Regioselective synthesis of 2,8-disubstituted 4-aminopyrido[3,2-d] pyrimidine-6-carboxylic acid methyl ester compounds

Article abstract of DOI:10.1021/jo201834d

We report herein the synthesis of 4-amino-2,8-dichloropyrido[3,2-d] pyrimidine derivatives 2 and their regioselective diversification through S _NAr and metal-catalyzed cross-coupling reactions. While amination of 2 took place selectively at C-2

Full text of DOI:10.1021/jo201834d

Article
pubs.acs.org/joc
Regioselective Synthesis of 2,8-Disubstituted 4-Aminopyrido[3,2-
d]pyrimidine-6-carboxylic Acid Methyl Ester Compounds
Gwenaelle Bouscary-Desforges,† Agnes Bombrun,† John Kallikat Augustine,‡ Gerald Bernardinelli,§
́
and Anna Quattropani*,†
†Merck Serono S.A., 9, Chemin des Mines, 1202 Geneva, Switzerland
‡Syngene International Ltd., Biocon Park, Plot Nos. 2 & 3, Bommasandra-Jigani Road, Bangalore 560 099, India
§Laboratoire de crystallographie, Universite
́ ̀
de Geneve, 24, quai Ernest-Ansermet, 1211 Geneva, Switzerland
S
* Supporting Information
ABSTRACT: We report herein the synthesis of 4-amino-2,8-
dichloropyrido[3,2-d]pyrimidine derivatives 2 and their regioselective
diversification through SNAr and metal-catalyzed cross-coupling
reactions. While amination of 2 took place selectively at C-2, the
regioselectivity of thiol or thiolate addition depended on the reaction
conditions. Selective C-8 addition was obtained in DMF with Hunig’s
̈
i
base and C-2 addition in PrOH. These C-2 or C-8 regioselective
thiolations provided an opportunistic way to selectively activate either of the two positions toward the metal-catalyzed cross-
coupling reaction. The chloride could be efficiently substituted by Suzuki−Miyaura reaction and the sulfanyl group by
Liebeskind−Srogl cross-coupling reaction, demonstrating the orthogonality of both reactive centers. The development of
regioselective conditions for these different transformations yielded the synthesis of 4-amino-2,6,8-trisubstituted pyrido[3,2-
d]pyrimidine derivatives, with various substituents.
1). Addition of anilines, substituted with neutral, electron-
donating, or electron-withdrawing groups, indicated the high
reactivity of the C-4−Cl bond toward SNAr (Table 1, entries
4−6). C-4 regioselectivity of this first addition was
unambiguously confirmed by X-ray crystal structure analysis
on further substituted analogues 5c and 6c. The regioselectivity
of the first amination is in line with the reported C-4 addition
to 2,4-dichloropyrido[3,2-d]pyrimidine and additional internal
investigations.6
To study the reactivity of the two remaining chloride at C-2
and C-8, various SNAr and metal-catalyzed cross-coupling
reactions were investigated on compounds 2b and 2c.
Amination was first explored, with three different amines,
butylamine and benzylamine as primary amines and diethyl-
amine as secondary amine. Reaction of a solution of 2b or 2c in
a mixture of MeCN and DMF with 5 equiv of amine at 90 °C
led after 1 h to derivatives 3a−d in good yields (Table 2, entries
1−4). Excess amine did not give multiple additions but allowed
complete conversion into a single regioisomer 3a−d. As C-2
showed good reactivity toward amination, reaction with aniline
was tried. A complete conversion could be achieved only in
dioxane as solvent. After 48 h at reflux, derivative 3e was
isolated in 72% yield (Table 2, entry 5).7
INTRODUCTION
■
Pyridopyrimidines are an important class of heterocycles that
display a range of significant biological properties, including
functioning as anticancer, antiviral, and anti-inflammatory
agents. With the aim to produce biased libraries, we were
particularly interested in the 4-aminopyrido[3,2-d]pyrimidine
heterocycle, a motif found in bioactive compounds such as
phosphoinositide 3-kinase (PI3K), tyrosine kinase and protein
kinases inhibitors,1,2 chemokine antagonists,3 and hepatitis C
virus (HCV) replication inhibitors.4 To be able to modulate
their biopharmaceutical profile and druglike properties, our goal
was to develop a flexible and efficient route to introduce
additional specificity handles on the main core. Starting from
the reported synthesis of 2,4,8-trichloropyrido[3,2-d]-
pyrimidine-6-carboxylic acid methyl ester 1,5 a first amination
at C-4 would leave chloride at C-2 and C-8 and ester at C-6 as
additional reactive centers for further diversity. To be of general
utility, regioselective transformation of each reactive center
must be achievable. We report herein the synthesis of 4-amino-
2,8-dichloropyrido[3,2-d]pyrimidine derivatives 2 and their
regioselective diversification, using two classes of reaction,
SNAr and metal-catalyzed cross-coupling reactions.
RESULTS AND DISCUSSION
The regioselective amination on 2 was further probed by
chloride reduction of compound 3c and 3e yielding 4a and 4b,
respectively (Scheme 1). The 1H NMR spectrum of
■
Diverse amines were selected for the preparation of a series of
2, including primary and secondary amines and anilines. When
a stoichiometric amount of the amine was added to 1 in the
presence of Hunig’s base, the corresponding regioselective
substitution products 2a−f were isolated in high yields (Table
̈
Received: September 6, 2011
Published: November 28, 2011
© 2011 American Chemical Society
243
dx.doi.org/10.1021/jo201834d | J. Org. Chem. 2012, 77, 243−252

The Journal of Organic Chemistry
Article
Table 1. SNAr with Diverse Amines on 1 at C-4
entry
amine
product
yield (%)
1
2
3
4
5
6
cHex-NH2
2a
2b
2c
2d
2e
2f
77
80
73
82
80
78
Me2NH
Et2NH
PhNH2
p-OMe-PhNH2
p-CF3-PhNH2
Table 2. SNAr with Diverse Amines on 2b−c at C-2
entry
2, R1R2N
R3R4NH
product
yield (%)
1
2
3
4
2b, Me2N
2b, Me2N
2c, Et2N
BuNH2
BnNH2
BnNH2
Et2NH
PhNH2
3a
3b
3c
3d
3e
77
79
82
81
72
2b, Me2N
2b, Me2N
a
5
a
Reaction was performed in dioxane at reflux.
dehalogenated products 4a and 4b consisted of a pair of
doublets at δ 7.88 and 8.23 ppm and at δ 7.80 and 8.17 ppm,
respectively, corresponding to H-7 and H-8, with a J3 coupling
constant of 8.7 Hz. These results conclusively proved that 3c
and 3e are substituted with benzylamine or aniline at C-2,
leaving a chloride substituent at position 8. In conclusion, 2
amination is highly C-2 regioselective and independent of the
nature of the amine.
Scheme 1. Reduction of C-8 Chloride on 3c and 3e
SNAr reactions on 2,8-dichloro-4-diethylaminopyrido[3,2-
d]pyrimidine 2c were further studied with thiols as
nucleophiles. Benzylthiol or p-thiocresol in the presence of
Hunig’s base or sodium methyl thiolate were added in DMF.
̈
Reactions were performed between 0 °C and room temper-
Table 3. SNAr with Diverse Thiols or Sodium Methyl Thiolate on 2c
b
a
entry
R1SH or R1SNa
base
Hunig’s base
products
UHPLC ratio
yield (%)
1
2
3
BnSH
5a/6a
5b/6b
5c/6c
73/25
68/32
97/3
65/17
62/28
77/0
̈
p-CH3-PhSH
MeSNa
Hunig’s base
̈
a
b
Ratio measured on reaction mixtures. 1 equiv of thiol or sodium methyl thiolate was used.
244
dx.doi.org/10.1021/jo201834d | J. Org. Chem. 2012, 77, 243−252

The Journal of Organic Chemistry
Article
Scheme 2. Addition of BnSH on 6b at C-8
Table 4. Influence of Basic or Acidic Media, Nature of the Solvent, and Temperature on Regioisomers Formation
entry
T (°C)
solvent
DMF
p-Me-PhSH (equiv)
additive
C-8 (5b)/C-2 (6b)
9/18
1
2
3
4
5
6
7
8
9
0
0
1
1
1
1
5
5
5
5
5
Hunig’s base (3 equiv)
̈
DMF
no reaction
90
0
DMF
0/1 (25% conversion)
a
DMF
iPrOH
iPrOH
iPrOH
DMF/iPrOH
DMF/iPrOH
HCl (1 equiv)
0/1
90
90
rt
Hunig’s base (3 equiv)
0/1
̈
0/1
0/1 (20% conversion)
90
90
Hunig’s base (3 equiv)
9/1
0/1
̈
a
With a 4 M solution of HCl in dioxane.
ature to avoid double addition, as observed at higher
temperature. After 2 h at 0 °C, the reaction mixture was
allowed to warm to room temperature. Under these conditions
and different from the above amination, two regioisomers were
formed with benzylthiol and p-thiocresol as nucleophiles in
ratios of 73/25 and 68/32, respectively (Table 3, entries 1 and
2). With sodium methylthiolate as nucleophile, the reaction was
more selective leading to the formation of only traces of the
second regioisomer (3%, Table 3, entry 3). These regioisomeric
ratios were accurately determined on the reaction mixtures by
UHPLC-MS (Table 3). All of the regioisomers were isolated
with overall yields ranging from 77 to 90% and fully
characterized.
