2-Amino-6-iodo-4-tosyloxypyrimidine: a versatile key intermediate for regioselective functionalization of 2-aminopyrimidines in 4- and 6-positions

Article abstract of DOI:10.1016/j.tet.2007.07.100

2-Amino-6-iodo-4-tosyloxypyrimidine, easily prepared from commercially available material, is a key intermediate for the preparation of differentially substituted 2-aminopyrimidines by means of sequenced Suzuki and/or Sonogashira reactions.

Full text of DOI:10.1016/j.tet.2007.07.100

Tetrahedron 63 (2007) 12465–12470
2-Amino-6-iodo-4-tosyloxypyrimidine: a versatile key
intermediate for regioselective functionalization
of 2-aminopyrimidines in 4- and 6-positions
a
Pascal Benderitter, Joao Xavier de Araujo Junior,a,b Martine Schmitta,
*
~
ꢀ
ꢀ
and Jean-Jacques Bourguignona
a
´
Laboratoire Commun 1 Institut Gilbert Laustriat (CNRS, UMR7175-LC1), 74 route Du Rhin, Faculte de Pharmacie,
´
Universite Louis Pasteur, 67400 Illkirch, France
bEscola de Enfermagem e Farmaꢀcia, Instituto de Quꢀımica e Biotecnologia, Universidade Federal de Alagoas,
Cidade Universitaꢀria, 57072-970, Maceioꢀ, AL, Brazil
Received 7 June 2007; revised 25 July 2007; accepted 26 July 2007
Available online 2 August 2007
Abstract—2-Amino-6-iodo-4-tosyloxypyrimidine, easily prepared from commercially available material, is a key intermediate for the
preparation of differentially substituted 2-aminopyrimidines by means of sequenced Suzuki and/or Sonogashira reactions.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
cyclization. After an activation step by means of POCl3,
the resulting iminochloride 7 could be subjected to various
palladium cross-coupling reactions (PCCR) such as
Suzuki9,10 (R2¼Ar) or Sonogashira11 (R2¼alkyne) with
specific catalysts and reagents leading to the disubstituted
compound 8. Pathway C involves cyclocondensation of gua-
nidine with diethylmalonate. The resulting 2-aminopyr-
imidine-4,6-dihydroxypyrimidine 9 constitutes a valuable
Various polysubstituted 2-aminopyrimidines exhibit impor-
tant pharmacological properties. For example, derivative 1
was reported as a 5HT2 receptor antagonist1 whereas bicy-
clic compound 2 shows sorbitol dehydrogenase inhibition
properties2 (Fig. 1). Polysubstituted 2-aminopyrimidines
also show purine receptor antagonist,3 or antibacterial,4
anticancer, and anti-inflammatory activities.5
NH2
R1
R2
R2
In drug discovery, great importance is given to reducing the
time needed for drug optimization. The most recent papers
described relatively tedious methods for the preparation of
2-aminopyrimidine derivative 8 (Scheme 1). Pathway A ini-
tially requires preparation of the starting alkynones 3,6 or
chalcone derivative 4 (X¼NH or O),7,8 which are cyclocon-
densed with guanidine. Pathway B involves a b-ketoester 5,
and yields the 2-amino-6-hydroxypyrimidine 6 after
O
HN
NH2
N
Pathway A
or
R2
N
NH2
R1
X
R1
3
4
8
X= NH, O
Pd(0)
R1
NH2
R1
N
O
POCl3
NH2
HO
HN
N
Pathway B
EtO
R1
F
Cl
Cl
N
NH2
N
NH2
O
5
6
7
Pd(0)
Cl
N
OH
N
NH2
NH2
N
N
N
NH2
OH
O
O
N
NH2
N
POCl3
HN
Pathway C
EtO
N
OEt
N
NH2
1
2
HO
N
NH2
Figure 1. Examples of 2-aminopyrimidines with pharmacological activities.
10
R1, R2 = Ar, alkyl, alkyne, NR'R'', etc
9
* Corresponding author. Tel.: +33 39 0244231; fax: +33 39 0244310;
e-mail: schmitt@pharma.u-strasbg.fr
Scheme 1. Alternative pathways leading to 4,6-disubstituted-2-aminopyri-
midines.
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.07.100

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P. Benderitter et al. / Tetrahedron 63 (2007) 12465–12470
synthon for introducing a high degree of structural diversity
at both positions 4 and 6 via the dichloro derivative 10.
synthesized. By performing a Finkelstein reaction on the
dichloropyrimidine 10 using NaI in a mixture of acetone
and HI 55%, the 4-iodo-6-hydroxypyrimidine 15 was
prepared in a quantitative yield. A further O-tosylation, per-
formed as previously described, led to the key intermediate
16 with a 90% yield (Scheme 3).
The aim of this communication is to investigate a pertinent
strategy starting from readily available starting materials
and leading to versatile functionalized scaffolds for building
pyrimidine libraries in both mono and bicyclic series. The
synthesis of unsymmetrical 4,6-pyrimidines was described
recently.12 However, the multistep sequences were applied
only to the simple pyrimidine and it was not tried on more
functionalized molecules such as 2-aminopyrimidines.
