Facile synthesis of 2,4-diamino-6-alkyl- or 6-aryl-pyrimidine derivatives

Article abstract of DOI:10.1002/jhet.419

(Chemical Equation Presented) Facile methods were developed to prepare a series of 6-phenyl and 6-alkyl-2,4-diaminopyrimidine derivatives. The pyrimidine ring of the final products was constructed by treatment of a 1,3-dicarbonyl derivative with an amidin

Full text of DOI:10.1002/jhet.419

1056
Facile Synthesis of 2,4-Diamino-6-alkyl- or 6-Aryl-Pyrimidine
Derivatives
Vol 47
Xihong Wang, Ramadas Sathunuru, Victor Melendez,
Michael P. Kozar, and Ai J. Lin*
Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring,
Maryland 20910
*E-mail: ai.lin@us.army.mil
Received November 23, 2009
DOI 10.1002/jhet.419
Published online 13 July 2010 in Wiley Online Library (wileyonlinelibrary.com).
Facile methods were developed to prepare a series of 6-phenyl and 6-alkyl-2,4-diaminopyrimidine
derivatives. The pyrimidine ring of the final products was constructed by treatment of a 1,3-dicarbonyl
derivative with an amidine or guanidine. The 6-phenyl-pyrimidine derivatives were also prepared by
Suzuki coupling reaction, using 2-methylthio-4,6-dichloropyrimidine as the starting material.
J. Heterocyclic Chem., 47, 1056 (2010).
INTRODUCTION
nidine [6,7]. The other method involved Suzuki coupling
or Grignard reactions to insert various aryl or alkyl
groups into 2,4,6-trichloropyrimidine [8] followed by
stepwise amination with appropriate amines.
As part of our efforts in search of malaria prophylac-
tic and/or therapeutic agents, a series of imidazolidine-
dione (IZ) derivatives was found to possess profound
activity against liver stage malarias in rodent and nonhu-
man primate models [1–4]. Subsequently, the IZ com-
pounds were found to metabolize to s-triazine deriva-
tives in microsomal preparations and in rodents [4].
Active in mice tests, the s-triazines were considered the
active metabolite of the IZ compounds. This finding
prompted us to develop methods to prepare a series of
N,N0-di-substituted 2,4-diamino-1,3,5-triazines and 2,4-
diamino-pyrimidine derivatives as potential antimalarial
agents. This report focused on the method development
for the synthesis of the latter class of compounds.
In this study, facile methods were developed to prepare
substituted 6-alkyl or 6-aryl-2,4-diaminopyrimidines.
RESULTS AND DISCUSSION
Methods were developed to prepare substituted 6-
alkyl or 6-arylpyrimidine-2,4-diamines. The pyrimidine
ring of the desired products was constructed by conden-
sation of a 1,3-dicarbonyl component with an amidine,
isopropylguanidine, or 3,4-dichloroguanidine as shown
in Scheme 1. The hydroxypyrimidines (2a–f) obtained
were converted to the corresponding chloropyrimidines
(3a–f) in high yields with phosphorus oxychloride [9–
11]. The amination of chloropyrimidine derivatives was
achieved via acid- or base-mediated nucleophilic substi-
tution [12]. Hartung et al. reported that the chloro group
of chloropyrimindines can be easily displaced with an
aromatic amine under acidic conditions, but it can only
be displaced by an aliphatic amino group under basic
Polyamino-pyrimidines play a very important role in
biological and pharmaceutical chemistry. A number of
applications as therapeutic agents have been documented
[5]. The most general method for the synthesis of 2,4,6-
trisubstituted pyrimidines involves the treatment of two
essential starting materials, a 1,3-dicarbonyl component
and a NACAN fragment such as urea, amidine, or gua-
Published 2010. This article is a US Government work and is in the public domain in the USA.

September 2010
Facile Synthesis of 2,4-Diamino-6-alkyl- or 6-Aryl-pyrimidine Derivatives
1057
Scheme 1. Synthesis of 6-phenyl or alkyl-2,4-diaminopyrimidine derivatives.
conditions [12]. The method was adapted to insert the 3,
4-dichloroanilino, and the isopropylamino groups into
the pyrimidine ring in high yield under the acidic and
basic conditions, respectively (Scheme 1). Likewise, 4-
alkyl analogs 4c–f were prepared using ethyl propiony-
lacetate or ethyl pivaloylacetate as 1,3-dicarbonyl
component.
