidine derivatives by reacting pyrimidines with appropriate alkyl halide in
MeCN under conventional heating (Method A) and/or under microwave irradiation

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Table 1. Optimal conditions for N-alkylation of uracil by ethyl bromoacetate using conven-
a
tional heating .
b
Entry
Ethyl bromoacetate (eq)
KI (eq)
Time (h)
Solvent
Yield (%)
1
2
3
4
5
6
7
a
1
1
1.5
2
2
–
0.5
0.5
0.5
0.25
–
12
12
12
5
5
5
CH
CH
CH
CH
CH
CH
3
3
3
3
3
3
CN
CN
CN
CN
CN
CN
54
68
82
94
83
62
89
2
2
0.5
5
2 2
ClCH CH Cl
ꢁ
Reaction Conditions: (1) 1a (1 mmol), (NH
Acetonitrile (2.5 ml), Temp: 80 C.
4
)
2
SO
4
(0.1 mmol), HMDS (1.5 ml), 120 C, 3 h. (2) 2a (2 mmol), KI (0.5 mmol),
ꢁ
b
Isolated yield.
(Method B). Thus, we have conducted several experiments to identify and optimize the
effect of the process parameters involved in the development of a slightly modified proced-
[
17]
ure of Hilbert–Johnson reaction using a catalytic amount of HMDS/KI
in acetonitrile.
Results and discussion
In order to optimize the reaction conditions of silyl-Hilbert–Johnson reaction (Table 1),
the reaction of uracil 1a with bromo-ethyl acetate 2a was studied as a model reaction.
To achieve this, we started by investigating the optimum conditions in detail by varying
several parameters such as the used catalyst (KI), the choice of solvent and the amount
of alkylating agent. The findings are described in Table 1. Initially, we developed a
control reaction without KI as catalyst; in the first step we prepared the silylated uracil
ꢁ
in-situ by heating the mixture of uracil, HMDS and ammonium sulfate at 120 C for
3
h. Then, one equivalent of ethyl bromoacetate in acetonitrile was added in the second
step (Table 1, entry 1). The product 3a was obtained in 54% yield. Thereafter, when
potassium iodide (0.5 equiv) was added in the second step the yield increased to 68%
(entry 2). Then, the effect of the amount (weight) of the alkylating agent (1, 1.5, 2
equiv) on reaction yield was investigated. The best yield was obtained using 2 equiva-
lents of alkylating agents, and the pure desired 3a was obtained in 94% yield.
Finally, we studied the effect of potassium iodide (KI), when the amount of KI
increases from 0, 0.25, and 0.5 equivalents the yield increased from 62% to reach 83%
and 94% respectively (Table 1, entries 6, 5, 4). On the other hand, many attempts have
been conducted with an aim to compare the catalytic activity of KI with others iodides.
The reaction was carried out using different catalyst such as Bu NI, CuI and NaI. The
4
obtained yields are 73, 78 and 84% respectively. It has been found that KI was the most
suitable catalyst for the modified Hilbert–Johnson reaction for N-Alkylation of
[
18]
pyrimidine.

4
A.-E. EL MANSOURI ET AL.
Table 2. Results of N-alkylation of pyrimidines (1a–c) by different alkylating agents (2a–c).
3
c, 12h, 89%
3
b, 12h, 61%
3
a, 5h, 94%
3d, 5h, 92%
3h, 12h, 78%
3l, 12h, 73%
3f, 12h, 94%
3e, 12h, 78%
3g, 12h, 96%
3i, 12h, 77%
3j, 12h, 78%
3k, 12h, 77%
3m, 12h, 76%
The optimal conditions (Table 1, entry 4) were generalized by changing the alkylating
agents and the nucleobases to obtain the N1-alkylated pyrimidines in a moderate to a
good yield. When Ethyl Bromoacetate was used as a reagent, the N1-alkylated uracil,
thymine and cytosine (3a, 3d, 3g) were obtained with excellent yields within only 5 h
(Table 2, entries 1, 4, and 7). When the bromoacetonitrile and the propargyl bromide
were used, we noticed that the reaction time increased from 5 to 12 h and the yield