The regioselectivity of the thiol addition was assigned on the
basis of the results of NOESY experiments performed on
derivatives 5a/6a, 5b/6b, and 5c/6c. NOESY correlation
between the benzylic protons of the thioether and H-7 for
derivative 5a and between the methyl of the thioether and H-7
for derivative 5c were observed, confirming that the thiol
addition takes place predominately at position 8. The structures
of 5c and 6c were confirmed from X-ray crystal structure
analysis. In addition, the X-ray crystal structures confirmed the
first amination at C-4. No relevant information on 5b or 6b
structures could be obtained from NOESY experiments. In
order to attribute the substitution pattern of 6b, the remaining
chloride was substituted with a nucleophile selected for its
reactivity and its potential to present NOESY correlations.
Benzylthiol was chosen for this purpose, and reaction with 6b
between the benzylic protons and H-7 confirmed that the
benzylthiol group was at the C-8 position and consequently
that p-thiocresol was at the C-2 position. The full character-
ization of 6a and 5b indicated that they were regioisomers of 5a
and 6b, showing, respectively, the same mass but different
1
retention time in UHPLC-MS and different H and 13C NMR
chemical shifts. For this reason, their identities were deduced
from the assignment of 5a and 6b structures.
Reaction conditions for the addition of thiol to 2c were
further explored with p-thiocresol in order to optimize the
regioselectivity and to find out which parameters were
influencing this regioselectivity, such as the nature of the
solvent, the presence of a base or an acid, and the temperature
of the reaction (Table 4). As before, the regioisomeric ratios
were determined on the reaction mixture by UHPLC-MS.
In DMF at 0 °C and in the presence of Hunig’s base, p-
̈
thiocresol added to 2c predominately at C-8 (Table 4, entry 1).
We could expect that the presence of the base ensures the
deprotonation of the p-thiocresol, affording the thiolate as
reactive species and the neutralization of the HCl liberated
during the reaction. Under such conditions, C-8 appears to be
the most reactive center. In the absence of base, no reaction
was observed at rt (Table 4, entry 2). In this reaction, p-
thiocresol is probably not nucleophilic enough to react with 2c.
At 90 °C, 25% of 6b was formed, leaving 75% of starting
material (Table 4, entry 3). The liberated HCl may influence
the regioselectivity and favor C-2 addition. Indeed, the presence
of 1 equiv of HCl yielded selectively C-2 addition, with
complete conversion at 0 °C to rt (Table 4, entry 4). This
observed inversion of regioselectivity can be explained via the
in DMF in the presence of Hunig’s base afforded derivative 7 in
̈
75% yield (Scheme 2). The NOESY correlation observed
245
dx.doi.org/10.1021/jo201834d | J. Org. Chem. 2012, 77, 243−252

The Journal of Organic Chemistry
Article
Table 5. SNAr of Diverse Thiols and Thiolates on 2c
entry
R1SH or R1SNa
solvent
products
UHPLC ratio
yield (%)
a
1
2
3
BnSH
iPrOH
iPrOH
MeOH
5a/6a
5b/6b
5c/6c
0/100
0/100
3/97
−/6
−/83
−/73
a
p-CH3-PhSH
b
MeSNa
a
b
5 equiv of thiol was used. 1 equiv of sodium methyl thiolate was used.
Table 6. SNAr with Amines on 5c at C-2
entry
amine
product
yield (%)
1
2
3
BnNH2
BuNH2
Et2NH
8a
8b
8c
74
71
72
Table 7. Suzuki−Miyaura Cross-Coupling Reactions on 3b at C-8
entry
R1B(OH)2
PhB(OH)2
product
yield (%)
1
2
3
9a
9b
9c
82
82
78
p-OMe-PhB(OH)2
p-CF3-PhB(OH)2
protonation of derivative 2c. On the basis of calculated pKa
values, N-1 is the most basic center.9 Protonation at this site
does not significantly affect the partial charges at C-2 and C-8,
respectively.10 In contrast, the LUMO density is the highest at
C-8 for the neutral and at C-2 for the protonated form. This
indicates that the reaction is not charge but orbital controlled.
These same reactions were performed in a protic solvent
9). In the presence of Hunig’s base, DMF could interfere with
hydrogen bonding between 2c and PrOH, yielding fast
addition of deprotonated form of p-thiocresol to C-8. In the
̈
i
absence of Hunig’s base, activation of 2c through hydrogen
̈
bonding with iPrOH is required to ensure p-thiocresol addition,
yielding C-2 regioselectivity.10
With the aim to study the C-2 or C-8 addition reversibility
under the different reaction conditions, p-thiocresol was added
i
such as PrOH. As 2c was not soluble in this solvent, the
i
reaction mixture was heated at refluxing temperature to ensure
the dissolution of the starting material. In addition, an excess of
p-thiocresol was used for a complete conversion, without
influencing the observed regioselectivity and multiple addition.
Addition of a base did not influence the regioselectivity and
yielded the formation of the C-2 adduct as unique regioisomer
(Table 4, entries 5 and 6). At rt, the same regioselectivity was
observed, with only 20% of conversion probably due to limited
solubility of 2c in iPrOH (Table 4, entry 7). The opportunity of
into a solution of 2c in PrOH, and the mixture was heated to
90 °C until 50% conversion into 6b. Then, DMF and Hunig’s
̈
base were added. After few hours at rt, a 50:50 mixture of both
regioisomers was obtained, demonstrating that the formation of
each regioisomer was irreversible. Regioisomers 5b and 6b were
stable in both reaction conditions, in DMF with Hunig’s base at
̈
i
0 °C and rt or in PrOH at 90 °C.
At this point, we could conclude that C-2 addition of thiol or
thiolate to derivative 2 was favored under acidic conditions
and/or protic solvents, while C-8 addition was majoritarly
observed in polar aprotic solvent in the presence of a tertiary
i
hydrogen bonding in PrOH could direct C-2 addition, even
under basic conditions.10 Interestingly, in a PrOH/DMF
i
mixture the regioselectivity was directly influenced by the
amine such as Hunig’s base.
Conditions favoring C-2 thiolation were used with the same
three thiols as previously described, namely: benzylthiol, p-
̈
base, yielding mainly C-8 addition in the presence of Hunig’s
̈
base and C-2 addition without any base (Table 4, entries 8 and
246
dx.doi.org/10.1021/jo201834d | J. Org. Chem. 2012, 77, 243−252

The Journal of Organic Chemistry
Article
Table 8. Suzuki−Miyaura Cross-Coupling Reaction on 5c at C-2
entry
R1B(OH)2
PhB(OH)2
product
yield (%)
1
2
3
10a
10b
10c
88
79
84
p-OMe-PhB(OH)2
p-CF3-PhB(OH)2
Table 9. Liebeskind−Srogl Cross-Coupling Reactions on 10a at C-8
entry
R1B(OH)2
PhB(OH)2
product
yield (%)
1
2
3
11a
11b
11c
84
88
87
p-OMe-PhB(OH)2
p-CF3-PhB(OH)2
a
2 equiv of boronic acid for completion.
thiocresol, and sodium methyl thiolate (Table 5). Only partial
conversion could be achieved with benzylthiol, even at refluxing
temperature, affording 6a in very low yield (Table 5, entry 1).
p-Thiocresol was more reactive under such conditions, and
compound 6b was isolated in 83% yield (Table 5, entry 2).
When sodium methyl thiolate was used, MeOH was selected as
solvent to avoid possible transesterification observed in iPrOH,
and compound 6c was isolated in 73% yield (Table 5, entry 3).
We took advantage of the optimized access to both
regioisomers 5c and 6c in order to further explore the
synthesis of diverse 2,8-disubstituted 4-aminopyrido[3,2-d]-
pyrimidine analogues. Chloride reactivity toward SNAr and
cross-coupling reactions, such as Suzuki−Miyaura reaction, and
transformation of methylsulfanyl group via Liebeskind−Srogl
cross-coupling reactions were investigated. We first studied the
reaction of derivative 5c with amines. Addition of primary or
secondary amines at 180 °C in MeCN under microwave
irradiations yielded 2,4-diamino-8-methylsulfanylpyrido[3,2-d]-
pyrimidines 8 in 71−74% yields (Table 6).
Further transformation of the C-8-SMe bond on derivative 8,
via Liebeskind-Srogl cross-coupling reactions, would give access
to the same products as Suzuki−Miyaura cross-coupling
reaction on derivative 3 (Table 7 below), which is synthetically
shorter (being two vs three steps from 1). For this reason, we
focused on this second approach, starting from derivative 3b
(Table 7). Suzuki−Miyaura cross-coupling reactions of 3b were
performed under classical conditions using Pd(PPh3)4 as
catalyst and Cs2CO3 as base in dioxane. Diverse boronic
acids with electron-donating or electron-withdrawing groups
were selected. Reaction mixtures were heated at 90 °C,
affording after 5−7 h derivatives 9a to 9c in good yields (Table
7, entries 1−3).
mono- and bis-coupling products was obtained. Taking
advantage of the differentiation of both reactive centers at C-
2 and C-8, and their known orthogonal reactivity,11 derivative
5c was first submitted to Suzuki−Miyaura cross-coupling
reactions (Table 8). The same reaction conditions as described
previously were selected, affording derivatives 10a−c in 79 to
88% yields (Table 8, entries 1−3). Under such conditions, the
methylsulfanyl group remained unchanged. Parallel to our
work, Guillaumet et al. published similar approach to
differentiate C-4 and C-2 chloride on the 2,4-dichloropyrido-
[3,2-d]pyrimidine.12
A different aryl group was further introduced at C-8 on
derivative 10a via Liebeskind−Srogl cross-coupling reaction.
