An efficient solid-phase synthesis of 2-alkyl-4,6-diaminopyrimidines and 2,4,6-triaminopyrimidines

Article abstract of DOI:10.1016/j.tet.2005.12.004

An efficient and simple approach for the solid-phase synthesis of 2,4,6-triaminopyrimidines and 2-alkyl-4,6-diaminopyrimidines is described. Primary amines were immobilized on 2-(4-formyl-3-methoxyphenoxy)ethyl polystyrene resin via reductive amination. A

Full text of DOI:10.1016/j.tet.2005.12.004

Tetrahedron 62 (2006) 2304–2312
An efficient solid-phase synthesis of
-alkyl-4,6-diaminopyrimidines and 2,4,6-triaminopyrimidines
2
´
Csaba W e´ ber, Ad a´ m Demeter and Istv a´ n Greiner
*
Chemical and Biotechnological Research and Development, Gedeon Richter Ltd, PO Box 27, H-1475 Budapest, Hungary
Received 26 September 2005; revised 11 November 2005; accepted 1 December 2005
Available online 20 December 2005
Abstract—An efficient and simple approach for the solid-phase synthesis of 2,4,6-triaminopyrimidines and 2-alkyl-4,6-diaminopyrimidines
is described. Primary amines were immobilized on 2-(4-formyl-3-methoxyphenoxy)ethyl polystyrene resin via reductive amination.
Attachment of two different 4,6-dichloropyrimidines led to the corresponding 4-chloro-6-aminopyrimidine intermediates. Aromatic
nucleophilic substitution with various aliphatic amines or the corresponding lithium amides afforded the desired aminopyrimidines in high
1
13
yield and excellent purity after acidic cleavage from the resin. The products were characterized by LC–MS, H and C NMR spectroscopy.
Deuterium exchange experiments revealed that the investigated aminopyrimidines have a general tendency toward C-5 protonation.
q 2005 Elsevier Ltd. All rights reserved.
1
0,11,15
1
. Introduction
alkylsulfinyl group
amide linker (Scheme 1).
support via an amino group using a carbamate bond has
or via the amino group of a Rink
1
2,13
Attachment to the solid
Di- and triaminopyrimidines are reported to exhibit diverse
biological and pharmacological activities including acting
1
4,17,18
been reported as well.
There are two disadvantages of
1
as tyrosine kinase and dihydrofolate reductase inhibitors,
2
using an alkylsulfenyl group as a linker. Firstly, for
substitution by amines the sulfide has to be oxidized to
sulfone or sulfoxide, which can result in formation of
undesired by-products (N-oxides). Secondly, removing of
the excess of amine used in the last step requires an extra
chemical step. The drawback of using methods based on a
Rink amide linker is that they afford aminopyrimidines that
are not substituted at one of the amino groups. Moreover, a
general problem originates from the introduction of the third
amino group, which requires very harsh conditions limiting
the field of amines that can be used in this step. Although
trimethyl aluminium catalyzed substitution of the sulfone
group at the C-2-position by aromatic amines under mild
conditions has been published recently, the method was
3
as well as antibacterial, antiallergenic and antimalarial
4
5
6
agents. Antiviral, antidepressant and antiprotozoan
7
8
activities of diaminopyrimidines have been disclosed as
well. With the potent biological and pharmacological
activities of aminopyrimidines in mind, the development
of an efficient solid-phase strategy for the synthesis of these
compounds was explored.
In addition to a number of reports describing the solution-
9
phase syntheses of aminopyrimidines examples of solid-
phase syntheses of these compounds can be found in the
literature. Thus, various aminopyrimidines have been
prepared on solid support starting either by de novo
synthesis of the pyrimidine core onto the resin,
by initial attachment of the pyrimidine to the resin and
subsequent modification. Most of the known methods
couple the pyrimidine core to the resin either via an
1
0,11
1
6
or
used only for the synthesis of 2,4-diaminopyrimidines.
1
2–18
Our aim was to develop a simple, efficient and robust
synthetic strategy for the synthesis of 2-alkyl-4,6-diamino-
pyrimidines and 2,4,6-triaminopyrimidines that would not
only allow the use of a wide range of primary and secondary
aliphatic amines but would easily be automated and would
also be amenable to either large or small focused library
synthesis. Our approach differs from previous ones by
using solid-phase supported amines instead of the Rink
linker and by using strongly nucleophilic lithium amides,
generated from the amines, for the introduction of the third
amino group.
Keywords: Solid-phase; Aliphatic amines; 4,6-Dichloropyrimidines.
Abbreviations: DCM, dichloromethane; DMF, N,N-dimethylformamide;
DMAC, N,N-dimethylacetamide; THF, tetrahydrofuran; TFA,
trifluoroacetic acid; TEA, triethylamine; DIEA, N,N-diisopropylethyla-
mine; m-CPBA, 3-chloroperbenzoic acid; Pip, piperidine; Pyr, pyrrolidine;
Pip-C(2,6), carbon atoms of piperidine at 2- and 6-positions; Pip-H(2,6),
hydrogen atoms connected to Pip-C(2,6); eq, equatorial; ax, axial; H and
y
H, chemically nonequivalent hydrogen atoms.
Corresponding author. Tel.: C36 1 431 5144; fax: C36 1 432 6002;
e-mail: cs.weber@richter.hu
x
*
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.12.004

C. W e´ ber et al. / Tetrahedron 62 (2006) 2304–2312
2305
O
O
N
1
HN
Cl
R
HN
Cl
i, HNR R2
1
H N
N
2
i, HNR R2
1
2
N
N
R
N
N
N
R
ii, TFA, DCM
ii, TFA, DCM
R
R
N
3
1
1
3
R
N
R
N
R
HO
O
R
N
4
4
2
N
R
2
i, POCl3, ii, HNR R2
1
R
v, HNR
5
R
6
R
R
N
N
N
O
N
N
S
iii, HNR R4
3
iv, m-CPBA
S
6
N
5
R
R
O
R = alkyl, SMe
1
2
3
4
5 6
HNR R , HNR R , HNR R : primary or secondary amines
Scheme 1. Linkage strategies for aminopyrimidines.
2
. Results and discussion
elemental analysis (N content). Primary amines branched at
the a-position were also applied successfully in this step.
Herein, we report an efficient solid-phase synthesis of 2,4,6-
triaminopyrimidines and 2-alkyl-4,6-diaminopyrimidines
from acid labile 2-(4-formyl-3-methoxyphenoxy)ethyl
polystyrene 1 in which sequential aromatic nucleophilic
substitutions of the chlorines of 4,6-dichloropyrimidines are
employed as key steps (Scheme 2).
We chose to make use of two different 4,6-dichloro-
pyrimidines (3a, 3b) in order to explore the chemistry
outlined in Scheme 2. Both 2-alkyl- and 2-aminopyrimi-
dines can easily be synthesized: 3a was prepared in one
2
1
step from 2-methyl-4,6-pyrimidinedione, 3b from 2,4,6-
trichloropyrimidine.
2
2
Although the use of 2-(4-formyl-3-methoxyphenoxy)ethyl
linker for the synthesis of aminopyrimidines had not been
demonstrated before, it was successfully employed
for solid-phase synthesis of diaminoquinazolines. For
the synthesis of aminopyrimidines the more acid sensitive
Attachment of the two pyrimidines (3a, 3b) to a supported
secondary amine 2 was achieved in the presence of N,N-
diisopropylethylamine (DIEA) in N,N-dimethylformamide
(DMF) at room temperature. Quantitative attachment was
obtained for a pyrimidine concentration of 1.5 M for 100 h
at room temperature. Resin loadings were verified by the N
content of the resin. At this point, it was checked whether
the o-methoxybenzyl group of aminopyrimidine inter-
mediate 4 can be cleaved by TFA/DCM mixture. Treatment
of 4 with 10% TFA in DCM resulted in the formation
of the expected 4-chloro-6-amino derivatives 5 in nearly
19
4
Arvanitis et al.
-formyl-3,5-dimethoxyphenoxy linker was employed by
1
6
In the first step, 2-(4-formyl-3-methoxyphenoxy)ethyl
polystyrene resin 1 was loaded with various primary
2
0
aliphatic amines by reductive amination (Scheme 2).
The conversion proved to be quantitative, as checked by
Scheme 2. Solid-phase synthesis of aminopyrimidines.

2306
C. W e´ ber et al. / Tetrahedron 62 (2006) 2304–2312
Table 1. Purities and yields of 6-amino-4-chloropyrimidines (5)
1
2
R
a
b
Product
R
Yield (%)
Purity (%)
1
2
3
4
5
6
5/1
5/2
5/3
5/4
5/5
5/6
n-Hexyl
N-Isopropylethylamino
N-Isopropylethylamino
N-Isopropylethylamino
Methyl
Methyl
Methyl
96
91
92
94
96
98
98
99
98
99
97
98
2-Methylbutyl
2-Heptyl
n-Hexyl
2-Methylbutyl
2-Heptyl
a
The yields were determined by weight based on the loading of 4.
The purities were determined by HPLC–MS at 254 nm.
b
quantitative yields and excellent purities (Table 1). The
structures of these products was confirmed by NMR and
mass spectrometry as well. Yields obtained from the N
content of 4 are equal, within experimental error, to those
calculated from the weight of 5.
aminopyrimidines, 6-amino-4-dimethylaminopyrimidine
side products were observed up to 15–45% of the product.