Suzuki coupling reaction was attempted using 2,4,6-tri-
chloropyrimidine as the starting material to introduce a
phenyl group at either the 4- or 6-position, followed by
amination. However, the success of this approach
depends on the relative reactivity of the 2- and 4-chloro
groups toward amination reactions, allowing for inser-
tion of an amino group selectively to either 2- or 4-posi-
tion of the pyrimidine ring. Although the Suzuki reac-
tion of 2,4,6-trichloropyrimidine gave a good yield of
2,4-dichloro-6-phenyl-pyrimidine, the followed up
The Suzuki coupling method was an alternative
approach used to make the 2,4-diamino-6-phenylpyrimi-
dine derivatives (4a and 4b) (Scheme 2). Initially, the
Scheme 2. Method involved Suzuki reaction on 4,6-dichloro-2-methylthiopyrimidine.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1058
X. Wang, R. Sathunuru, V. Melendez, M. P. Kozar, and A. J. Lin
Vol 47
phase 150 microns silica gel plates (Analtech, Newark, DE).
Visualization of the developed chromatogram was performed
by UV absorbance, or spreading with aqueous potassium per-
manganate or ethanolic anisaldehyde. Liquid chromatography
was performed using a Horizon HPFC System (Biotage, Char-
lottesville, VA) with Flash 25M or 40M cartridges (KP-SilTM
amination gave a mixture consisting almost equal
amount of 2-amino- and 4-aminopyrimidine derivatives.
The low selectivity of 2,4-dichloro-6-phenyl-pyrimidine
in the amination reaction led us to use 4,6-dichloro-2-
methylthio-pyrimidine as the starting material. On treat-
ment with phenylboronic acid in the presence of triphe-
nylphosphine and palladium acetate, 4,6-dichloro-2-
methylthio-pyrimidine (5) gave 4-chloro-2-methylthio-6-
phenylpyrimidine (6) in very high yield. The first amina-
tion of compound 6 gave intermediate 7a or 7b readily,
whereas the second amination on the 2-methylthio group
failed to produce the desired products 4a and 4b [13–
15]. Thus, oxidative activation of the 2-methylthio group
in 7a and 7b was necessary before the amination reac-
tion on the 2-position can be carried out. The oxidation
was achieved by treatment of the 2-methylthiopyrimi-
dine derivative with hydrogen peroxide under the cataly-
sis of sodium tungstate dehydrate [14,15]. The mixture
of sulfone and sulfoxide (8) formed was used without
purification for further reactions with 3, 4-dichloroani-
line or isopropylamine to give the products 4a (11%)
and 4b (84%), respectively. The striking disparity in
yields between 4a and 4b is, most likely, a result of dif-
ference in nucleophilicity of the two amines used.
˚
Silica, 32–63 lm, 60 A). Preparative TLC was performed
using silica gel GF Tapered Uniplates (Analtech, Newark,
1
DE). H NMR and 13C NMR spectra were recorded in deuter-
iochloroform, unless otherwise noted, on a Bruker Avance 300
spectrometer (Bruker Instruments, Wilmington, DE). Chemical
shifts are reported in parts per million on the d scale from an
internal standard of tetramethylsilane. Combustion analyses
were performed by Atlantic Microlab, (Norcross, GA). Where
analyses are indicated by symbols of the elements, the analyti-
cal results obtained were within þ/ꢀ 0.4% of the theoretical
values.
2-(3,4-Dichlorophenylamino)-4-hydroxy-6-phenylpyrimidine
(2a). Ethyl benzoylacetate (15 mL) was added dropwise to a
suspension of 3,4-dichlorophenylguanidine (1a, 7.23g. 35.4
mmol) [2] in 100 mL of anhydrous DMF. The mixture was
heated at 100ꢁC for 48 h. After cooling, the reaction mixture
was poured into 500 mL of ice water. The precipites were col-
lected, washed with water, and dried to give 64% yield of
compound 2a as a pink solid. The product was used for further
reactions without purification. 1H NMR (CD3OD): d 8.24 (d,
1H, J ¼ 2.4Hz), 8.00 (m, 2H), 7.57 (m, 2H), 7.47 (m, 3H),
6.45 (s, 1H). ms: m/z 331 (Mþ).