Compounds 11 were obtained using a stoichiometric amount
of boronic acid derivatives, with Pd(PPh3)4 as catalyst and
copper(I) thiophene-2-carboxylate (CuTC) as cofactor (Table
9). After 3.5 h in dioxane at 90 °C, compounds 11 were isolated
in good yields (Table 9). With the poorly reactive p-
trifluoromethylphenylboronic acid, the reaction had to be
repeated twice to get a complete conversion. These two
successive cross-coupling reactions, i.e., the first Suzuki−
Miyaura followed by the Liebeskind−Srogl cross-coupling,
allowed the introduction of two different aryl groups at
positions C-2 and C-8, yielding novel and diverse compounds
11 in good yields and selectivity.
CONCLUSIONS
■
We have reported the synthesis of 4-amino-2,8-dichloropyrido-
[3,2-d]pyrimidines derivatives 2 and their controlled regiose-
lective diversification through different set of SNAr and metal-
catalyzed cross-coupling reactions. While amination took place
selectively at C-2 of 2, the regioselectivity of thiol or thiolate
addition depended on the nature of the solvent (protic or polar
aprotic solvents) and the pH of the reaction mixture. Addition
Second, derivative 5c was diversified via two successive
metal-catalyzed cross-coupling reactions. Selective mono-cross-
coupling reaction on its precursor 2c was tedious. A mixture of
at C-8 took place in DMF with Hunig’s base and at C-2 in
̈
247
dx.doi.org/10.1021/jo201834d | J. Org. Chem. 2012, 77, 243−252

The Journal of Organic Chemistry
Article
iPrOH. These C-2 or C-8 regioselective thiolations provided an
opportunistic way of differentiating the two positions toward
metal-catalyzed cross-coupling reaction. 2-Chloro-4-amino-8-
(methylthio)pyrido[3,2-d]pyrimidine derivative 5c was further
diversified either through amination or through two successive
metal-catalyzed cross-coupling reactions. In this second
alternative, a first aryl group was introduced selectively at C-2
through Suzuki−Miyaura reaction, demonstrating the ortho-
gonality of both reactive centers (C−Cl vs C−SMe). A second
aryl group was introduced through Liebeskind−Srogl cross-
coupling reaction at the C−SMe bond. With the development
of highly regioselective conditions for the synthesis of 2,6,8-
trisubstituted 4-aminopyrido[3,2-d]pyrimidine derivatives, we
were able to prepare a wide variety of analogues. This strategy
is currently being applied to structurally related polysubstituted
heterocyclic derivatives and will be reported in the future.
2,8-Dichloro-4-phenylaminopyrido[3,2-d]pyrimidine-6-car-
boxylic acid methyl ester (2d): yield = 82%; dark orange solid; mp
1
223−224 °C dec; IR νmax 3338, 1731, 1574 cm−1; H NMR (300
MHz, CDCl3) δ 4.07 (s, 3H), 7.24 (t, J = 8 Hz, 1H), 7.45 (t, J = 8 Hz,
2H), 7.90 (d, J = 8 Hz, 2H), 8.49 (s, 1H), 9.45 (br s, 1H); 13C NMR
(75.47 MHz, CDCl3) δ 53.8, 121.6, 126.0, 129.3, 129.6, 131.3, 137.0,
143.7, 145.3, 145.8, 158.5, 161.4, 163.9; HPLC tR = 4.48 min; ES-MS
m/z 349.19 (M + H)+. Anal. Calcd for C15H10Cl2N4O2: C, 51.60; H,
2.89; N, 16.05; Cl, 20.31. Found: C, 51.24; H, 2.76; N, 15.82; Cl,
19.95.
2,8-Dichloro-4-(4-methoxyphenylamino)pyrido[3,2-d]-
pyrimidine-6-carboxylic acid methyl ester (2e): yield = 80%;
yellow solid; mp 231−232 °C dec; IR νmax 3333, 1729, 1574, 1248
1
cm−1; H NMR (300 MHz, CDCl3) δ 3.85 (s, 3H), 4.07 (s, 3H),
6.96−6.99 (m, 2H), 7.78−7.81 (m, 2H), 8.48 (s, 1H), 9.36 (br s, 1H);
13C NMR (75.47 MHz, CDCl3) δ 53.8, 55.9, 114.7, 123.3, 129.2,
130.1, 131.4, 143.5, 145.3, 145.6, 157.8, 158.2, 161.6, 164.0; HPLC tR
= 4.42 min; ES-MS m/z 379.22 (M + H)+. Anal. Calcd for
C16H12Cl2N4O3: C, 50.68; H, 3.19; N, 14.77. Found: C, 51.03; H,
3.52; N, 14.48.
2,8-Dichloro-4-(4-trifluoromethylphenylamino)pyrido[3,2-
d]pyrimidine-6-carboxylic acid methyl ester (2f): yield = 78%;
dark orange solid; mp 192−193 °C dec; IR νmax 1723, 1572, 1316,
1106 cm−1; 1H NMR (300 MHz, CDCl3) δ 4.09 (s, 3H), 7.72 (d, J =
8.5 Hz, 2H), 8.08 (d, J = 8.5 Hz, 2H), 8.53 (s, 1H), 9.61 (br s, 1H);
13C NMR (75.47 MHz, CDCl3) δ 53.9, 121.3, 124.2 (q, J = 267.2 Hz),
126.9 (q, J = 3.7 Hz), 127.5 (q, J = 32 Hz), 129.5, 131.1, 140.1, 144.1,
145.4, 146.2, 158.6, 161.1, 163.8; HPLC tR = 5.23 min; ES-MS m/z
417.20 (M + H)+. Anal. Calcd for C16H9Cl2F3N4O2: C, 46.07; H, 2.17;
N, 13.43. Found: C, 45.72; H, 2.47; N, 13.34.
EXPERIMENTAL SECTION
■
General Procedures. The commercially available starting materi-
als were used without further purification. 1H NMR spectra were
recorded at 300 or 400 MHz and 13C NMR spectra were recorded at
75.47 or 100.63 MHz, as indicated next to each NMR analysis. 1H and
13C chemical shifts (δ) were internally referenced to the residual
solvent peak. Mass spectra were acquired by electrospray ionization.
Melting points were reported without correction. The preparative
HPLC purifications were performed with a mass-directed autopur-
ification system. All HPLC purifications were performed with a
gradient of MeCN/H2O.
4-(4-Methoxyphenylamino)pyrido[3,2-d]pyrimidine-6-car-
boxylic Acid Methyl Ester (2g). To a solution of 2e (500 mg, 1.32
mmol) in a 1:1 mixture of methanol and dichloromethane (50 mL)
was added 10% Pd/C (50 mg), and the reaction mixture was put
under 1.5 bar of hydrogen for 6 h at rt. The catalyst was removed by
filtration, and the filtrate was concentrated. The crude product was
purified by column chromatography using 10−12% ethyl acetate in
petroleum ether as eluent to afford compound 2g as pale yellow solid
(0.292 mg, 73% yield): mp 131−132 °C; IR νmax 3464, 1726, 1604,
1541, 1280, 1031 cm−1; 1H NMR (400 MHz, CDCl3) δ 3.86 (s, 3H),
4.09 (s, 3H), 6.99−7.01 (dd, J = 6.8, 2.2 Hz, 2H), 7.79−7.81 (dd, J =
6.8, 2.2 Hz, 2H), 8.36−8.38 (d, J = 8.7 Hz, 1H), 8.45−8.47 (d, J = 8.7
Hz, 1H), 8.77 (s, 1H), 9.39 (br s, 1H); 13C NMR (100 MHz, CDCl3)
δ 53.1, 55.5, 114.3, 123.3, 128.2, 130.4, 131.5, 136.8, 145.7, 145.8,
156.9, 157.7, 157.8, 164.5; HPLC tR = 2.75 min; ES-MS m/z 311.2 (M
+ H)+. Anal. Calcd for C16H14N4O3: C, 61.93; H, 4.55; N, 18.05.
Found: C, 61.98; H, 4.59; N, 18.01.
The microwave chemistry was performed on a single-mode
microwave reactor Emrys Optimiser from Personal Chemistry or a
single-mode microwave reactor Initiator 60 from Biotage in sealed
reaction vessels.
General Procedure for SNAr with Amines on Derivative 1 at
C-4. To a solution of 2,4,8-trichloropyrido[3,2-d]pyrimidine-6-
carboxylic acid methyl ester 1 (50 mg, 0.17 mmol) in MeCN (0.25
mL) was added an amine (0.17 mmol) dissolved in MeCN (0.25 mL)
in the presence of Hunig’s base (90 μL; 0.51 mmol) at 0 °C. The
̈
reaction mixture was allowed to warm to rt and was stirred for 3 h.
MeCN was removed under reduced pressure. The resulting solid was
triturated in MeOH, filtered, and dried under vacuum to afford
compounds 2a to 2f.
2,8-Dichloro-4-cyclohexylaminopyrido[3,2-d]pyrimidine-6-
carboxylic acid methyl ester (2a): yield = 77%; dark pink solid;
1
mp 205−206 °C dec; IR νmax 3548, 1725, 1231 cm−1; H NMR (300
MHz, CDCl3) δ 1.16−1.33 (m, 1H), 1.33−1.57 (m, 3H), 1.65−1.77
(m, 1H), 1.77−1.92 (m, 3H), 2.05−2.15 (m, 2H), 4.04 (s, 3H), 4.20
(br m, 1H), 7.56 (d, J = 8 Hz, 1H), 8.42 (s, 1H); 13C NMR (75.47
MHz, CDCl3) δ 25.2, 25.8, 32.8, 50.8, 53.7, 129.0, 131.4, 143.0, 145.1,
145.2, 160.3, 161.9, 164.2; HPLC tR = 4.77 min; ES-MS m/z 355.27
(M + H)+. Anal. Calcd for C15H16Cl2N4O2: C, 50.72; H, 4.54; N,
15.77. Found: C, 50.38; H, 4.21; N, 15.39.
General Procedure for SNAr with Amines on Derivative 2 at
C-2. To a solution of derivative 2 (0.32 mmol) in a mixture of MeCN
(2.0 mL) and DMF (2.0 mL) was added an amine (1.6 mmol) inthe
presence of Hunig’s base (0.17 mL, 0.96 mmol). The reaction mixture
̈
was stirred at 90 °C for 1 h. Solvents were removed under vacuum.