Formation of this type of side product in reaction of
chloropyrimidines and amines in DMF was reported by
2
3
Load previously. Cyclic amines branched at a-position
did not give pure product with 4a, probably because of steric
effects (Table 2, entries 12 and 13). While reactions of
2-methyl derivatives 4a with primary and secondary
In the next step, aromatic nucleophilic substitution reaction
of solid-phase bound 4-chloro-6-aminopyrimidine deriva-
tives 4 with various aliphatic amines was studied. Release
from the resin was achieved by treating 6 with 10% TFA in
DCM to yield the desired product 7. Formation of 7 in high
aliphatic amines in n-BuOH or MeNO afforded the desired
2
products in high yield and purity (Table 2, entries 14–19),
2-amino derivatives 4b did not give pure products under
the same conditions. This is probably due to the fact that the
chlorine in 4b is less reactive than it is in 4a because of the
stronger electron donating effect of the N-isopropylethy-
lamino group compared to the methyl group.
1
13
purity was proven by HPLC, H and C NMR analysis of
the unpurified material.
Reactions of 2-methyl- and 2-(N-isopropylethylamino)pyri-
midine derivatives 4 with primary and secondary aliphatic
amines, branched and unbranched four to six-membered
cyclic amines were investigated in different solvents (N,N-
To replace the chlorine of 4b by aliphatic amines under mild
conditions a new approach was examined. Since we could
not achieve high conversion neither by prolonged reaction
times nor by higher concentrations of the amines we tried to
increase the nucleophilic character of the reagent. Amines
were deprotonated by n-BuLi, forming lithium amides,
before adding resin to the solution. The reaction conducted
at room temperature afforded the desired triaminopyrimi-
dines in moderate yield and high purity after acidic cleavage
from the resin (Table 2, entries 20 and 21).
dimethylacetamide (DMAC), n-BuOH, MeNO ) using 20
2
fold excess of amines. Because in the course of our former
experiments DMAC was found to be the best solvent of
amines, it was tried first. While in the case of using
unbranched four to six-membered cyclic amines the
reaction was complete in 140 h in DMAC at 100 8C
(
Table 2, entries 1–11), primary and acyclic secondary
aliphatic amines did not give pure products under these
conditions. In the latter cases, in addition to the desired
Table 2. Purities and yields of 4,6-diaminopyrimidines (7)
1
R
2
R
3
HNR R
4
a
b
Product
Solvent
Yield (%)
Purity (%)
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
7/1
7/2
7/3
7/4
7/5
7/6
7/7
7/8
n-Hexyl
N-Isopropylethylamino
N-Isopropylethylamino
N-Isopropylethylamino
N-Isopropylethylamino
Methyl
Methyl
Methyl
Methyl
Methyl
Methyl
Methyl
Methyl
Methyl
Methyl
Methyl
Methyl
Methyl
4-Methylpiperidin-1-yl
4-Methylpiperidin-1-yl
Pyrrolidin-1-yl
DMAC
DMAC
DMAC
DMAC
DMAC
DMAC
DMAC
DMAC
DMAC
DMAC
DMAC
DMAC
DMAC
n-BuOH
89
84
89
87
95
94
93
86
77
96
84
—
—
82
79
87
85
85
87
61
57
95
98
99
81
99
99
99
99
99
99
99
28
0
95
91
98
80
98
98
91
93
2-Methylbutyl
2-Methylbutyl
2-Methylbutyl
n-Hexyl
2-Methylbutyl
2-Heptyl
2-Methylbutyl
2-Methylbutyl
2-Heptyl
2-Methylbutyl
2-Methylbutyl
2-Methylbutyl
2-Methylbutyl
2-Methylbutyl
n-Hexyl
Azetidin-1-yl
4-Methylpiperidin-1-yl
4-Methylpiperidin-1-yl
4-Methylpiperidin-1-yl
4-Phenylpiperazin-1-yl
Pyrrolidin-1-yl
7/9
0
1
2
3
4
5
6
7
8
9
0
1
7/10
7/11
7/12
7/13
7/14
7/14
7/15
7/15
7/16
7/17
7/18
7/19
Pyrrolidin-1-yl
Azetidin-1-yl
2-Ethylpiperidin-1-yl
2,6-Dimethylpiperidin-1-yl
Bis(n-butyl)amino
Bis(n-butyl)amino
n-Hexylamino
n-Hexylamino
n-Hexylamino
n-Hexylamino
Bis(n-butyl)amino
n-Hexylamino
MeNO
n-BuOH
MeNO
2
n-Hexyl
2
2-Methylbutyl
2-Heptyl
n-Hexyl
Methyl
Methyl
N-Isopropylethylamino
N-Isopropylethylamino
n-BuOH
n-BuOH
THF
n-Hexyl
THF
a
The yields were determined by weight based on the loading of 4.
The purities were determined by HPLC–MS at 254 nm.
b

C. W e´ ber et al. / Tetrahedron 62 (2006) 2304–2312
2307
In summary, the next conditions were found to be optimal
for the synthesis of 7:
The observed deuterium exchange proves the ongoing C(5)
protonation indirectly, since the exchange process involves
the presence of the C(5) protonated sigma complex form (9).
The observed deuterium exchange characteristic of the
investigated compounds, that is, the rate of exchange,
qualitatively seems to show correlation with the electron
donating effect of amino substituents. However, further
investigations (precise exchange rate measurements) are
required to prove this correlation.
1
. DMAC, 100 8C, 140 h, camineZ1.8 mmol/1 mL sol-
vent, for the introduction of four to six-membered
unbranched cyclic aliphatic amines.
2
. n-BuOH, 100 8C, 140 h, camineZ1.8 mmol/1 mL
solvent, for the introduction of unbranched primary and
secondary aliphatic amines into 2-alkylpyrimidines.
3
. Lithium amide salt of the amine, room temperature,
THF, 24 h, cLi–amideZ0.5 M for the introduction of
unbranched primary and secondary aliphatic amines into
3. Conclusion
2
-aminopyrimidines.
A simple and efficient four-step strategy has been
described for the solid-phase synthesis of 2,4,6-triamino-
pyrimidines and 2-alkyl-4,6-diaminopyrimidines. The
synthetic approach provides convenient access to phar-
macologically interesting aminopyrimidine derivatives in
good yields and excellent purities. To the best of our
knowledge, this is the first example of using 2-(4-formyl-
0
0
00 00
We have recently showed that N,N,N ,N ,N ,N -hexa-
1
methyl-2,4,6-pyrimidinetriamine (8, R ZR ZR ZNMe ,
Fig. 1) could be carbon-protonated at the C(5) position in
2
addition to the expected N(1) protonation. We also
described the synthesis of the first stable cationic sigma
complex in the pyrimidine series. In a forthcoming paper,
we gave detailed account of the structure determination
aspect of that work. In the case of compound 8 (R ZR Z
2
3
2
2
2
4
3
-methoxyphenoxy)ethyl linker for the synthesis of
2
5
1
2
aminopyrimidines and the first solid-phase method
applying lithium amide as nucleophile for displacing the
chlorine of chloropyrimidines. Deuterium exchange
experiments proved that 2,4,6-triaminopyrimidines and
2-alkyl-4,6-diaminopyrimidines have a general tendency
toward C(5) protonation.
3
R ZNMe ) the C(5) and N(1) protonated forms could be
2
detected simultaneously, showing that the exchange
between the two protonated forms is slow on the NMR
chemical shift timescale. Keeping on this track, in this paper
we investigated the generality of carbon protonation of
aminopyrimidines on aminopyrimidine derivatives (5 and
Further investigation to assess the applicability of the
synthetic strategy to the automated synthesis of large
aminopyrimidine libraries as well as a detailed study of
C-5 protonation of aminopyrimidines are in progress.
7
). The C(5) protonated forms of the investigated
compounds could not be detected directly due to their
small population. An indirect proof, however, was observed
via deuterium exchange NMR experiments (Fig. 1).
4. Experimental
4.1. General
Reagents were obtained from Sigma-Aldrich. 2-(4-Formyl-
-methoxyphenoxy)ethyl polystyrene resin was purchased
3
from Novabiochem (cat number: 01-64-0399, batch
number: A26869, 100–200 mesh, 1% cross-linked,
1
.2 mmol/g). Solvents were obtained from Merck and
were used as received. Small scale parallel solid-phase
reactions were performed using an Advanced ChemTech
PLS 4!6 system in 8 mL glass reaction vials (1.5!5 cm)
with Teflon-lined screw-cap. Cleavage and washing of the
resin were performed in 8 mL Teflon vials (1.5!5 cm)
equipped with a filter at the bottom.
Figure 1. Deuterium exchange via the C(5) protonated sigma complex.
D O (5%) was added to the DMSO-d solutions of selected
2
6
1
derivatives prepared as TFA salts, and their H NMR
spectra were recorded at 30 8C immediately after addition of
D O and again several hours later.
2
Purity was determined by HPLC (Hewlett-Packard HP
1100) using an acetonitrile/water gradient (100% water to
95% acetonitrile v/v, with 0.1% TFA with a run time of
We observed nearly complete deuterium exchange of the
H(5) proton for 7/1, 7/2, 7/3 within 1–3 h. Deuterium
exchange of H(5) proceeded on a somewhat slower
timescale (3–24 h) for 7/6–10. After 2 days 70, 50 and
20 min) on a Discovery RP C –amide column (5 cm!
