An efficient and simple methodology for the synthesis of 2-amino-4-(N-alkyl/arylamino)-6-chloropyrimidines

Article abstract of DOI:10.1016/j.tetlet.2015.01.153

In this study, twenty-nine 2-aminopyrimidine derivatives are synthesized in good to excellent yields by fusing 2-amino-4,6-dichloropyrimidine with different amines in the presence of triethylamine without using any solvent or catalyst. Nucleophilic substitution reactions of 2-amino-4,6-dichloropyrimidine with amines have also been performed in ethanol. Comparisons of the yields and reaction times for both solvent and solvent-free conditions have shown that the newly developed solvent-free protocol is high yielding, more efficient, and simpler compared to conventional methods.

Full text of DOI:10.1016/j.tetlet.2015.01.153

Accepted Manuscript
An efficient and simple methodology for the synthesis of 2-amino-4-(N-alkyl/
arylamino)-6-chloropyrimidines
Khalid Mohammed Khan, Sarosh Iqbal, Muhammad Arslan Bashir, Nida
Ambreen, Shahnaz Perveen, Volfgang Voelter
PII:
S0040-4039(15)00191-4
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.01.153
TETL 45823
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
18 July 2014
28 December 2014
22 January 2015
Please cite this article as: Khan, K.M., Iqbal, S., Bashir, M.A., Ambreen, N., Perveen, S., Voelter, V., An efficient
and simple methodology for the synthesis of 2-amino-4-(N-alkyl/arylamino)-6-chloropyrimidines, Tetrahedron
Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.01.153
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Graphical Abstract
An efficient and simple methodology for the synthesis
of 2-amino-4-(N-alkyl/arylamino)-6-chloropyrimidines
Khalid Mohammed Khan, Sarosh Iqbal, Muhammad Arslan Bashir, Nida Ambreen, Shahnaz Perveen, Wolfgang
Voelter

1
Tetrahedron Letters
journal homepage: www.elsevier.com
An efficient and simple methodology for the synthesis of 2-amino-4-(N-
alkyl/arylamino)-6-chloropyrimidines
Khalid Mohammed Khana,, Sarosh Iqbala, Muhammad Arslan Bashira, Nida Ambreena, Shahnaz Perveenb,
Volfgang Voelterc
a
H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi-75270, Pakistan
b
PCSIR Laboratories Complex, Karachi, Shahrah-e-Dr. Salimuzzaman Siddiqui, Karachi-75280, Pakistan
c
Interfakultäres Institut für Biochemie, Universität Tübingen, Hoppe-Seyler-Str. 4, D-72076 Tübingen, Germany
ARTICLE INFO
ABSTRACT
In this study, twenty-nine 2-aminopyrimidine derivatives are synthesized in good to excellent
yields by fusing 2-amino-4,6-dichloropyrimidine with different amines in the presence of
triethylamine without using any solvent or catalyst. Nucleophilic substitution reactions of 2-
amino-4,6-dichloropyrimidine with amines have also been performed in ethanol. Comparisons
of the yields and reaction times for both solvent and solvent-free conditions have shown that the
newly developed solvent-free protocol is high yielding, more efficient, and simpler compared to
conventional methods.
Article history:
Received
Received in revised form
Accepted
Available online
Keywords:
2-Amino-4,6-dichloropyrimidine
Dimethylmalonate
2009 Elsevier Ltd. All rights reserved.
Guanidine hydrochloride
Heterocycles
Nucleophilic substitution
Among
heterocycles,
pyrimidines
constitute
a
intermediates. Some of these methods suffer from shortcomings
such as tedious work-ups, low yields, the use of expensive and
uncommon starting materials or catalysts, and non-eco-friendly
solvents. Consequently, simpler, high yielding, and efficient
approaches towards this valuable nucleus are still desirable.
pharmaceutically important nucleus which is the key constituent
of a variety of bioactive compounds available by synthesis or
from Nature, and are often of considerable complexity.1-9 Amino-
and imino-pyrimidines are constituents of various biological
systems and play a significant role in many biological processes.
They are constituents of DNA, RNA, B group vitamins,
antibiotics, and vessel-expanding medicines, and correct heart
action and stimulate metabolic processes.10-14
We have developed a new and rapid route for the synthesis of
substituted pyrimidine derivatives, i.e., 2-amino-4-(N-
alkyl/arylamino)-6-chloropyrimidines, without using any solvent
or catalyst and starting from 2-amino-4,6-dichloropyrimidine,
which was in turn synthesized from cheap and commercially
available starting materials: guanidine hydrochloride and
dimethyl malonate in the presence of sodium methoxide. 2-
Therefore, syntheses of highly substituted pyrimidine rings
have attracted significant attention from organic chemists. A
number of protocols have been developed for the synthesis of
substituted pyrimidines either by using a variety of substituted
starting materials, or by substitution on newly synthesized
pyrimidine rings. These procedures include condensation of
cyanic acid with N-vinyl or N-arylamides in the presence of 2-
chloropyridine and trifluoromethanesulfonic anhydride,15
coupling of enamines, triethyl orthoformate and ammonium
acetate using ZnCl2 as the catalyst,16 organolithium-promoted
three-component approaches,17,18 copper iodide and PdCl2(PPh3)
mediated substitutions on pyrimidine rings,19,20 etc. Moreover,
nucleophilic substitution of 2-amino-4,6-dichloropyrimidine
leads to the formation of several complex structures, for example,
7-deazaguanine-based urea (DeUG)21 and pteridines22 have been
by using 2-amino-4,6-dichloropyrimidines as
Amino-4-(N-alkyl/arylamino)-6-chloropyrimidine
derivatives
were also synthesized using ethanol as the solvent to compare the
yields and reaction times of both strategies (see Figures 2 and 3).
2-Amino-4-(N-alkyl/arylamino)-6-chloropyrimidine derivatives
3-31 were synthesized in high yields in a three-step sequence.
Firstly, commercially available guanidine hydrochloride and
dimethyl malonate were reacted in the presence of sodium
methoxide to yield 2-amino-4,6-dihydroxypyrimidine (1). This
was then converted into 2-amino-4,6-dichloropyrimidine (2) on
treatment with POCl3 in the presence of N,N-dimethylaniline.
Subsequently,
a range of 2-amino-4-(N-alkyl/arylamino)-6-
chloropyrimidine derivatives 3-31 was synthesized by
nucleophilic substitution of 2-amino-4,6-dichloropyrimidine (2)
s—yn—the—sized
 Corresponding author. Tel.: 0092-21-34824910; fax: 0092-21-34819018; e-mail: khalid.khan@iccs.edu