OTs
N
OH
i
ii
N
10
90%
99%
I
N
16
NH2
I
N
NH2
15
2. Results and discussion
Scheme 3. Synthesis of 2-amino-4-iodo-6-tosyloxypyrimidine. Reagents:
(i) HI 55%, acetone, m-waves, 100 ꢀC, 5 min; (ii) TsCl, K2CO3, CH3CN,
reflux, 3 h.
The commercially available 2-amino-4,6-dichloro-pyrimi-
dine 10 seemed to be an useful starting material for a quick
introduction to structural diversity in a monocyclic series
including pyrimidines13 by means of PCCR. However, as
found with other symmetrical dichlorodiazines, in particular
with pyridazines, the first PCCR performed on the 4,6-
dichloropyrimidine 10 produced a mixture of mono and
disubstituted-adducts.14–16
Suzuki or Sonogashira procedures were successfully applied
to give the expected monosubstituted adduct (compounds 13
and 17) in good yields (80–95%). Finally, by performing
a second palladium cross-coupling reaction, the synthesis
of 4,6-disubstituted 2-aminopyrimidines was carried out
considering two different alkynes (compound 18), an aryl
and an alkyne (compound 19), or two different aryl groups
(compound 20, Scheme 4).
In order to differentiate the reactivities of both iminochlorides
in 4,6-dichloropyrimidines, the authors attempted to replace
one chlorine atom by iodine (by treatment with a mixture of
HI and NaI), however a mixture of mono and disubstituted-
iodo derivatives was obtained under these conditions.17
Ar2
OTs
N
i
N
65-93%
i
NH2
Ar1
N
NH2
N
Ar1
80-85%
The differentiation of the two positions of substitution was
investigated with the introduction of an O-tosyl group
(Scheme 2), which is known to be less reactive in PCCR.
Therefore, the 4,6-dichloropyrimidine 10 was firstly re-
fluxed in an aqueous sodium hydroxide solution to give
the 2-amino-6-chloro-4-hydroxypyrimidine 11 in 88%
yield. Then the O-tosyl derivative 12 was obtained in nearly
quantitative yield using tosylchloride and potassium carbon-
ate in refluxing acetonitrile.18 Although PCCR performed on
the intermediate 12 did not allow to recover the monosubsti-
tuted adduct in good yield, it was determined that the substi-
tution firstly occurred on the chlorine.
Ar1 Ar2
20
13a Ar1= Ph
13b Ar1= 4-MeOPh
ii
65-71%
Ar
N
16
i
OTs
N
NH2
N
20%
R1
ii
19
R2
> 95%
NH2
N
R1
ii
17
60%
R1 = Ph
R2 = TMS
N
NH2
R2
N
Cl
OH
OTs
N
R1
i
ii
18
R1
N
N
88%
98%
Cl
Ar
Cl
N
NH2
Cl
N
NH2
N
NH2
NH2
Scheme 4. Use of 2-amino-4-iodo-6-tosyloxypyrimidine (16) for sequential
discriminative approach to 4,6 disubstituted 2-aminopyrimidines. Reagents:
(i) ArB(OH)2, Pd(PPh3)4, Na2CO3, DMF–H2O, m-waves; (ii) R–^, CuI,
PdCl2(PPh3)2, NEt3, m-waves.
10
11
12
Ar
N
OTs
iii
N
+
The bicyclic 2-amino-4-hydroxypyrimidine 22 is another
example, which gave access to bicyclic compounds offering
a single element of diversity at position 4 (Fig. 1). It was eas-
ily prepared by cyclocondensation of the ethyl 4-oxopiperi-
dine-3-carboxylate 21 with guanidine (Scheme 5).19 As
described for the synthesis of 16, the expected O-tosyl deriv-
atives 23a and 23b were recovered in good yields (82–90%)
and provided various derivatives by means of Suzuki and
Sonogashira reactions (Table 1, compounds 24a–f).
Ar
13a Ar = Ph
13b Ar = 4-MeO-Ph
N
NH2
N
14
Scheme 2. Formation of 2-amino-4-chloro-6-tosyloxypyrimidine and
attempt to perform monosubstitution. Reagents: (i) NaOH 1 M, reflux,
2 h; (ii) TsCl, K2CO3, CH3CN, reflux, 3 h; (iii) ArB(OH)2, Pd(PPh3)4,
Na2CO3, DMF–H2O, m-waves.
In order to improve the regioselectivity of the substitution,
we decided to replace the chlorine by a more reactive group.
Therefore the 2-amino-6-iodo-4-tosyloxypyrimidine 16 was
In summary, starting from a commercially available mate-
rial, a two-step sequence allowed an easy access to the key

P. Benderitter et al. / Tetrahedron 63 (2007) 12465–12470
12467
OH
was collected by suction filtration and dried in vacuo to give
2-amino-6-iodo-4-hydroxypyrimidine 15 as a light brown
solid (1.44 g, 99%). Mp>250 ꢀC; TLC Rf¼0.46 (CH2Cl2–
step. 1H NMR (DMSO-d6) d: 6.05 (s, 1H, ArH), 6.91 (br s,
2H, NH2), 11.11 (br s, 1H, NH); 13C NMR (DMSO-d6) d:
112.6, 130.6, 154.9, 161.5. ESMS m/z: 253.9 (MꢁH).
