Synthesis of 2,4,6-tris(4-N-isopropylamidinophenyl)pyrimidine trihydrochloride

Article abstract of DOI:10.3390/60500477

The synthesis of 2,4,6-tris(4-N-isopropylamidinophenyl)pyrimidine from 1,3-di(4-bromophenyl)propen-3-one and 4-bromobenzamidine is reported.

Full text of DOI:10.3390/60500477

Molecules 2001, 6, 477-480
molecules
ISSN 1420-3049
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Synthesis of 2,4,6-Tris(4-N-isopropylamidinophenyl)pyrimidine
trihydrochloride
Miroslav Bajić1,* and David W. Boykin2
1
Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of
Zagreb, 10000 Zagreb, Croatia.
2
Department of Chemistry and Center for Biotechnology and Drug Design, Georgia State University,
Atlanta, Georgia 30303-3083, USA; E-mail: dboykin@gsu.edu
*Author to whom correspondence should be addressed; E-mail: mbajic@pierre.fkit.hr
Received: 20 January 2001 / Accepted: 17 March 2001 / Published: 30 April 2001
Abstract: The synthesis of 2,4,6-tris(4-N-isopropylamidinophenyl)pyrimidine from 1,3-
di(4-bromophenyl)propen-3-one and 4-bromobenzamidine is reported.
Keywords: Amidine, triarylamidine, triarylpyrimidine.
Introduction
In previous reports, we have described the synthesis, DNA binding results and significant anti-
pneumocystic activity for a series of dicationic diarylpyrimidines [1-3]. We demonstrated that by
careful manipulation of structure highly DNA selective molecules could be developed. This report
describes the synthesis of a new tricationic triarylpyrimidine which is expected to show strong DNA
binding affinity.
Results and Discussion
The synthetic route employed to make 2,4,6-tris(4-N-isopropylamidinophenyl)pyrimidine trihydro-
chloride (5) is outlined in Scheme 1. The key intermediate 2,4,6-tris(4-bromophenyl)pyrimidine (3)

Molecules 2001, 6
478
was obtained in good yield by base-promoted condensation between 1,3-di(4-bromophenyl)propen-3-
one (1) and 4-bromobenzamidine benzensulfonate (2), using an approach similar to the one described
by Dodson and Seyler [4]. This reaction sequence uses two moles of the α,β-unsaturated ketone, one
mole becomes incorporated in the pyrimidine ring and the other is employed as the oxidizing agent for
the intermediate dihydropyrimidine.
Tribromo compound 3 was converted into the corresponding tris-nitrile 4, which was then
transformed into the tricationic target compound employing the standard approach [1,2].
Scheme 1
R
NH NH2
O
i
N
N
+
Br
Br
Br
R
R
1
2
3 R = Br
ii
4 R = CN
iii
C=NH(NH-iPr)
5 R =
i) KOH, EtOH; ii) CuCN, quinoline; iii) HCl, EtOH; H2N-iPr, EtOH.
Experimental
General
Melting points were recorded using a Thomas Hoover (Uni-Melt) capillary melting point apparatus
and are uncorrected. 1H-NMR and 13C-NMR spectra were recorded employing a Varian GX400
spectrometer and chemical shifts (δ) are in ppm relative to TMS. High resolution mass spectra were
recorded with a VG Instruments 70-SE spectrometer (Georgia Institute of Technology, Atlanta, GA);
others were recorded by a Shimadzu GC-MS 5000 instrument at 70 eV chamber voltage on a direct
inlet system. Elemental analysis were obtained from Atlantis Microlab Inc. (Norcross, GA). All
chemicals and solvents were purchased from Aldrich Chemical Co. or Fisher Scientific.
2,4,6-Tris(4-bromophenyl)pyrimidine (3)
1,3-Di(4-bromophenyl)propen-3-one (1), prepared by a standard literature method [5] (15 g, 41
mmol) and 4-bromobenzamidine benzensulfonate [1] (7.32 g, 20.5 mmol) was dissolved in ethanol