2
Tetrahedron Letters
with substituted amines in the presence of triethylamine under
spectroscopy and by mass spectrometry.24 The structures of the
synthesized pyrimidine derivatives are shown in Table 1. Of the
solvent-free conditions23 (Scheme 1). The structures of the
compounds synthesized were confirmed by H and 13C NMR
twenty-nine
synthesized
2-amino-4-(N-alkyl/arylamino)-6-
1
chloropyrimidine derivatives, compounds 4, 5, 7–12, 14, 17–22,
24 and 26, are novel.
Scheme 1: Synthesis of 2-amino-4-(N-alkyl/arylamino)-6-chloropyrimidine derivatives
Table 1: Structures of the 2-amino-4-(N-alkyl/arylamino)-6-chloropyrimidine derivatives 3-31
Mp
(C)
Mp
(C)
Mp
(C)
Product
R
Product
R
Product
R
175-
177
190-
192
178-
180
325
1325
2325
240-
242
180-
182
172-
174
4
5
14
24
178-
180
182-
184
1526
2527
>300
222-
223
177-
179
200-
202
625
1625
26
182-
184
250-
252
210-
212
2728
7
8
17
18
245-
247
170-
172
140-
142
2828

3
185-
187
176-
178
255-
257
2929
3030
3131
-
9
19
20
21
22
185-
187
173-
175
257-
258
10
11
12
180-
182
175-
177
116-
118
175-
177
178-
180
-
-
During the course of this work, we observed that 2-
nitroaniline did not undergo the nucleophilic substitution reaction
with 2-amino-4,6-dichloropyrimidine, and we assumed that this
may have been due to the electron-withdrawing nature of the
nitro group, which decreases the nucleophilicity of the amino
group in nitroaniline. In order to confirm our hypothesis, we
performed reactions with other anilines possessing electron-
withdrawing substituents. We observed that all the nitro- and
carboxyl group containing anilines examined failed to produce
the required product. In the case of halogen-substituted
compounds, we discovered the following behavior of the
differently substituted haloanilines: 2-chloro-, 2-bromo-, and 2-
iodoanilines did not undergo any reaction, however, 3-bromo-, 4-
bromo-, 3-chloro-, 4-chloro-, and 4-iodo- gave the expected
products in satisfactory yields.
This interesting situation set a new direction to our research:
we assumed that 2-chloro-, 2-bromo-, and 2-iodoanilines were
unable to yield the required product due to their electron-
withdrawing nature and due to steric hindrance which hampers
the approach of the nucleophile to the electrophilic center. To
validate our assumption, we focused on anilines with bulky
groups at both the 2 and 6 positions. 2,6-Disubstituted anilines,
regardless of the electron-withdrawing or electron-donating
nature of the substituents, did not undergo any reaction even after
prolonged heating. However, if the aniline was only singly 2- or
6-substituted then, depending on the electronic nature and size of
the substituent, it underwent nucleophilic substitution. A list of
anilines that did not undergo this reaction is given (Figure 1).
Figure 1: Examples of anilines that did not undergo the nucleophilic substitution reaction with
2-amino-4,6-dichloropyrimidine
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NO2
COOH
COOH
SH
Ph
H3C
CH3
Cl
Br
C2H5
C2H5
NO2
NH2
NO2
NH2
CH3
NH2
NH2
NH2
NH2
I
H3CO
OCH3
COOH