1
6
4.6 mm, 5 mm) operating at a flow rate of 1 mL/min;
analysis was conducted at 254 nm wavelength, and
retention times were recorded. The sample concentration
was 1.0 mg/mL. Molecular parent ion identity was
confirmed via mass spectrometry using electrospray
ionization and a probe voltage of 4.0 kV.
8
0% deuterium exchange was observed on the H(5) signal
of 7/14, 7/16 and 7/17, respectively. It is interesting to note
that 7/11 did not show considerable deuterium exchange,
which is attributed to the presence of the strained azetidine
ring. For the 4-chloro derivatives, deuterium exchange at
H(5) was nearly complete for 5/2, while 5/5 and 5/6 did not
show exchange after 2 days.
The structures of compounds having at least 80% purity
were confirmed by nuclear magnetic resonance (NMR)

2308
C. W e´ ber et al. / Tetrahedron 62 (2006) 2304–2312
spectroscopy. NMR spectra were recorded either at 300 or
5
INOVA spectrometer. The chemical shifts are reported in
4.2. General procedure for the preparation of polymer-
bound 4-chloropyrimidines (4)
1 13
00 MHz for H and 125 or 75 MHz for C on a Varian
ppm relative to TMS in CDCl or in DMSO-d at 30 8C.
6
HRMS were performed on a FinninganMAT 95XP
apparatus (EI, 70 eV, resolution: 10,000).
To a suspension of polymer-bound amine (1.3 g,
y1.4 mmol) 2 in DMF (4 mL) was added 4,6-dichloro-
pyrimidine derivative 3 (20.7 mmol) and DIEA (1.25 mL,
3
7
mmol). The mixture was shaken for 120 h at room
temperature. The polymer was filtered off, washed
3!20 mL DMF, 3!20 mL MeOH, 3!20 mL DCM,
Melting points are uncorrected.
(
3
3
4
!20 mL MeOH, 3!20 mL DCM, 3!20 mL MeOH,
!20 mL DCM), and dried in vacuo for 48 h to give resin
. Capacities of the resins ranged from 0.85 to 0.94 mmol/g
4
.1.1. Resin-bound amines (2). Resin (3.0 g, 3.6 mmol)
was added to a mixture of DMF (30 mL) and DCM (20 mL).
Aliphatic primary amine (36 mmol) and acetic acid
based on a N content ranging from 2.7 to 3.5 mmol/g.
Conversions calculated from the N content were 95–98%.
(36 mmol, 2.2 mL) were added dropwise. The resulting
mixture was shaken for 2 h and then NaBH(OAc) (3.68 g,
3
1
7 mmol) was added in 4 portions. After 24 h reaction at
room temperature the resin was washed [3!30 mL DMF,
!30 mL MeOH, 3!30 mL DCM, 3!30 mL DMF (5%
4
6
.3. Cleavage of 4 from the resin: preparation of
-amino-4-chloropyrimidines 5
3
TEA), 3!30 mL DCM (5% TEA), 3!30 mL MeOH (5%
TEA), 4!30 mL MeOH, 4!30 mL DCM] and dried under
vacuo for 48 h. The loading of the resin was determined by
N content: 2a (N-hexyl): 1.06 mmol/g (conversionZ97%);
Resin 4 (50 mg, 0.042–0.048 mmol) was shaken in
DCM–TFA (9/1) (2 mL) for 2 h, then it was filtered off.
The filtrate was combined with washes of DCM (2!1 mL)
and MeOH (2!1 mL), the solvent was evaporated then the
residue was dried under vacuo overnight to give 5. The
products as trifluoroacetate salts were obtained as glassy
colourless or yellowish oils or semisolids. The weight of the
products ranged from 14 to 17 mg. The yields were
calculated from weight of 5 based on the loading of 4, and
ranged from 91 to 99%.
2
b (N-2-methylbutyl): 1.08 mmol/g (conversionZ98%); 2c
(
N-2-heptyl): 1.04 mmol/g (conversionZ95%).
2
.1.2. 4,6-Dichloro-2-methylpyrimidine (3a). 4,6-Di-
1
4
hydroxy-2-methylpyrimidine (5.0 g, 0.04 mol) was stirred
in POCl (30 mL) at 140 8C for 3 h. The excess of POCl
3
3
was distilled off and the residue was poured onto crushed ice
50 g). The precipitate was filtered off and purified by silica
gel column chromatography (50 g silica gel, CHCl ) to
4
.3.1. 6-(n-Hexylamino)-2-(N-isopropylethylamino)-4-
chloropyrimidine (5/1). Yield: 96%. Glassy yellowish oil.
(
1
3
H NMR (DMSO-d , 500 MHz, 30 8C): d 0.86 (t, 3H, JZ
6
give 5.4 g product (colourless crystal). Yield: 84%. Mp
2
7
Hz, CH (CH ) CH CH NH–), 1.11 (t, 3H, JZ7 Hz,
3 2 3 2 2
1
C
4
(
[
6–47 8C. Mp published: 49 8C. HPLC–MS: M Z162
CH CH N–), 1.12 [d, 6H, JZ7 Hz, (CH ) CHN–],
1.22–1.34 [m, 6H, CH (CH ) CH CH NH–], 1.44–1.53 [m,
2H, CH (CH ) CH CH NH–], 3.15–3.45 [br m, 4H, CH
3 2 3 2 2 3
3
2
3 2
1
EI); H NMR (CDCl , 500 MHz): d 2.64 (s, 3H, CH ), 7.18
3 3
3 2 3 2 2
1
s, 1H, H(5)]. C NMR (CDCl , 125 MHz, 30 8C): d 25.7
3
3
CH , 118.4 C(5), 161.6, 169.8 C(4, 6), C(2).
3
(CH ) CH CH NH–, CH CH N–], 4.78 [m, 1H, JZ7 Hz,
2 3 2 2 3 2
–NCH(CH ) ], 5.70 [s, 1H, H(5)], 7.13 [br s, 1H, CH (CH ) -
CH CH NH–]. C NMR (DMSO-d , 125 MHz): d 13.8
3 2 3 2 3
1
3
2
2
6
4
.1.3. 4,6-Dichloro-2-(N-isopropylethylamino)-pyrimi-
dine (3b). A solution of 2,4,6-trichloropyrimidine (6.6 g,
.036 mol) in DCM (100 mL) was cooled to K40 8C under
a N atmosphere. A solution of N,N-diisopropylethylamine
CH (CH ) NH–, 14.9 CH CH N–, 20.1 (CH ) CHN–, 22.0
3
2 5
3
2
3 2
CH CH (CH ) CH NH–, 26.1 CH (CH ) CH (CH ) NH–,
2 2
3
2
2 3
2
3
2 2
2
0
2
NH–, 36.1 CH CH N–, 40.4 CH (CH ) CH NH–, 45.4
8.9 CH (CH ) CH CH NH–, 30.9 CH CH CH (CH )
3 2 3 2 2 3 2 2 2 3
2
3
2
3
2 5
2
(
0
7.26 mL, 0.04 mol) and N-isopropylethylamine (4.84 mL,
.04 mol) in DCM (100 mL) was added dropwise to the
(
CH ) CHN–, 91.8 C(5), 156.7 C(6), 160.0 C(2), 163.4 C(4);
3 2
C
HPLC–MS: M Z298 (EI); Purity: 98%. HRMS: (EI), m/z
solution of trichloropyrimidine over 30 min. The reaction
was allowed to warm up to room temperature over 2 h and
was refluxed for 6 h. The solution was washed with water
C 35
M ] found: 298.1931, calcd for C H ClN : 298.1924.
[
15 27 4
4.3.2. 4-Chloro-2-(N-isopropylethylamino)-6-(2-methyl-
n-butylamino)pyrimidine (5/2). Yield: 91%. Glassy
(
2!200 mL), dried over Na SO , following which solvent
2 4
removal was performed at reduced pressure and at
temperature less than 40 8C. The 2-amino isomer was
separated from its regioisomer by column chromatography
1
yellowish oil. H NMR (DMSO-d , 300 MHz): d 0.85
6
[
d, 3H, JZ7 Hz, CH CH (CH )CHCH NH–], 0.87 [t, 3H,
3 2 3 2
JZ7 Hz, CH CH (CH )CHCH NH–], 1.11 (t, JZ7 Hz,
3
2
3
2
(
(
450 g silica gel, hexane/ethyl acetateZ98:2). mZ3.0 g
3
1
H, CH CH N–), 1.12 [d, 6H, JZ7 Hz, (CH ) CHN–],
3 2 3 2
x y
C
colourless oil). YieldZ38%. HPLC–MS: M Z233 (EI);
.14–1.25 [m, 1H, CH CH H (CH )CHCH NH–],
3
3
2
1
x
y
H NMR (DMSO-d , 500 MHz, 30 8C): d 1.13 (t, 3H, JZ
6
1.25–1.50 [m, 1H, CH CH H (CH )CHCH NH–]
3 3 2
7
Hz, CH CH N–), 1.14 (d, 6H, JZ6.5 Hz, (CH ) CHN–),
3 2 3 2
1.50–1.70 [m, 1H, CH CH (CH )CHCH NH–], 2.9–3.1
3 2 3 2
x
y
3
(
.39 (q, 2H, JZ7 Hz, CH CH N–), 4.79–4.88 [m, 1H,
3
2
[m, 1H, CH CH (CH )CHCH H NH–], 3.15–3.35 [br m,
3 2 3
1
CH ) CHN–], 6.40 [s, 1H, H(5)]. C NMR (DMSO-d6,
3
x
y
3 2
1H, CH CH (CH )- CHCH H NH–], 3.36 [q, 2H, JZ7 Hz,
3 2 3
1
3
1
25 MHz, 50 8C): d 14.3, 20.3 [(CH ) CHN–, CH CH N–],
2
CH CH N–], 4.78 [heptett, 1H, JZ7 Hz, CH CH
3
2
3
3 2 3 2
7.4 CH CH N–, 47.1 (CH ) CHN–, 107.0 C(5), 160.3,
3
(N–)CH(CH ) ], 5.73 [s, 1H, H(5)], 7.21 [br s, 1H,
2
3 2
3 2
C
61.2 C(2, 4, 6). Anal. Calcd for: C H Cl N ; C, 46.17%;
13
CH (CH ) CH CH NH–]. HPLC–MS: M Z284 (EI);
9
2
3
3
2 3
2
2
C
Purity: 99%. HRMS: (EI), m/z [M ] found: 284.1774,
H, 5.60%; Cl, 30.28%; N, 17.95%. Found: C, 46.25%; H,
.58%; Cl, 30.35%; N, 18.01%.