The major difference between the two methods used
in Scheme 1 (Method 1) and Scheme 2 (Method 2) to
prepare compounds 4a and 4b is the order of introduc-
tion of 2-amino, 4-amino-, and 6-phenyl groups to the
pyrimidine ring. The former method assembled the 2-
amino and the 6-phenyl groups during the formation of
the pyrimidine ring followed by insertion of the aryla-
mino or alkylamino group at either 2- or 4-posion under
the acidic or basic conditions, respectively. The overall
yield of the Method 1 is good and the reaction condi-
tions are mild. The latter method as described in
Scheme 2 started from the commercially available start-
ing material 4,6-dichloro-2-methylthio-pyrimidine. The
6-phenyl substituent was constructed first by the Suzuki
coupling reaction followed by stepwise amination reac-
tions to yield the substituted 2, 4-diamino-6-phenylpyri-
midines 4a or 4b. The yield of the 2nd nucleophilic
substitution reaction is good when alkylamines were
used, but poor when aromatic amines were the
nucleophiles.
4-Hydroxy-2-isopropylamino-6-phenylpyrimidine (2b). Ethyl
benzoylacetate (11.7 mL) was added dropwise to a suspension
of isopropylguanidine (1b) [2] (2.3 g, 22.7 mmol) in 50 mL of
anhydrous DMF. The reaction mixture was heated at 100ꢁC
for 3 days. After cooling, the solution was poured into crushed
ice water. The mixture was extracted with EtOAc three times
and the EtOAc extracts were combined, washed with water,
and brine successively, dried over Na2SO4 and evaporated to
dryness in vacuole. The residue was applied to a silica gel
flash column and eluted with 2.5% MeOH in CHCl3 to give
35% yield of compound 2b as a white solid. 1H NMR
(CDCl3): d 8.01 (d, 2H, J ¼ 3.6 Hz), 7.48 (m, 3H), 6.24 (s,
1H), 4.37 (m, 1H), 1.36 (d, 6H, J ¼ 6.6 Hz). ms: m/z 229
(Mþ).
2-(3,4-Dichlorophenylamino)-6-ethyl-4-hydroxy-pyrimidine
(2c). Compound 2c was prepared by the same method for the
preparation of 2a, using ethyl propionylacetate as starting ma-
1
terial to yield 75% of 2c as a white solid. H NMR (CD3OD)
d 8.06 (d, 1H, J ¼ 2.2 Hz), 7.46 (dd, 1H, J ¼ 2.2 Hz, 8.7 Hz),
7.42 (d, 1H, J ¼ 8.7 Hz), 5.82 (s, 1H), 2.54 (q, 2H, J ¼ 7.5
Hz), 1.25 (t, 3H, J ¼ 7.5 Hz). ms: m/z 283 (Mþ).
6-t-Butyl-2-(3,4-dichlorophenylamino)-4-hydroxy-pyrimidine
(2d). The title compound was prepared by the same method as
for the preparation of 2a, using ethyl pivaloylacetate as start-
ing material to yield 60% of 2d as an off-white solid. 1H
NMR (CD3OD): d 8.22 (s, 1H), 7.41 (m, 2H), 5.93 (s, 1H),
1.28 (s, 9H). ms: m/z 311 (Mþ).
In conclusion, the method described in Scheme 1 is
superior to that of Scheme 2 for the preparation of the
desired pyrimidine derivatives 4a-f, with better yield,
milder reaction conditions and cheaper reagents.
6-t-Butyl-4-hydroxy-2-isopropylamino-pyrimidine (2e). Com-
pound 2e was prepared by the same method as for the prepara-
tion of 2b, using ethyl pivaloylacetate as starting material to
afford the product as a white solid (33% yield). 1H NMR
(CDCl3): d 5.73 (s, 1H), 4.17 (m, 1H), 1.21 (m, 15H). ms: m/z
209 (Mþ).
EXPERIMENTAL
Melting points were determined on a Mettler FP62 melting
point apparatus and are uncorrected. Analytical thin layer chro-
matography (TLC) was performed using HPTLC-HLF normal
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2010
Facile Synthesis of 2,4-Diamino-6-alkyl- or 6-Aryl-pyrimidine Derivatives
1059
2H), 7.47 (m, 3H), 7.33 (d, 2H, J ¼ 1.8 Hz), 7.00 (brs, 1H),
6.28 (s, 1H), 4.72 (s, 1H), 4.14 (m, 1H), 1.32 (d, 6H, J ¼
6.4Hz). ms: m/z 372 (Mþ). Anal. calcd. for C19H18Cl2N4.HCl:
C, 55.69; H, 4.67; N, 13.67; Cl, 25.96. Found: C, 55.80; H,
4.65; N, 13.66; Cl, 25.90.