The resulting solid was triturated in MeOH, filtered, and dried under
vacuum to afford derivatives 3a−d.
2,8-Dichloro-4-dimethylaminopyrido[3,2-d]pyrimidine-6-
2-Butylamino-8-chloro-4-dimethylaminopyrido[3,2-d]-
pyrimidine-6-carboxylic acid methyl ester (3a): yield = 77%;
carboxylic acid methyl ester (2b): yield = 80%; pink solid; mp
1
216−217 °C dec; IR νmax 1716, 1208 cm−1; H NMR (300 MHz,
1
yellow solid; mp 112−113 °C; IR νmax 3400, 1697, 1537 cm−1; H
CDCl3) δ 3.45 (s, 3H), 4.01 (s, 6H), 8.40 (s, 1H); 13C NMR (75.47
MHz, CDCl3) δ 42.3, 43.3, 53.5, 128.0, 133.3, 142.5, 143.2, 147.9,
160.1, 160.7, 164.3; HPLC tR = 3.81 min; ES-MS m/z 301.00 (M +
H)+. Anal. Calcd for C11H10Cl2N4O2: C, 43.87; H, 3.35; N, 18.61.
Found: C, 43.71; H, 3.34; N, 18.93.
NMR (300 MHz, CDCl3) δ 0.96 (t, J = 7.4 Hz, 3H), 1.43 (m, 2H),
1.57−1.72 (br m, 2H), 2.99−4.20 (br m, 8H), 3.96 (s, 3H), 5.30 (br s,
1H), 8.23 (s, 1H); 13C NMR (75.47 MHz, CDCl3) δ 14.2, 20.5, 32.3,
41.8, 42.2, 53.0, 127.6, 137.3, 149.2, 160.3, 160.8, 165.3; HPLC tR =
3.08 min; ES-MS m/z 338.38 (M + H)+. Anal. Calcd for
C15H20ClN5O2: C, 53.33; H, 5.97; N, 20.73. Found: C, 53.64 H,
5.59; N, 20.51.
2,8-Dichloro-4-diethylaminopyrido[3,2-d]pyrimidine-6-car-
boxylic acid methyl ester (2c): yield = 73%; dark orange solid; mp
1
128−129 °C; IR νmax 2932, 1742, 1254 cm−1; H NMR (300 MHz,
CDCl3) δ 1.33 (t, J = 7 Hz, 3H), 1.44 (t, J = 7 Hz, 3H), 3.89 (q, J = 7
Hz, 2H), 3.99 (s, 3H), 4.01 (s, 3H), 4.34 (q, J = 7 Hz, 2H), 8.38 (s,
1H); 13C NMR (75.47 MHz, CDCl3) δ 12.1, 14.2, 47.2, 47.4, 53.4,
127.9, 132.8, 142.3, 143.3, 148.0, 159.6, 160.4, 164.4; HPLC tR = 4.83
min; ES-MS m/z 328.99 (M + H)+. Anal. Calcd for C13H14Cl2N4O2:
C, 47.43; H, 4.29; N, 17.02. Found: C, 47.18; H, 4.29; N, 16.89.
2-Benzylamino-8-chloro-4-dimethylaminopyrido[3,2-d]-
pyrimidine-6-carboxylic acid methyl ester (3b): yield = 79%;
1
yellow solid; mp 157−158 °C; IR νmax 3381, 1699, 1534 cm−1; H
NMR (300 MHz, CDCl3+ 0.7% TFA)13 δ 3.45 (s, 3H), 4.01 (s, 3H),
4.07 (s, 3H), 4.72 (d, J = 6.0 Hz, 2H), 7.25−7.38 (m, 5H), 8.38 (s,
1H), 9.02 (br t, J = 6.0 Hz, 1H); 13C NMR (75.47 MHz, CDCl3+ 0.7%
248
dx.doi.org/10.1021/jo201834d | J. Org. Chem. 2012, 77, 243−252

The Journal of Organic Chemistry
Article
TFA) δ 43.2, 43.7, 45.8, 53.6, 127.5, 127.9, 128.9, 129.3, 129.5, 133.0,
136.7, 137.4, 142.2, 151.9, 158.2, 163.3; HPLC tR = 3.05 min; ES-MS
m/z 372.04 (M + H)+. Anal. Calcd for C18H18ClN5O2: C, 58.15; H,
4.88; N, 18.83. Found: C, 57.70; H, 5.05; N, 18.90.
3H), 6.99−7.09 (m, 1H), 7.17 (br s, 1H), 7.28−7.39 (m, 2H), 7.65−
7.75 (m, 2H), 7.80 (d, J = 8.7 Hz, 1H), 8.17 (d, J = 8.7 Hz, 1H); 13
C
NMR (75.47 MHz, CDCl3 + 0.7% TFA)13 δ 42.9, 43.3, 53.1, 122.1,
125.4, 126.5, 128.4, 128.9, 129.3, 136.6, 140.0, 142.6, 150.2, 158.7,
164.0; HPLC tR = 3.02 min; ES-MS m/z 324.38 (M + H)+. Anal.
Calcd for C17H17N5O2-0.1 H2O: C, 62.80; H, 5.33; N, 21.54. Found:
C, 62.82; H, 5.71; N, 21.23.
General Procedure for SNAr Reaction of Thiol to Derivative
2c in DMF. To a solution of 2,8-dichloro-4-diethylaminopyrido[3,2-
d]pyrimidine 2c (151 mg, 0.46 mmol) in DMF (4.0 mL) was added a
2-Benzylamino-8-chloro-4-diethylaminopyrido[3,2-d]-
pyrimidine-6-carboxylic acid methyl ester (3c): yield = 82%;
light yellow solid; mp 100.7−101.9 °C; IR νmax 1707, 1561, 1535, 1338
1
cm−1; H NMR (300 MHz, CDCl3 + 0.7% TFA)13 δ 1.20 (t, J = 7.0
Hz, 3H), 1.46 (t, J = 6.8 Hz, 3H), 3.77 (q, J = 7.0, 2H), 3.99 (s, 3H),
4.36 (q, J = 6.8 Hz, 2H), 4.70 (d, J = 5.9 Hz, 2H), 7.22−7.35 (m, 5H),
8.38 (s, 1H), 9.35 (br t, J = 5.9 Hz, 1 H); 13C NMR (75.47 MHz,
CDCl3 + 0.7% TFA) δ 11.5, 13.7, 45.5, 47.9, 48.0, 53.2, 127.0, 127.6,
128.8, 128.9, 129.2, 133.0, 137.0, 137.5, 142.1, 152.2, 157.1, 163.2,
HPLC tR = 3.90 min; ES-MS m/z 400.40 (M + H)+. Anal. Calcd for
C20H22ClN5O2: C, 60.07; H, 5.55; N, 17.51; Cl, 8.87. Found: C, 59.73;
H, 5.39; N, 17.19; Cl, 8.68.
thiol (0.46 mmol) in the presence of Hunig’s base (0.24 mL, 1.38
̈
mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 2 h and
allowed warm to rt for 14 h. The solvents were evaporated. The
resulting mixture was dissolved in a mixture 1:1 mixture of MeCN and
DMSO (1.5 mL) and was purified by preparative HPLC to isolate
both regioisomers 5a−b and 6a−b.
2-Chloro-4-diethylamino-8-benzylsulfanylpyrido[3,2-d]-
pyrimidine-6-carboxylic acid methyl ester (5a): yield = 65%; off-
white solid; mp 101.4−102.4 °C; IR νmax 1504, 1346, 1248, 1128
2-Diethylamino-8-chloro-4-dimethylaminopyrido[3,2-d]-
pyrimidine-6-carboxylic acid methyl ester (3d): yield = 81%;
1
yellow solid; mp 119−120 °C; IR νmax 1711, 1537 cm−1; H NMR
1
cm−1; H NMR (300 MHz, DMSO-d6) δ 1.23−1.26 (m, 3H), 1.33−
(300 MHz, CDCl3) δ 1.24 (br s, 6H), 3.35−3.95 (br m, 10H), 3.95 (s,
3H), 8.20 (s, 1H); 13C NMR (75.47 MHz, CDCl3) δ 13.62, 41.93,
42.50, 52.93, 127.33, 130.96, 136.58, 138.75, 149.39, 158.67, 160.54,
165.47; HPLC tR = 3.07 min; ES-MS m/z 338.39 (M + H)+; Anal.
Calcd for C15H20ClN5O2: C, 53.33; H, 5.97; N, 20.73. Found: C,
53.25; H, 5.93; N, 20.47.
1.37 (m, 3H), 3.73−3.75 (m, 2H), 3.91 (s, 3H), 4.31−4.33 (m, 2H),
4.42 (s, 2H), 7.29−7.39 (m, 3H), 7.50−7.52 (m, 2H), 8.13 (s, 1H),
13C NMR (75.47 MHz, DMSO-d6) δ 11.6, 13.9, 33.9, 45.9, 46.3, 52.9,
120.7, 127.6, 128.7, 129.0, 129.4, 135.6, 142.6, 146.5, 148.8, 156.8,
158.9, 164.3; HPLC tR = 6.17 min; ES-MS m/z 417.3 (M + H)+. Anal.
Calcd for C20H21ClN4O2S: C, 57.62; H, 5.08; N, 13.44; Cl, 8.50.