3
5
5
calcd for C H ClN : 284.1768.
14 25 4

C. W e´ ber et al. / Tetrahedron 62 (2006) 2304–2312
2309
4.3.3. 4-Chloro-6-(2-heptylamino)-2-(N-isopropylethyl-
amino)pyrimidine (5/3). Yield: 92%. Glassy yellowish
(1.0 mL), and the amine (1.7–1.84 mmol) was added. The
mixture was shaken for 140 h at 100 8C. The resin was
filtered off and washed (3!2 mL DMF, 3!2 mL MeOH,
3!2 mL DCM, 3!2 mL DMF, 3!2 mL MeOH, 3!2 mL
DCM) to give 6. Method B. (For reaction of 2,6-diamino-4-
chloropyrimidines with acyclic aliphatic amines): to a
solution of amine (0.85–0.94 mmol) in THF (4 mL, water
content !0.01% v/v) n-BuLi (0.76 mmol, 0.48 mL 15%
solution m/m in n-hexane) was added dropwise. (The vials
had been dried and purged with argon previously). The
reaction mixture was shaken for 20 min at room tempera-
ture. Resin 4 (0.085–0.094 mmol, 100 mg) was washed with
dry THF (3!3 mL), then it was added to the solution of
lithium amide. The mixture was shaken for 24 h at room
temperature, and then the resin was filtered off and washed
(3!4 mL MeOH, 3!4 mL THF, 3!4 mL DCM, 3!4 mL
MeOH, 3!4 mL DCM).
1
oil. H NMR (DMSO-d , 500 MHz): d 0.82 [t, 3H,
6
CH CH(NH–)(CH ) CH ],
1.05–1.20
[m,
12H,
CH CH N–, (CH ) CHN–, CH CH(NH–)(CH ) CH ],
3
2 4
3
3
2
3 2
3
2 4
3
1
1
.20–1.35 [m, 6H, CH CH(NH–)CH (CH ) CH ], 1.35–
3 2 2 3 3
x
.40 [m, 1H, CH CH(NH–)CH H (CH ) CH ], 1.40–1.55
y
3
2 3
3
x
y
[
m, 1H, CH CH(NH–)CH H (CH ) CH ], 3.35–3.50 [q,
3 2 3 3
2
CH ], 4.65–4.85 [m, 1H, –NCH(CH ) ], 5.69 [s, 1H, H(5)],
H, CH CH N–], 4.00–4.15 [m, 1H, CH CH(NH)(CH ) -
3 2 3 2 4
3
3 2
6
.95 [br m, 1H, CH CH(NH)(CH ) CH ], 8.9–9.0 [br s, 1H,
3 2 4 3
C
CF COOH]. HPLC–MS: M Z312 (EI); Purity: 98%.
3
C
HRMS: (EI), m/z [M ] found: 312.2092, calcd for
3
29
5
C H ClN : 312.2081.
1
6
4
4
(
.3.4. 6-(n-Hexylamino)-4-chloro-2-methylpyrimidine
5/4). Yield: 94%. Glassy colourless oil. NMR (DMSO-d6,
5
1
00 MHz): d 0.87 [t, 3H, JZ7 Hz, CH (CH ) CH CH NH–],
3 2 3 2 2
.22–1.34 [m, 6H, CH (CH ) CH CH NH–], 1.50 [p, 2H,
4.5. Cleavage of 6 from the resin: preparation of 2-alkyl-
4,6-diaminopyrimidines and 2,4,6-triaminopyrimidines
(7)
3
2 3
2
2
JZ7 Hz, CH (CH ) CH CH NH–], 2.32 [s, 3H, Me(C2)],
3
2 3
2
2
3
H(5)], 7.4–8.1 [br m, 1H, CH (CH ) CH CH NH–],
.0–3.4 [br m, 2H, CH (CH ) CH CH NH–], 6.35 [s, 1H,
3 2 3 2 2
1
3
C
NMR (DMSO-d , 125 MHz): d 13.8 CH (CH ) CH NH–,
3
2 3
2
2
The same procedure was followed as in the case of 6-amino-
4-chloropyrimidines (5).
6
3
2 4
2
2
2.0 CH CH (CH ) CH NH–, 25.2 CH C(2), 25.9 CH
3
3
2
2 3
2
3
(
CH ) CH CH CH NH–, 28.51 CH (CH ) CH CH NH–,
2 2 2 2 2 3 2 3 2 2
3
0.9 CH CH CH (CH ) NH–, 40.9 CH (CH ) CH CH -
2
4.5.1. 6-(n-Hexylamino)-2-(N-isopropylethylamino)-4-
(4-methylpiperidin-1-yl)pyrimidine (7/1). Yield: 89%.
3
2
2
2 3
3
2 3
2
NH–, 100.6 C(5), 163.2 C(4), 167.4 C(2), The C(6) signal
is broadened to the extent that it escapes detection.
1
Yellowish semisolid. H NMR (DMSO-d , 500 MHz): d
6
C
HPLC–MS: M Z227 (EI); Purity: 99%. HRMS: (EI), m/z
0.88 (t, 3H, JZ7 Hz, CH (CH ) CH CH NH–), 0.92 (d, 3H,
3
2 3
2
2
C 35
M ] found: 227.1178, calcd for C H ClN : 227.1189.
[
JZ6 Hz, Pip-CH ), 0.98–1.1 [m, 2H, Pip-H (3, 5)], 1.15
1
1
18
3
3 ax
(
t, 3H, JZ7 Hz, CH CH N–), 1.20 [d, 6H, JZ7 Hz,
3 2
4.3.5. 4-Chloro-2-methyl-6-(2-methyl-n-butylamino)pyri-
midine (5/5). Yield: 96%. Glassy colourless oil. H NMR
(CH ) CHN–], 1.22–1.40 [m, 6H, CH (CH ) CH CH
3 2 3 2 3 2 2
NH–], 1.49–1.60 [m, 2H, CH (CH ) CH CH NH–],
3 2 3 2 2
1
(
CH (CH )CHCH NH–), 0.87 (t, 3H, CH CH (CH )-
DMSO-d , 300 MHz): d 0.86 (d, 3H, JZ6.9 Hz, CH -
1.64–1.74 [m, 3H, Pip-H (3, 5), Pip-H(4)], 2.82–3.0 [m,
eq
6
3
2
3
2
3
2
3
2H, Pip-H (2,6)], 3.15–3.25 (br m, 2H, CH (CH ) CH -
ax
3
2 3
2
x
CH CH H
y
CHCH NH–),
1.05–1.20
(m,
1H,
CH )CHCH NH–), 1.25–1.50 (m, 1H, CH CH H (CH )-
CH NH–), 3.35–3.42 [q, 2H, CH CH (N–)CH(CH ) ,],
2 3 2 3 2
2
3
y
x
(
CHCH NH–), 1.50–1.68 (m, 1H, CH CH (CH )CHCH -
4.0–4.2 [br m, 2H, Pip-H (2,6)], 4.51 [m, 1H, CH CH
eq 3
3
2
3
3
2
2
3
2
3
2
(N–)CH(CH ) ], 5.35 [s, 1H, H(5)], 7.14 (br t, 1H, CH
3 2
(CH ) CH CH NH–), 10.54 (br s, 1H, CF COOH). C NMR
2 3 2 2 3
3
1
3
NH–), 2.31 [s, 3H, CH (C2)], 2.80–3.35 [m, 2!1H,
3
x
CH CH (CH )CHCH H NH–], 6.37 [s, 1H, H(5)], 7.60
y
3
2
3
(DMSO-d , 125 MHz): d 13.6, CH (CH ) CH CH NH–,
6 3 2 3 2 2
14.0 CH CH N–, 19.6 (CH ) CHN–, 21.2 Pip-CH , 21.7
3 2 3 2 3
CH CH (CH ) NH–, 25.7 CH (CH ) CH (CH ) NH–, 27.6
3 2 2 4 3 2 2 2 2 2
C
(
2
2
br s, 1H, CH CH (CH )CHCH NH–). HPLC–MS: M Z
3
2
3
2
C
13 (EI); Purity: 97%. HRMS: (EI), m/z [M ] found:
3
5
13.1039, calcd for C H ClN : 213.1033.