Method 2. A mixture of sulfone/sulfoxide 8a (2.0 g) and
3,4-dichloroaniline (3.34 mL, 3.0 equiv) was heated in a sealed
tube at 140ꢁC for 2 h. The mixture was cooled and the crude
product was purified by a silica gel flash column, eluting with
hexane/EtOAc (4:1 v/v) to give the desired compound 4a in
11% yield. The NMR and MS spectra data are identical to
compound 4a prepared by method 1 as shown in Scheme 1.
4-(3,4-Dichlorophenylamino)-2-isopropylamino-6-phenyl-
pyrimidine (4b)
6-Ethyl-4-hydroxy-2-isopropylamino-pyrimidine (2f). Com-
pound 2f was prepared by the same method as for the prepara-
tion of 2b, using ethyl propionylacetate as starting material to
give 31% yield of the desired product as a white solid. 1H
NMR (CDCl3): d 6.04 (s, 1H), 4.17 (m, 1H), 2.45 (q, 2H, J ¼
7.2 Hz), 1.25 (t, 3H, J ¼ 7.2 Hz), 1.21 (d, 6H, J ¼ 6.6 Hz).
ms: m/z 181 (Mþ).
4-Chloro-2-(3,4-dichlorophenylamino)-6-phenylpyrimidine
(3a). 2-(3, 4-Dichlorophenylamino)-4-hydroxy-6-phenylpyrimi-
dine (2a) in 100 mL of POCl3 was stirred at room temperature
overnight. The excess POCl3 was removed under reduced pres-
sure to give a gummy residue which solidified upon addition
of excessive amount of crushed ice. The solid was purified by
silica gel flash column chromatography, eluting with 10%
EtOAc in hexane to afford the desired compound 3a in 82%
yield as a light yellow solid. 1H NMR (CDCl3): d 8.07 (m,
3H), 7.56 (m, 3H), 7.46 (m, 1H), 7.42 (d, 1H, J ¼ 8.7 Hz),
7.24 (s, 1H). ms: m/z 349 (Mþ).
Method 1. Concentrated hydrochloric acid (1.5 mL) was
added to a solution of 4-chloro-2-isopropylamino-6-phenylpyri-
midine (3b) (886 mg) and 3,4-dichloroaniline (815 mg, 1.5
equiv) in 15 mL of isopropanol. The reaction mixture was
heated at 100ꢁC overnight. The crude product was purified by
silica gel flash column chromatography and eluted with 2.5%
MeOH in CH2Cl2 to give the desired compound as an off-
4-Chloro-2-isopropylamino-6-phenylpyrimidine (3b). The
title compound was prepared by the same method for the prep-
aration of 3a, using hydroxyl intermediate 2b as the starting
material giving the desired 4-chloro product 3b as light yellow
oil in 47% yield. 1H NMR (CDCl3): d 8.01 (d, 2H, J ¼ 3.6
Hz), 7.48 (m, 3H), 6.97 (s, 1H), 4.28 (m, 1H), 1.27 (d, 6H, J
¼ 6.5 Hz). ms: m/z 247 (Mþ).
1
white solid, yield 97%, mp 79.7ꢁC. H NMR (CDCl3): d 7.93
(m, 3H), 7.43 (m, 2H), 7.37 (s, 1H), 7.28 (d, 1H, J ¼ 2.6 Hz),
7.25 (d, 1H, J ¼ 2.6 Hz), 6.48 (s, 1H), 6.36 (s, 1H), 4.98 (br,
1H), 4.25 (m, 1H), 1.32 (d, 6H, J ¼ 6.4 Hz). 13C NMR:
(CDCl3) d 163.21, 161.89, 161.74, 141.51, 138.41, 131.35,
130.68, 130.27, 129.01, 126.74, 122.72, 120.45, 119.27, 92.51,
79.64, 42.77, 23.00. ms: m/z 374 (Mþ). Anal. calcd. for
C19H18Cl2N4.HCl: C, 55.69; H, 4.67; N, 13.67; Cl, 25.96.
Found: C, 55.40; H, 4.62; N, 13.50; Cl, 25.69.
Method 2. The mixture of sulfone/sulfoxide 8b (3.0g) and
isopropylamine (6.21mL, 10.0 equiv) was heated in a sealed
tube at 140ꢁC for 20 min. The mixture was cooled and the
crude product was purified by silica gel flash column chroma-
tography and eluted with hexane/EtOAc (4:1 v/v) to give com-
pound 4b in 84% yield. The NMR and MS spectra data are
identical to compound 4b prepared by method 1 as shown in
Scheme 1.