Found: C, 57.42; H, 5.17; N, 13.34; Cl, 8.46.
Methyl 2-Anilino-8-chloro-4-(dimethylamino)pyrido[3,2-d]-
pyrimidine-6-carboxylate (3e). To a solution of 2,8-dichloro-4-
dimethylaminopyrido[3,2-d]pyrimidine-6-carboxylic acid methyl ester
2b (95 mg; 0.32 mmol) in dioxane (4 mL) was added aniline (36 mg;
0.38 mmol). The reaction mixture was stirred at reflux for 2 days. The
resulting precipitate was filtered, triturated in MeOH, filtered, and
dried under vacuum to afford compound 3e as a pale yellow solid
(85.9 mg, 75% yield): mp 204−205 °C dec; IR νmax 3370, 1707, 1519,
2-Benzylsulfanyl-4-diethylamino-8-chloropyrido[3,2-d]-
pyrimidine-6-carboxylic acid methyl ester (6a): yield = 17%; off-
1
white solid; mp 118.3−119.3 °C; IR νmax 1713, 1440, 1352 cm−1; H
NMR (300 MHz, DMSO-d6) δ 1.16−1.27 (br m, 3H), 1.30−1.42 (br
m, 3H), 3.67−3.81 (br m, 2H), 3.92 (s, 3H), 4.21−4.33 (br m, 2H),
4.48 (s, 2H), 7.23−7.34 (m, 3H), 7.48−7.51 (m, 2H), 8.36 (s, 1H);
13C NMR (75.47 MHz, DMSO-d6) δ 11.6, 13.9, 34.6, 45.7, 46.3, 52.8,
1
1261 cm−1; H NMR (300 MHz, CDCl3 + 0.7% TFA)13 δ 3.50 (s,
3H), 4.02 (s, 3H), 4.11 (s, 3H), 7.15−7.24 (m, 1H), 7.33−7.42 (m,
2H), 7.56−7.62 (m, 2H), 8.39 (s, 1H), 11.24 (br s, 1H); 13C NMR
(75.47 MHz, CDCl3+ 0.7% TFA) δ 43.5, 43.8, 53.5, 122.6, 126.1,
129.1, 129.5, 129.6, 133.5, 136.2, 137.8, 142.3, 150.3, 158.4, 163.3;
HPLC tR = 3.56 min; ES-MS m/z 358 (M + H)+. Anal. Calcd for
C17H16ClN5O2: C, 57.07; H, 4.51; N, 19.57. Found: C, 57.11; H, 4.53;
N, 19.36.
General Procedure for Chloride Reduction of Derivative 3.
A mixture of 2,4-diamino-8-chloropyrido[3,2-d]pyrimidine-6-carbox-
ylic acid methyl ester 3 (0.24 mmol), ammonium formate (4.87
mmol), and 10% Pd/C (25.5 mg, 0.024 mmol) in EtOH (20 mL) was
stirred at reflux for 45 min. The reaction mixture was concentrated in
vacuo. The residue was taken up in 5% MeOH in DCM and filtered
through a short plug of Celite, which was further washed with the
same solvents mixture. The solvents were evaporated, and the resulting
solid was dissolved in DCM (25 mL),washed with saturated solution
of NaHCO3 (20 mL) and brine (20 mL), and dried on anhydrous
MgSO4. After evaporation of the solvents, the resulting solid was
triturated in MeOH, filtered, and dried under vacuum to afford
derivatives 4a and 4b.
126.9, 127.1, 128.4, 128.8, 131.6, 138.3, 139.7, 141.2, 145.7, 156.9,
163.6, 169.4; HPLC tR = 6.13 min; ES-MS m/z 417.3 (M + H)+. Anal.
Calcd for C20H21ClN4O2S: C, 57.62; H, 5.08; N, 13.44; Cl, 8.50.
Found: C, 57.85; H, 5.09; N, 13.43; Cl, 8.48.
2-Chloro-4-diethylamino-8-p-tolylsulfanylpyrido[3,2-d]-
pyrimidine-6-carboxylic acid methyl ester (5b): yield = 62%;
light yellow solid; mp 195.2−196.2 °C; IR νmax 2940, 2356, 1716,
1
1347, 1129 cm−1; H NMR (300 MHz, DMSO-d6) δ 1.23−1.27 (m,
3H), 1.31−1.37 (m, 3H), 2.43 (s, 3H), 3.65−3.90 (m, 2H), 3.80 (s,
3H), 4.30−4.33 (m, 2H), 7.35 (s, 1H), 7.44 (d, J = 7.9 Hz, 2H), 7.54
(d, J = 8.2 Hz, 2H); 13C NMR (75.47 MHz, DMSO-d6) δ 11.6, 13.8,
20.9, 45.9, 46.3, 52.8, 120.4, 124.2, 126.7, 131.3, 135.6, 140.6, 141.1,
142.7, 145.5, 150.6, 158.8, 164.2; HPLC tR = 6.06 min; ES-MS m/z
417.1 (M + H)+. Anal. Calcd for C20H21ClN4O2S: C, 57.62; H, 5.08;
N, 13.44; Cl, 8.50. Found: C, 57.62; H, 4.85; N, 13.70; Cl, 8.10.
2-Chloro-4-diethylamino-8-methylsulfanylpyrido[3,2-d]-
pyrimidine-6-carboxylic Acid Methyl Ester (5c). To a solution of
2,8-dichloro-4-diethylaminopyrido[3,2-d]pyrimidine 2c (151 mg, 0.46
mmol) in DMF (4.0 mL) was added sodium methyl thiolate (0.46
mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 2 h and
was allowed to warm to rt for 14 h. The solvents were evaporated. The
resulting mixture was dissolved in a 1:1 mixture of MeCN and DMSO
(1.5 mL) and was purified by preparative HPLC, affording 5c as a light
yellow solid (120.7 mg, 77% yield). The other regioisomer, 6c (3% of
the crude mixture), could not be isolated: mp 153−154 °C; IR νmax
2-Benzylamino-4-diethylaminopyrido[3,2-d]pyrimidine-6-
carboxylic acid methyl ester (4a): yield = 69%; yellow solid; mp
1
138.5−139.5 °C; IR νmax 2940, 1714, 1536, 1337, 1290 cm−1; H
NMR (300 MHz, CDCl3 + 0.7% TFA)13 δ 1.14 (t, J = 7.1 Hz, 3H),
1.39 (t, J = 7.0 Hz, 3H), 3.70 (q, J= 7.1 Hz, 2H), 3.93 (s, 3H), 4.34 (q,
J = 7.0 Hz, 2H), 4.63 (d, J = 5.8 Hz, 2H), 7.15−7.31 (m, 5H), 7.88 (d,
J = 8.7 Hz, 1H), 8.23 (d, J = 8.7 Hz, 1H), 8.99 (br t, J = 5.3 Hz, 1H),
13.13 (br s, 1H); 13C NMR (75.47 MHz, CDCl3 + 0.7% TFA) δ 11.6,
13.8, 45.3, 47.5, 47.6, 53.0, 126.1, 127.0, 127.6, 128.0, 128.8, 129.3,
137.3, 139.5, 142.7, 152.1, 157.5, 164.1; HPLC tR = 3.90 min; ES-MS
m/z 366.30 (M + H)+. Anal. Calcd for C20H23N5O2: C, 65.74; H, 6.34;
N, 19.16. Found: C, 65.36; H, 6.41; N, 18.89.
1
1716, 1251 cm−1; H NMR (300 MHz, CDCl3) δ 1.30 (br m, 3H),
1.41 (br m, 3H), 2.53 (s, 3H), 3.81 (br m, 2H), 3.97 (s, 3H), 4.36 (br
m, 2H), 7.97 (s, 1H); 13C NMR (75.47 MHz, CDCl3) δ 12.25, 14.25,
14.40, 46.82, 47.16, 53.21, 120.07, 129.96, 143.17, 147.86, 151.03,
158.52, 159.80, 165.63; HPLC tR = 5.05 min; ES-MS m/z 341.32 (M +
H)+. Anal. Calcd for C14H17ClN4O2S: C, 49.34; H, 5.03; N, 16.44.
Found: C, 49.07; H, 5.03; N, 16.29.
4-Dimethylamino-2-phenylaminopyrido[3,2-d]pyrimidine-
6-carboxylic acid methyl ester (4b): yield = 75%; light yellow
solid; mp 159.2−160.3 °C; IR νmax 2944, 1706, 1523, 1441, 1258
cm−1; 1H NMR (300 MHz, CDCl3) δ 3.18−4.21 (br m, 6H), 3.98 (s,
2-p-Tolylsulfanyl-4-diethylamino-8-chloropyrido[3,2-d]-
pyrimidine-6-carboxylic Acid Methyl Ester (6b). To a solution of
2,8-dichloro-4-diethylaminepyrido[3,2-d]pyrimidine-6-carboxylic acid
i
methyl ester 2c (60 mg, 0.18 mmol) in PrOH (5.4 mL) was added
249
dx.doi.org/10.1021/jo201834d | J. Org. Chem. 2012, 77, 243−252

The Journal of Organic Chemistry
Article
p-thiocresol (112 mg, 0.9 mmol). After 16 h at reflux, solvents were
removed under vacuo. The resulted residue was dissolved in a 1:1
mixture of MeCN and DMSO (1.5 mL) and was purified by
preparative HPLC, affording derivative 6b as a beige solid (62.2 mg,
83% yield): mp 137.8−138.8 °C; IR νmax 1713, 1532, 1504, 1435,
1345, 1245, 1129 cm−1; 1H NMR (300 MHz, DMSO-d6) δ 0.82 (br m,
3H), 1.29 (br m, 3H), 2.37 (s, 3H), 3.36 (br m, 2H), 3.90 (s, 3H),
4.17−4.19 (br m, 4H), 7.29 (d, J = 7.7 Hz, 2H), 7.52 (d, J = 7.8 Hz,
2H), 8.31 (s, 1H); 13C NMR (75.47 MHz, DMSO-d6) δ 11.4, 13.7,
20.8, 45.7, 46.1, 52.8, 126.1, 127.0, 129.5, 131.6, 135.4, 138.9, 139.8,
141.2, 146.1, 156.8, 163.6, 170.2, HPLC tR = 5.69 min; ES-MS m/z
417.1 (M + H)+. Anal. Calcd for C20H21ClN4O2S: C, 57.62; H, 5.08;
N, 13.44; Cl, 8.50. Found: C, 57.21; H, 4.99; N, 13.08; Cl, 8.12.