1
CH (CH ) CH CH NH–, 30.2 Pip-C(4), 30.7 CH CH CH
3 2 3 2 2 3 2
0
16
3
2
(
CH ) NH–, 33.2 Pip-C(3, 5) 36.3 CH CH N–, 41.0 CH
2 3 3 2
3
4
(
.3.6. 4-Chloro-6-(2-heptylamino)-2-methylpyrimidine
5/6). Yield: 98%. Glassy colourless oil. H NMR (DMSO-
(CH ) CH CH NH–, 44.3 Pip-C(2,6), 47.1 (CH ) CHN–,
2 3 2 2 3 2
1
C
69.0 C(5), 150.4 C(2), 154.4 160.1 C(4). HPLC–MS: M Z
361 (EI); Purity: 95%. HRMS: (EI), m/z [M ] found:
C
d , 300 MHz): d 0.85 [t, 3H, JZ6.6 Hz, CH CH(NH–)
6
3
(
(
CH ) CH ], 1.09 [d, 3H, JZ6.6 Hz, CH CH(NH–)
361.3211, calcd for C H N 361.3205.
21 39 5
2
4
3
3
CH ) CH ], 1.18–1.35 [m, 6H, CH CH(NH–)CH (CH ) -
2
4
3
3
2
2 3
CH ], 1.35–1.55 [m, 2H, CH CH(NH–)CH (CH ) CH ],
3
4.5.2. 6-(2-Methyl-n-butylamino)-4-(4-methylpiperidin-
1-yl)-2-(N-isopropylethylamino)pyrimidine (7/2). Yield:
3
2
2 3
3
2
CH ], 6.2–6.4 [br s, 1H, H(5)], 7.5–7.7 [br m, 1H,
.31 [s, 3H, CH (2)], 4.0–4.3 [br m, 1H, CH CH(NH)(CH ) -
3
3
2 4
1
84%. Yellowish semisolid. H NMR (DMSO-d , 300 MHz):
3
6
C
CH CH(NH)(CH ) CH ]. HPLC–MS: M Z241 (EI);
d 0.89 [t, 3H, JZ6.3 Hz, CH CH CH(CH )CH NH–], 0.91
3
2 4
3
3
2
3
2
C
Purity: 98%. HRMS: (EI), m/z [M ] found: 241.1360,
(d, 3H, JZ5.1 Hz, Pip-Me), 0.92 (d, 3H, JZ6.6 Hz,
CH CH CH(CH )CH NH–), 0.98–1.1 [m, 2H, Pip-H (3,
3
20
5
calcd for C H ClN : 241.1346.
1
2
3
3
2
3
2
ax
x
y
5
)], 1.1–1.3 [m, 1H, CH CH H CH(CH )CH NH–], 1.15 (t,
3 3 2
4
2
.4. Preparation of resin-bound 4,6-diamino- and
,4,6-triaminopyrimidines (6)
3H, JZ6.9 Hz, CH CH N–), 1.20 [d, 6H, JZ6.9 Hz,
3 2
x y
(CH ) CHN–], 1.34–1.52 (br m, 1H, CH CH H CH(CH )-
3
2
3
3
CH NH–), 1.55–1.78 [m, 4H, Pip-H (3, 5), Pip-H(4),
2
eq
Method A. Resin 4 (100 mg, y0.085–0.094 mmol) was
swollen in DMAC (for reaction with four to six member
cyclic amines) or in n-BuOH (for reaction of acyclic
primary and secondary amines with 2-alkylpyrimidines)
CH CH CH(CH )CH NH–], 2.8–3.0 [br m, 2H, Pip-
3 2 3 2
H (2,6)], 3.0–3.2 [br m, 2H CH CH CH(CH )CH NH–],
2
ax
3
2
3
3.37 (q, 2H, CH CH N–), 4.0–4.3 [br m, 2H, Pip-H (2,6)],
3
2
eq
4.3–4.5 [br m, 1H, (CH ) CHN–], 5.37 [s, 1H, H(5)],
3
2

2310
C. W e´ ber et al. / Tetrahedron 62 (2006) 2304–2312
7
.0–7.4 (br s, 1H, NH), 10.4–10.7 [br s, 1H, CF COOH].
3
Pip-CH , Me(C2), 21.9 CH CH (CH ) CH NH–, 25.8
3 3 2 2 3 2
CH (CH ) CH (CH ) NH–, 27.9 CH (CH ) CH CH NH–,
3 2 2 2 2 2 3 2 3 2 2
30.1 Pip-C(4), 30.8 CH CH CH (CH ) NH–, 33.3 Pip-C(3,
3 2 2 2 3
C
HPLC–MS: M Z347 (EI); Purity: 98%. HRMS: (EI), m/z
C
M ] found: 347.3040, calcd for C H N : 347.3049.
[
2
0
37
5
5
C(5), 154.7 C(6), 158.5 C(2), 159.7 C(4). HPLC–MS:
), 41.2 CH (CH ) CH CH NH–, 44.7 Pip-C(2,6), 75.6
3 2 3 2 2
4.5.3. 2-(N-Isopropylethylamino)-6-(2-methyl-n-butyl-
amino)-4-(pyrrolidin-1-yl)pyrimidine (7/3). Yield: 89%.
C
C
M Z290 (EI); Purity: 99%. HRMS: (EI), m/z [M ] found:
290.2479, calcd for C17 : 290.2470.
1
Yellowish foam. H NMR (DMSO-d , 300 MHz): d 0.90 [t,
H N
30 4
6
3
H, JZ7.5 Hz, CH CH CH(CH )CH NH–], 0.92 [d, 3H, JZ
3 2 3 2
6
CH CH N–], 1.10–1.18 [m, 1H, CH CH H CH(CH )CH -
.6 Hz, CH CH CH(CH )CH NH–], 1.15 [t, 3H, JZ6.9 Hz,
4.5.6. 2-Methyl-6-(2-methyl-n-butylamino)-4-(4-methyl-
piperidin-1-yl)pyrimidine (7/6). Yield: 94%. Yellowish
3
2
3
2
x
y
3
2
3
3
2
1
NH–], 1.20 [d, 6H, JZ6.6 Hz, (CH ) CHN–], 1.30–1.50 [br
semisolid. H NMR (DMSO-d , 500 MHz): d 0.87 [t, 3H, JZ
3
2
6
x
m, 1H, CH CH H CH(CH )CH NH–], 1.50–1.75 [br m, 1H,
y
7.5 Hz, CH CH CH(CH )CH NH–], 0.90 [d, 3H, JZ7.5 Hz,
3
3
2
3
2
3
2
CH CH CH(CH )CH NH–], 1.75–2.0 [m, 4H, Pyr-H(3, 4)],
2
CH CH CH(CH )CH NH–], 0.92 [d, 3H, JZ7 Hz, Pyp-
CH ], 0.98–1.12 [br m, 2H, Pip-H (3, 5)], 1.12–1.22 [m, 1H
3 ax
3
3
2
3 2 3 2
x
.90–3.20 [m, 2H, CH CH CH(CH )CH H NH–], 3.30–3.70
y
2
3
2
3
[
(
m, 6H, CH CH N–, Pyr-H(2, 5)], 4.4–4.8 [br m, 1H,
3
CH CH H CH(CH )CH NH–], 1.38–1.48 [m, 1H, CH CH -
3 x y 3 2 3 x
H CH(CH )CH NH–], 1.60–1.76 [br m, 4H, Pip-H (3, 5),
y 3 2 eq
2
CH ) CHN–], 5.04 [s, 1H, H(5)], 7.1–7.3 [br s, 1H,
3
2
CH CH CH(CH )CH NH–], 10.4–10.7 (br s, 1H, CF -
3
Pip-H(4), CH CH CH(CH )CH NH–], 2.36 [s, 3H, Me-
3 2 3 2
C(2)], 2.8–3.04 [m, 2H, Pip-H (2,6)], 3.05–3.13 [m, 1H,
ax
2
3
2
3
1
COOH). C NMR (DMSO-d , 125 MHz): d 10.7 CH CH -
3
6
3
2
CH(CH )CH NH–, 14.1 CH CH N–, 16.9 CH CH CH(CH )
2
CH CH CH(CH )CH H NH–], 3.14–3.22 [m, 1H, CH CH -
2
3
2
3
2
3
3
3
2
3
x
y
3
CH NH, 19.8 (CH ) CHN–, 22.0 Pyr-C(3, 4), 27.0 CH CH -
2
CH(CH )CH H NH–], 3.9–4.6 [br m, 2H, Pip-H (2,6)], 5.75
3 x y eq
2
3 2
3
1
3
CH(CH )CH NH–, 33.8 CH CH CH(CH )CH NH–, 36.1
3
[s, 1H, H(5)], 8.15 (br s, 1H, NH). C NMR (DMSO-d6,
125 MHz): d 10.9 CH CH CH(CH )CH NH–, 16.8 CH -
2
3
2
3
2
CH CH N–, 46.5 Pyr-C(1, 5), 46.9 CH CH CH(CH )CH -
3
2
3
2
3
2
3
2
3
2
3
NH–, 47.5 (CH ) CHN–, 69.9 C(5), 150.0 C(2), 153.5 C(6),
3
CH CH(CH )CH NH–, 21.3 Me-C(2), Pip-CH , 26.2 CH -
2 3 2 3 3
CH CH(CH )CH NH–, 30.1 Pip-C(4), 33.3 Pip-C(3, 5), 33.7
2 3 2
CH CH CH(CH )CH NH–, 44.7 Pip-C(2,6), 46.8 CH CH -
3 2 3 2 3 2
2
C
53.7 C(4). HPLC–MS: M Z319 (EI); Purity: 99%. HRMS:
1
C
EI), m/z [M ] found: 319.2742, calcd for C H N :
(
18
33
5
3
19.2736.