2-(3,4-Dichlorophenylamino)-4-chloro-6-ethylpyrimidine
(3c). The title compound was prepared by the same method as
for the preparation of 3a, using compound 2c as the starting
material, to give 75% yield of the desired compound as off-
white solid. 1H NMR (CDCl3,): d 8.06 (s, 1H), 7.38 (s, 1H),
7.10 (s, 1H), 6.70 (s, 1H), 2.70 (q, 2H, J ¼ 7.5 Hz), 1.30 (t,
3H, J ¼ 7.5 Hz). ms: m/z 301 (Mþ).
6-t-Butyl-4-chloro-2-(3,4-dichlorophenylamino)-pyrimidine
(3d). Compound 3d was prepared by the same method as for
the preparation of 3a, using 2d as the starting material to give
83% yield of the product as off-white solid. 1H NMR
(CDCl3): d 8.01 (s, 1H), 7.38 (s, 2H), 6.83 (s, 1H), 1.38 (s,
9H). ms: m/z 329 (Mþ).
2-(3,4-Dichlorophenylamino)-6-ethyl-4-isopropylamino-
pyrimidine (4c). Compound 4c was prepared by the same
method as for the preparation of 4a, using 3c as starting mate-
rial to give the gummy desired compound. The product was
dissolved in anhydrous ether and 2.0M HCl ether solution was
added to form HCl salt. The HCl salt was recrystallized from
hexanes/CHCl3 to give a white solid in 95% yield, mp
6-t-Butyl-4-chloro-2-isopropylamino-pyrimidine (3e). Com-
pound 3e was prepared from 2e using the same method as for
the preparation of 3a; giving 50% yield of the desired com-
pound as white oil. 1H NMR (CDCl3): d 6.55 (s, 1H), 4.97
(brs, 1H), 4.15 (m, 1H), 1.25 (m, 15H). ms: m/z 227 (Mþ).
4-Chloro-6-ethyl-2-isopropylamino-pyrimidine (3f). Com-
pound 3f was prepared by the same method as for the prepara-
tion of 3a, starting from 2f to get the desired compound as
1
211.3ꢁC. H NMR (CD3OD): d 8.02 (s, 1H), 7.55 (d, 1H, J ¼
1
8.7 Hz), 7.42 (d, 1H, J ¼ 8.7 Hz), 6.05 (s, 1H), 4.24 (m, 1H),
2.65 (q, 2H, J ¼ 7.5 Hz), 1.31 (m, 9H). 13C NMR (CDCl3): d
170.9, 162.9, 159.3, 140.2, 132.2, 129.9, 123.8, 120.0, 117.8,
94.0, 42.8, 30.7, 22.8, 12.7. ms: m/z 324 (Mþ). Anal. calcd.
for C15H18Cl2N4: C, 55.39; H, 5.58; N, 17.23; Cl, 21.80.
Found: C, 55.18; H, 5.67; N, 16.95; Cl, 22.05.
6-t-Butyl-2-(3,4-dichlorophenylamino)-4-isopropylamino-
pyrimidine (4d). Compound 4d was prepared by the same
method as for the preparation of 4a, starting from 3d to give
the desired compound in 99% yield as an off-white solid, mp
125.8–126.5ꢁC. 1H NMR (CDCl3): d 8.20 (s, 1H), 7.30 (m,
2H), 7.05 (br, 1H), 5.88 (s, 1H), 4.59 (s, 1H), 4.08 (m, 1H),
1.30 (s, 9H), 1.25 (d, 6H, J ¼ 6.4 Hz). 13C NMR (CDCl3): d
177.1, 162.9, 158.9, 140.5, 132.2, 129.9, 123.5, 119.9, 117.5,
91.9, 42.7, 37.1, 19.3, 22.9. ms: m/z 352 (Mþ). Anal. calcd.
white oil in 47% yield. H NMR (CDCl3): d 6.44 (s, 1H), 5.04
(brs, 1H), 4.15 (m, 1H), 2.58 (q, 2H, J ¼ 7.2 Hz), 1.25 (m,
9H). ms: m/z 199 (Mþ).