COOEt
O
R
i
R
N
N
N
85-89%
1
N
22
NH2
MeOH 9:1). H NMR showed adequate purity for the next
21a R=Bn
21b R=Boc
ii
82-90%
R1
OTs
N
3.3. Typical procedure for sulfonation
R
R
iii
N
N
N
78-99%
TsCl (201 mg, 1.05 mmol) and K2CO3 (146 mg, 1.05 mmol)
were added to a stirred solution of 15 or 22 (1.05 mmol) in
CH3CN (15 mL). The resulting mixture was heated to
100 ꢀC for 3 h then cooled to room temperature. The slurry
was concentrated under reduced pressure. The residue was
dissolved with ethyl acetate (50 mL) and water (10 mL).
The organic layer was washed with a saturated solution of
NaHCO3, followed by water, and brine. The combined or-
ganic layers were dried by addition of Na2SO4 and concen-
trated under vacuum. The crude product was purified by
column chromatography (CH2Cl2–MeOH 99:1) to yield
pure aminopyrimidines 16, 24a or 24b.
N
24
NH2
N
NH2
23
Scheme 5. Application of the tosylate activation for the synthesis of bicyclic
aminopyrimidines. Reagents: (i) guanidine, Na, EtOH, 100 ꢀC, 16 h; (ii)
TsCl, K2CO3, MeCN, 3 h; (iii) ArB(OH)2, Pd(PPh3)4, Na2CO3, DMF–
H2O, m-waves; or R–^, CuI, PdCl2(PPh3)2, NEt3, m-waves.
Table 1. PCCR’s with compound 24
Entry
24
R
Reagent
Yield %
1
2
3
4
5
6
a
b
c
d
e
f
Bn
PhB(OH)2
PhB(OH)2
99
98
84
99
83
78
Boc
Boc
Boc
Boc
Boc
4-ClPhB(OH)2
4-OMePhB(OH)2
3,4-OMePhB(OH)2
Ph
3.3.1. 2-Amino-6-iodopyrimidin-4-yl methyl benzenesul-
fonate (16). Starting from 2-amino-6-iodo-4-hydroxypyri-
midine 15 and following the general procedure, 2-amino-
6-iodopyrimidin-4-yl methyl benzenesulfonate 16 was
obtained as a white solid (373 mg, 90%). Mp 176–178 ꢀC;
1
intermediate 16 leading to various libraries of compounds
with three different anchor points (R1, R2, NR). In a similar
manner, activation of aminopyrimidinol by a tosylate also
opens an interesting pathway for the preparation of bicyclic
aminopyrimidines’ libraries.
TLC Rf¼0.57 (CH2Cl2–MeOH 98:2); H NMR (CDCl3) d:
2.44 (s, 3H, CH3), 5.44 (br s, 2H, NH2), 6.77 (s, 1H, ArH),
7.34 (d, 2H, J¼8.3, ArH), 7.88 (d, 2H, J¼8.3, ArH); 13C
NMR (CDCl3) d: 22.2, 109.1, 129.4, 130.3, 131.3, 133.4,
ꢂ
146.4, 162.4, 163.2. (EI) m/z: 391.9582 (MH+ C11H11I1-
N3O3S1 requires 391.9560).
3. Experimental section
3.1. General
3.3.2. 2-Amino-6-benzyl-5,6,7,8-tetrahydropyrido[4,3-
d]pyrimidin-4-yl 4-methyl benzenesulfonate (23a).
Starting from 2-amino-6-benzyl-5,6,7,8-tetrahydro[4,3-
d]pyrimidin-4-ol 22a and following the general procedure,
2-amino-6-benzyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimi-
din-4-yl 4-methybenzenesulfonate 23a was obtained as
a white solid (319 mg, 74%). Mp 149–151 ꢀC; TLC
Chemicals and solvents were purchased puriss p.A. and used
without purification. For thin-layer chromatography (TLC),
silica gel plates Merck 60F254 were used and compounds
were visualized by irradiation with UV light. Flash chroma-
tography was performed using silica gel Merck 60 (particle
size 0.040–0.063 mm). Melting points were measured on a
BUCHI B-450 apparatus. 1H NMR (300 MHz) and 13C
NMR (75 MHz) were recorded on Bruker Avance Spectro-
meter. Chemical shifts are given in d relative to tetramethyl-
silane (TMS), the coupling constants J are given in hertz.
High-resolution mass spectra were recorded on a Bruker
MicroTof mass spectrometer. Microwave irradiation has
been performed using Biotage Initiator EXP (http://www.
biotage.com).
1
Rf¼0.37 (CH2Cl2–MeOH 95:5); H NMR (CDCl3) d: 2.50
(s, 3H, Me), 2.68 (t, J¼5.50, 2H, CH2), 2.78 (t, J¼5.50,
2H, NCH2), 3.50 (s, 2H, CH2), 3.73 (s, 2H, CH2), 4.87 (br
s, 2H, NH2), 7.25–7.50 (m, 7H, ArH), 7.89–8.10 (d,
J¼8.3, 2H, ArH). ESMS m/z: 411.3 (M+H).