CH(CH )CH NH–, 75.6 C(5), 154.6 C(6), 158.4, 158.8 C(2,
3 2
C
4
). HPLC–MS: M Z276 (EI); Purity: 99%. HRMS: (EI),
C
4
.5.4. 4-(Azetidin-1-yl)-2-(N-isopropylethylamino)-6-
2-methyl-n-butylamino)pyrimidine (7/4). Yield: 87%.
m/z [M ] found: 276.2325, calcd for C16H N : 276.2309.
28 4
(
Yellowish semisolid. H NMR (DMSO-d , 500 MHz): d
1
4.5.7. 6-(2-Heptylamino)-2-methyl-4-(4-methylpiperi-
din-1-yl)pyrimidine (7/7). Yield: 93%. Yellowish semi-
6
0
.89 [t, 3H, JZ7.5 Hz, CH CH CH(CH )CH NH–], 0.92
3
2
3
2
1
[
d, 3H, JZ7.0 Hz, CH CH CH(CH )CH NH–], 1.10–1.22
solid. H NMR (DMSO-d
6
, 300 MHz): d 0.86 [t, 3H, JZ
CH ], 0.92 (d, 3H, JZ6.3 Hz,
Pip-Me), 0.98–1.10 [m, 2H, Pip-Hax(3, 5)], 1.13 [d, 3H, JZ
6.3 Hz, CH CH(NH–)(CH CH ], 1.18–1.40 [m, 6H, CH
CH(NH–)CH (CH CH ], 1.40–1.58 [m, 2H, CH CH(NH–)
CH (CH CH ], 1.60–1.78 [m, 3H, Pip-Heq(3, 5), Pip-H(4)],
3
2
3
2
x
y
[
m, 1H, CH CH H CH(CH )CH NH–], 1.14 [t, 3H, JZ
6.9 Hz, CH
3
CH(NH–)(CH
2
)
4
3
3
3
2
7
1
1
2
Hz, CH CH N–], 1.19 [d, 6H, JZ7 Hz, (CH ) CHN–],
3 2 3 2
x y
.38–1.48 [br m, 1H, CH CH H CH(CH )CH NH–], 1.58–
.68 [br m, 1H, CH CH CH(CH )CH NH–], 2.28–2.38 [m,
2
)
-
3
3
3
2
3
2
4
3
)
3
2
3
2
2
3
3
3
H, azetidine–H(3)], 2.90–3.20 [m, 2H, CH CH CH(CH )-
3
2
2
)
3
3
3
2
x
y
CH H NH–], 3.35–3.50 [m, 2H, CH CH N–], 4.00–4.15
3
2.36 [s, 3H, Me-C(2)], 2.85–3.20 [m, 2H, Pip-Hax(2,6)],
3.70–3.90 [m, 2H, Pip-Heq(2,6)], 4.0–4.60 [br m, 1H,
2
[
(
m, 4H, azetidine–H(2, 4)], 4.50–4.70 [br m, 1H,
CH ) CHN–], 4.90 [s, 1H, H(5)], 7.34 [br s, 1H, CH CH -
CH CH(NH–)(CH ) CH ], 5.76 [s, 1H, H(5)], 8.01 (d, 1H,
3 2 4 3
3
2
3
2
1
3
C
CH(CH )CH NH–], 10.4–10.9 (br s, 1H, CF COOH). C
NMR (DMSO-d , 125 MHz): d 10.9 CH CH CH(CH )-
JZ8.4 Hz, NH). HPLC–MS: M Z304 (EI); Purity: 99%.
HRMS: (EI), m/z [M ] found: 304.2622, calcd for
3
2
3
C
6
3
2
3
CH NH–, 14.2 CH CH N–, 15.5 azetidine–C(3), 16.9
2
C H N : 304.2627.
18 32 4
3
2
CH CH CH(CH )CH NH–, 19.7 (CH ) CHN–, 26.2 CH -
2
3
3
2
3 2
3
CH CH(CH )CH NH–, 33.5 CH CH CH(CH )CH NH–,
3
4.5.8. 2-Methyl-4-(4-phenylpiperazin-1-yl)-6-(2-methyl-
n-butylamino)pyrimidine (7/8). Yield: 86%. Red glassy
2
3
2
3
2
2
3
CH(CH )CH NH–, 49.7 azetidine–C(2, 4), 67.9
6.3 CH CH N–, 47.0 (CH ) CHN–, 47.3 CH CH -
3
2
3 2
3
2
1
oil. H NMR (DMSO-d , 300 MHz): d 0.89 [t, 3H,
3
2
6
C(5), 150.6 C(2), 153.6 C(6), 161.6 C(4). HPLC–MS:
M Z305 (EI); Purity: 81%. HRMS: (EI), m/z [M ] found:
JZ7.2 Hz, CH CH CH(CH )CH NH–], 0.91 [d, 3H,
3
2
3
2
C
C
JZ6.9 Hz, CH CH CH(CH )CH NH–], 1.10–1.30 [m,
3 2 3 2
x y
3
05.2567, calcd for C H N : 305.2579.
1H, CH CH H CH(CH )CH NH–], 1.36–1.54 [m, 1H,
3 3 2
1
7
31
5
x
CH CH H CH(CH )CH NH–], 1.59–1.75 [m, 1H, CH -
y
3
3
2
3
4.5.5. 6-(n-Hexylamino)-4-(4-methylpiperidin-1-yl)-2-
methylpyrimidine (7/5). Yield: 95%. Colourless semisolid.
CH
[m, 2H, CH
2
CH(CH
3
)CH
CH
NH–], 2.39 [s, 3H, Me-C(2)], 3.0–3.30
2
CH(CH )CH H NH–], 3.70–4.0 [m, 8H,
2 3
x
y
3
1
H NMR (DMSO-d , 500 MHz): d 0.87 [t, 3H, JZ7 Hz,
piperazine,], 5.85 [s, 1H, H(pyrimidin–C5)], 6.78–6.86 (m,
1H), 6.95–7.04 (m, 2H), 7.20–7.30 (m, 2H) (phenyl-H), 8.0–
8.20 (br s, 1H, NH). HPLC–MS: M Z339 (EI); Purity:
99%. HRMS: (EI), m/z [M ] found: 339.2410, calcd for
6
CH (CH ) CH CH NH–], 0.92 [d, 3H, JZ6 Hz, Me-Pip],
3
2 3
2
2
C
0
.98–1.12 [m, 2H, Pip-H (3, 5)], 1.24–1.38 [m, 6H,
ax
C
CH (CH ) CH CH NH–], 1.54 [p, 2H, JZ7 Hz, CH
3
2 3
2
2
3
(
Pip-H(4)], 2.36 [s, 3H, Me(C2)], 2.90–3.10 [m, 2H, Pip-
CH ) CH CH NH–], 1.64–1.76 [m, 3H, Pip-H (3, 5),
C H N : 339.2423.
20 29 5
2
3
2
2
eq
H (2,6)], 3.20–3.30 [m, 2H, CH (CH ) CH CH NH–],
2
4.5.9. 2-Methyl-6-(2-methyl-n-butylamino)-4-(pyrro-
lidin-1-yl)pyrimidine (7/9). Yield: 77%. Yellowish
ax
3
2 3
2
3
8
.90–4.80 [br m, 2H, Pip-H (2,6)], 5.74 [s, 1H, H(5)],
eq
1
.31 [m, 1H, CH (CH ) CH CH NH–]. C NMR (DMSO-
3
1
semisolid. H NMR (DMSO-d , 500 MHz): d 0.88 (t,
3
2 3
2
2
6
d , 125 MHz): d 13.7 CH (CH ) CH CH NH–, 21.3
6
3H, JZ7.5 Hz, CH CH (CH )CHCH NH–), 0.90 (d, 3H,
3
2 3
2
2
3
2
3
2

C. W e´ ber et al. / Tetrahedron 62 (2006) 2304–2312
2311
1
3
JZ6.5 Hz, CH CH (CH )CHCH NH–), 1.11–1.21 [m, 1H,
H(5)], 7.82 [br m, 2H, CH (CH ) CH CH NH–]. C NMR
3 2 3 2 2
3
2
3
2
x
y
CH CH H (CH )CHCH NH–], 1.37–1.47 [m, 1H, CH -
(DMSO-d , 125 MHz): d 13.8 CH (CH ) CH NH–, 21.8 br,
6 3 2 4 2
MeC(2), 22.0 CH CH (CH ) CH NH–, 25.9 CH (CH ) -
3 2 2 3 2 3 2 2
3
3
2
3
x
CH H (CH )CHCH NH–], 1.60–1.70 [m, 1H, CH CH
y
3
2
3
2
(
CH )CHCH NH–], 1.84–2.06 [m, 4H, Pyr-H(3, 4)], 2.38
3
CH CH CH NH–, 28.1 CH (CH ) CH CH NH–, 30.8
2 2 2 3 2 3 2 2
2
[
CHCH H NH–], 3.30–3.65 [br m, 4H, Pyr-H(2, 5)], 5.41
s, 3H, Me-C(2)], 3.0–3.3 [br m, 2H, CH CH (CH )-
CH CH CH (CH ) NH–, 40.9 CH (CH ) CH CH NH–,
3 2 2 2 3 3 2 3 2 2
3
2
3
x
y
C
75.5 C(5), 156.0–162.0 br, C(2, 4, 6). HPLC–MS: M Z
292 (EI); Purity: 98%. HRMS: (EI), m/z [M ] found:
1
3
C
[
s, 1H, H(5)], 7.99 (br s, 1H, NH). C NMR (DMSO-d6,
25 MHz): d 10.9 CH CH (CH )CHCH NH–, 16.8 CH -
CH (CH )CHCH NH–, 21.3 CH (2), 24.5 Pyr-C(3, 4), 26.2
1
292.2622, calcd for C H N : 292.2627.