Molecules 2001, 6
479
(600 mL) and a solution of potassium hydroxide (2.3 g, 41 mmol) in ethanol (200 mL) was added. The
reaction mixture was refluxed for 3 hr, cooled and precipitate was collected by filtration and washed
with water. White solid was recrystallized from glacial acetic acid to yield 9.78 g (87.6%) of white
crystals; Mp: >290 oC; MS (EI, 70eV): 542/544/546/548 (peaks in the molecular ion region); 1H-NMR
(400 MHz, CDCl3): 8.55 (d, 2H, J = 8.5 Hz); 8.14 (d, 4H, J = 8.8 Hz); 7.95 (s, 1H); 7.70 (d, 4H, J =
8.6 Hz); 7.66 (d, 2H, J = 8.8 Hz); 13C-NMR (100 MHz, CDCl3): 164.2; 164.1; 136.9; 136.3; 132.3;
131.8; 130.2; 128.8; 125.8; 109.9; Anal. calcd. for C22H13Br3N2 (545.07): C 48.47, H 2.40, N 5.14.
Found: C 48.36, H 2.42, N 5.08.
2,4,6-Tris(4-cyanophenyl)pyrimidine (4)
A mixture of 2,4,6-tris(4-bromophenyl)pyrimidine (3) (5 g, 9.17 mmol) and copper(I)cyanide (4.1
g, 45.9 mmol) in freshly distilled quinoline (75 mL) was refluxed for 3 hr [1,2]. After cooling the
reaction mixture was poured into ether (100 mL), filtered and solid was washed with ether and water,
and than extracted in a Soxhlet apparatus using acetone as a solvent. Acetone solution was passed
through a short alumina column to remove copper salts. Solvent was evaporated and solid was
crystallized from acetone to yield 1.95 g (55.6%) of white fluffy needles; Mp: >290 oC; MS (EI, 70
eV) : 383 (M+); 1H-NMR (400 MHz, DMSO-d6): 8.88 (s, 1H); 8.83 (d, 2H, J = 8.3 Hz); 8.73 (d, 4H, J
= 8.5 Hz); 8.13 (d, 4H, J = 8.3 Hz); 8.09 (d, 2H, J = 8.3 Hz); 13C-NMR (100 MHz, DMSO-d6): 163.1;
162.0; 140.8; 140.0; 132.5; 132.4; 128.5; 128.1; 118.2; 118.0; 113.5; 113.3; 112.9; Anal. calcd. for:
C25H13N5 (383.39): C 78.31, H 3.42, N 18.27. Found: C 78.27, H 3.42, N 18.19.
2,4,6-Tris(4-N-isopropylamidinophenyl)pyrimidine trihydrochloride (5)
A stirred suspension of 4 (0.36 g, 0.94 mmol) in anhydrous dioxane (50 mL) and absolute ethanol
(20 mL) was chilled to 0-5 oC, and was saturated with HCl(g). The contents were stirred at room
temperature until IR spectra indicated the disappearance of the nitrile peak. The crude triimidate ester
was collected by filtration and washed with dry ether. To a stirred suspension of crude triimidate ester
in absolute ethanol (100 mL) freshly distilled isopropylamine (0.95 g, 16 mmol) was added and the
mixture was stirred for 72 hr at room temperature. Solvent was partially evaporated and acetone was
added to the residue. Solid was collected by filtration, washed with acetone and dry ether. The free
base was suspended in absolute ethanol saturated with HCl (50 mL) and heated at reflux for 4 hr. After
cooling, the solid was collected by filtration, washed with acetone and dried in vacuum at 90 oC for 48
hr to yield 0.23 g (35%) of white powder; Mp: > 290 oC; MS (FAB): 561.3 (M++1); HRMS (FAB):
calcd. for C34H40N8: 561.3454 (M++1). Found: 561.3451; 1H-NMR (400 MHz, DMSO-d6): 9.85 (bs,
3H, NH); 9.68 (bs, 3H, NH); 9.29 (bs, 3H, NH); 8.91 (s, 1H, H-5); 8.84 (d, 2H, J = 8.5 Hz, H-a'); 8.77
(d, 4H, J = 8.4 Hz, H-a); 8.02 (d, 4H, J = 8.6 Hz, H-b); 7.99 (d, 2H, J = 8.9 Hz, H-b'); 4.15 (m, 3H, J =
6.6 Hz, CH); 1.34 (d, 18H, J = 6.3 Hz, CH ); 13C-NMR (100 MHz, DMSO-d6+D2O): 163.8; 162.9;
3

Molecules 2001, 6
480
161.6; 161.3; 141.2; 140.2; 132.3; 132.0; 129.0; 128.9; 128.4; 128.0; 112.7; 45.3; 21.4; Anal. calcd. for
.
.
C34H40N8 3HCl 1.5H2O (697.14): C 58.57, H 6.65, N 16.07. Found: C 58.32, H 6.63, N 15.89.
References
1. Kumar, A.; Boykin, D. W.; Wilson, W. D.; Jones, S. K.; Bender, B. C.; Dykstra, C. C.; Hall, J. E.;
Tidwell, R. R. Eur. J. Med. Chem. 1996, 31, 767-773.
2. Boykin, D. W.; Kumar, A.; Bajić, M.; Xiao, G.; Wilson, W. D.; Bender, B. C.; McCurdy, D. R.;
Hall, J. E.; Tidwell, R. R. Eur. J. Med. Chem. 1997, 32, 965-972.
3. Kumar, A.; Zhao, M.; Wilson, W. D.; Boykin, D. W. Bioorg. Med. Chem. Lett. 1994, 4, 2913-
2918.
4. Dodson, R. M.; Seyler, J. K. J. Org. Chem. 1951, 16, 461-465.
5. Kohler, E. P.; Chadwell, H. M. Org. Synth. Coll. Vol. 1, 1941, 78-80.
Sample availability: Not available.
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