3.3.3. tert-Butyl-2-amino-4-{[(4-methylphenyl)sulfo-
nyl]oxy}-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carb-
oxylate(23b). Starting from tert-butyl-2-amino-4-hydroxy-7,
8-dihydropyrido [4,3-d]pyrimidine-6(5H)-carboxylate 22b and
following the general procedure, tert-butyl-2-amino-4-{[4-
methylphenyl)sulfonyl]-oxy}-7,8-dihydropyrido[4,3-d]pyr-
imidine-6(5H)-carboxylate 23b was obtained as a viscous oil
3.2. 2-Amino-6-iodo-4-hydroxypyrimidine (15)
1
(438 mg, 99%). TLC Rf¼0.50 (CH2Cl2–MeOH 95:5); H
4,6-Dichloro-2-aminopyrimidine 10 (1.0 g, 6.01 mmol), NaI
(1.1 g, 7.32 mmol), 55% of HI (10 mL), and acetone (10 mL)
were mixed in a process vial (25–30 mL) heated by micro-
waves to 100 ꢀC for 5 min. The residue was dissolved in
20 mL of H2O and the resulting solution was adjusted to
pH 7.0 with a saturated solution of NaHCO3. Finally a 10%
NaHSO3 solution (20 mL) was added and the precipitate
NMR (CDCl3) d: 1.47 (s, 9H, C(CH3)3), 2.46 (s, 3H, Me),
2.59 (t, J¼5.8, 2H, CH2), 3.60 (t, J¼5.8, 2H, NCH2), 4.39
(s, 2H, CH2), 5.09 (br s, 2H, NH2), 7.37 (d, J¼8.1, 2H,
ArH), 7.96 (d, J¼8.1, 2H, ArH); 13C NMR (CDCl3) d:
21.82, 22.19, 28.80, 41.15, 47.75, 80.87, 107.28, 129.23,
130.08, 134.31, 146.07, 154.81, 160.70, 163.35. ESMS m/z:
421.2 (M+H).

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P. Benderitter et al. / Tetrahedron 63 (2007) 12465–12470
3.4. Typical procedure for microwave-assisted Suzuki
reaction
130.75, 138.35, 162.05, 164.02, 166.07, 166.41. (EI) m/z:
ꢂ
278.1295 (MH+ C17H15N3O requires 278.1288).
A suspension of 13, 16 or 23 (0.256 mmol), sodium carbon-
ate (54 mg, 0.511 mmol, 2.0 equiv), Pd(PPh3)4 (29 mg,
0.025 mmol, 0.10 equiv), and the corresponding arylboronic
(0.258 mmol, 1.01 equiv) in a 9:1 mixture of DMF–H2O
(4 mL) was flushed with argon for 2 min. The reaction
mixture was then heated by microwaves. The resulting
slurry was concentrated to dryness under reduced pressure.
The resulting residue was extracted with AcOEt, washed
with water, and brine. The organic layer was dried over
Na2SO4, concentrated under vacuum, and then purified
by column chromatography on silica gel to give the
desired aminopyrimidine 13a, 13b, 20, 24a, 24b, 24c, 24d,
and 24e.
3.4.4. 6-Benzyl-4-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]-
pyrimidin-2-amine (24a). Starting from 2-amino-6-benzyl-
5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl 4-methyl
benzenesulfonate 23a in presence of phenylboronic acid (ex-
perimental conditions: 100 ꢀC, 10 min), 6-benzyl-4-phenyl-
5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine 24a was
obtained as a light yellow solid (80 mg, 99%). Mp 106–
107 ꢀC; TLC Rf¼0.38 (CH2Cl2–MeOH 95:5); 1H NMR
(CDCl3) d: 2.67 (t, J¼5.1, 2H, CH2), 2.74 (t, J¼5.1, 2H,
NCH2), 3.58 (s, 2H, NCH2), 3.70 (s, 2H, CH2), 5.08 (br s,
2H, NH2), 7.23–7.63 (m, 10H, ArH); 13C NMR (CDCl3) d:
26.74, 50.84, 58.43, 62.92, 115.58, 127.77, 128.72, 128.81,
129.48, 129.60, 137.87, 138.52, 161.31, 165.42, 166.82.
3.4.1. 2-Amino-6-phenylpyrimidin-4-yl 4-methyl benz-
enesulfonate (13a). Starting from 2-amino-6-iodopyrimi-
din-4-yl methyl benzenesulfonate 16 and following the
general procedure in presence of phenylboronic acid (exper-
imental conditions: 100 ꢀC, 25 min), 2-amino-6-phenylpyri-
midin-4-yl 4-methyl benzenesulfonate 13a was obtained
as a white solid (70 mg, 80%). Mp 167–169 ꢀC; TLC
3.4.5. tert-Butyl-2-amino-4-phenyl-7,8-dihydropyr-
ido[4,3-d]pyrimidine-6(5H)-carboxylate (24b). Starting
from
tert-butyl-2-amino-4-{[4-methylphenyl)sulfonyl]-
oxy}-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxyl-
ate 23b in presence of phenylboronic acid (experimental
conditions: 100 ꢀC, 10 min), tert-butyl-2-amino-4-phenyl-
7,8-dihydropyrido
[4,3-d]pyrimidine-6(5H)-carboxylate
1
Rf¼0.78 (CH2Cl2–MeOH 99:1); H NMR (CDCl3) d: 2.48
24b was obtained as a white solid (82 mg, 98%). Mp 153–
154 ꢀC; TLC Rf¼0.44 (CH2Cl2–MeOH 95:5); 1H NMR
(CDCl3) d: 1.51 (s, 9H, C(CH3)3), 2.74 (t, J¼5.1, 2H,
CH2), 3.58 (t, J¼5.1, 2H, NCH2), 4.57 (s, 2H, NCH2),
5.51 (br s, 2H, NH2), 7.41–7.68 (m, 5H, ArH); 13C NMR
(CDCl3) d: 26.57, 28.86, 44.27, 48.81, 80.72, 114.23,
115.43, 130.08, 130.66, 132.41, 154.92, 161.11, 161.16.
