A highly facile approach to the synthesis of novel 2-(3-benzyl-2,4-dioxo-1, 2,3,4-tetrahydropyrimidin-1-yl)-N-phenylacetamides

Article abstract of DOI:10.1016/j.tetlet.2012.11.090

A series of heterocyclic compounds were designed as potential nonnucleoside HIV reverse transcriptase inhibitors. Although the compounds ultimately proved inactive against HIV, during the course of the synthesis, a new and highly facile method to realize N-phenylacetamides was developed. Notably, the new route avoids the intractable workups and byproducts previously reported procedures have been associated with, thereby making this approach highly attractive to adaptation with other heterocyclics.

Full text of DOI:10.1016/j.tetlet.2012.11.090

Tetrahedron Letters xxx (2012) xxx–xxx
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Tetrahedron Letters
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A highly facile approach to the synthesis of novel
2-(3-benzyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)-N-phenylacetamides
Mikhail S. Novikov a, Denis A. Babkov a, Maria P. Paramonova a, Alexander O. Chizhov b,
Anastasia L. Khandazhinskaya c, Katherine L. Seley-Radtke d,
⇑
a Department of Pharmaceutical & Toxicological Chemistry, Volgograd State Medical University, PavshikhBortsov Sq., 1, Volgograd 400131, Russia
b Zelinsky Institute of Organic Chemistry, Russian Academy of Science, Leninsky pr., 47, Moscow 119991, Russia
c Engelhardt Institute of Molecular Biology, Russian Academy of Science, Vavilov Str., 32, Moscow 119991, Russia
d Department of Chemistry & Biochemistry, University of Maryland, Baltimore County, 1000 Hilltop Circle, Baltimore, MD 21250, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of heterocyclic compounds were designed as potential nonnucleoside HIV reverse transcriptase
inhibitors. Although the compounds ultimately proved inactive against HIV, during the course of the syn-
thesis, a new and highly facile method to realize N-phenylacetamides was developed. Notably, the new
route avoids the intractable workups and byproducts previously reported procedures have been associ-
ated with, thereby making this approach highly attractive to adaptation with other heterocyclics.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 5 November 2012
Revised 17 November 2012
Accepted 21 November 2012
Available online xxxx
Keywords:
Heterocycles
NNRTI
Heteroaromatic
Pyrimidines
As
a
part of our ongoing efforts to synthesize aryl and
other references describe condensation promoted by triethylamine
in acetic acid.9 Examples of aniline acylation in acetate buffer10 and
aqueous K2CO311 are also known, while another approach proposes
the synthesis of 2-chloroacetanilides in base-free conditions. In the
latter case, the reaction takes place in nonpolar solvent12 or in a
mixed solvent system.13 Although there are many options avail-
able, it is important to note that most of these methods suffer from
numerous side reactions arising from either N-quaternization of
the organic base or hydrolysis, which lead to low yields and te-
dious work-up procedures.
It has however, been shown that amide bond formation could
be achieved by the cleavage of the silicon–nitrogen bonds in
TMS-protected alkylamines and anilines by acid halides.14 The
absence of a base renders the silyl method very attractive for the
synthesis of 2-chloroacetanilides, as this serves to bypass the prob-
lems with side reactions such as quaternization and hydrolysis that
are common with the aforementioned routes. Surprisingly, there
was no information in the literature for the preparation of 2-chlo-
roacetanilides that utilized the silyl methodology. As a result, we
have now employed this approach to synthesize a series of 2-chlo-
roacetanilides, as shown in Scheme 1, which were then used for
the synthesis of the desired NNRTIs.
heteroaromatic nonnucleoside HIV reverse transcriptase inhibitors
(NNRTIs), we sought to construct a new series of N-3 phenylaceta-
mides for use in alkylating various uracils. The amide unit is one of
the most important and widely occurring functional groups; it is
present in many natural products and is a key feature of many
important drugs. Among the more notable examples of amide-
containing compounds, those found in conjunction with N-hetero-
cycles exhibit diverse and marked pharmacological activities. In
particular, the HIV-1 NNRTIs,1 dihydrofolate reductase (DHFR)
inhibitors,2 and histone deacetylase (HDAC) inhibitors stand out.3
It is not surprising therefore that there are numerous papers in
which amide bond formation has been described.4 Despite the
plethora of available routes, most are plagued with problems, in
particular, low yields and difficult workups. As a result, a new and
more facile route was sought.
A preliminary search of the literature revealed several known
methods for the formation of 2-chloroacetanilides. The most com-
monly used methodology involves condensation of chloroacetyl
chloride with various anilines in aprotic solvents (e.g. ether, diox-
ane, chloroform, dichloromethane, ethyl acetate, or DMF) in the
presence of anhydrous K2CO3,5 triethylamine6 or pyridine7 as the
base. Another variant utilizes methylethylketone and CaCO38 while
As shown in Scheme 1, the starting anilines were converted into
N-trimethylsilyl derivatives by refluxing in excess HMDS to form
the N-silylated intermediates, followed by treatment with chloro-
acetyl chloride in anhydrous 1,2-dichloroethane to produce target
⇑
Corresponding author. Tel.: +1 410 455 8684 (O); fax: +1 410 455 2608.
E-mail address: kseley@umbc.edu (K.L. Seley-Radtke).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.11.090
Please cite this article in press as: Novikov, M. S.; et al. Tetrahedron Lett. (2012), http://dx.doi.org/10.1016/j.tetlet.2012.11.090