2-Methylsulfanyl-4-diethylamino-8-chloropyrido[3,2-d]-
pyrimidine-6-carboxylic Acid Methyl Ester (6c). To a solution of
2,8-dichloro-4-diethylaminopyrido[3,2-d]pyrimidine-6-carboxylic acid
methyl ester 2c (60 mg, 0.18 mmol) in MeOH (5.4 mL) was added
sodium methyl thiolate (12.6 mg, 0.18 mmol). After 16 h at reflux,
solvent was removed under vacuo. The resulting residue was dissolved
in a 1:1 mixture of MeCN and DMSO (1.5 mL) and was purified by
preparative HPLC, affording derivative 6c as an orange solid (45 mg,
73% yield): mp 122.5−123.5 °C; IR νmax 2359, 1737, 1435, 1244, 1130
cm−1; 1H NMR (300 MHz, CDCl3) δ 1.25−1.41 (br m, 6H), 2.61 (s,
3H), 3.84 (br m, 2H), 3.91 (s, 3H), 4.33 (br m, 2H), 8.33 (s, 1H); 13C
NMR (75.47 MHz, CDCl3) δ 11.9, 14.0, 14.6, 46.3, 46.8, 52.8, 127.3,
132.0, 140.8, 140.9, 146.6, 157.3, 164.5, 171.5, HPLC tR = 4.31 min;
ES-MS m/z 341.1 (M + H)+. Anal. Calcd for C14H17ClN4O2S: C,
49.34; H, 5.03; N, 16.44. Found: C, 49.39; H, 5.07; N, 16.39.
0.93 (t, J = 7 Hz, 3H), 1.33−1.40 (m, 6H), 1.41−1.45 (m, 2H), 1.58−
1.62 (m, 2H), 2.49 (s, 3H), 3.45 (d, J = 6 Hz, 2H), 3.60−3.86 (br m,
2H), 3.93 (s, 3H), 4.04−4.40 (br m, 2H), 5.29 (br s, 1H), 7.84 (s,
1H); 13C NMR (75.47 MHz, CDCl3) δ 12.2, 13.2, 13.7, 13.8, 20.2,
26.8, 32.0, 41.3, 45.8, 52.3, 119.2, 127.0, 127.6, 137.6, 145.3,
148.7,159.2, 166.0; HPLC tR = 3.91 min; ES-MS m/z 378.07(M +
H)+. Anal. Calcd for C18H27N5O2S: C, 57.27; H, 7.21; N, 18.55.
Found: C, 57.33; H, 7.23; N, 18.51.
2,4-Diethylamino-8-methylsulfanylpyrido[3,2-d]pyrimidine-
6-carboxylic acid methyl ester (8c): yield =72%; yellow solid; mp
127−128 °C; IR νmax 1706, 1527 cm−1; 1H NMR (300 MHz, CDCl3)
δ 1.22−1.26 (m, 6H), 1.31−1.36 (m, 6H), 2.49 (s, 3H), 3.69−3.70 (m,
4H), 3.95 (s, 3H), 4.03−4.28 (br m, 4H), 7.93 (s, 1H); 13C NMR
(75.47 MHz, CDCl3) δ 13.7, 14.1, 42.4, 46.2, 52.7, 119.5, 127.0, 137.5,
146.4, 149.1, 158.0, 159.3, 166.6; HPLC tR = 3.97 min; ES-MS m/z
378.10 (M + H)+. Anal. Calcd for C18H27N5O2S: C, 57.27; H, 7.21; N,
18.55. Found: C, 56.94; H, 7.01; N, 18.21.
General Procedure for Suzuki-Myaura Cross-Coupling
Reactions on Derivative 3b at C-8. To a suspension of 2-
benzylamino-8-chloro-4-dimethylaminopyrido[3,2-d]pyrimidine-6-car-
boxylic acid methyl ester 3b (112 mg, 0.30 mmol) and a boronic acid
(1.50 mmol) in dioxane (2.0 mL) were added Cs2CO3 (293 mg, 0.90
mmol) and Pd(PPh3)4 (17.3 mg, 0.015 mmol) under inert
atmosphere. The reaction mixture was heated at 90 °C for 5−7 h.
After complete conversion, water was added (10 mL), and the desired
product was extracted with DCM (3 × 10 mL). The combined organic
layers were washed with brine (10 mL), dried on anhydrous Na2SO3,
and filtered on Celite. After evaporation of the solvents, the crude
products were dissolved in a 1:1 mixture of MeCN and DMSO (1.5
mL) and were purified by preparative HPLC, affording derivatives 9.
2-Benzylamino-4-dimethylamino-8-phenylpyrido[3,2-d]-
pyrimidine-6-carboxylic acid methyl ester (9a): yield = 82%;
yellow solid; mp 118−119 °C; IR νmax 2922, 1713, 1533, 1243 cm−1;
1H NMR (300 MHz, CDCl3) δ 3.40−3.90 (br s, 6H), 3.98 (s, 3H),
8-Benzylsulfanyl-4-diethylamino-2-p-tolylsulfanylpyrido-
[3,2-d]pyrimidine-6-carboxylic Acid Methyl Ester (7). To a
solution of 6b (200 mg, 0.48 mmol) in DMF (5 mL) was added
benzylthiol (89 mg, 0.72 mmol) in the presence of Hunig’s base (0.25
̈
mL, 1.44 mmol). The reaction mixture was stirred at 90 °C for 18 h.
The solvent was removed under vacuum. The crude product was
purified by flash column chromatography using 2−3% ethyl acetate in
petroleum ether as eluent to afford derivative 7 as pale yellow solid
(180 mg, 75% yield): mp 131−132 °C; IR νmax 1715, 1502, 1435,
4.62 (br s, 2H), 5.39 (br s, 1H), 7.24−7.39 (m, 8H), 7.75−7.78 (m,
2H), 8.20 (s, 1H); 13C NMR (75.47 MHz, CDCl3) δ 30.1, 42.0, 46.0,
52.9, 127.1, 127.2, 127.4, 128.0, 128.2, 128.6, 128.8, 130.6, 137.4,
140.2, 143.6, 159.5, 161.6, 166.2; HPLC tR = 3.73 min; ES-MS m/z
414.05 (M + H)+. Anal. Calcd for C24H23N5O2: C, 69.72; H, 5.61; N,
16.94. Found: C, 69.29; H, 6.02; N, 16.63.
1
1345, 1243, 1128 cm−1; H NMR (400 MHz, CDCl3), 0.88−0.92 (br
m, 3H), 1.35 (br m, 3H), 2.36 (s, 3H), 3.41 (br m, 2H), 3.94 (s, 3H),
4.21 (s, 2H), 4.27 (br m, 2H), 7.18−7.20 (d, J = 7.8 Hz, 2H), 7.27−
7.30 (m, 1H), 7.33−7.36 (m, 2H), 7.45−7.48 (d, J = 8.5 Hz, 2H),
7.53−7.55(d, J = 8.0 Hz, 2H), 8.04 (s, 1H); 13C NMR (100 MHz,
CDCl3), 11.7, 14.0, 21.2, 35.5, 46.0, 46.3, 52.6, 120.4, 127.3, 127.5,
128.6, 129.0, 129.1, 129.3, 135.4, 135.8, 138.7, 141.1, 146.8, 148.07,
157.5, 165.4, 169.7; HPLC tR = 7.05 min; ES-MS m/z 505.0 (M +
H)+. Anal. Calcd for C27H28N4O2S2: C, 64.26; H, 5.59; N, 11.10.
Found: C, 64.31; H, 5.63; N, 11.07.
2-Benzylamino-4-dimethylamino-8-(4-methoxyphenyl)-
pyrido[3,2-d]pyrimidine-6-carboxylic acid methyl ester (9b):
yield = 82%; yellow solid; mp 151−152 °C; IR νmax 3392, 1698, 1532,
1
1247 cm−1; H NMR (300 MHz, CDCl3) δ 3.40−3.75 (br m, 6H),
3.80 (s, 3H), 3.92 (s, 3H), 4.57 (d, J = 6 Hz, 2H), 5.38 (br s, 1H), 6.88
(d, J = 8 Hz, 2H), 7.26−7.28 (m, 5H), 7.70−7.73 (m, 2H), 8.13 (s,
1H); 13C NMR (75.47 MHz, CDCl3) δ 29.7, 41.7, 45.6, 52.5, 55.3,
113.3, 126.1, 127.0, 127.6, 128.1, 128.4, 129.1, 129.3, 131.5, 135.9,
138.0, 139.9, 159.2, 159.7, 161.3, 165.9; HPLC tR = 3.42 min; ES-MS
m/z 444.19 (M + H)+. Anal. Calcd for C25H25N5O3: C, 67.71; H, 5.68;
N, 15.79. Found: C, 67.41; H, 5.94; N, 15.59.