(s, 3H, CH3), 5.20 (s, 2H, NH2), 6.79 (s, 1H, ArH), 7.39
(d, 2H, J¼8.3, ArH), 7.43–7.56 (m, 3H, ArH), 7.89–7.98
(m, 2H, ArH), 7.97 (d, 2H, J¼8.3, ArH); 13C NMR
(CDCl3) d: 22.1, 95.2, 127.5, 129.1, 129.3, 130.3, 131.4,
133.9, 137.0, 146.1, 162.2, 163.4, 165.9, 168.8. (EI) m/z:
ꢂ
341.0861 (MH+ C17H16I1N3O3S1 requires 341.0834).
ꢂ
(EI) m/z: 327.1833 (MH+ C18H23N4O2 requires 327.1816).
3.4.2. 2-Amino-6-(4-methoxyphenyl)-pyrimidin-4-yl 4-
methyl benzenesulfonate (13b). Starting from 2-amino-6-
iodopyrimidin-4-yl methyl benzenesulfonate 16 and following
the general procedure in presence of 4-methoxyphenyl-
boronic acid (experimental conditions: 100 ꢀC, 25 min),
2-amino-6-(4-methoxyphenyl)-pyrimidin-4-yl 4-methyl benz-
enesulfonate 13b was obtained as a white solid (80 mg,
82%). Mp 161–163 ꢀC; TLC Rf¼0.58 (AcOEt–heptane
3.4.6. tert-Butyl-2-amino-4-(4-chlorophenyl)-7,8-dihy-
dropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (24c).
Starting from 2-amino-6-benzyl-5,6,7,8-tetrahydropyr-
ido[4,3-d]pyrimidin-4-yl 4-methyl benzenesulfonate 23b
in presence of 4-chloro-phenylboronic acid (experimental
conditions: 100 ꢀC, 10 min), tert-butyl-2-amino-4-(4-chloro-
phenyl)-7,8-dihydro pyrido[4,3-d] pyrimidine-6(5H)-carb-
oxylate 24c was obtained as a white solid (78 mg, 84%).
1
1:1); H NMR (CDCl3) d: 2.49 (s, 3H, CH3), 3.89 (s, 3H,
1
OCH3), 5.16 (s, 2H, NH2), 6.75 (s, 1H, ArH), 6.99 (d, 2H,
J¼8.6, ArH), 7.39 (d, 2H, J¼8.3, ArH), 7.94 (d, 2H, J¼
8.3, ArH), 7.98 (d, 2H, J¼8.6, ArH); 13C NMR (CDCl3) d:
21.7, 56.4, 100.1, 115.4, 126.3, 129.2, 129.5, 132.3, 139.4,
145.2, 152.3, 154.1, 162.2, 163.1. (EI) m/z: 372.1032
Mp 133–135 ꢀC; TLC Rf¼0.49 (CH2Cl2–MeOH 95:5); H
NMR (CDCl3) d: 1.53 (s, 9H, C(CH3)3), 2.71 (t, J¼5.5,
2H, CH2), 3.59 (t, J¼5.1, 2H, NCH2), 4.54 (s, 2H, NCH2),
5.25 (br s, 2H, NH2), 7.45 (d, J¼8.6, 2H, ArH), 7.52 (d,
J¼8.6, 2H, ArH); 13C NMR (CDCl3, 75 MHz) d: 28.44,
28.85, 44.20, 48.73, 80.85, 118.80, 129.08, 130.42,
132.40, 136.16, 152.65, 154.87, 161.26, 164.56. (EI) m/z:
ꢂ
(MH+ C18H18I1N3O4S1 requires 372.1013).
ꢂ
3.4.3. 4-Methoxyphenyl-6-phenylpyrimidin-2-amine
(20). Starting from 2-amino-6-phenylpyrimidin-4-yl
4-methyl benzenesulfonate 13a and following the general
procedure in presence of 4-methoxy-phenylboronic acid (ex-
perimental conditions: 120 ꢀC, 15 min), 4-methoxyphenyl-
6-phenylpyrimidin-2-amine 20 was obtained as a white solid
(66 mg, 93%). Starting from 2-amino-6-(4-methoxyphenyl)-
pyrimidin-4-yl 4-methyl benzenesulfonate 13b in presence
of phenylboronic acid (experimental conditions: 140 ꢀC,
20 min) 20 was obtained in 65% yield. Mp 160–161 ꢀC;
361.1444 (MH+ C18H22 Cl1N4O2 requires 361.1426).