2-(3,4-Dichlorophenylamino)-4-isopropylamino-6-phenyl-
pyrimidine.HCl (4a)
Method 1. 4-Chloro-2-(3,4-dichlorophenylamino)-6-phenyl-
pyrimidine (3a, 5g) in 100 mL of isopropylamine was heated
in a sealed tube at 110ꢁC overnight. Upon cooling, the reaction
mixture was poured into ice water and the mixture was
extracted with EtOAc three times. The EtOAc extracts were
combined, washed with brine, dried over Na2SO4 and concen-
trated. The residue was applied to a silica gel flash column
and eluted with hexane: EtOAc (10:1, v/v) to give the desired
product 4a as light yellow solid in 90% yield, mp 277.6ꢁC
(decomposed). 1H NMR (CDCl3): d 8.16 (br, 1H), 7.95 (m,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1060
X. Wang, R. Sathunuru, V. Melendez, M. P. Kozar, and A. J. Lin
Vol 47
for C17H22Cl2N4: C, 57.79; H, 6.28; N, 15.86; Cl, 20.07.
Found: C, 58.01; H, 6.18; N, 15.80; Cl, 20.05.
13.1. ms: m/z: 361 (Mþ). Anal. calcd. for C17H13Cl2N3S: C,
56.36, H, 3.62, Cl, 19.57, N, 11.60. Found: C, 56.74, H, 3.98,
Cl, 20.08, N, 12.10.
6-t-Butyl-4-(3,4-dichlorophenylamino)-2-isopropylamino-
pyrimidine (4e). Compound 4e was prepared by the same
method as for the preparation of 4b, using 6-t-butyl-4-chloro-2-
isopropylamino-pyrimidine (3e) as starting material to give the
desired compound as a white solid in 71% yield, mp 249.5–
4-Isopropylamino-2-methanesulfonyl/sulfinyl-6-phenylpyri-
midine (mixture of sulfone and sulfoxide) (8a). 4-Isopropyla-
mino-2-methylthio-6-phenylpyrimidine (7a) (2.0g, 7.7 mmol)
was dissolved in 50 mL of ethyl acetate/toluene mixture.
Water (2 ml) was added to the solution followed by a catalytic
amount of sodium tungstate dihydrate (0.18 g, 0.1 equiv). The
mixture was cooled to 0ꢁC and hydrogen peroxide (30% aque-
ous solution, 1.69 mL, 10 equiv) was added dropwise. The
reaction was stirred for 30 min, warmed to room temperature,
and monitored by TLC until the disappearance of the starting
material 7a (ꢂ2 h). The mixture was cooled to 0ꢁC again and
excess H2O2 was decomposed carefully by addition of satu-
rated sodium sulfide (20 mL). The organic layer was separated,
concentrated under vacuum at 50ꢁC to a volume of 100 mL.
The mixture was cooled to room temperature and diluted with
hexanes (20 mL). Compound 8a, as a mixture of sulfone and
sulfoxide, precipitated out from the solution, was collected and
washed with hexanes to give 8a in yield 71%. The product
was used for further reaction without purification. 1H NMR
(CD3OD): d 7.50 (d, 2H, J ¼ 6.0 Hz), 7.27 (m, 3H), 6.77 (s,
1H), 4.77 (m, 1H), 1.59 (s, 6H), 1.32 (d, 6H, J ¼ 6.4 Hz). 13C
NMR (DMSO-d6): d 166.3, 163.2, 160.7, 136.2, 131.2, 129.4,
127.5, 126.9, 103.1, 98.8, 42.7, 22.4. ms: m/z 291 (Mþ).
4-(3,4-Dichlorophenylamino)-2-methanesulfonyl/sulfinyl-
6-phenylpyrimidine (mixture of sulfone and sulfoxide)
(8b). Compound 8b was prepared from 7b according to the
same method for the preparation of 8a to give the desired prod-
1
250.8ꢁC. HNMR (CDCl3): d 11.94 (s, 1H), 11.04 (s, 1H), 8.30
(d, 1H, J ¼ 6.9 Hz), 8.25 (s, 1H), 7.71 (d, 1H, J ¼ 8.7 Hz),
7.33 (d, 1H, J ¼ 6.9 Hz), 6.78 (s, 1H), 4.14 (m, 1H), 1.36 (s,
9H), 1.32 (t, 6H, J ¼ 6.5 Hz). ms: m/z 352 (Mþ). Anal. calcd.
for C17H22Cl2N4.HCl: C, 52.39; H, 5.95; N, 14.38; Cl, 27.29.
Found: C, 52.46; H, 5.96; N, 14.33; Cl, 27.16.