General Procedure for SNAr with Amines on Derivative 5c at
C-2. To
a solution of 2-chloro-4-diethylamino-8-methyl-
sulfanylpyrido[3,2-d]pyrimidine-6-carboxylic acid methyl ester 5c
(100 mg, 0.29 mmol) in MeCN (4 mL) was added an amine (1.47
mmol) in the presence of Hunig’s base (0.16 mL, 0.9 mmol). The
̈
2-Benzylamino-4-dimethylamino-8-(4-trifluoro-
methylphenyl)pyrido[3,2-d]pyrimidine-6-carboxylic acid
methyl ester (9c): yield = 78%; yellow solid; mp 176−177 °C; IR
reaction was heated at 180 °C under MW irradiations for 20 min.
Solvent was removed under vacuum, and the resulting solid was
triturated in MeOH, filtered, and dried under vacuum to afford
derivatives 8a to 8c.
1
νmax 3411, 1700, 1522, 1251 cm−1; H NMR (300 MHz, CDCl3) δ
3.34−3.74 (br m, 6H), 3.99 (s, 3H), 4.59 (br s, 2H), 5.44 (br s, 1H),
7.28−7.32 (m, 5H), 7.65−7.72 (m, 2H), 7.82−7.85 (m, 2H), 8.18 (s,
1H); 13C NMR (75.47 MHz, CDCl3) δ 29.7, 41.9, 45.7, 52.6, 124.3 (q,
J = 272.0 Hz), 124.9 (q, J = 4.1 Hz), 127.2, 127.5, 127.6, 128.6, 130.6,
130.7 (q, J = 34.8 Hz), 138.0, 139.7, 140.2, 140.6, 148.2, 156.7, 159.3,
165.7, 169.1; HPLC tR = 4.23 min; ES-MS m/z 482.16 (M + H)+.
Anal. Calcd for C25H22F3N5O2: C, 62.37; H, 4.61; N, 14.55. Found: C,
61.98; H, 5.01; N, 14.82.
General Procedure for Suzuki−Myaura cross-Coupling
Reactions on Derivative 5c at C-2. A solution of 2-chloro-4-
diethylamino-8-methylsulfanylpyrido[3,2-d]pyrimidine-6-carboxylic
acid methyl ester 5c (82 mg, 0.24 mmol), boronic acid (1.20 mmol),
Cs2CO3 (238 mg, 0.72 mmol), and Pd(PPh3)4 (14 mg, 0.012 mmol)
in dioxane (2.0 mL) was heated at 90 °C for 3.5 h under inert
atmosphere. After complete conversion, water was added (10 mL),
2-Benzylamino-4-diethylamino-8-methylsulfanylpyrido[3,2-
d]pyrimidine-6-carboxylic acid methyl ester (8a): yield = 74%;
1
yellow solid; mp 121−122 °C; IR νmax 3548, 1725, 1231 cm−1; H
NMR (300 MHz, CDCl3) δ 1.04−1.48 (br m, 6H), 2.50 (s, 3H),
3.50−3.88 (br m, 2H), 3.95 (s, 3H), 4.00−4.51 (br m, 2H), 4.56−4.78
(m, 2H), 5.50 (br s, 1H), 7.18−7.49 (m, 5H), 7.86 (s, 1H); 13C NMR
(75.47 MHz, CDCl3) δ 14.0, 14.2, 46.1, 46.3, 52.8, 119.7, 127.4, 127.9,
128.3, 128.8, 129.1, 138.4, 140.1, 148,9, 159.4, 159.7, 166.4; HPLC tR
= 3.90 min; ES-MS m/z 412.52 (M + H)+. Anal. Calcd for
C21H25N5O2S: C, 61.29; H, 6.12; N, 17.02. Found: C, 61.17; H,
6.12; N, 16.95.
2-Butylamino-4-diethylamino-8-methylsulfanylpyrido[3,2-
d]pyrimidine-6-carboxylic acid methyl ester (8b): yield = 71%;
1
yellow oil; IR νmax 1712, 1530 cm−1; H NMR (300 MHz, CDCl3) δ
250
dx.doi.org/10.1021/jo201834d | J. Org. Chem. 2012, 77, 243−252

The Journal of Organic Chemistry
Article
and the desired product was extracted with DCM (3 × 10 mL).
Combined organic layers were washed with brine (10 mL), dried over
Na2SO4, and filtered on Celite. After evaporation of the solvents, the
resulting solid was triturated in MeOH, filtered, and dried under
vacuum to afford derivatives 10a to 10c.
ES-MS m/z 443.09 (M + H)+. Anal. Calcd for C26H26N4O3: C, 70.57;
H, 5.92; N, 12.66. Found: C, 70.38; H, 6.05; N, 12.48.
2-Phenyl-4-diethylamino-8-(4-trifluoromethylphenyl)-
pyrido[3,2-d]pyrimidine-6-carboxylic acid methyl ester (11c):
yield = 87%; yellow solid; mp 193−194 °C; IR νmax 1712, 1521, 1320
1
cm−1; H NMR (300 MHz, CDCl3) δ 1.35−1.65 (br m, 6H), 3.85−
2-Phenyl-4-diethylamino-8-methylsulfanylpyrido[3,2-d]-
pyrimidine-6-carboxylic acid methyl ester (10a): yield = 88%;
4.20 (br m, 2H), 4.03 (s, 3H), 4.25−4.65 (br s, 2H), 7.45−7.47 (m,
3H), 7.80 (d, J = 8 Hz, 2H), 7.98 (d, J = 8 Hz, 2H), 8.37 (s, 1H),
8.44−8.46 (m, 2H); 13C NMR (75.47 MHz, CDCl3) δ 12.1, 14.4, 46.7,
52.8, 124.2 (q, J = 272.2 Hz), 125.0 (q, J = 3.6 Hz), 126.6, 128.5,
128.9, 130.6 (q, J = 32.6 Hz), 130.8, 131.2, 133.2, 138.6, 140.5, 142.5,
145.3, 147.2, 159.2, 161.4, 165.5; HPLC tR = 6.23 min; ES-MS m/z
481.16 (M + H)+.
1
yellow solid; mp 167−168 °C; IR νmax 1718, 1519 cm−1; H NMR
(300 MHz, CDCl3) δ 1.44 (t, J = 7 Hz, 6H), 2.58 (s, 3H), 3.85−4.15
(br m, 2H), 4.00 (s, 3H), 4.25−4.55 (br m, 2H), 7.46−7.48 (m, 3H),
8.01 (s, 1H), 8.56−8.59 (m, 2H); 13C NMR (75.47 MHz, CDCl3) δ
12.5, 14.3, 14.7, 46.7, 53.1, 119.7, 128.6, 129.1, 130.1, 131.0, 138.7,
142.4, 147.3, 151.8, 159.2, 160.8, 166.1; HPLC tR = 5.77 min; ES-MS
m/z 383.40 (M + H)+. Anal. Calcd for C20H22N4O2S: C, 62.81; H,
5.80; N, 14.65. Found: C, 62.47; H, 5.88; N, 14.74.
ASSOCIATED CONTENT
■
2-(4-Methoxyphenyl)-4-diethylamino-8-methyl-
sulfanylpyrido[3,2-d]pyrimidine-6-carboxylic acid methyl
ester (10b): yield = 79%; yellow solid; mp 147−148 °C; IR νmax
1733, 1519, 1240 cm−1; 1H NMR (300 MHz, CDCl3) δ 1.43 (t, J = 7
Hz, 6H), 2.56 (s, 3H), 3.75−4.10 (br m, 2H), 3.88 (s, 3H), 3.99 (s,
3H), 4.10−4.55 (br m, 2H), 6.98 (d, J = 9 Hz, 2H), 7.98 (s, 1H), 8.52
(d, J = 9 Hz, 2H); 13C NMR (75.47 MHz, CDCl3) δ 12.3, 13.9, 14.1,
46.2, 52.6, 55.3, 113.5, 119.1, 129.4, 130.4, 131.0, 141.6, 146.9, 150.8,
158.7, 160.1, 161.8, 165.7; HPLC tR = 5.40 min; ES-MS m/z 413.40
(M + H)+. Anal. Calcd for C21H24N4O3S: C, 61.15; H, 5.86; N, 13.58.
Found: C, 61.13; H, 5.54; N, 13.44.
S
* Supporting Information
1H and 13C NMR spectra of the synthesized compounds and
ORTEP representation of 5c and 6c. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: anna.quattropani@merckgroup.com.
2-(4-Trifluoromethylphenyl)-4-diethylamino-8-
methylsulfanylpyrido[3,2-d]pyrimidine-6-carboxylic acid
methyl ester (10c): yield = 84%; yellow solid; mp 148−149 °C;
IR νmax 1721, 1521, 1321 cm−1; 1H NMR (300 MHz, CDCl3) δ 1.25−
1.85 (br m, 6H), 2.58 (s, 3H), 3.75−4.15 (br m, 2H), 4.01 (s, 3H),
4.20−4.65 (br m, 2H), 7.72 (d, J = 8 Hz, 2H), 8.02 (s, 1H), 8.67 (d, J
= 8 Hz, 2H); 13C NMR (75.47 MHz, CDCl3) δ 12.1, 14.1, 14.2, 46.6,
46.7, 52.9, 119.5, 124.6 (q, J = 272.5 Hz), 125.3 (q, J = 3.4 Hz), 129.1,
130.0, 132.1 (q, J = 31.2 Hz), 141.8, 142.7, 146.9, 151.8, 159.0, 159.1,
165.8; HPLC tR = 6.54 min; ES-MS m/z 451.41 (M + H)+. Anal.
Calcd for C21H21F3N4O2S: C, 55.99; H, 4.70; N, 12.44. Found: C,
55.61; H, 4.53; N, 12.24.