3.4.7. tert-Butyl-2-amino-4-(4-methoxyphenyl)-7,8-dihy-
dropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (24d).
Starting from 2-amino-6-benzyl-5,6,7,8-tetrahydropyr-
ido[4,3-d] pyrimidin-4-yl 4-methyl benzenesulfonate 23b
in presence of 4-methoxy-phenylboronic acid (experimental
conditions: 100 ꢀC, 10 min), tert-butyl-2-amino-4-(4-
methoxyphenyl)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-
carboxylate 24d was obtained as a white solid (90 mg, 99%).
Mp 118–120 ꢀC; TLC Rf¼0.33 (CH2Cl2–MeOH 95:5).
1H NMR (CDCl3) d: 1.53 (s, 9H, C(CH3)3), 2.75 (t, J¼5.5,
2H, CH2), 3.58 (t, J¼5.5, 2H, NCH2), 3.88 (s, 3H, OMe),
4.53 (s, 2H, NCH2), 5.30 (br s, 2H, NH2), 7.00 (d, J¼8.6,
2H, ArH), 7.54 (d, J¼8.6, 2H, ArH); 13C NMR (CDCl3)
1
TLC Rf¼0.58 (CH2Cl2–MeOH 99:1); H NMR (CDCl3) d:
3.91 (s, 3H, CH3), 5.34 (br s, 2H, NH2), 7.04 (d, 2H,
J¼8.8, 2H, ArH), 7.29 (s, 1H, ArH), 7.49–7.62 (m, 3H,
ArH), 8.07 (d, 2H, J¼8.8, ArH); 13C NMR (CDCl3) d:
55.82, 103.95, 114.51, 127.51, 129.05, 129.16, 130.51,

P. Benderitter et al. / Tetrahedron 63 (2007) 12465–12470
12469
d: 26.57, 28.86, 44.27, 48.81, 55.80, 80.72, 114.23, 115.43,
130.08, 130.66, 136.16, 154.92, 161.15, 161.16, 162.9,
121.62, 128.93, 130.22, 132.77, 152.34, 162.26, 163.32.
ꢂ
(EI) m/z: 292.1257 (MH+ C17H17N3Si requires 292.1265).
ꢂ
168.1. (EI) m/z: 357.1936 (MH+ C19H25N4O3 requires
357.1921).
3.5.3. 4-Phenyl-6-(phenylethynyl)pyrimidin-2-amine
(19a). Starting from 2-amino-6-phenylpyrimidin-4-yl
4-methyl benzenesulfonate 13a and following the general
procedure in presence of phenylacetylene (experimental
conditions: 120 ꢀC, 10 min), 4-phenyl-6-(phenylethynyl)
pyrimidin-2-amine 19a was obtained as an orange solid
(90 mg, 65%). Mp 120–122 ꢀC; TLC Rf¼0.55 (CH2Cl2–
3.4.8. tert-Butyl-2-amino-4-(3,4-dimethoxyphenyl)-7,8-
dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate
(24e). Starting from 2-amino-6-benzyl-5,6,7,8-tetrahydro-
pyrido[4,3-d]pyrimidin-4-yl 4-methyl benzenesulfonate
23b in presence of 3,4-dimethoxy-phenylboronic acid
(experimental conditions: 100 ꢀC, 10 min), tert-butyl-2-
amino-4-(3,4-dimethoxyphenyl)-7,8-dihydropyrido[4,3-d]pyri-
midine-6(5H)-carboxylate 24e was obtained as a white solid
(82 mg, 83%). Mp 168–170 ꢀC; TLC Rf¼0.32 (CH2Cl2–
1
MeOH 98:2). H NMR (CDCl3) d: 5.38 (br s, 2H, NH2),
7.27 (s, 1H, ArH), 7.45–7.55 (m, 6H, ArH), 7.56–7.68 (m,
2H, ArH), 7.95–8.05 (m, 2H, ArH); 13C NMR (CDCl3) d:
87.83, 92.27, 110.80, 121.93, 127.52, 128.90, 129.22,
130.01, 131.26, 132.75, 137.21, 152.28, 163.65, 166.36.