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Table 3. Comparison of N-alkylation conditions with literature.
Time (h)
Yield (%)
Entry
Product
In this work
Literature
13
In this work
Literature
[
19]
1
2
3
3a
3a
3b
5
5
12
94
94
61
60
92[19]
[
1]
[1]
20[
19]
73
66
a
Table 4. Conditions survey for N-alkylation of uracil by ethyl bromoacetate using MW .
c
Entry
2a (equi)
Catalyst KI (equi)
First step time (min)
Second step time (min)
Yield (%)
1
2
3
4
5
6
a
2
2
1.2
1.2
1.2
1.2
0.5
0
0.5
0.5
0.5
0.5
10
10
10
5
5
20
87
60
75
59
88
88
b
b
b
20
30
40
Reaction conditions one-pot: Uracil (1 mmol), alkylating agent (1.2 mmol), HMDS (1 ml), KI (0.5 mmol), CH
time (30 min).
3
CN (4 ml),
b
All the reagents have been mixed in the beginning of the reaction (one-step reaction).
c
Isolated yield.
decreased especially for Bromoacetonitrile (Table 2, compounds: 3b, 3e). Moreover, the
introduction of halogen in C or nitrogen in the position C of the nucleobase had a
5
6
negative effect on the reaction time and yields (Table 2). It should be noted that no
reaction occurred when alkyl halides were used, for instance Br–CH –CH –CO Et,
2
2
2
or Br–CH –CH –CN.
2
2
As shown in Table 3, the obtained yields at variable reaction times in this study were
compared with those published in the literature. For instance, the reaction time was
[
19]
reduced for N-alkylation of uracil using Ethyl bromoacetate from 13 h to 5 h
from 20 h to 5 h, while improving the yield of the reaction.
and
[
1]
The influence of the use of microwave activation on the parameters of the silyl-
Hilbert–Johnson reaction was investigated. In the first three experiments, the reaction
was carried out in two steps. First, the silylated thymine in-situ was prepared by irradi-
ating the mixture of thymine, HMDS, and ammonium sulfate in acetonitrile. Then, in
the second step two equivalents of ethyl bromoacetate and 0.5 equivalent of potassium
iodide was added, and the mixture was irradiated for 5 minutes to give product 3d with
a yield of 87% (Table 4, entry 1). In addition, the same reaction was carried out without
using potassium iodide, in this case, the yield decreased from 87% to 66% (Table 4,
entries 1 and 2). Moreover, the effect of the quantity of ethyl bromoacetate was studied
by decreasing it from 2 to1.2 equivalents (Table 4, entries 1 and 3). Thereafter, ethyl
bromacetate and potassium iodide were added from the beginning to obtain the acyclo-
nucleoside 3d in 59%. Next, the same reaction (one-pot) was carried out in 30 min

6
A.-E. EL MANSOURI ET AL.
Table 5. Results of N-alkylation of pyrimidines by ethyl bromoacetate using MW.
3a, 87%
3d, 88%
3g, 87%
3j, 18%
a
Table 6. Optimal conditions for N-alkylation of 5-bromouracil 1f by ethyl bromoacetate using MW .
b
Entry
Alkylating Agent
Time (min)
Yield (%)
1
2
3
4
5
a
1.2
1.2
1.2
1.5
2
30
40
60
60
60
18
34
41
50
62
3
Reaction conditions: 1f (1 mmol), 2a (2 mmol), HMDS (1 ml), KI (0.5 mmol), CH CN (4 ml), time (60 min).
b
Isolated yield.
instead of 20 min to lead to 3d in 88% yield. Finally, the reaction time was increased to
40 min without any significant change in the reaction yield.
The conditions (Table 4, entry 5) were generalized by changing the nucleobases. The
N-alkylation of uracil, thymine and cytosine by ethyl bromoacetate provided the corre-
sponding products 3a, 3d and 3 g with excellent yields (Table 5, entries 1, 2, 3). When
the 5-bromouracil was used as a nucleobase the product 3j was prepared only
with 18%.
In order to optimize the N-alkylation of 5-bromouracil using ethyl bromoacetate, the
effect of reaction time and the number of equivalents of alkylating agent were studied.
The results are shown in Table 6. Initially, the reaction time was optimized to 60 min
(Table 6, entry 3). Then, two equivalents of ethyl bromoacetate was used to give the