17 32 4
3
2
3
2
3
2
3
2
3
CH CH (CH )CHCH NH–, 33.7 CH CH (CH )CHCH -
3
4.5.15. 6-(n-Hexylamino)-2-methyl-4-(2-methyl-n-butyl-
amino)pyrimidine (7/16). Yield: 85%. Yellowish semi-
2
3
2
3
2
3
2
NH–, 46.9 CH CH (CH )CHCH NH–, 47.2 Pyr-C(2, 4),
3
2
3
2
C
1
solid. H NMR (DMSO-d , 300 MHz): d 0.80–0.96 [m, 9H,
7
2
2
6.0 C(5), 158.4, 158.7, 159.0 C(2, 4, 6). HPLC–MS: M Z
6
C
48 (EI); Purity: 99%. HRMS: (EI), m/z [M ] found:
CH (CH ) CH NH–, CH CH CH(CH )CH NH–], 1.08–
3
2 4
2
3
2
3
2
48.2011, calcd for C H N : 248.2001.
4
1.70 [m, 11H, CH (CH ) CH NH–, CH CH CH(CH )CH -
3 2 4 2 3 2 3 2
1
4
24
NH–], 2.36 [s, 3H, Me-C(2)], 2.80–3.40 [br m, 4H,
CH (CH ) CH NH–,CH CH CH(CH )CH NH–], 5.47 [s,
4
yl)pyrimidine (7/10). Yield: 96%. Yellowish foam.
.5.10. 6-(2-Heptylamino)-2-methyl-4-(pyrrolidin-1-
H
3
2 4
2
3
2
3
2
1
C
1H, H(5)], 7.7–8.4 (br s, 2H, NH). HPLC–MS: M Z278
(EI); Purity: 98%. HRMS: (EI), m/z [M ] found: 278.2461,
C
NMR (DMSO-d , 300 MHz): d 0.86 [t, 3H, JZ6.6 Hz,
6
CH CH(NH–)(CH ) CH ], 1.13 [d, 3H, JZ6.6 Hz, CH -
calcd for C H N : 278.2470.
16 30 4
3
2 4
3
3
CH(NH–)(CH ) CH ], 1.20–1.58 [br m, 8H, CH CH(NH–)
CH (CH ) CH ], 1.84–2.08 [br m, 4H, Pyr-H(3, 4)], 2.38 [s,
2
4
3
3
2
2 3
3
4.5.16. 4-(2-Heptylamino)-6-(n-hexylamino)-2-methyl-
pyrimidine (7/17). Yield: 87%. Yellowish semisolid. H
1
3
[
H, Me-C(2)], 3.20–3.60 [br m, 4H, Pyr-H(2, 5)], 4.20–5.20
br m, 1H, CH CH(NH–)(CH ) CH ], 5.41 [s, 1H, H(5)],
.05 (d, 1H, JZ8.4 Hz, NH). HPLC–MS: M Z276 (EI);
3
2 4
3
NMR (DMSO-d , 500 MHz): d 0.87 [q, 6H, JZ7 Hz,
6
C
8
Purity: 99%. HRMS: (EI), m/z [M ] found: 276.2324, calcd
CH (CH ) CH NH–, CH CH(NH–)(CH ) CH ], 1.13 [d,
3H, JZ6.5 Hz, CH CH(NH–)(CH ) CH ], 1.18–1.35 [m,
3
2 4
2
3
2 4
3
C
3 2 4 3
for C H N : 276.2314.
28
12H, CH (CH ) CH CH NH–, CH CH(NH–)CH (CH ) -
3 2 3 2 2 3 2 2 3
16
4
CH ], 1.40–1.65 [m, 4H, (CH ) CH CH NH–, CH -
3
3
2 3
2
2
4.5.11. 4-(Azetidin-1-yl)-2-methyl-6-(2-methyl-n-butyl-
amino)pyrimidine (7/11). Yield: 84%. Yellowish glassy
CH(NH–)CH (CH ) CH ], 2.34 [s, 3H, Me-C(2)], 3.0–
2 2 3 3
3.40 [br m, 2H, CH (CH ) CH CH NH–], 3.50–4.00 [br m,
3 2 3 2 2
1
oil. H NMR (DMSO-d , 300 MHz): d 0.86 [t, 3H, JZ6.6 Hz,
1H, CH CH(NH–)(CH ) CH ], 5.46 [s, 1H, H(5)], 8.14 (br
3 2 4 3
6
1
3
m, 2H, NH). C NMR (DMSO-d , 125 MHz): d 13.7
CH CH CH(CH )CH NH–], 0.88 [d, 3H, JZ6.6 Hz, CH -
3
2
3
2
3
6
CH CH(CH )CH NH–], 1.08–1.24 [br m, 1H, CH -
CH (CH ) CH NH–, CH CH(NH–)(CH ) CH , 19.9 CH -
3
CH(NH–)(CH ) CH , 21.1 Me(C2), 21.9 CH CH (CH ) -
2 4 3 3 2 2 4
NH–, CH CH(NH–)(CH ) CH CH , 25.0 CH CH(NH–)
3 2 3 2 3 3
2
3
2
3
2 4
2
3
2 4
3
3
x
CH H CH(CH )CH NH–], 1.32–1.50 [br m, 1H,
y
3
2
x
CH CH H CH(CH )CH NH–], 1.54–1.74 [br m, 1H,
y
3
3
2
CH CH CH(CH )CH NH–], 2.36 [s, 3H, Me-C(2)], 2.90–
3
CH CH (CH ) CH , 25.9 CH (CH ) CH (CH ) NH–,
2 2 2 2 3 3 2 2 2 2 2
27.9 CH (CH ) CH CH NH–, 30.8 CH CH CH (CH ) -
3 2 3 2 2 3 2 2 2 3
2
3
2
x
.30 [br m, 2H, CH CH CH(CH )CH H NH–], 4.0–4.30 (m,
y
3
3
2
3
6
H, azetidine–H), 5.26 [s, 1H, H(5)], 8.05–8.25 (br s, 1H, NH
NH–, 31.0 CH CH(NH–)(CH ) CH CH CH , 35.6 CH -
3 2 2 2 2 3 3
CH(NH–)CH (CH ) CH , 41.1 CH (CH ) CH CH NH–,
2 2 3 3 3 2 3 2 2
C
)
[
. HPLC–MS: M Z234 (EI); Purity: 99%. HRMS: (EI), m/z
C
M ] found: 234.1857, calcd for C H N : 234.1844.
1
3
22
4
47.0 CH CH(NH–)(CH ) CH , 73.5–76.8 br, C(5), 156–
3 2 4 3
C
1
63 br, C(2, 4, 6). HPLC–MS: M Z306 (EI); Purity: 98%.
C
HRMS: (EI), m/z [M ] found: 306.2795, calcd for
4.5.12. 4-(2-Ethylpiperidin-1-yl)-2-methyl-6-(2-methyl-
n-butylamino)pyrimidine (7/12). Yellowish oil.
C H N : 306.2783.
18 34 4
C
HPLC–MS: M Z290 (EI); Purity: 28%. HRMS: (EI),
C
m/z [M ] found: 290.2478, calcd for C H N : 290.2470.
1
7 30 4
4.5.17. 4-Bis(n-butyl)amino-6-(n-hexylamino)-2-(N-
isopropylethylamino)pyrimidine (7/18). Yield: 61%.
1
Yellowish semisolid. H NMR (DMSO-d , 500 MHz): d
4.5.13. 4-Bis(n-butyl)amino-2-methyl-6-(2-methyl-n-
butylamino)pyrimidine (7/14). Yield: 82% Yellowish
6
0.88 [t, 3H, JZ7 Hz, CH (CH ) CH NH–], 0.90 [m, 6H,
3
2 4
2
1
semisolid. H NMR (DMSO-d , 300 MHz): d 0.84–0.98
6
(CH (CH ) CH ) N–], 1.14 (t, 3H, JZ7 Hz, CH CH N–),
3 2 2 2 2 3 2
[
N–], 1.08–1.72 [m, 11H, CH CH H CH(CH )CH NH–,
m, 12H, CH CH CH(CH )CH NH–, (CH (CH ) CH ) -
1.19 [d, 6H, JZ7 Hz, (CH ) CHN–], 1.22–1.37 [m,
3
2
3
2
3
2 2
2 2
3 2
x
y
3
3
2
10H, CH (CH ) CH CH NH–, (CH CH CH CH ) N–],
1.48–1.60 [m, 6H, CH (CH ) CH CH NH–, (CH CH CH -
3 2 3 2 2 3 2 2
3
2 3
2
2
3
2
2
2 2
(
[
CH (CH ) CH ) N–], 2.35 [s, 3H, Me-C(2)], 2.90–3.20
3
2 2
2 2
x
m, 2H, CH CH CH(CH )CH H NH–], 3.20–3.70 [br m,
y
3
2
3
CH ) N–], 3.18 [m, 2H, CH (CH ) CH NH–], 3.36 [m,
2 2 3 2 4 2
X
y
4
1
H, (CH (CH ) CH ) N–], 5.50 [s, 1H, H(5)], 7.86 (br s,
3
2H, CH (CH ) CH N(K)CH (CH ) CH ], 3.42 [q, 2H,
3 2 2 2 2 2 2 3
x
2 2
2 2
C
H, NH). HPLC–MS: M Z306 (EI); Purity: 95%. HRMS:
JZ7 Hz, CH CH N–], 3.51 [m, 2H, CH (CH ) CH N
3 2 3 2 2 2
Y
C
(
EI), m/z [M ] found: 306.2771, calcd for C H N :
1
(K)CH (CH ) CH ], 4.55 [br m, 1H, (CH ) CHN–], 5.08
2 2 2 3 3 2
8
34
4
3
06.2783.