1
MeOH 95:5); H NMR (CDCl3) d: 1.52 (s, 9H, C(CH3)3),
2.76 (t, J¼5.5, 2H, CH2), 3.58 (t, J¼5.5, 2H, NCH2), 3.94
(s, 6H, OMe), 4.52 (s, 2H, NCH2), 5.28 (br s, 2H, NH2),
6.95 (s, 1H, ArH), 7.12 (s, 1H, ArH), 7.15 (s, 1H, ArH);
13C NMR (CDCl3) d: 26.67, 28.86, 41.01, 48.61, 56.42,
80.73, 111.07, 112.27, 115.45, 122.12, 130.36, 149.34,
149.52, 150.62, 154.94, 161.27, 164.46. (EI) m/z: 387.2043
3.5.4. 4-(4-Methoxyphenyl)-6-(phenylethynyl)pyrimidin-
2-amine (19b). Starting from 2-amino-6-(4-methoxy-
phenyl)-pyrimidin-4-yl 4-methyl benzenesulfonate 13b
and following the general procedure in presence of phenyl-
acetylene (experimental conditions: 120 ꢀC, 10 min), 4-(4-
methoxyphenyl)-6-(phenylethynyl)pyrimidin-2-amine 19b
was obtained as an yellow solid (110 mg, 71%). Mp 98–
99 ꢀC; TLC Rf¼0.48 (CH2Cl2–MeOH 98:2); 1H NMR
(CDCl3) d: 3.88 (s, 3H, CH3), 5.23 (br s, 2H, NH2), 6.99
(d, J¼9.1, 2H, ArH), 7.22 (s, 1H, ArH), 7.32–7.46 (m, 3H,
ArH), 7.55–7.70 (m, 2H, ArH), 8.01 (d, J¼9.1 Hz, 2H,
ArH); 13C NMR (CDCl3) d: 55.80, 87.99, 91.89, 110.07,
114.56, 122.03, 128.86, 129.08, 129.56, 129.90, 132.71,
(MH+ C20H27N4O4 requires 387.2027).
ꢂ
3.5. Typical procedure for microwave-assisted
Sonogashira reaction
A suspension of 13, 16, 17 or 23 (0.51 mmol), PdCl2(PPh3)2
(27 mg, 0.05 mmol, 0.1 equiv), CuI (7.5 mg, 0.05 mmol,
0.1 equiv) in a 5:1 mixture of CH3CN–NEt3 (5 mL) was
mixed in a process vial (2–5 mL) and flushed with argon
for 2 min. The corresponding alkyne (0.56 mmol) was
finally added. The reaction mixture was then heated by
microwaves (excepted for compound 16). The resulting
suspension was concentrated to dryness under reduced
pressure. The resulting residue was purified by column chro-
matography on silica gel to obtain the aminopyrimidine 17,
18, 19a, 19b, and 24f.
ꢂ
151.99, 162.41, 163.58, 165.73. (EI) m/z: 302.1281 (MH+
C19H15N3O requires 302.1288).
3.5.5. tert-Butyl-2-amino-4-(phenylethynyl)-7,8-dihydro-
pyrido[4,3-d]pyrimidine-6(5H)-carboxylate (24f). Starting
from tert-butyl-2-amino-4-{[4-methylphenyl)sulfonyl]-oxy}-
7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate 24b
in presence of phenylacetylene (experimental conditions:
100 ꢀC, 20 min), tert-butyl-2-amino-4-(phenylethynyl)-7,8-
dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate 25f was
obtained in 78% yield. TLC Rf¼0.53 (CH2Cl2–MeOH
3.5.1. 2-Amino-6-(phenylethynyl)pyrimidin-4-yl 4-meth-
yl benzenesulfonate (17). Starting from 2-amino-6-iodopyr-
imidin-4-yl methyl benzenesulfonate 16 and following the
general procedure (experimental conditions: RT, 30 min) in
presence of phenylacetylene, 2-amino-6-(phenylethynyl)-
pyrimidin-4-yl 4-methyl benzenesulfonate 17 was obtained
as a yellow solid (137 mg, 98%). Mp 147–149 ꢀC; TLC
1
95:5); H NMR (CDCl3) d: 1.48 (s, 9H, C(CH3)3), 2.85 (t,
J¼5.5, 2H, CH2), 3.68 (t, J¼5.5, 2H, NCH2), 4.45 (s, 2H,
NCH2), 5.30 (br s, 2H, NH2), 7.31–7.45 (m, 3H, ArH),
ꢂ
7.53–7.63 (m, 2H, ArH). (EI) m/z: 351.1835 (MH+
C20H23N4O2 requires 351.1816).
1
Rf¼0.56 (AcOEt–heptane 1:1). H NMR (CDCl3) d: 2.48
(s, 3H, CH3), 5.42 (br s, 2H, NH2), 6.58 (s, 1H, ArH),
7.33–7.49 (m, 5H, ArH), 7.59 (dd, J¼8.28, 2H, ArH), 7.95
(d, J¼8.28, 2H, ArH); 13C NMR (CDCl3) d: 22.18, 86.64,
93.96, 103.29, 121.31, 128.96, 129.15, 130.23, 130.42,
132.83, 133.63, 146.35, 154.32, 162.95, 165.28.
3.6. Typical procedure for preparation of N-protected
2-amino-5,6,7,8-tetrahydro[4,3-d]pyrimidin-4-ol (22)
Sodium ethanolate was prepared from sodium (0.25 g) and
30 mL of anhydrous ethanol. Protected ethyl 4-oxopiperi-
din-4(3H)-one 21 (10.1 mmol, 1.0 equiv) and guanidine
(2.18 g, 12.1 mmol, 1.2 equiv) were then added and the mix-
ture was refluxed for 16 h. After cooling to room temperature
the slurry was filtered and the solvent was evaporated. The
residue was taken up in a minimum of 95% ethanol and water
was added until precipitation. The white solid precipitatewas
collected and dried in vacuo to give the aminopyrimidines
22a and 22b.