2
M. S. Novikov et al. / Tetrahedron Letters xxx (2012) xxx–xxx
Cl
O
Cl
H
N
SiMe3
NH
HMDS
H
NH2
O
Cl
NH
N
R
Cl
R
O
R
R
O
1,2-Dichloro-
ethane
N
O
6
13
-
K2CO3, DMF
1
5
-
R1
Scheme 1. Proposed pathway to 2-chloroacetanilides.
14
1 - 5
Scheme 2. Synthesis of target uracil derivatives.
Table 1
Physical properties of 2-chloroacetanilides
of them proved to be active against any of the strains tested includ-
ing HIV-1, HIV-2, HSV-1, HSV-2, HCMV, VZV, Vaccinia virus, Para-
influenza-3 virus, Reovirus-1, Sindbis virus, Vesicular stomatitis
virus, Respiratory syncytial virus, Coxsackie virus B4 or Feline Cor-
ona Virus.20,21
In summary, while the target NNRTIs synthesized proved inac-
tive, a facile and high-yielding route to N-phenylacetamides was
developed, which should prove useful for many synthetic applica-
tions employing heterocyclic amides.
H
N
Cl
R
O
Compd
R
Rfa
Yield (%)
Mp (°C)
1
2
3
4
5
H
0.70
0.60
0.67
0.71
0.73
82
86
87
97
98
135–136.5
111.5–113
163–165
110–112
143–145
2-Me
4-Me
3,4-Me2
3,5-Me2
a
Ethyl acetate/hexane 1:1.
Acknowledgments
This work was supported by the Russian Foundation for Basic
Research (Grant 10-04-0056a). The authors would like to thank
Professor Jan Balzarini of the Rega Institute for antiviral evaluation
of synthesized compounds.
Table 2
Physical properties of 2-(1-benzyluracil-3-yl)-N-phenylacetamides
O
N
O
N
O
N
H
N
H
N
H
N
H
3C
N
N
Supplementary data
N
R
O
O
O
O
O
O
Supplementary data (specific experimental details for each of
the target compounds including 1H and 13C NMR data) associated
with this article can be found, in the online version, at http://
dx.doi.org/10.1016/j.tetlet.2012.11.090.
R1
6-13
15
16
Compd
R1
R
Rfa
Yield (%)
Mp (°C)
References and notes
6
7
8
9
10
11
12
13
15
16
H
H
H
H
H
0.57
0.65
0.61
0.63
0.48
0.59
0.56
0.64
0.71
0.78
96
90
84
90
84
83
78
87
90
96
212–213
175–176.5
248–250
219–220
201–202
221–222
222.5–224
214–215
197.5–198.5
125–127
2,5-Me2
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3,5-Me2
4-tBu
H
2-Me
4-Me
3,4-Me2
3,5-Me2
—
H
H
H
—
—
—
a
Ethyl acetate/1,2-dichloroethane 1:1.
amides 1–5 in 82–98% yield (Table 1).15 Notably, this occurred
without any of the tar-like by-products typically observed with
these reactions.
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The target 2-(1-benzyluracil-3-yl)-N-phenylacetamides 6–13
were then obtained in excellent to almost quantitative yields
(78–96%, see Table 2) by alkylation of 1-benzyluracils16 14 with
the appropriate 2-chloroacetanilides 1–5 in the presence of a 1.5-
fold molar excess of K2CO3 in DMF as shown in Scheme 2.17
In an analogous fashion, N-phenylacetamides 15 and 16 were
synthesized starting with 1-benzylthymine18 and 1-(benzhy-
dryl)uracil,19 respectively. It should be noted that all the com-
pounds were obtained without suffering the intractable workups
or side products the typical procedures have been associated with,
thereby making this approach highly attractive to adaptation with
other heterocyclic compounds.
ˇ
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Compounds 6–13, 15, and 16 were evaluated as inhibitors
against a large set of DNA and RNA viruses. Disappointingly, none
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M. S. Novikov et al. / Tetrahedron Letters xxx (2012) xxx–xxx
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20. The methodology of the anti-HIV assays in MT-4 cell cultures was as follows: Virus
stocks were titrated in MT-4 cells and expressed as the 50% cell culture
infective dose (CCID50). MT-4 cells were suspended in culture medium at
1 Â 105 cells/ml and infected with HIV at a multiplicity of infection of 0.02.
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Immediately after viral infection, 100 ll of the cell suspension was placed in
each well of a flat-bottomed microtiter tray containing various concentrations
of the test compounds. After 4 days of incubation at 37°C, the number of
viable cells was determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-
diphenyltetrazolium bromide (MTT) method. The selection and
characterization of mutant virus strains have been performed previously.
21. The compounds were evaluated against the following viruses: Herpes simplex
virus type 1 (HSV-1) strain KOS, thymidine kinase-deficient (TKÀ) HSV-1 KOS
strain resistant to ACV (ACVr), herpes simplex virus type 2 (HSV-2) strains
Lyons and G, varicella-zoster virus (VZV) strain Oka, TKÀ VZV strain 07À1,
human cytomegalovirus (HCMV) strains AD-169 and Davis, vaccinia virus
Lederle strain, respiratory syncytial virus (RSV) strain Long, vesicular
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15. General method for synthesis of 2-chloro-N-phenylacetamides 1–5. A mixture of
16.50 mmol of aniline, 20 mL of HMDS and NH4Cl (250 mg) was refluxed for
10 h until
a homogeneous solution was obtained. Excess of HMDS was
removed under reduced pressure, and the residual clear oil dissolved in 40 mL
of anhydrous 1,2-dichloroethane. A solution of chloroacetyl chloride (1.4 ml,
17.60 mmol) in 1,2-dichloroethane (10 mL) was added dropwise with stirring
at 0 °C. The reaction mixture was stirred overnight at rt and then evaporated to
1/3 volume. Hexane (30 mL) was added and the mixture was kept overnight in
a refrigerator. The resulting precipitate was filtered and recrystallized from
EtOAc/hexane.
stomatitis virus (VSV), Coxsackie B4, Parainfluenza 3, Influenza virus
A
(subtypes H1N1, H3N2), influenza virus B, Reovirus-1, Sindbis and Punta
Toro. The antiviral assays were based on the inhibition of virus-induced
cytopathicity or plaque formation in human embryonic lung (HEL) fibroblasts,
African green monkey cells (Vero), human epithelial cells (HeLa) or Madin-
Darby canine kidney cells (MDCK). Confluent cell cultures in microtiter 96-well
plates were inoculated with 100 CCID50 of virus (1 CCID50 being the virus dose
to infect 50% of the cell cultures) or with 20 plaque forming units (PFU) (VZV)
in the presence of varying concentrations of the test compounds. Viral
cytopathicity or plaque formation was recorded as soon as it reached
completion in the control virus-infected cell cultures that were not treated
with the test compounds. Antiviral activity was expressed as the EC50 or
compound concentration required to reduce virus-induced cytopathogenicity
or viral plaque formation by 50%.
16. Kundu, N. G.; Sikdar, S.; Hertzberg, R. P.; Schmitz, S. A.; Khatri, S. G. Perkin
Trans. 1 1985, 1295–1300.
17. General method for the synthesis of 2-(3-benzyl-2,4-dioxo-1,2,3,4-
tetrahydropyrimidin-1-yl)-N-phenylacetamides 6–13, 15 and 16. A suspension
of 7.72 mmol of 1-benzyluracil16 14, 1-benzylthymine18 or 1-
(diphenylmethyl)uracil19 and K2CO3 (1.6 g, 11.58 mmol) in 15 mL of DMF
was stirred at 80 °C for 1 h then cooled to rt. After addition of 2-
chloroacetanilide 1–5 (7.66 mmol), the reaction mixture was stirred for 2 h,
chilled overnight, filtered and the solvent removed under reduced pressure.
The residue was treated with 50 mL of water, and the resulting precipitate
filtered and recrystallized from a mixture of acetone-iPrOH-DMF.
Please cite this article in press as: Novikov, M. S.; et al. Tetrahedron Lett. (2012), http://dx.doi.org/10.1016/j.tetlet.2012.11.090