[s, 1H, H(5)], 7.28 (s, 1H, NH), 10.70 (br s, 1H, CF COOH).
3
1
3
C NMR (DMSO-d , 125 MHz): d 13.6 (CH (CH ) CH ) -
6
3
2 2
2 2
4
(
.5.14.
7/15). Yield: 87%. Yellowish semisolid. H NMR (DMSO-
4,6-Bis(n-hexylamino)-2-methylpyrimidine
N–, 13.8 CH (CH ) CH NH–, 14.4 CH CH N–, 19.4
3 2 4 2 3 2
(CH CH CH CH ) N–, 19.8 (CH ) CHN–, 21.9 CH CH
3 2 2 2 2 3 2 3 2
1
d , 500 MHz): d 0.87 [t, 6H, JZ7 Hz, CH (CH ) CH NH–],
(CH ) CH N–, 25.9 CH (CH ) CH CH CH N–, 27.9
2
CH (CH ) CH CH N–, 29.2 CH CH CH CH N(K)CH -
3 2 3 2 2 3 2 2 2 2
y x y
CH CH CH , 29.7 CH CH CH CH N(K)CH CH CH -
2 2 3 3 2 2 2 2 2 2
6
3
2 4
2
2 3
2
3
2 2
2
2
X
1
.22–1.36 [m, 12H, CH (CH ) CH CH NH–], 1.52 [p, 4H,
3
2 3
2
2
JZ7 Hz, CH (CH ) CH CH NH–], 2.31 [s, 3H, Me(C2)],
3
2 3
2
2
3
.10–3.30 [br m, 4H, CH (CH ) CH CH NH–], 5.39 [s, 1H,
CH , 30.8 CH CH CH (CH ) N–, 36.2 CH CH N–, 41.2
3 3 2 2 2 3 3 2
3
2 3
2
2

2312
C. W e´ ber et al. / Tetrahedron 62 (2006) 2304–2312
CH (CH ) CH N–, 47.2 (CH ) CHN–, 47.8 (CH CH CH -
2
Hobbs, F. W.; Wilde, R. G.; Arnold, C.; Chidester, D.; Curry, M.;
He, L.; Hollis, A.; Klaczkiewicz, J.; Krenitsky, P. J.;
Rescinito, J. P.; Scholfield, E.; Culp, S.; De Souza, E. B.;
Fitzgerald, L.; Grigoriadis, D.; Tam, S. W.; Wong, Y. N.;
Huang, S.-M.; Shen, H. L. J. Med. Chem. 1999, 42, 805–818.
. Franchetti, P.; Capellacci, L.; Abu Sheikha, G.; Grifantini, M.;
Loi, A. G.; De Montis, A.; Spiga, M. G.; La Colla, P.
Nucleosides Nucleotides 1995, 14, 607–610.
3
2 4
2
3 2
3
2
CH ) N–, 69.1 C(5), 150.15 C(2), 153.8 C(6), 158.20 br,
2
2
C
C(4). HPLC–MS: M Z391 (EI); Purity: 91%. HRMS:
C
EI), m/z [M ] found: 391.3668, calcd for C H N :
(
23 45 5
3
91.3675.
7
4.5.18. 4,6-Bis(n-hexylamino)-2-(N-isopropylethyl-
amino)pyrimidine (7/19). Yield: 57%. Yellowish
1
semisolid. H NMR (DMSO-d , 500 MHz): d 0.87 [t, 6H,
6
8. Kinnamon, K. E.; Engle, R. R.; Poon, B. T.; Ellis, W. Y.;
Mc Call, J. W.; Dzimianski, M. T. Ann. Trop. Med. Parasitol.
1999, 93, 851–858.
JZ7 Hz, CH (CH ) CH NH–], 1.14 [t, 3H, JZ7 Hz,
3
2 4
2
CH CH N–], 1.19 [d, 6H, JZ6.5 Hz, (CH ) CHN–],
3
2
3 2
1
1
4
.22–1.40 [br m, 12H, CH (CH ) CH CH NH–], 1.44–
.62 [br m, 4H, CH (CH ) CH CH NH–], 3.0–3.30 [br m,
3 2 3 2 2
9. Vorbrueggen, H. Adv. Heterocycl. Chem. 1990, 49, 117–192
and references there in.
3
2 3
2
2
H, CH (CH ) CH CH NH–], 3.30–3.50 [br m, 2H,
3
2 3
2
2
10. Obrecht, D.; Abrecht, C.; Gieder, A.; Villalgordo, J. M. Helv.
Chim. Acta 1997, 80, 65–72.
CH CH N–], 4.45–4.70 [br m, 1H, (CH ) CHN–], 5.03 [s,
3 2
3
2
1
1
1
1
H, H(5)], 7.60–8.20 [br m, 2H, CH (CH ) CH CH NH–],
0.72 [br m, 1H, CF COOH].
3 2 2
2 3
C NMR (DMSO-d6,
11. Masquelin, T.; Sprenger, D.; Baer, R.; Gerber, F.; Mercadal, Y.
Helv. Chim. Acta 1998, 81, 646–660.
1
3
3
25 MHz): d 13.8 CH (CH ) CH NH–, 14.4 CH CH N–,
3
3
2 4
2
2
12. Guillier, F.; Roussel, P.; Moser, H.; Kane, P.; Bradley, M.
Chem. Eur. J. 1999, 5, 3450–3458.
9.8 (CH ) CHN–, 221.0 CH CH (CH ) CH NH–, 26.0
3
2
3
2
2 3
2
CH (CH ) CH CH CH NH–, 26.9 CH (CH ) CH CH -
2
NH–, 30.9 CH CH CH (CH ) NH–, 38.8.CH CH N–,
3
41.3 CH (CH ) CH CH NH–, 47.4 (CH ) CHN–, 70.8
3 2 3 2 2 3 2
C(5), Signals due to the C(2, 4, 6) carbons could not be
3
2 2
2
2
2
3
2 3
2
1
1
1
1
1
1
3. Di Lucrezia, R.; Gilbert, I. H.; Floyd, C. D. J. Comb. Chem.
000, 2, 249–253.
4. Barillari, C.; Barlocco, D.; Raveglia, L. F. Eur. J. Org. Chem.
001, 4737–4741.
2
2
2 3
3
2
2
2
C
detected. HPLC–MS: M Z363 (EI); Purity: 93%. HRMS:
5. Yoo, K. H.; Kim, S. E.; Shin, K. J.; Kim, D. C.; Park, S. W.;
Kim, D. J. Synth. Commun. 2001, 31, 835–840.
C
EI), m/z [M ] found: 363.3369, calcd for C H N :
(
21 41 5
3
63.3362.
6. Arvanitis, E. A.; Chadha, N.; Pottorf, R. S.; Player, M. R.
J. Comb. Chem. 2004, 6, 414–419.
Acknowledgements
7. Zucca, C.; Bravo, P.; Volonterio, A.; Zanda, M.; Wagner, A.;
Mioskowski, C. Tetrahedron Lett. 2001, 42, 1033–1035.
8. Montebugnoli, D.; Bravo, P.; Brenna, E.; Mioskowski, C.;
Panzeri, W.; Viani, F.; Volonterio, A.; Wagner, A.; Zanda, M.
Tetrahedron 2003, 59, 7147–7156.
The authors wish to thank Gy o¨ rgyi I. Szendrei for
HPLC–MS and G a´ bor Czira for HRMS measurements.
1
9. Dener, J. F.; Lease, T. G.; Novack, A. R.; Plunkezz, M. J.;
Hocker, M. D.; Fantauzzi, P. P. J. Comb. Chem. 2001, 3,
References and notes
5
90–597.
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86077.
2
2
0. W e´ ber, C.; Bielik, A.; Szendrei, G. I.; Keser u˝ , G. M.; Greiner, I.
Bioorg. Med. Chem. Lett. 2004, 14, 1279–1281.
2
2. Ayer, D. E. WO 9106542, 1991; Chem. Abstr., 115, 114546.
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1. Hanan, G. S.; Schubert, U. S.; Volkmer, D.; Riviere, E.;
Lehn, J. M. Can. J. Chem. 1997, 75, 169–182.
3
23, 379–384.
4
. Mulin, R. J.; Keith, B. R.; Bigham, E. C.; Duch, D. S.; Ferone, R.;
Heath, L. S.; Singer, S.; Waters, K. A.; Wilson, H. R. Biochem.
Pharmacol. 1992, 43, 1627–1634.
22. Delia, T. J.; Stark, D.; Glenn, S. K. J. Heterocycl. Chem. 1995,
32, 1177–1180.
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