ACKNOWLEDGMENTS
■
We thank Prof. Lanny Liebeskind from Emory University as
well as Prof. Jer
́
o
̂
me Lacour, Prof. Alexandre Alexakis from
University of Geneva, and Dr. Dominique Swinnen from Merck
Serono for their advice and fruitful discussions. We acknowl-
edge Dr. Wolfgang Sauer from Merck Serono for semiempirical
́
calculations, Dr. Pierre-Andre Pittet from Merck Serono for his
support in NMR experiments and interpretation, and Gordon
Campbell from Merck Serono for proofreading this manuscript.
General Procedure for Liebeskind−Srogl Cross-Coupling
Reaction on Derivative 10a at C-8. To a mixture of 2-phenyl-4-
diethylamino-8-methylsulfanylpyrido[3,2-d]pyrimidine-6-carboxylic
acid methyl ester 10a (54 mg, 0.14 mmol), a boronic acid (0.14
mmol), copper(I) thiophene-2-carboxylate (27 mg, 0.14 mmol), and
Pd(PPh3)4 (8 mg, 0.007 mmol) was added dioxane (3.0 mL) under
inert atmosphere. The reaction was stirred at 90 °C and monitored by
LCMS. After 3.5 h, a saturated solution of NaHCO3 (10 mL) was
added, and the desired product was extracted with DCM (3 × 10 mL).
Combined organic layers were washed with brine (10 mL), dried over
Na2SO4, and filtered on Celite. After evaporation of the solvents, the
resulting solid was triturated in MeOH, filtered and dried under
vacuum to afford derivatives 11a to 11c.
REFERENCES
■
(1) (a) Hayakawa, M.; Kaizawa, H.; Moritomo, H.; Koizumi, T.;
Ohishi, T.; Okada, M.; Ohta, M.; Tsukamoto, S.; Parker, P.; Workman,
P.; Waterfield, M. Bioorg. Med. Chem. 2006, 14, 6847−6858.
(b) Rueckle, T.; Quattropani, A.; Pomel, V.; Dorbais, J.; Covini, D.;
Bischoff, A. WO2006024666, 2006. (c) Parrish, C. A.; Newlander, K.
A. WO2009039140, 2009. (d) Pomel, V.; Gaillard, P.; Desforges, G.;
Quattropani, A.; Montagne, C. WO2010037765, 2010. (e) Montagne,
C.; Bombrun, A.; Desforges, G.; Quattropani, A.; Gaillard, P.
WO2010091996, 2010. (f) Castanedo, G.; Chan, B.; Lucas, M. C.;
Safina, B.; Sutherlin, D. P.; Sweeney, Z. K. WO2011101429, 2011.
(2) (a) Aliagas, I.; Gradl, S.; Gunzner, J.; Lee, W.; Mathieu, S.;
Rudolph, J.; Wen, Z.; Zhao, G.; Buckmelter, A. J.; Grina, J.; Hansen, J.
D.; Laird, E.; Moreno, D.; Ren, L.; Wenglowsky, S. M.
WO2011025938, 2011. (b) Ettmayer, P.; Mantoulidis, A.; Steurer, S.
WO2010094695, 2010. (c) Aronov, A.; Lauffer, D. J.; Li, H. Q.;
Tomlinson, R. C.; Li, P. WO2004037814, 2004. (d) Smaill, J. B.;
Rewcastle, G. W.; Loo, J. A.; Greis, K. D.; Chan, O. H.; Reyner, E. L.;
Lipka, E.; Showalter, H. D. H.; Vincent, P. W.; Elliott, W. L.; Denny,
W. A. J. Med. Chem. 2000, 43, 1380−1397, and references cited
therein.
(3) (a) Carter, P. H.; Cavallaro, C. L.; Duncia, J. V.; Gardner, D. S.;
Hynes, J.; Liu, R.-Q.; Santella, J. B.; Dodd, D. S. WO2007092681,
2007. (b) Carson, K. G.; Raman, P.; Soucy, F.; Ye, Q.; Ghosh, S.
WO2006071875, 2006.
(4) (a) Canales, E.; Chong, L. S.; Clarke, M.; O’Neil H.; Lazerwith, S.
E.; Lew, W.; Liu, Q.; Mitchell, M. L.; Watkins, W. J.; Zhang, J. R.
WO2010002998, 2010. (b) De Jonghe, S. C. A.; Dolusic, E.; Gao, L.-J.;
Maria Herdewijn, P. A. M.; Pfleiderer, W. E. WO2009003669, 2009.
(c) Bondy, S. S.; Chou, C.-H.; Watkins, W. J.; Chong, L. S.; Zhang, J.
R.; Mishra, R. WO2008077651, 2008.
4-Diethylamino-2,8-diphenylpyrido[3,2-d]pyrimidine-6-car-
boxylic acid methyl ester (11a:). yield = 84%; yellow solid; mp
1
147−147 °C; IR νmax 2921, 1737, 1524, 1231 cm−1; H NMR (300
MHz, CDCl3) δ 1.25−1.65 (br m, 6H), 3.75−4.20 (br m, 2H), 4..02
(s, 2H), 4.20−4.55 (br m, 2H), 7.43−7.45 (m, 3H), 7.49−7.58 (m,
3H), 7.91−7.94 (m, 2H), 8.38 (s, 1H), 8.45−8.49 (m, 2H); 13C NMR
(75.47 MHz, CDCl3) δ 10.9, 13.0, 46.7, 52.6, 126.6, 128.1, 128.2,
128.7, 128.9, 130.6, 130.7, 136.3, 136.6, 139.2, 142.5, 146.7, 150.2,
151.4, 159.2, 160.8; HPLC tR = 5.09 min; ES-MS m/z 428.99 (M +
H)+. Anal. Calcd for C25H24N4O2: C, 72.80; H, 5.86; N, 13.58. Found:
C, 72.58; H, 5.46; N, 13.83.
2-Phenyl-4-diethylamino-8-(4-methoxyphenyl)pyrido[3,2-
d]pyrimidine-6-carboxylic acid methyl ester (11b): yield = 88%;
1
yellow solid; mp 165−166 °C; IR νmax 1715, 1511, 1242 cm−1; H
NMR (300 MHz, CDCl3) δ 1.30−1.65 (br m, 6H), 3.80−4.20 (br m,
2H), 3.93 (s, 3H), 4.02 (s, 3H), 4.20−4.60 (br m, 2H), 7.10 (d, J = 8
Hz, 2H), 7.47 (m, 3H), 7.92 (d, J = 8 Hz, 2H), 8.36 (s, 1H), 8.47−
8.49 (m, 2H); 13C NMR (75.47 MHz, CDCl3) δ 13.7, 14.3, 46.6, 52.7,
55.4, 113.6, 125.9, 128.2, 128.8, 129.0, 130.4, 132.2, 133.0, 138.7,
142.4, 146.3, 147.1, 159.3, 160.2, 160.7, 165.7; HPLC tR = 4.93 min;
(5) Srinivasan, A.; Broom, A. D. J. Org. Chem. 1979, 44, 435−440.
251
dx.doi.org/10.1021/jo201834d | J. Org. Chem. 2012, 77, 243−252

The Journal of Organic Chemistry
Article
(6) (a) Tikad, A.; Routier, S.; Akssira, M.; Guillaumet, G. Org. Biomol.
Chem. 2009, 7, 5113−5118. (b) C-4 regioselective addition of amines,
including anilines, was further confirmed by chloride reduction of
compound 2e. The 1H NMR spectrum of dehalogenated products 2g
consisted of a pair of doublets at δ 8.37 and 8.46 ppm, corresponding
to H-7 and H-8, with an J3 coupling constant of 8.7 Hz. This result
proved that 2e is substituted with a chloride at C-8. Additional NMR
experiments on 2g did not give us the confirmation that aniline is at
position 4, but regioselective C-4 addition was proven for secondary
amine addition such as diethyl amine (confirmed by X-ray analysis of
5c and 6c). This result was also in line with the reported regioselective
C-4 amination of 2,4-dichloropyrido[3,2-d]pyrimidine.6a
(7) Tikad, A.; Routier, S.; Akssira, M.; Leg
Guillaumet, G. Synthesis 2009, 14, 2379−2384.
́
er, J.-M.; Jarry, C.;
(8) This reaction was performed in the presence of an internal
standard, confirming the complete conversion of 2c into 5b and 6b
and the reported UHPLC regioisomer’s ratio (unpublished results).
(9) pKa values were calculated with the Marvin method from
Chemaxon, ACD/PhysChem Suite (version 12.01), from Advanced
Chemistry Development, Inc., Toronto, ON, Canada, and with
semiempirical calculations. All three methods indicated N-1 as the
most basic center.
(10) Semiempirical calculations of the neutral or N-1 protonated
form of 2c; minimization, followed by conformational search (60°
steps) around 5 rotatable bonds (i.e. 7776 points each) using MM3.
All local minima (94 and 106, resp.) extracted and minimized with
PM5. All calculations done with Scigress Explorer 7.7 (Fujitsu Ltd).
(11) Kusturin, C.; Liebeskind, L. S.; Rahman, H.; Sample, K;
Schweitzer, B.; Srogl, J.; Neumann, W. L. Org. Lett. 2003, 5, 4349−
4352.
(12) Tikad, A.; Routier, S.; Akssira, M.; Leger, J.-M.; Jarry, C.;
Guillaumet, G. Org. Lett. 2007, 9, 4673−4676.
(13) Addition of 0.7% of TFA to NMR samples prepared in CDCl3
yielded 1H and 13C NMR spectra with higher resolution (see the
Supporting Information).
252
dx.doi.org/10.1021/jo201834d | J. Org. Chem. 2012, 77, 243−252