4
Tetrahedron Letters
The last step was also repeated using ethanol as the solvent, and
In conclusion, a simple and efficient protocol for the synthesis
of 2-amino-4-(N-alkyl/arylamino)-6-chloropyrimidines has been
developed using readily available starting materials. The newly
developed method shows advantages in terms of its simplicity,
short reaction times and high yields. Furthermore, this protocol
does not require any expensive catalyst.
was found to be more time-consuming and lower yielding
compared to solvent-free conditions. Moreover, in some cases,
the reaction was not complete even after 24 hours and therefore
column chromatography was performed to purify the resulting
crude products. Comparisons of the reaction times and yields are
given in Figures 2 and 3.
30
25
20
15
10
5
Figure 2: Comparison of the reaction time (h) for the syntheses performed in EtOH and under solvent-free conditions, respectively.
100
90
80
70
60
50
40
30
20
Figure 3: Comparison of the yields for the syntheses performed in EtOH and under solvent-free conditions, respectively.
Acknowledgements: The authors are thankful to the
Organization for Prohibition of Chemical Weapons (OPCW),
The Netherlands (Project No. L/ICA/ICB/173681/12) for
financial support and DAAD (Deutscher Akademischer
Austauschdienst), Bonn, Germany, for granting a fellowship to
Supplementary data: supplementary data associated with this
manuscript can be found in the online version, at
http://dx.doi.org. These data include synthetic procedures and
characterization data of all the compounds reported in the
manuscript
Prof.
Dr.
Khalid
Mohammed
Khan.

5
Characterization data of compound 30: Yield: 89%;
References and Notes
°
solid, m.p. 257-258 C; Rf: 0.52 (EtOAc–hexanes, 3:7);
1H-NMR (300 MHz, DMSO-d6): δ 7.08 (s, 1H, NH),
6.34 (s, 2H, NH2), 5.71 (s, 1H, H-5), 3.17 (br s, 2H, 2×H-
1ꞌ), 1.50 (m, 2H, H-2ꞌ), 0.88 (t, 3H, H-3ꞌ); EI MS: m/z
(rel. abund. %) 186 (M+, 50.7), 188 (M+ + 2, 17.2), 171
(22.3), 157 (100), 128 (11.9); HR-EIMS calcd for
C7H11ClN4: 186.0672; observed: 186.0676.
O'Brien, D. E.; Baiocchi, F.; Robins, R. K.; Cheng, C. C.
J. Org. Chem. 1962, 27, 1104.
Bhatt, R.; Gong, B.; Hong, F.; Jenkins, S. A.; Klein, J.
P.; Kohm, C. T.; Tulinsky, J. US 20040204386, 2004;
Chem. Abstr. 2004, 141, 350185.
Ge, H.-X.; Wang, L.-C.; Jiang, Z.-Z.; Ni, S.-L.
Arzneimittel-Forsch. 2006, 56, 673.
Mengel, R.; Schroeder, L.; Stransky, W.; Linden, G.;
Schneider, G. DE 3717480, 1988; Chem. Abstr. 1990,
112, 7500.
Sander, K.; Kottke, T.; Kulu, Y. T.; Proschak, E.;
Weizel, L.; Schneider, E. H.; Seifert, R.; Schneider, G.;
Stark, H. Bioorg. Med. Chem. 2009, 17, 7186.
Noell, C. W.; Robins, R. K. J Med. Pharm. Chem. 1962,
5, 558.
1.
Mohammed, S. K.; Soliman, A, M.; El-Remaily, M. A.;
Abdel-Ghany, H. Chem. Sci. J. 2013, 110, 1.
Kappe C. O. Tetrahedron, 1993, 49, 6937.
Russowsky, D.; Canto, R. F. S.; Sanches, S. A. A.;
D’Oca, M. G. M.; de Fátima, Â.; Pilli, R. A. Bioorg.
Chem. 2006, 34, 173.
Cho, H.; Ueda, M.; Shima, K.; Mizuno, A.;
Hayashimatsu, M.; Ohnaka, Y. J. Med. Chem. 1989, 32,
2399.
Joffe, A. M.; Fareley, J. D.; Lindon, D.; Goldsand, G.
Am. J. Med. 1989, 87, 332.
Rosowsky, A.; Frosch, R. A.; Friesheim, J. H.; Moran,
R. G. J. Med. Chem. 1989, 32, 517.
Gangjee, A.; Zeng, Y.; McGuire, J. J.; Mehraein, F.;
Kiliuk, R. L. J. Med. Chem. 2004, 47, 6893.
Hu, E. H.; Sidler, D. R.; Dolling, U. H. J. Org. Chem.
1998, 63, 3454.
Chauhan, N.; Nimavat, K.; Vyas, K. Der. Pharm. Sinica
2012, 3, 394.
Borisenko, V. E.; Krekov, S. A.; Niyazova, M. A.; Koll,
A.; Lipkowski, P. Vib. Spectrosc. 2005, 37, 97.
El-Gengaighi, S.; Karawya, M. S.; Motawe, H. M.;
Ibrahim, N.; Faddah, L. M. Pharmazie 1995, 50, 361.
Fox, J. J.; Bloch, A.; Watanabe, K. A. Prog. Nucl. Acid
Res. Mol. Biol. 1966, 5, 251.
Bendiritter, P.; de Araujo Junior, J. X.; Schmidt, M.;
Bourgignon, J.-J. Tetrahedron 2007, 63, 12465.
Rospenk, M.; Koll, A. J. Mol. Struct. 2007, 844-845,
232.
Ahmad, O. K.; Hill, M. D.; Movassaghi, M. J. Org.
Chem. 2009, 74, 8460.
Sasada, T.; Kobayashi, F.; Sakai, N.; Konakahara, T.
Org. Lett. 2009, 11, 2161.
Wang, Z.; Wang, Y.; Zhang, W. X.; Hou, Z.; Xi, Z. J.
Am. Chem. Soc. 2009, 131, 15108.
2.
3.
4.
25.
26.
5.
6.
27.
28.
7.
8.
29.
9.
10.
11.
12.
13.
14.
15.
16.
17.
30.
31.
Konkel, M. J.; Vince, R. J. Org. Chem. 1996, 61, 6199.
18.
19.
20.
Lechel, T.; Mohl, S.; Reissig, H.-U. Synlett 2009, 1059.
Deng, X.; Mani, N. Org. Lett. 2006, 8, 269.
Hockova, D.; Holy, A.; Masojidkova, T.; Votruba, I.
Tetrahedron 2004, 60, 4983.
21.
22.
23.
Kuykendall, D. W.; Anderson, C. A.; Zimmerman, S. C.
Org. Lett. 2009, 11, 61.
Elion, G. B.; Hitchings, G. H. J. Am. Chem. Soc. 1953,
75, 4311.
General procedure for the synthesis of 2-amino-4-(N-
alkyl/arylamino)-6-chloropyrimidine derivatives 3-31
under solvent-free conditions: finely ground 2-amino-
4,6-dichloropyrimidine (2) (3 mmol), substituted amine
(3 mmol), and Et3N (6 mmol) were added to a round-
bottomed flask and heated. The reaction was monitored
by TLC (hexane–EtOAc). After completion, distilled
H2O was added and the precipitate obtained was filtered.
In most cases, single spot products were obtained,
thereby crystallization was not needed. In a few cases,
where precipitates were not formed upon addition of
H2O, the solvent was evaporated under vacuum and the
resulting crude material was crystallized from EtOH.
Characterization data of compound 4: Yield: 84%; solid,
24.
°
m.p. 240-242 C; Rf: 0.57 (EtOAc–hexanes, 4:6); 1H-
NMR (400 MHz, DMSO-d6): δ 8.49 (s, 1H, NH), 8.01
(d, J6',5' = 8.0 Hz, 1H, H-6'), 7.05 (m, 2H, H-3',4'), 6.92
(dt, J5',4' = J5',6' = 8.0 Hz, J5',3' = 2.4 Hz, 1H, H-5'), 6.58
(s, 2H, NH2), 6.13 (s, 1H, H-5), 3.81 (s, 3H, OCH3). EI-
MS m/z (rel. int. %): 250.04 (M+, 11.2), 252 (M+ + 2,
3.7), 219 (100), 172 (6.2), 158 (11.6), 128 (6); HR-EIMS
calcd for C11H11ClN4O: 250.0621; observed 250.0619.