4-(3,4-dichlorophenylamino)-6-ethyl-2-isopropylamino-py-
rimidine (4f). Compound 4f was prepared by the same method
as for the preparation of 4b, using compound 3f as the starting
material to afford the desired compound as a pink solid in 92%
yield, mp 251.3ꢁC (decomposed).1H NMR (CDCl3): d 7.92 (d,
1H, J ¼ 2.5 Hz), 7.33 (d, 1H, J ¼ 8.7 Hz), 7.20 (dd, 1H, J ¼
2.5Hz, 8.7Hz), 6.47 (br, 1H), 5.80 (s, 1H), 4.82 (d, 1H, J ¼ 7.0
Hz), 4.11 (m, 1H), 2.48 (q, 2H, J ¼ 7.6 Hz), 1.25 (d, 6H, J ¼
6.5 Hz), 1.21 (t, 3H, J ¼ 7.6 Hz). 13C NMR (CDCl3): d 161.7,
158.8, 154.1, 138.7, 131.5, 131.1, 126.3, 122.7, 121.4, 95.9,
43.9, 25.8, 22.3, 11.8. ms: m/z 324 (Mþ). Anal. calcd. for
C15H18Cl2N4.HCl: C, 49.81; H, 5.29; N, 15.49; Cl, 29.41.
Found: C, 49.98; H, 5.28; N, 15.52; Cl, 29.31.
4-Chloro-2-methylthio-6-phenylpyrimidine (6). A catalytic
amount of palladium acetate (0.286 g, 0.05 equiv) and triphenyl-
phosphine (0.668 g, 0.10 equiv) were added to the solution of 4,6-
dichloro2-methylthio-pyrimidine (5) (5.0 g, 25.42 mmol), phe-
nylboronic acid (3.10 g, 1.0 equiv), and sodium carbonate (8.3 g,
3.1 equiv dissolved in a minium amount of water) in 250 mL of
glyme. The reaction mixture was heated to reflux for 18 h, and the
solvent was removed under reduced pressure. The crude product
was extracted with methylene chloride and the extracts were
combined, washed with water three times, dried over Na2SO4 and
evaporated to dryness. The residue was purified by flash column
chromatography, using hexane/ethyl acetate as eluent to yield
compound 6 as a white solid in 84% yield, mp 59.8ꢁC. 1H NMR
(CDCl3): d 8.06 (m, 2H), 7.68 (m, 3H), 7.38 (s, 1H), 1.54 (s, 3H).
13C NMR (CDCl3): d 173.55, 165.29, 161.53, 135.31, 131.66,
128.98, 127.35, 111.70, 14.41. ms: m/z 236 (Mþ).
1
uct in 74 % yield. H NMR (DMSO-d6): d 10.59 (s, 1H), 8.18
(d, 1H, J ¼ 2.8 Hz), 8.10 (m, 2H), 7.64 (m, 3H), 7.60 (d, 1H, J
¼ 2.8 Hz), 7.40 (s, 1H), 2.73 (s, 3H). ms: m/z 393 (Mþ).
Acknowledgments. Material has been reviewed by the Walter
Reed Army Institute of Research. There is no objection to its pre-
sentation and/or publications. The opinions or assertions con-
tained herein are the private views of the author, and are not to be
construed as official, or as reflecting true views of the Department
of the Army or the Department of Defense. This research is sup-
ported by funding from Military Infectious Diseases Research
Program (A40096_06_WR_CSPP), US Army Medical Research
and Materiel Command, Department of Defense, USA; Peer
Reviewed Medical Research Program (PRMRP) (grant
#PR054609), and Malaria and Medicine Venture (MMV), Ge-
neva, Switzerland, (grant #MMV04/0013).
4-Isopropyl-amino-2-methylthio-6-phenylpyrimidine (7a). A
suspension of 4-chloro-2-methylthio-6-phenylpyrimidine (6,
2.0g) and isopropylamine (1.0 mL, 1.5 equiv) in 100 mL of 1-
BuOH was heated under reflux for 6 h. The solution was
evaporated to dryness under reduced pressure. The residue was
purified by silica gel column chromatography, and eluted with
hexane/EtOAc (8:2 v/v) to yield 68% of the desired compound
REFERENCES AND NOTES
1
7a, mp 89.6ꢁC. H NMR (CDCl3): d 7.98 (d, 2H, J ¼ 6.0 Hz),
[1] Guan, J.; Zhang, Q.; Gettayacamin, M.; Karle, J. M.;
Ditusa, C. A.; Milhous, W. K.; Skillman, D. R.; Lin, A. J. Bioorg Med
Chem 1991, 13, 699.
7.43 (m, 3H), 6.38 (s, 1H), 4.77 (br, 1H), 4.10 (m, 1H), 1.54
(s, 3H), 1.27 (d, 6H, J ¼ 6.4 Hz). 13C NMR (CDCl3): d 171.5,
162.7, 162.0, 137.7, 94.9, 42.8, 22.7, 14.0. ms: m/z 259 (Mþ).