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Table 7. Results of N-alkylation of 5-halogenouracils and 6-azapyrimidines by 2a using MW.
3
3
h, 12h, 59%
k, 12h, 50%
3i, 12h, 57%
3l, 12h, 57%
3j, 12h, 62%
3m, 12h, 84%
corresponding product 3j in 62%. With these optimized conditions in hand (Table 6,
entry 4), the outcome of N-alkylation of 5-halogenouracils and 6-azapyrimidines was
investigated. As can be seen in Table 7, the N-alkylation of 5-halogenouracils and 1,2,4-
triazines (6-aza-pyrimidines) was studied with ethyl-bromoacetate using MW activation
(one–pot reaction) the products (3h–l) were obtained in moderate to good yields.
Moreover, taking into account the low reactivity of bromoacetonitrile and propargyl
bromide we have chosen to use 1.5 equivalent of alkyl bromide. The results are sum-
marized in the Table 8. The yield of the reactions was in general excellent for the N-
alkylation of uracil. In addition, a wide range of nucleoside analogs could be prepared
[
6c]
using N-alkylated pyrimidines 3, for instance 1, 2, 3-triazolyl,
1, 3, 4 and 1, 2, 4-
Oxadiazolyl nucleoside analogs.
Experimental
Typical experimental procedure for the reaction of various pyrimidines and alkyl
bromides using conventional heating
A mixture of uracil (1 mmol, 112 mg) and ammonium sulfate (0.10mmol) in HMDS
(
(
1.5 ml) was refluxed until clear solution was obtained (3h). Then bromo-ethylacetate
2 mmol, 0.22ml), KI (0.5mmol, 83 mg) and acetonitrile (2.5ml) were added. Reaction
ꢁ
mixture was heated at 90 C for 5 h. After completion of the reaction (monitored by
TLC), the reaction mixture was diluted with dichloromethane and evaporated to dry-
ness. The residue was purified by flash chromatography eluting with MeOH/dichloro-
methane (1:10).

8
A.-E. EL MANSOURI ET AL.
Table 8. Results of N-alkylation of uracil and thymine by 2b or 2c using MW.
3
b, 56%
3c, 85%
3e, 85%
3f, 83%
Typical experimental procedure for the reaction of various pyrimidines and alkyl
bromides using Microwave irradiation
Uracil (0.5 mmol), ammonium sulfate (5 mg), potassium iodide (0.25 mmol, 41 mg),
acetonitrile (2 ml), hexamethyldisilazane (0.5ml) and Ethyl bromoacetate (1.2 mmol)
ꢁ
were mixed into a pressure-resistant closed vessel and heated at 120 C (400W) for
30–60 minutes in a professional microwave. Then the mixture cooled, treated with
methanol and evaporated under reduced pressure. The residue was purified by flash
chromatography using a mixture of methanol/dichloromethane as eluting to obtain the
corresponding N-1 alkylated pyrimidines 3a, m.
Conclusions
In conclusion, the comparison of the results of N-alkylation of pyrimidine with appro-
priate alkyl halide (ethyl bromoacetate, propargyl bromide, bromo acetonitrile), using
HMDS/KI as catalyst, under microwave irradiation (MWI) and conventional method
shows that both methods gave higher yields in shorter time for MWI without the for-
mation of by-products such as oxygen atom alkylation and bis N and N alkylation. All
1
3
prepared N-alkylated pyrimidines are of potential practical interest in the PNA
series and used as a starting material for the synthesis of 1,2,3-triazolyl, 1, 3, 4 and 1, 2,
4
-oxadiazolyl nucleoside analogs.
Additional information associated with this article can be found in the
Supplementary material.
Acknowledgments
th
This paper is dedicated to the memory of Professor J. L. Imbach deceased on 8 April 2018. The
authors would like to thank Professor Marcus Wright (Wake Forest University, North Carolina,
USA) for technical assistance, also the technical staff of the CAC (Centre of Analysis and
Characterization) University Cadi Ayyad for running the spectroscopic analysis, and Faculty of
Sciences and Technologies Mohammedia, University Hassan II Casablanca.

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Disclosure statement
The authors declare no competing financial interest.
Funding
This work was supported by the university Cadi Ayyad Marrakech and the University Hassan
II Casablanca
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