3.5.2. 4-(Phenylethynyl)-6-[(trimethylsilyl)ethynyl]pyri-
midin-2-amine (18). Starting from 2-amino-6-(phenyl-
ethynyl) pyrimidin-4-yl 4-methyl benzenesulfonate 17 and
following the general procedure (experimental conditions:
120 ꢀC, 15 min) in presence of trimethylsilylacetylene,
4-(phenylethynyl)-6-[(trimethylsilyl)ethynyl]pyrimidin-2-
amine 18 was obtained as an yellow solid (89 mg, 60%). Mp
1
80–82 ꢀC; TLC Rf¼0.56 (AcOEt–heptane 1:1). H NMR
(CDCl3) d: 0.29 (s, 9H; Me), 5.36 (br s, 2H, NH2), 6.96 (s,
1H, ArH), 7.33–7.45 (m, 3H, ArH), 7.52–7.66 (m, 2H, ArH);
13C NMR (CDCl3) d: 0.08, 93.43, 99.93, 101.91, 116.69,
3.6.1. 2-Amino-6-benzyl-5,6,7,8-tetrahydropyrido[4,3-d]-
pyrimidin-4-ol (22a). Starting from ethyl-1-benzyl-4-
oxopiperidine-3-carboxylate 21a and following the general

12470
P. Benderitter et al. / Tetrahedron 63 (2007) 12465–12470
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procedure, 2-amino-6-benzyl-5,6,7,8-tetrahydropyrido[4,3-
d]pyrimidin-4-ol 22a was obtained as a white solid (2.3 g,
89%). Mp 190–195 ꢀC; TLC Rf¼0.38 (CH2Cl2–MeOH
1
9:1); H NMR (DMSO-d6) d: 2.24 (CH2, J¼5.27), 2.54 (t,
2H, CH2, J¼5.27), 3.05 (s, 2H, CH2Ar), 6.38 (br s, NH2),
7.18–7.37 (m, 5H, ArH); 13C NMR (DMSO-d6) d: 21.9,
49.8, 56.7, 61.5, 106.3, 127.5, 128.6, 129.2, 138.2, 154.1,
162.5. ESMS m/z: 257 (M+H).
3.6.2. tert-Butyl-2-amino-4-hydroxy-7,8-dihydropyr-
ido[4,3-d]pyrimidine-6(5H)-carboxylate (22b). Starting
from 1-tert-butyl-3-ethyl 4-oxopiperidine-1,3-dicarboxylate
21b and following the general procedure, tert-butyl-2-amino-
4-hydroxy-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carb-
oxylate 22b was obtained as a yellow oil (2.33 g, 85%). TLC
1
Rf¼0.27 (CH2Cl2–MeOH 95:5); H NMR (DMSO-d6) d:
1.41 (s, 9H, C(CH3)3), 2.25 (t, J¼5.60, 2H, CH2), 3.45 (t,
J¼5.6, 2H, NCH2), 4.01 (s, 2H, NCH2), 6.62 (br s, 2H,
NH2), 11.61 (br s, 1H, OH); 13C NMR (DMSO-d6) d:
21.98, 28.92, 42.22, 48.05, 79.84, 106.54, 154.63, 156.17,
158.52, 164.87. ESMS m/z: 272.3 (M+H).
11. Deng, X.; Mani, N. S. Org. Lett. 2006, 8, 269–272.
12. Zhou, B.; Taylor, B.; Kornau, K. Tetrahedron Lett. 2005, 46,
3977–3979.
13. Li, J. J.; Gribble, G. W. Palladium in Heterocyclic Chemistry;
Baldwin, J. E., William, R. M., Eds.; Pergamon: Oxford, 2002;
Vol. 20, pp 375–401.
Acknowledgements
14. Turck, A.; Ple, N.; Mojovic, L.; Queguiner, G. Bull. Soc. Chim.
Fr. 1993, 130, 488–492.
15. Schmitt, M.; De Araujo-Junior, J. X.; Bourguignon, J. J. Mol.
Divers. 2006, 10, 429–439.
16. Matyus, P.; Maes, B. U. W.; Riedl, Z.; Hajos, G.; Lemiere,
G. L. F.; Tapolcsanyi, P.; Monsieurs, K.; Elias, O.;
Dommisse, R. A.; Krajsovszky, G. Synlett 2004, 1123–
1139.
Financial support from the Agence Nationale de Recherche
et Technologie (ANRT) and Neuro3D is gratefully acknowl-
edged. Financial support (Proc No. 0085057) of CAPES/
Brazil to J.X.A.-Jr. and Cofecub are acknowledged. The
authors thank Dr. Gilbert Schlewer for helpful discussions
and encouragement.
17. Goodman, A. J.; Stanford, S. P.; Tarbit, B. Tetrahedron 1999,
15067–15070.
References and notes
ꢀ
18. Czernecki, S.; Hoang, A.; Valery, J.-M. Tetrahedron Lett. 1996,
37, 8857–8860.
ꢀ
2004, 15, 3281–3287.
1. Berger, J.; Flippin, L. A.; Greenhouse, R.; Jaime-Figueroa,
S.; Liu, Y.; Miller, A. K.; Putman, D. G.; Weinhardt, K. K.;
Zhao, S. US 5,958,934, 1999.
ꢀ
19. Solymar, M.; Forro, E.; Fulop, F. Tetrahedron: Asymmetry
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