4-(3,4-Dichlorophenylamino)-2-methylthio-6-phenylpyri-
midine (7b). The title compound was prepared by the same
method as for the preparation of 7a using 3,4-dichloroaniline
as nucleophile to give compound 7b in 65% yield. 1H NMR
(CD3OD): d 8.13 (d, 1H, J ¼ 2.4 Hz), 7.82 (m, 2H), 7.62 (m,
3H), 7.57 (s, 1H), 7.54 (d, 1H, J ¼ 2.4 Hz), 6.85 (s, 1H), 2.73
(s, 3H). 13C NMR (CD3OD):: d 169.6, 160.3, 157.5, 137.3,
132.1, 131.8, 130.4, 129.1, 127.9 127.1, 123.3, 121.1, 99.7,
[2] Zhang, Q.; Guan, J.; Sacci, J.; Ager, A.; Ellis, W.; Milhous,
W. K.; Kyle, D.; Lin, A. J. J Med Chem 2005, 48, 6472.
[3] Lin, A. J.; Zhang, Q.; Guan, J.; Milhous, W. K. US Pat.
7,101,902, 2006.
[4] Guan, J.; Wang, X.; Smith, K.; Ager, A.; Gettayacamin,
M.; Kyle, D. E.; Milhous, W. K.; Kozar, M. P.; Magill, A. J.; Lin, A.
J. J Med Chem 2007, 50, 6226.
[5] Montebugnoli, D.; Bravo, P.; Brenna, E.; Mioskowski, C.;
Panzeri, W.; Viani, F.; Volonterio, A.; Wagner, A.; Zanda, M. Tetra-
hedron 2003, 59, 7147.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2010
Facile Synthesis of 2,4-Diamino-6-alkyl- or 6-Aryl-pyrimidine Derivatives
1061
[6] Joule, J. A.; Mills, K. Heterocyclic Chemistry; Blackwell
[13] Nagamatsu, T.; Islam R.; Ashida, N. Heterocycles 2007, 72,
[14] Liverton, N. J.; Butcher, J. W.; Claiborne, C. F.; Claremon
science: Oxford, UK, 2006. pp 194–232.
573.
[7] Hill, M. D.; Movassaghi, M. Chem Euro J 2008, 14, 6836.
[8] Schomasker, J. M.; Delia, T. J. J Org Chem 2001, 66, 7125.
[9] Gong, B.; Hong, F.; Kohm, C.; Jenkins, S.; Tulinsky, J.; Bhatt,
R.; Vries, P.; Singer, J. W.; Klein, P. Bioorg Med Chem Lett 2004, 14, 2303.
[10] Provins, L.; Christophe, B.; Danhaive, P.; Dulieu, J.; Dur-
ieu, V.; Gillard, M.; Lebon, F.; Lengele, S.; Quere, L.; Keulen, B. Bio-
org Med Chem Lett 2006, 16, 1834.
D. A.; Libby, B. E.; Nguyen, K. T.; Pitzenberger, S. M.; Selnick, H.
G.; Smith, G. R.; Tebben, A.; Vacca, J. P.; Varga, S. L.; Agarwal, L.;
Dancheck, K.; Forsyth, A. J.; Fletcher, D. S.; Frantz, B.; Hanlon, W.
A.; Harper, C. F.; Hofsess, S. J.; Kostura, M.; Lin, J.; Luell, S.;
O’Neill, E. A.; Orevillo, C. J.; Pang, M.; Parsons, J.; Rolando, A.;
Sahly, Y.; Visco, D. M.; O’Keefe, S. J. J Med Chem 1999, 42, 2180.
[15] Barvian, M.; Boschelli, D. H.; Cossrow, J.; Dobrusin, E.;
Fattaey, A.; Fritsch, A.; Fry, D.; Harvey, P.; Keller, P.; Garrett, M.;
La, F.; Leopold, W.; McNamara, D.; Quin, M.; Trumpp-Kallmeyer, S.;
Toogood, P.; Wu, Z.; Zhang, E. J Med Chem 2000, 43, 4606.
[11] Biagi, G.; Giorgi, I.; Livi, O.; Scarton, VV.; Lucacchini, A.
IL Farmaco 1997, 52, 61.
[12] Hartung, C. G.; Backes, A. C.; Felber, B.; Missio, A.; Phil-
ipp, A. Tetrahedron 2006, 62, 10055.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet