Access and regioselective transformations of 6-substituted 4-aryl-2,8-dichloropyrido[3,2-d ]pyrimidine compounds

Article abstract of DOI:10.1021/jo300189q

We report herein an efficient route for the synthesis of 2,4,8-trichloropyrido[3,2-d]pyrimidines 1 with R¹ substituents at C-6. The potential of such scaffolds was demonstrated by the possibility to displace regioselectively each aromatic chloride to introduce diversity. Sequential sulfur nucleophilic addition followed by Liebeskind-Srogl cross-coupling reaction yielded unprecedented aryl introduction at C-4 on a trichloropyrido[3,2-d]pyrimidine derivative. The reactivity difference of the remaining two chlorides toward S_NAr reactions was investigated. Amination yielded high C-2 regioselectivity, while thiolation was influenced by C-6 substituents, resulting in medium to high C-2 versus C-8 regioselectivity. The last chloride was efficiently displaced by S_NAr, Suzuki-Miyaura cross-coupling reaction, or reduction. C-2 arylation as a final step was also possible by Liebeskind-Srogl cross-coupling reaction on the previously introduced C-2 thioether. A concise and highly divergent synthetic use of 1 was developed, thereby providing an efficient approach to explore the structure-activity relationship of pyrido[3,2-d]pyrimidine derivatives such as 9, 10, 15, and 16.

Full text of DOI:10.1021/jo300189q

Article
pubs.acs.org/joc
Access and Regioselective Transformations of 6-Substituted
4-Aryl-2,8-dichloropyrido[3,2-d]pyrimidine 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 and 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 an efficient route for the synthesis of 2,4,8-trichloropyrido[3,2-d]pyrimidines 1 with R1
substituents at C-6. The potential of such scaffolds was demonstrated by the possibility to displace regioselectively each aromatic
chloride to introduce diversity. Sequential sulfur nucleophilic addition followed by Liebeskind−Srogl cross-coupling reaction
yielded unprecedented aryl introduction at C-4 on a trichloropyrido[3,2-d]pyrimidine derivative. The reactivity difference of the
remaining two chlorides toward SNAr reactions was investigated. Amination yielded high C-2 regioselectivity, while thiolation was
influenced by C-6 substituents, resulting in medium to high C-2 versus C-8 regioselectivity. The last chloride was efficiently
displaced by SNAr, Suzuki−Miyaura cross-coupling reaction, or reduction. C-2 arylation as a final step was also possible by
Liebeskind−Srogl cross-coupling reaction on the previously introduced C-2 thioether. A concise and highly divergent synthetic
use of 1 was developed, thereby providing an efficient approach to explore the structure−activity relationship of pyrido-
[3,2-d]pyrimidine derivatives such as 9, 10, 15, and 16.
cross-coupling reactions,7 starting with a C-4 arylation, and
leading to a set of novel and diverse C−N- and C−C-substituted
pyrido[3,2-d]pyrimidines 9, 10, 15, and 16 (Scheme 1).
INTRODUCTION
■
Given the vastness of the chemical space, the challenge for
medicinal chemists is to identify cores that are more likely to
lead to drug candidates.1,2 In our continued effort to design
lead-like arrays of compounds to be included in our corporate
screening collection, we were particularly interested in the
accessibility of heterocyclic scaffolds bearing several reactive
sites, which could be functionalized regioselectively for straight-
forward synthesis of analogues. In this context, we have recently
reported the synthesis of 4-amino-2,8-dichloropyrido[3,2-d]-
pyrimidine-6-carboxylic acid methyl ester derivative 1c and its
regioselective diversification through SNAr and metal-catalyzed
cross-coupling reactions (Scheme 1).3 We report herein an
extension of our studies on pyrido[3,2-d]pyrimidines with a
general synthesis of 2,4,8-trichloropyrido[3,2-d]pyrimidines 1
having methyl, phenyl, and ester groups at C-6 and the
successive and selective displacement of the different chlorides.
The synthesis of such a scaffold 1, with different groups at C-6,
provided an interesting challenge. Only two examples were
reported.4,5 Then regiocontrolled diversification of the result-
ing scaffold 1 is described through SNAr6 and metal-catalyzed
RESULTS AND DISCUSSION
■
We first developed a general protocol for the synthesis of 1,
substituted at C-6 with a methyl or an aryl group, starting from
aminouracil 2 and 3-substituted 3-alkoxyacrylic acid alkyl esters
3 (Table 1).
Aminouracil 2 and 3-substituted 3-alkoxyacrylic acid alkyl
8
i
esters 3 were heated at 140 °C in PrOH under microwave
irradiation, yielding enamines 4a,b as a mixture of ethyl and
isopropyl esters having E and Z isomers. This mixture was used
without any purification in the next step. In the second step,
cyclization of enamines 4 into 6-substituted 2,4,8-trihydroxy-
pyrido[3,2-d]pyrimidines 5 was performed at 250 °C under
microwave irradiation. The reaction was performed in a mixture
of dimethylacetamide (DMA) and 1,2-dichlorobenzene (DCB)
Received: January 25, 2012
Published: April 13, 2012
© 2012 American Chemical Society
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Scheme 1. Regioselective Transformations of 1
Table 1. Synthesis of 1
entry
SM
R1
R2
products (% yield)
a
1
2
3a
3b
Me
Et
5a (84)
5b (86)
1a (78)
b
Ph
Me
1b (85)
a
b
Chlorination conditions: POCl3, PhNEt2, reflux, 16 h. Chlorination conditions: POCl3, 200 °C under microwave irradiations, 1.5 h.
in a 5/1 ratio, a solvent mixture which ensured the solubiliza-
tion of the starting material and guaranteed complete conver-
sion. Following these conditions, derivatives 5a and 5b were
isolated in 84% and 86% yields, respectively (Table 1, step 2,
entries 1 and 2).
Two protocols were used for the last step, chlorination of
derivatives 5. A solution of 5a with N,N-diethylaniline in an
excess of POCl3 was heated at reflux to lead after 16 h to
derivative 1a in 78% yield (Table 1, step 3, entry 1). We found
that 5b was efficiently transformed into 6-substituted 2,4,8-
trichloropyrido[3,2-d]pyrimidine 1b in neat POCl3 heated for
1.5 h at 200 °C under microwave irradiation. Derivative 1b was
obtained in 85% yield (Table 1, step 3, entry 2). An efficient
access to 6-substituted 2,4,8-trichloropyrido[3,2-d]pyrimidines
1a,b was developed in three steps with 30−52% overall yield.
The use of microwave irradiation allowed us to shorten the
reaction time from overnight to 1.5 to 2.5 h.9
Selective displacement of the different chlorides in com-
pounds 1 was then investigated. We focus this study on
the regioselective metal-catalyzed cross-coupling reaction of 1
at C-4 (Scheme 1). For this, in addition to derivatives 1a,b,
derivative 1c was also used and prepared according to the
literature.5 Suzuki−Miyaura cross-coupling reaction, using
various reaction conditions, yielded either partial conversion
or multiple product mixtures.10 Coupling conditions described
to be selective on 2,4-dichloropyrido[3,2-d]pyrimidine, using
Pd(PPh3)4 as catalyst and K2CO3 as base, in toluene at 100 °C,
did neither improve the regioselectivity nor the conversion.11
Alternative cross-coupling reactions on derivative 1c such as
Stille cross-coupling reactions were not successful either.10
At this point, Liebeskind−Srogl cross-coupling reaction was
investigated as an option.12 As previously reported, SNAr
reactions on 1c is highly regioselective at C-4.3,5 Taking advan-
tage of it, sulfur nucleophilic addition was performed
regioselectively at C-4 to lead to 6. Sodium methylthiolate
was added to a solution of derivative 1 in THF at −10 °C. At
this temperature, derivatives 6a−c were obtained in good yields
(Table 2, entries 1−3). At higher temperatures, multiple
methylsulfanyl addition products were formed.13
Table 2. SNAr with Sodium Methylthiolate on 1 at C-4
entry
SM
R1
product
yield (%)
1
2
3
1a
1b
1c
Me
Ph
6a
6b
6c
84
85
84
COOMe
Arylation of derivatives 6a−c was then achieved via Liebeskind−
Srogl cross-coupling reactions with boronic acid derivatives having
different electronic properties such as unsubstituted or substi-
tuted aryl with electron-donating or -withdrawing groups (Table 3).
The reactions were performed in dioxane at 100 °C under
microwave irradiation with Pd(PPh3)4 as catalyst and copper(I)
thiophene-2-carboxylate (CuTC) as cofactor.14 4-Aryl-2,8-
dichloropyrido[3,2-d]pyrimidine derivatives 7a−e were isolated
in 77−82% yields (Table 3). No side reaction took place at
the two remaining C−Cl bonds, which is in agreement with
the orthogonality of the Liebeskind−Srogl methylsulfanyl
cross-coupling protocol versus the Suzuki−Miyaura reaction.15
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Table 3. Liebeskind−Srogl Cross-Coupling Reactions on 6
at C-4
Table 5. Reduction of C-8 Chloride on 8a−c
entry
R1
product
yield (%)
1
2
3
Me
Ph
9a
9b
9c
75
71
73
entry
SM
R1
R2
time (h) product yield (%)
1
2
3
4
5
6a
6b
6c
6c
6c
Me
Ph
H
H
H
0.5
1.5
1
7a
7b
7c
7d
7e
81
78
79
82
77
COOMe
a
Dehalogenation using continuous-flow hydrogenation reactor: 10%
COOMe
COOMe
COOMe
Pd/C cartridge at 70 °C with a flow of 4 mL/min at 5−7 bar (“Full
4-MeO
4-CF3
1.5
0.5
Hydrogen” mode).16
This first succession of transformations proceeded well to
provide 2,4,6-trisubstituted pyrido[3,2-d]pyrimidine derivatives
9. Alternatively, reactivity of the chloride at C-8 on derivatives 8
was evaluated toward metal-catalyzed cross-coupling reactions.
Suzuki−Miyaura cross-coupling reaction, with Pd(PPh3)4 as
catalyst and cesium carbonate as base, afforded 10a−c in 76−
86% yields (Table 6, entries 1−3). It was possible to use
In addition, the nature of C-6 substituent of derivatives 6 (Table 3,
entries 1−3) and the electronic properties of the boronic acid
derivatives (Table 3, entries 3−5) had no impact on the
reaction time or on the isolated yield. This two-step process,
methylsulfanyl aromatic substitution followed by Liebeskind−
Srogl cross-coupling reaction, yielded the selective introduction
of C−C bond at position 4.
The reactivity difference between the two remaining chlo-
rides at positions 2 and 8 of derivatives 7 was then studied. SNAr
and metal-catalyzed cross-coupling reactions were investigated.
Amination of 7 was achieved with the addition of an amine at
90 °C in MeCN under microwave irradiation.9 Reaction of
derivatives 7a−c with benzylamine yielded derivatives 8a−c in
yield ranging from 69 to 83% (Table 4, entries 1−3). Similar
Table 6. Suzuki−Miyaura Cross-Coupling Reaction on 8e at
C-8
Table 4. SNAr with Diverse Amines on 7a−c at C-2
entry
R1B(OH)2
PhB(OH)2
time (h)
product
yield (%)
1
2
3
7
10a
10b
10c
80
86
82
4-MeO-C6H4B(OH)2
4-CF3- C6H4B(OH)2
4
3.5
boronic acid derivatives with electron-donating and electron-
withdrawing group substitution.
Thus, we have described C-2 amination of derivatives 7 and
C-8 reactivity of the resulting 4-aryl-2-aminopyrido[3,2-d]-
pyrimidines 8 toward reduction and Suzuki−Miyaura cross-
coupling reactions. C-2-regioselective arylation of 7 is next reported.
As already observed for compound 1 or 4-amino-2,8-dichloro-
pyrido[3,2-d]pyrimidine derivatives,3 direct arylation of de-
rivative 7 via metal-catalyzed cross-coupling reactions yielded
either partial conversion or multiple site reactions. As pre-
viously described, the two remaining chlorides needed to be
first differentiated by selective thiolation of one of them. The
regioselectivity of the thiolation was studied with benzylthiol
and sodium methylthiolate. Benzylthiol in the presence of
entry
SM
R1
R2R3NH2
product
yield (%)
1
2
3
4
5
7a
7b
7c
7c
7c
Me
Ph
BnNH2
BnNH2
BnNH2
BuNH2
Et2NH
8a
8b
8c
8d
8e
71
69
83
81
85
COOMe
COOMe
COOMe
yields were obtained with addition to 7c of primary amine and
secondary amines, such as butylamine and diethylamine, afford-
ing derivatives 8d and 8e in 81 and 85% yield, respectively
(Table 4, entries 4 and 5). Selective C-2 addition was always
obtained even in the presence of an excess of amine.
Dehalogenation of the remaining chloride of 8a−c afforded
compounds 9a−c in 70−75% yield (Table 5, entries 1−3). As
partial reduction of the pyrido[3,2-d]pyrimidines core occurred
during this reaction, MnO2 was added to rearomatize the
Hunig’s base was added to a solution of derivatives 7a−c in a
̈
mixture of MeCN and DMF. Contrary to the regioselective
amination, two regioisomers were formed, derivatives 11 and
12, with the benzylsulfanyl substituent at C-2 or C-8 positions,
respectively (Table 7, entries 1−3). While thiolation of 7a and
7b took place at 90 °C under microwave irradiation (Table 7,
entries 1 and 2), this reaction surprisingly occurred at room
temperature with derivative 7c (R1 = COOMe, Table 7, entry 3).
The higher reactivity of 7c compared to 7a and 7b may be
explained by the presence of an electron-withdrawing group at
1
pyridopyrimidine ring. The H NMR spectra of dehalogenated
products 9a−c consisted of a pair of doublets corresponding to
H-7 and H-8, with a J3 coupling constant of 8.9 Hz. These
results conclusively proved that benzylamine added regioselecti-
vely to 7 at C-2, leaving a chloride substituent at position 8.
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Table 7. SNAr with Benzylthiol on 7a−c
a
entry
SM
R1
T (°C)
product
UHPLC ratio
yield (%)
1
2
3
7a
7b
7c
Me
Ph
90
90
rt
11a/12a
11b/12b
11c/12c
74/26
72/28
83/17
60/20
60/18
73/12
COOMe
a
The ratios were determined on the reaction mixtures by UHPLC−MS to evaluate most accurately the regioisosomer ratio. All regioisomers were
isolated and fully characterized.
Table 8. SNAr with Sodium Methylthiolate on 7c−d
entry
SM
R1
product
UPLC ratio
yield (%)
1
2
7c
H
11d/12d
11e/12e
92/8
92/8
60/0
57/0
7d
4-OMe
C-6. Regioisomers 11a−c and 12a−c were isolated in 60−73%
and 12−20% yields, respectively.
obtained in 57 and 60% yield, respectively (Table 8, entries 1
and 2). Such a transformation offered a convenient way to dif-
ferentiate the two remaining reactive centers at C-2 and C-8,
leading to key scaffolds 11. Derivative 11d was selected for
further diversification.
The remaining chloride of derivative 11d was readily
substituted with diverse primary and secondary amines in
MeCN. After 2 h at 90 °C, derivatives 13a−c were isolated in
73−84% yields (Table 9, entries 1−3). The position and nature
Attribution of the substitution pattern of derivatives 12a−c
was based on the results of NOESY experiments. For these
derivatives, NOESY correlation between the benzylic protons
of the thioether and H-7 were observed, confirming that the
minor regioisomers resulted from thiol addition at position 8.
No relevant information on major regioisomers 11a−c could be
obtained from NOESY experiments, but they show the same
mass but a different retention time in UHPLC−MS and
1
different H and 13C NMR chemical shifts than 12a−c. The
Table 9. SNAr with Diverse Amines on 11d at C-8
identity of 11a−c was deduced from the assignment of 12a−c
structure, respectively, confirming that thiolation of 7a−c took
place predominantly at C-2. Partial charge distribution between
C-2 and C-8 of 7 may drive the observed regioselectivity at
C-2.17 It is slightly influenced by the nature of R1, possibly
explaining the higher regioselectivity obtained with R1
=
COOMe compared with R1 = Me or Ph (Table 7, entry 3
versus 1 and 2). Interestingly, a pyrido[3,2-d]pyrimidine
derivative with an aryl substituent at C-4 activates more the
C-2 position for nucleophilic attack compared with an electron-
donating group, such an amine at C-4.18 In addition, the pre-
ferred C-2 regioselectivity is not influenced by the nature of the
nucleophile, such as an amine, a thiol, or a thiolate.
entry
R1R2N
product
yield (%)
1
2
3
BnNH
BuNH
Et2N
13a
13b
13c
73
83
84
Thiolation was further investigated with sodium methyl-
thiolate on derivatives 7c and 7d, having phenyl and 4-OMe-
phenyl groups at C-4, respectively. This reaction was performed
at −10 °C in THF to avoid double thiolation observed at
higher temperature. Under these conditions, conversion did not
exceed 75%, but a good regioselectivity for 11d−e was obtained
with an 11d−e/12d−e ratio of 92/8. Derivatives 11d−e were
of each substituent of derivatives 13 corroborate with X-ray
crystallographic analysis of derivative 13b. This result also con-
firms the reactivity order of the three chlorides of derivatives 1.
Alternatively, derivatives 11d and 11e were transformed by
Suzuki−Miyaura reaction into 14a and 14b in 75−82% yield,
respectively (Table 10). When previously described conditions
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Table 10. Suzuki−Miyaura Cross-Coupling Reaction on 11d
and 11e at C-8
and regioselective conditions for the displacement of the three
chlorides, we were able to prepare a wide variety of analogues,
as shown with representative examples in this paper, such as
compounds 9, 10, 15, and 16. This versatile strategy has been
applied for the production of a large array of compounds that
are currently under biological evaluation, in particular as lipid,
tyrosine, and protein kinase inhibitors.
EXPERIMENTAL SECTION
General Procedures. The commercially available starting
materials were used without further purification. Melting points were
reported without correction. IR analyses were performed by attenuated
■
entry
SM
R1
R2
product
yield (%)
1
2
11d
11e
H
4-MeO
H
14a
14b
75
82
1
total reflectance (ATR) FT-IR spectroscopy. H 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
4-MeO
(Table 6) were used, the methylsulfanyl group remained
unchanged, demonstrating for this transformation the ortho-
gonality of both reactive centers at C-2 and C-8.
Then, compounds 13a−c and 14a,b could be used as
obvious intermediates for Liebeskind−Srogl reaction for the
introduction of an additional C−C bond at C-2. A stoichio-
metric amount of boronic acid derivatives was used, with
Pd(PPh3)4 as catalyst and copper(I) thiophene-2-carboxylate
(CuTC) as cofactor. After 3.5 h in dioxane at 90 °C, com-
pounds 15 and 16 were isolated in 69−80% yields (Table 11).
solvent peak. Mass spectra and high-resolution mass spectra were
acquired by electrospray ionization. The HPLC analysis were
performed on a C8 column (50 × 4.6 mm 3.5 μm) with a gradient
from 95% H2O (0.1% TFA)/5% MeCN (0.1% TFA) to 5% H2O
(0.1% TFA)/95% MeCN (0.1% TFA) over 8 min with a flow of
2 mL/min. The preparative HPLC purifications were performed with a
mass-directed autopurification system. All HPLC purifications were
performed with a gradient of MeCN/H2O.
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.
Table 11. Liebeskind−Srogl Cross-Coupling Reaction on 13
or 14 at C-2
Unless otherwise mentioned, all reactions described in this paper
were monitored by LC−MS and stopped when all of the starting
material was converted into the product(s) or when no further
conversion was observed.
General Procedure for Synthesis of Enamine 4 and
Trihydroxypyrido[3,2-d]pyrimidines 5. A mixture of 5-aminouracil
2 (1.0 g; 7.87 mmol) and derivative 3 (8.65 mmol) in iPrOH (5.0 mL)
was heated at 140 °C for 2.5 h under microwave irradiation. The
resulting yellow precipitate was filtered off, washed twice with MeOH
and once with diethyl ether, and dried under suction affording enamines 4.
A mixture of ethyl and isopropyl esters (products from trans-esterification)
was obtained. Compounds 4a,b were used without further purification
in the next step. A suspension of derivative 4 (4.18 mmol) in a mixture
of DMA (1.0 mL) and 1,2-dichlorobenzene (5.0 mL) was heated at
250 °C for 1.2 h under microwave irradiation. A solid precipitated out.
It was filtered, washed twice with MeOH and once with diethyl ether,
and dried under suction, affording derivatives 5.
entry
SM
R1
R2
BnNH
product
yield (%)
1
2
3
3
13a
13c
14a
14b
H
H
H
15a
15b
16a
16b
71
76
80
69
Et2N
4-MeO-C6H4
Ph
4-MeO
6-Methyl-1,5-dihydropyrido[3,2-d]pyrimidine-2,4,8-trione (5a):
These combinations of SNAr and cross-coupling reactions
allowed the successive and regioselective introduction of a wide
diversity of groups at C-4, C-2, and C-8, yielding novel and
diverse compounds 15 and 16 in good yields.
yield = 84%; pale brown solid; mp >300 °C dec; IR νmax 3195,
1
1684, 1633, 1552, 1417 cm−1; H NMR (300 MHz, DMSO-d6) δH
2.29 (s, 3H), 6.15 (s, 1H), 10.48 (s, 1H), 11.70 (s, 1H), 11.99 (br s,
1H); 13C NMR (75.47 MHz, DMSO-d6), δC 18.7, 113.3, 116.1, 119.8,
131.7, 148.2, 148.9, 159.8; HPLC tR = 0.41 min; ES-MS m/z 194.0
(M + H)+. Anal. Calcd for C8H7N3O3: C, 49.75; H, 3.65; N, 21.75.
Found: C, 49.66; H, 3.49; N, 21.96.
6-Phenyl-1,5-dihydropyrido[3,2-d]pyrimidine-2,4,8-trione (5b):
yield = 86%; beige solid; mp >300 °C dec; IR νmax 3010, 2843,
1681, 1479 cm−1; 1H NMR (300 MHz, DMSO-d6) δH 7.48−7.88
(m, 6H), 10.66 (s, 1H), 11.55 (br s, 1H), 11.85 (br s, 1H), 13C NMR
(75.47 MHz, DMSO-d6) δC 126.8, 127.0, 128.6, 129.4, 141.8, 143.0,
149.2, 169.3; HPLC tR = 1.51 min; ES-MS m/z 254 (M − H)−. Anal.
Calcd for C13H9N3O3·0.08H2O: C, 60.83; H, 3.60; N, 16.37. Found:
C, 60.44; H, 3.48; N, 16.47.
2,4,8-Trichloro-6-methylpyrido[3,2-d]pyrimidine (1a). A suspen-
sion of derivative 5a (600 mg, 3.11 mmol) in a mixture of POCl3
(15.0 mL) and N,N-diethylaniline (0.6 mL) was stirred at reflux for
16 h. The mixture was then cooled down to room temperature and
POCl3 was removed under vacuum at 40 °C. The reaction mixture was
then cooled down to 0 °C and ice was added. A solid precipitated out.
It was filtered, washed twice with MeOH and once with diethyl ether,
and dried under suction, affording 1a as a beige solid (600 mg, 78%
CONCLUSIONS
■
Following an efficient synthetic route for compounds 1 with
various groups at C-6, we have reported the potential of tri-
chloropyrido[3,2-d]pyrimidine scaffolds and their regioselective
chloride displacement. Selective C-4 arylation was achieved via
the tandem sulfur nucleophilic addition followed by Liebeskind−
Srogl cross-coupling reaction. The reactivity difference of the
remaining two chlorides toward SNAr reactions was inves-
tigated, with the preferred C-2 addition of amine, thiol, or
thiolate derivatives. The last chloride at C-8 was efficiently
displaced by SNAr, Suzuki−Miyaura cross-coupling reaction, or
reduction. The observed reactivity order was not influenced by
the nature of the C-6 substituent. C-2 arylation as a final step
was also possible by Liebeskind−Srogl cross-coupling reac-
tion on the previously introduced C-2 thioether. With the
development of a robust route for the synthesis of scaffold 1
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yield): mp >219 °C dec; IR νmax 1545, 1454, 1388, 1145, 795 cm−1;
1H NMR (300 MHz, CDCl3) δH 2.83 (s, 3H), 7.85 (s, 1H); 13C NMR
(75.47 MHz, CDCl3) δC 25.5, 130.6, 137.2, 142.7, 145.2, 155.3, 162.7,
165.5; HPLC tR = 3.55 min; ES-MS m/z 248.0 (M + H)+. Anal. Calcd
for C8H4Cl3N3: C, 38.67; H, 1.62; N, 16.91; Cl, 42.8. Found: C, 38.29;
H, 1.70; N, 16.62; Cl, 42.52.
56.96; H, 3.26; N, 14.23; Cl, 24.02. Found: C, 56.58; H, 3.11; N,
14.23; Cl, 24.09.
2,8-Dichloro-4,6-diphenylpyrido[3,2-d]pyrimidine (7b): yield =
78%; off-white solid; mp 158 °C dec; IR νmax 2361, 2341, 1461,
1
774, 686 cm−1; H NMR (300 MHz, CDCl3) δH 7.54−7.62 (m, 6H),
8.13 (br s, 2H), 8.41 (s, 1H), 8.50 (m, 2H); 13C NMR (75.47 MHz,
CDCl3) δC 125.7, 127.7, 128.3, 129.3, 131.0, 131.8, 132.4, 134.8, 136.8,
138.1, 143.4, 146.2, 157.6, 158.0, 169.8; HPLC tR = 5.56 min; ES-MS
m/z 352.0 (M + H)+. Anal. Calcd for C19H11Cl2N3: C, 64.79; H, 3.15;
N, 11.93; Cl, 20.13. Found: C, 64.34; H, 3.15; N, 11.85; Cl, 19.92.
2,8-Dichloro-4-phenylpyrido[3,2-d]pyrimidine-6-carboxylic acid
methyl ester (7c): yield = 79%; brown solid; mp 230−231 °C; IR
2,4,8-Trichloro-6-phenylpyrido[3,2-d]pyrimidine (1b). A suspen-
sion of derivative 5b (793 mg, 3.11 mmol) in POCl3 (15 mL) was
heated at 200 °C under microwave irradiation for 1.5 h. The reaction
mixture was then cooled to 0 °C, and ice was added. A solid pre-
cipitated out. It was filtered, washed twice with MeOH and once with
diethyl ether, and dried under suction, affording 1b as a brown solid
(816 mg, 85% yield): mp >300 °C dec; IR νmax 3012, 2843, 1681,
1479, 1420 cm−1; 1H NMR (300 MHz, CDCl3) δH 7.56−7.58
(m, 3H), 8.19−8.22 (m, 2H), 8.43 (s, 1H); 13C NMR (75.47 MHz,
CDCl3) δC 126.6, 127.2, 128.7, 130.9, 135.6, 137.0, 142.8, 144.8, 154.8,
158.8, 165.7; HPLC tR = 5.13 min; ES-MS m/z 310.00 (M + H)+.
Anal. Calcd for C13H6Cl3N3·0.05H2O: C, 50.13; H, 1.97; N, 13.49; Cl,
34.15. Found: C, 49.74; H, 2.07; N, 13.85; Cl, 34.12.
General Procedure for Synthesis of Derivatives 6. To a
suspension of derivative 1 (0.32 mmol) in THF (2 mL) was added
sodium methylthiolate (22.4 mg, 0.32 mmol) at −10 °C. The reaction
was stirred at −10 °C for 3 h. A solid precipitated out. It was filtered,
washed twice with MeOH and once with diethyl ether, and dried
under suction, affording derivatives 6.
1
νmax 1712, 1524, 1246 cm−1; H NMR (300 MHz, CDCl3) δH 4.08
(s, 3H), 7.57−7.65 (m, 3H), 8.59−8.62 (m, 2H), 8.64 (s, 1H); 13C
NMR (75.47 MHz, CDCl3) δC 53.8, 128.5, 128.7, 132.8, 132.9, 134.2,
137.8, 144.6, 147.8, 148.5, 160.2, 164.0, 170.6; HPLC tR = 4.75 min;
ES-MS m/z 333.94 (M + H)+. Anal. Calcd for C15H9Cl2N3O2: C,
53.92; H, 2.71; N, 12.57. Found: C, 53.65; H, 2.93; N, 12.23.
2,8-Dichloro-4-(4-methoxyphenyl)pyrido[3,2-d]pyrimidine-6-car-
boxylic acid methyl ester (7d): yield = 82%; brown solid; mp 247−
1
248 °C; IR νmax 1723, 1251 cm−1; H NMR (300 MHz, CDCl3), δH
3.94 (s, 3H), 4.09 (s, 3H), 7.09 (d, J = 9 Hz, 2H), 8.60 (s, 1H), 8.79
(d, J = 9 Hz, 2H); 13C NMR (75.47 MHz, CDCl3) δC 54.0, 56.0,
114.6, 127.1, 128.5, 135.4, 138.0, 144.6, 148.0, 148.1, 160.4, 164.1,
164.3, 169.4; HPLC tR = 4.87 min; ES-MS m/z 363.93 (M + H)+.
Anal. Calcd for C16H11Cl2N3O3: C, 52.77; H, 3.04; N, 11.54. Found:
C, 52.38; H, 3.16; N, 11.19.
2,8-Dichloro-4-(4-trifluoromethylphenyl)pyrido[3,2-d]pyrimidine-
6-carboxylic acid methyl ester (7e): yield = 77%; beige solid; mp
183−184 °C; IR νmax 1731, 1320 cm−1; 1H NMR (300 MHz, CDCl3)
δH 4.09 (s, 3H), 7.86 (d, J = 8 Hz, 2H), 8.67 (s, 1H), 8.73 (d, J = 8 Hz,
2H); 13C NMR (75.47 MHz, CDCl3) δC 53.9, 124.0 (q, J = 278.9 Hz),
125.5 (q, J = 3.6 Hz), 128.8, 133.0, 133.9 (q, J = 31.2 Hz), 137.3,
137.6, 145.0, 148.0, 148.9, 160.2, 163.8, 169.2; HPLC tR = 5.31 min;
ES-MS m/z 401.94 (M + H)+. Anal. Calcd for C16H8Cl2F3N3O2: C,
47.79; H, 2.00; N, 10.45. Found: C, 47.94; H, 2.24; N, 10.13.
General procedure for Synthesis of Derivatives 8. To a
solution of derivative 7 (0.21 mmol) in MeCN (1 mL) was added the
2,8-Dichloro-4-methylsulfanyl-6-methylpyrido[3,2-d]pyrimidine
(6a): yield = 84%; off-white solid; mp 145.5−146.5 °C; IR νmax 1534,
1382, 1152, 799 cm−1; 1H NMR (300 MHz, CDCl3) δH 2.67 (s, 3H),
2.75 (s, 3H), 7.72 (s, 1H), 13C NMR (75.47 MHz, CDCl3) δC 13.2,
25.1, 129.7, 138.1, 141.1, 142.1, 156.4, 160.1, 178.1; HPLC tR
=
4.20 min; ES-MS m/z 260.00 (M + H)+. Anal. Calcd for C9H7Cl2N3S:
C, 41.55; H, 2.71; N, 16.15; Cl, 27.26. Found: C, 41.67; H, 2.82; N,
16.11; Cl, 27.10.
2,8-Dichloro-4-methylsulfanyl-6-phenylpyrido[3,2-d]pyrimidine
(6b): yield = 85%; pale yellow solid; mp 186.6−187.6 °C; IR νmax
1
1510, 1447, 1172, 803, 679 cm−1; H NMR (300 MHz, CDCl3) δH
2.72 (s, 3H), 7.55−7.59 (m, 3H), 8.16−8.19 (m, 2H), 8.33 (s, 1H);
13C NMR (75.47 MHz, CDCl3) δC 13.2, 126.2, 127.6, 129.2, 130.9,
amine (0.42 mmol) in the presence of Hunig’s base (0.075 mL;
̈
136.5, 138.4, 141.5, 142.9, 156.7, 157.1, 179.0; HPLC tR = 5.40 min;
ES-MS m/z 322.0 (M + H)+. Anal. Calcd for C14H9Cl2N3S: C, 52.19;
H, 2.82; N, 13.04. Found: C, 52.10; H, 2.85; N, 13.02.
0.42 mmol). The reaction mixture was heated at 90 °C for 20 min to
1 h under microwave irradiation. After solvents were removed under
vacuum at 40 °C, the resulting solid was suspended in MeOH, filtered,
washed twice with MeOH and once with diethyl ether, and dried
under suction to afford derivatives 8a to 8e.
2,8-Dichloro-4-methylsulfanylpyrido[3,2-d]pyrimidine-6-carboxy-
lic Acid Methyl Ester (6c): yield = 84%; gray solid; mp 229−230 °C;
IR νmax 1720, 1248 cm−1; 1H NMR (300 MHz, CDCl3) δH 2.71
(s, 3H), 4.06 (s, 3H), 8.56 (s, 1H); 13C NMR (75.47 MHz, CDCl3) δC
13.6, 54.0, 129.6, 138.4, 144.1, 144.3, 147.9, 159.5, 164.1, 180.7; HPLC
tR = 4.10 min; ES-MS m/z 303.93 (M + H)+. Anal. Calcd for
C10H7Cl2N3O2S: C, 39.49; H, 2.32; N, 13.82. Found: C, 39.19; H,
2.37; N, 13.71.
2-Benzylamino-4-phenyl-6-methyl-8-chloropyrido[3,2-d]-
pyrimidine (8a): yield = 71%; off-white solid; mp 127.2−128.2 °C; IR
1
νmax 1556, 1450, 1355 cm−1; H NMR (300 MHz, CDCl3) δH 2.63
(s, 3H), 4.82 (d, J = 5.70 Hz, 2H), 5.86 (br s, 1H), 7.28−7.37
(m, 3H), 7.46−7.52 (m, 5H), 7.56 (s, 1H), 8.28 (br s, 2H); 13C NMR
(75.47 MHz, CDCl3) δC 24.8, 46.0, 127.4, 127.9, 128.0, 128.1, 128.6,
130.6, 131.6, 131.7, 134.2, 135.4, 136.2, 139.0, 154.0, 158.6, 167.8;
HPLC tR = 5.82 min, ES-MS m/z 361.10 (M + H)+. Anal. Calcd for
C21H17ClN4: C, 69.90; H, 4.75; N, 15.53; Cl, 9.82. Found: C, 69.83;
H, 4.78; N, 15.47; Cl, 9.77.
General Procedure for Synthesis of Derivatives 7. To a
solution of derivative 6 (0.78 mmol) in dioxane (4 mL) were added a
boronic acid derivative (1.55 mmol), copper(I) thiophene-2-carboxylate
(295.6 mg, 1.55 mmol), and Pd(PPh3)4 (46.2 mg, 0.04 mmol) under
inert atmosphere. The reaction was heated under microwave
irradiation at 110 °C for 0.5−1.5 h. After filtration through Celite,
the residue was diluted with DCM (15 mL), washed with NaHCO3
saturated solution (10 mL) and brine (10 mL), and dried over
Na2SO4. After solvents were removed under vacuum at 40 °C, the
solid obtained was suspended in MeOH, filtered, washed twice with
MeOH and once with diethyl ether, and dried under suction to afford
derivatives 7a−e.
2-Benzylamino-4-phenyl-6-phenyl-8-chloropyrido[3,2-d]-
pyrimidine (8b): yield = 69%; off-white solid; mp 126.2−127.2 °C; IR
1
νmax 1556, 1450, 1355 cm−1; H NMR (300 MHz, CDCl3) δH 4.87
(d, J = 5.1 Hz, 2H), 5.94 (br s, 1H), 7.29−7.39 (m, 3H), 7.47−7.49
(m, 5H), 7.52−7.61 (m, 3H), 8.04−8.06 (m, 2H), 8.20 (s, 1H), 8.34
(br s, 2H); 13C NMR (75.47 MHz, CDCl3) δC 46.1, 124.7, 126.9,
127.4, 127.9, 128.2, 128.6, 129.0, 129.5, 130.0, 130.6, 131.7, 131.8,
134.3, 136.3, 137.9, 138.9, 151.9, 160.4, 166.1, HPLC tR = 6.01 min;
ES-MS m/z 423.230 (M + H)+. Anal. Calcd for C26H19ClN4: C,
73.84; H, 4.53; N, 13.25; Cl, 8.38. Found: C, 73.43; H, 4.56; N, 12.96;
Cl, 8.32.
2-Benzylamino-4-phenyl-8-chloro-pyrido[3,2-d]pyrimidine-6-car-
boxylic acid methyl ester (8c): yield = 83%; yellow solid; mp 200−
201 °C; IR νmax 3374, 1706, 1551 cm−1; 1H NMR (300 MHz, CDCl3)
δH 3.99 (s, 3H), 4.85 (br s, 2H), 6.10 (br s, 1H), 7.84−7.53 (m, 8H),
8.38−8.41 (m, 3H); 13C NMR (75.47 MHz, CDCl3) δC 46.5, 53.5,
2,8-Dichloro-4-phenyl-6-methylpyrido[3,2-d]pyrimidine (7a):
yield = 81%; pale yellow solid; mp 158.5−159.5 °C; IR νmax 1524,
1
1329, 1150 cm−1; H NMR (300 MHz, CDCl3) δH 2.78 (s, 3H),
7.55−7.60 (m, 3H), 7.79 (s, 1H), 8.42−8.45 (m, 2H); 13C NMR
(75.47 MHz, CDCl3) δC 25.5, 128.3, 129.1, 131.8, 132.3, 134.7, 137.8,
142.5, 145.9, 157.3, 160.8, 169.1; HPLC tR = 4.75 min; ES-MS m/z
290.00 (M + H)+; HRMS (ESI) m/z calcd for C14H9Cl2N3 [M + 1]+
290.0246, found 290.0266. Anal. Calcd for C14H9Cl2N3·0.28H2O: C,
4591
dx.doi.org/10.1021/jo300189q | J. Org. Chem. 2012, 77, 4586−4595

The Journal of Organic Chemistry
Article
128.0, 128.2, 128.6, 128.7, 129.1, 131.7, 132.1, 132.5, 135.7, 138.7,
141.6, 142.5, 148.4, 159.9, 165.1, 169.6; HPLC tR = 5.34 min; ES-MS
m/z 405.03 (M + H)+. Anal. Calcd for C22H17ClN4O2: C, 65.27; H,
4.23; N, 13.84. Found: C, 65.29; H, 4.27; N, 13.46.
2-Butylamino-4-phenyl-8-chloropyrido[3,2-d]pyrimidine-6-car-
boxylic acid methyl ester (8d): yield = 81%; yellow solid; mp 183−
184 °C; IR νmax 3382, 1704, 1556 cm−1; 1H NMR (300 MHz, CDCl3)
δH 0.99 (t, J = 7 Hz, 3H), 1.48 (q, J = 7 Hz, 2H), 1.69−1.71 (m, 2H),
3.66−3.68 (m, 2H), 4.00 (s, 3H), 5.80 (br s, 1H), 7.55 (br m, 3H),
8.41−8.62 (m, 3H); 13C NMR (75.47 MHz, CDCl3) δC 14.0, 20.3,
31.5, 41.8, 53.2, 128.0, 128.3, 129.6, 131.4, 132.0, 135.6, 141.2, 141.9,
148.2, 159.9, 164.9, 169.2; HPLC tR = 5.60 min; ES-MS m/z 370.93
(M + H)+. Anal. Calcd for C19H19ClN4O2: C, 61.54; H, 5.16; N, 15.11;
Cl, 9.56. Found: C, 61.57; H, 5.00; N, 14.72; Cl, 9.58.
2-Diethylamino-4-phenyl-8-chloropyrido[3,2-d]pyrimidine-6-car-
boxylic acid methyl ester (8e): yield = 85%; yellow solid; mp 123−
124 °C; IR νmax 1717, 1520, 1335 cm−1; 1H NMR (300 MHz, CDCl3)
δH 1.33 (br s, 6H), 3.88 (q, J = 7 Hz, 4H), 4.00 (s, 3H), 7.53−7.56
(m, 3H), 8.38 (s, 1H), 8.50−8.52 (m, 2H); 13C NMR (75.47 MHz,
CDCl3) δC 12.9, 14.0, 43.1, 53.3, 127.8, 128.5, 131.4, 132.2, 134.7,
136.5, 141.0, 141.3, 148.9, 158.8, 165.3, 168.2; HPLC tR = 6.10 min;
ES-MS m/z 371.07 (M + H)+. Anal. Calcd for C19H19ClN4O2: C,
61.54; H, 5.16; N, 15.11. Found: C, 61.25; H, 5.18; N, 14.76.
General Procedure for Synthesis of Derivatives 9. A solution
of derivative 8 (0.25 mmol) in a mixture of MeOH and EtOAc
(11 mL) was passed through a continuous-flow hydrogenation reactor
equipped with a 10% Pd/C cartridge at 70 °C with a flow of 0.4 mL/
min at 5−7 bar (“Full Hydrogen” mode).16 Partial reduction of the
heterocycle was observed together with the desired product 9. After
evaporation of the solvents, the residue was dissolved in dichloro-
ethane (3 mL), and MnO2 (5.0 mmol) was added. The reaction
mixture was heated under microwave irradiation at 100 °C for 15 min.
After filtration through Celite and evaporation of the solvent under
vacuum at 40 °C, the residue was dissolved in a minimum mixture of
MeCN/DMSO and purified by a mass-directed autopurification
system to afford derivatives 9a−c.
0.01 mmol) in dioxane (2 mL) was heated at 90 °C under inert
atmosphere. After 3.5−7 h, the reaction mixture was cooled to rt and
filtered through Celite. The filtrate was evaporated under reduced
pressure. The residue was diluted with DCM (15 mL), washed with
water (10 mL), brine (10 mL), and dried over Na2SO4. After
evaporation of the solvents under vacuum at 40 °C, the resulting solid
was suspended in MeOH, filtered, washed twice with MeOH and
once with diethyl ether, and dried under suction to afford derivatives
10a−10c.
2-Diethylamino-4,8-diphenylpyrido[3,2-d]pyrimidine-6-carbox-
ylic acid methyl ester (10a): yield = 80%; yellow solid; mp 133−134 °C;
IR νmax 1555, 1240 cm−1; 1H NMR (300 MHz, CDCl3) δH 1.24−1.29
(m, 6H), 3.76 (br m, 4H), 4.01 (s, 3H), 7.45−7.52 (m, 3H), 7.56−
7.58 (m, 3H), 7.90−7.93 (m, 2H), 8.36 (s, 1H), 8.52−8.55 (m, 2H);
13C NMR (75.47 MHz, CDCl3) δC 13.4, 14.2, 42.9, 53.2, 127.2, 128.2,
128.4, 128.9, 130.7, 131.1, 132.3, 134.8, 136.8, 137.1, 142.0, 145.0,
149.9, 158.5, 166.3, 168.2; HPLC tR = 5.16 min; ES-MS m/z 345.99
(M + H)+. Anal. Calcd for C25H24N4O2: C, 72.80; H, 5.86; N, 13.58.
Found: C, 72.40; H, 5.82; N, 13.35.
2-Diethylamino-4-phenyl-8-(4-methoxyphenyl)pyrido[3,2-d]-
pyrimidine-6-carboxylic acid methyl ester (10b): yield = 86%; yellow
1
solid; mp 129−130 °C; IR νmax 1721, 1557, 1248 cm−1; H NMR
(300 MHz, CDCl3) δH 1.28 (t, J = 7 Hz, 6H), 3.79 (br m, 4H), 3.91
(s, 3H), 4.01 (s, 3H), 7.03 (d, J = 9 Hz, 2H), 7.54−7.56 (m, 3H), 7.93
(d, J = 9 Hz, 2H), 8.34 (s, 1H), 8.51−8.54 (m, 2H); 13C NMR
(75.47 MHz, CDCl3) δC 13.7, 13.9, 42.9, 53.2, 55.7, 113.8, 114.5,
126.5, 128.1, 128.3, 129.2, 131.0, 132,0, 132.3, 134.8, 137.2, 142.1,
144.5, 149.5, 158.4, 160.4, 166.4, 168.2; HPLC tR = 6.43 min; ES-MS
m/z 443.56 (M + H)+. Anal. Calcd for C26H26N4O3: C, 70.57; H, 5.92;
N, 12.66. Found: C, 70.52; H, 5.95; N, 12.61.
2-Diethylamino-4-phenyl-8-(4-trifluoromethylphenyl)pyrido[3,2-
d]pyrimidine-6-carboxylic acid methyl ester (10c): yield = 82%;
yellow solid; mp 165−166 °C; IR νmax 1711, 1558, 1321 cm−1;
1H NMR (300 MHz, CDCl3) δH 1.27 (br s, 6H), 3.77 (br m, 4H),
4.02 (s, 3H), 7.55−7.57 (m, 3H), 7.75 (d, J = 8 Hz, 2H), 8.02 (d, J =
8 Hz, 2H), 8.35 (s, 1H), 8.53−8.54 (m, 2H); 13C NMR (75.47 MHz,
CDCl3) δC 13.3, 13.8, 42.8, 53.0, 124.3 (q, J = 277.8 Hz), 124.8 (q, J =
3.6 Hz), 127.0, 128.2, 130.4 (q, J = 30.0 Hz), 130.7, 131.0, 132.0,
134.7, 136.6, 140.2, 141.6, 143.1, 148.9, 158.3, 165.8, 168.1,
HPLC tR = 6.94 min; ES-MS m/z 481.36 (M + H)+. Anal. Calcd
for C26H23F3N4O2: C, 64.99; H, 4.82; N, 11.66. Found: C, 64.65; H,
4.82; N, 11.45.
2-Benzylamino-4-phenyl-6-methylpyrido[3,2-d]pyrimidine (9a):
yield = 75%; pale yellow solid; mp 115.2−116.4 °C; IR νmax 3253,
1591, 1352, 685 cm−1; 1H NMR (300 MHz, DMSO-d6), δH 2.56
(s, 3H), 4.64 (d, J = 6.2 Hz, 2H), 7.19−7.24 (m, 1H), 7.28−7.34
(m, 2H), 7.39−7.42 (m, 2H), 7.52−7.56 (m, 3H), 7.57 (d, J = 8.9 Hz,
1H), 7.82 (d, J = 8.9 Hz, 1H), 8.10 (br s, 1H), 8.19−8.22 (m, 2H), 13C
NMR (75.47 MHz, DMSO-d6), δC 24.4, 44.2, 126.5, 127.2, 127.6,
128.2, 128.9, 130.0, 131.0, 133.6, 133.8, 136.4, 140.2, 152.6, 154.0,
158.6; HPLC tR = 4.37 min, ES-MS m/z 327.09 (M + H)+; HRMS
(ESI) m/z calcd for C21H18N4 [M + 1]+ 327.1609, found 327.1605.
2-Benzylamino-4,6-diphenylpyrido[3,2-d]pyrimidine (9b): yield =
71%; pale yellow solid; mp 119.0−120.0 °C; IR νmax 3255, 1592, 1537,
General Procedure for SNAr with Benzylthiol on Derivatives
7a−c. To a solution of derivative 7 (0.21 mmol) in MeCN (1.0 mL)
and DMF (1.0 mL) was added benzylthiol (123.3 mL, 1.05 mmol) in
the presence of Hunig’s base (0.11 mL; 0.62 mmol). The reaction
̈
mixture was heated at 90 °C for 1 h under microwave irradiation. As
two regioisomers were formed during the reaction, the reaction
mixture was purified by mass-directed autopurification system.
Derivatives 11a−c and 12a−c were isolated.
1
1454, 693 cm−1; H NMR (300 MHz, DMSO-d6) δH 4.69 (d, J =
6.1 Hz, 2H), 7.23−7.25 (m, 1H), 7.30−7.35 (m, 2H), 7.42−7.52
(m, 5H), 7.59−7.61 (m, 3H), 7.99 (d, J = 8.9 Hz, 1H), 8.12−8.15
(m, 2H), 8.27−8.30 (m, 3H), 8.33 (d, J = 8.9 Hz, 1H); 13C NMR
(75.47 MHz, DMSO-d6), δC 44.2, 125.3, 126.6, 127.3, 127.6, 127.8,
128.2, 128.9, 129.2, 130.2, 130.3, 131.1, 134.4, 134.6, 138.1, 138.2,
142.9, 149.7, 151.3, 160.1; HPLC tR = 4.62 min, ES-MS m/z 389.20
(M + H)+. Anal. Calcd for C26H20N4: C, 80.39; H, 5.19; N, 14.42.
Found: C, 80.25; H, 5.22; N, 14.38.
2-Benzylamino-4-phenylpyrido[3,2-d]pyrimidine-6-carboxylic
acid methyl ester (9c): yield = 73%; pale yellow solid; mp 151.4−
152.4 °C; IR νmax 1715, 1591, 1291; 1H NMR (300 MHz, DMSO-d6)
δH 3.89 (s, 3H), 4.69 (d, J = 6.1 Hz, 2H), 7.21−7.44 (m, 5H), 7.56−
7.61 (m, 3H), 8.00 (d, J = 8.9 Hz, 1H), 8.23 (d, J = 8.9 Hz, 1H), 8.30−
8.32 (m, 2H), 8.67 (t, J = 6.0 Hz, 1H); 13C NMR (75.47 MHz,
DMSO-d6) δC 44.5, 52.5, 126.7, 127.2, 127.3, 127.8, 127.9, 128.3,
2-Benzylsulfanyl-4-phenyl-6-methyl-8-chloropyrido[3,2-d]-
pyrimidine (11a): yield = 60%; pale yellow solid; mp 121.5−122.5 °C;
IR νmax 1529, 1455, 1147, 690 cm−1; 1H NMR (300 MHz, CDCl3) δH
2.67 (s, 3H), 4.57 (s, 2H), 7.21−7.31 (m, 3H), 7.48−7.50 (m, 3H),
7.55−7.58 (m, 2H), 7.65 (s, 1H), 8.30−8.33 (m, 2H); 13C NMR
(75.47 MHz, CDCl3) δC 25.2, 35.9, 127.2, 128.0, 128.4, 128.6, 129.3,
131.0, 132.0, 135.5, 137.1, 138.0, 141.9, 144.4, 158.2, 166.0, 168.0;
HPLC tR = 5.90 min; ES-MS m/z 378.10 (M + H)+. Anal. Calcd for
C21H16ClN3S: C, 66.75; H, 4.26; N, 11.05; Cl, 9.38. Found: C, 66.73;
H, 4.26; N, 11.05; Cl, 9.36.
2-Benzylsulfanyl-4,6-diphenyl-8-chloropyrido[3,2-d]pyrimidine
1
(11b): yield = 60%; pale yellow solid; mp 146−147 °C; H NMR
(300 MHz, CDCl3) δH 4.63 (s, 2H), 7.23−27 (m, 1H), 7.27−7.36
(m, 2H), 7.54−7.56 (m, 3H), 7.59−7.65 (m, 5H), 8.23−8.31 (m, 4H),
8.85 (s, 1H); 13C NMR (75.47 MHz, CDCl3) δC 34.9, 125.7,127.1,
127.4, 128.0, 128.4, 129.0, 129.1, 130.5, 131.1, 131.7, 135.0, 136.7,
136.8, 137.9, 141.7, 144.1, 155.4, 166.3, 167.4; HPLC tR = 6.47 min;
ES-MS m/z 440.10 (M + H)+. Anal. Calcd for C26H18ClN3S: C, 70.98;
H, 4.12; N, 9.55. Found: C, 70.91; H, 4.16; N, 9.51.
130.7, 131.2, 132.8, 134.4, 139.5, 142.0, 159.5, 164.6; HPLC tR
=
4.75 min, ES-MS m/z 371.0 (M + H)+; HRMS (ESI) m/z calcd for
C22H18N4O2 [M+1]+ 371.1508, found 371.1499.
General Procedure for Synthesis of Derivatives 10. A solution
of boronic acid derivative (0.25 mmol), 8e (89.0 mg, 0.24 mmol),
cesium carbonate (237.8 mg, 0.73 mmol), and Pd(PPh3)4 (11.6 mg,
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2-Benzylsulfanyl-4-phenyl-8-chloropyrido[3,2-d]pyrimidine-6-
carboxylic acid methyl ester (11c): yield =73%; pale orange solid;
mp 135.4−136.4 °C; IR νmax 1724, 1531, 1314, 1244, 1108; 1H NMR
(300 MHz, DMSO-d6) δH 3.95 (s, 3H), 4.63 (s, 2H), 7.23−7.36
(m, 3H), 7.56−7.68 (m, 5H), 8.33−8.34 (m, 2H), 8.35 (s, 1H);
13C NMR (75.47 MHz, DMSO-d6) δC 35.0, 53.2, 127.2, 128.0, 128.1,
128.4, 129.1, 131.6, 131.9, 134.7, 136.7, 137.7, 141.8, 145.5, 146.2,
163.5, 166.9, 170.1; HPLC tR = 5.91 min; ES-MS m/z 422.20
(M + H)+. Anal. Calcd for C22H16ClN3O2S: C, 62.63; H, 3.82; N, 9.96;
Cl, 8.40. Found: C, 62.30; H, 3.72; N, 9.84; Cl, 8.49.
2-Chloro-4-phenyl-6-methyl-8-benzylsulfanylpyrido[3,2-d]-
pyrimidine (12a): yield = 20%; pale orange solid; mp 172.3−173.3 °C;
IR νmax 1521, 1448, 1332, 1153, 689, 639 cm−1; 1H NMR (300 MHz,
CDCl3) δH 2.70 (s, 3H), 4.29 (s, 2H), 7.34−7.35 (m, 2H), 7.37
(s, 1H), 7.38−7.40 (m, 1H), 7.46−7.51 (m, 2H), 7.52−7.56 (m, 3H),
8.42−8.46 (m, 2H); 13C NMR (75.47 MHz, CDCl3) δC 25.8, 35.5,
122.3, 128.0, 128.2, 128.9, 129.0, 131.4, 132.2, 134.6, 135.2, 135.8,
144.1, 146.6, 149.6, 160.0, 168.6; HPLC tR = 5.62 min; ES-MS m/z
378.10 (M + H)+. Anal. Calcd for C21H16ClN3S: C, 66.75; H, 4.27; N,
11.12; Cl, 9.38. Found: C, 66.95; H, 4.32; N, 10.72; Cl, 9.45.
2-Chloro-4,6-diphenyl-8-benzylsulfanylpyrido[3,2-d]pyrimidine
(12b): yield = 18%; off-white solid; mp 180.5−181.5 °C; IR νmax 1524,
1455, 684 cm−1; 1H NMR (400 MHz, CDCl3) δH 4.41 (s, 2H), 7.30−
7.37 (m, 1H), 7.37−7.45 (m, 2H), 7.50−7.55 (m, 3H), 7.55−7.70 (m,
5H), 7.96 (s, 1H), 7.98−8.07 (m, 2H), 8.50−8.60 (m, 2H); 13C NMR
(75.47 MHz, DMSO-d6), δC 33.7, 119.9, 126.1, 127.6, 127.7, 128.0,
128.1, 128.7, 129.1, 130.6, 131.5, 131.9, 134.8, 135.8, 137.4, 146.5,
149.9, 154.5, 156.6, 168.9; HPLC tR = 6.20 min; ES-MS m/z 440.1
(M + H)+. Anal. Calcd for C26H18ClN3S: C, 70.98; H, 4.12; N, 9.55;
Cl, 8.06. Found: C, 70.56; H, 4.38; N, 9.39; Cl, 7.90.
under vacuum at 40 °C, and the solid obtained was suspended in
MeOH, filtered, washed twice with MeOH and once with diethyl
ether, and dried under suction. Derivative 13a was further purified by
mass-directed autopurification system. Derivatives 13a−c were
isolated.
2-Methylsulfanyl-4-phenyl-8-benzylaminopyrido[3,2-d]-
pyrimidine-6-carboxylic acid methyl ester (13a): yield = 73%; yellow
solid; mp 150.0−151.0 °C; IR νmax 1720, 1528, 1266, 1112 cm−1;
1H NMR (300 MHz, CDCl3) δH 2.69 (s, 3H), 3.98 (s, 3H), 4.63
(d, J = 5.8 Hz, 2H), 6.70 (t, J = 5.6 Hz, 1H), 7.33−7.41 (m, 5H), 7.43
(s, 1H), 7.53−7.55 (m, 3H), 8.61−8.64 (m, 2H); 13C NMR (75.47
MHz, CDCl3) δC 14.9, 46.8, 53.0, 102.7, 127.3, 127.9, 128.2, 129.0,
131.2, 132.2, 135.0, 135.8, 137.0, 140.2, 147.5, 149.2, 165.9, 166.2,
167.7; HPLC tR = 0.42 min; ES-MS m/z 417.30 (M + H)+. Anal.
Calcd for C23H20N4O2S: C, 66.33; H, 4.84; N, 13.45. Found: C, 66.15;
H, 4.80; N, 13.34.
2-Methylsulfanyl-4-phenyl-8-butylaminopyrido[3,2-d]-
pyrimidine-6-carboxylic acid methyl ester (13b): yield = 83%;
yellow-orange solid; mp 124.5−125.5 °C; IR νmax 1527, 1253, 1017
1
cm−1; H NMR (300 MHz, DMSO-d6) δH 0.95 (t, J = 7.3 Hz, 3H),
1.38−1.48 (m, 2H), 1.61−1.71 (m, 2H), 2.73 (s, 3H), 3.40 (q, J =
6.8 Hz, 2H), 3.89 (s, 3H), 7.29 (s, 1H), 7.53−7.60 (m, 3H), 8.44−8.47
(m, 2H), 13C NMR (75.47 MHz, DMSO-d6) δC 13.8, 14.8, 20.3, 30.9,
42.5, 53.0, 102.1, 128.1, 131.1, 132.2, 135.0, 135.9, 140.2, 147.5, 149.3,
165.8, 166.4, 167.3, HPLC tR = 5.81 min; ES-MS m/z 383.3 (M + H)+.
Anal. Calcd for C20H22N4O2S: C, 62.81; H, 5.80; N, 14.65. Found: C,
62.79; H, 5.83; N, 14.62.
2-Methylsulfanyl-4-phenyl-8-diethylaminopyrido[3,2-d]-
pyrimidine-6-carboxylic acid methyl ester (13c): yield = 84%; yellow
1
solid; mp 110.5−111.0 °C; IR νmax 1736, 1530, 1236 cm−1; H NMR
2-Chloro-4-phenyl-8-benzylsulfanylpyrido[3,2-d]pyrimidine-6-
(300 MHz, DMSO-d6) δH 1.28 (t, J = 6.9 Hz, 6H), 2.63 (s, 3H), 3.87
(s, 3H), 3.92 (q, J = 6.4 Hz, 4H), 7.42 (s, 1H), 7.51−7.63 (m, 3H),
8.28−8.31 (m, 2H); 13C NMR (75.47 MHz, DMSO-d6) δC 12.7, 13.9,
46.4, 52.6, 107.7, 127.7, 130.6, 131.6, 136.0, 137.0, 141.7, 146.4, 149.4,
164.4, 165.5, 166.3, HPLC tR = 4.64 min; ES-MS m/z 383.3 (M + H)+.
Anal. Calcd for C20H22N4O2S: C, 62.81; H, 5.80; N, 14.65. Found: C,
62.68; H, 5.47; N, 14.81.
carboxylic acid methyl ester (12c): yield = 12%; pale yellow solid;
1
mp 150.8−151.8 °C; IR νmax 1719, 1430, 1244, 1139; H NMR (300
MHz, DMSO-d6) δH 4.04 (s, 3H), 4.62 (s, 2H), 7.23−7.35 (m, 3H),
7.51−7.61 (m, 5H), 8.48−8.52 (m, 2H), 8.55 (s, 1H); 13C NMR
(75.47 MHz, DMSO-d6) δC 36.1, 53.4, 127.4, 128.0, 128.3, 128.5,
129.3, 131.8 132.3, 134.8, 137.0, 137.5, 143.4, 145.9, 146.2, 164.3,
166.9, 167.2, 169.1, 171.6; HPLC tR = 5.87 min; ES-MS m/z 422.1
(M + H)+. Anal. Calcd for C22H16ClN3O2S: C, 62.63; H, 3.82; N, 9.96;
Cl, 8.40. Found: C, 62.55; H, 3.83; N, 10.00; Cl, 8.39.
General Procedure for Synthesis of Derivatives 14. A solution
of boronic acid derivative (0.24 mmol), derivative 11 (0.24 mmol),
cesium carbonate (234.6 mg, 0.72 mmol), and Pd(PPh3)4 (11.5 mg,
0.01 mmol) in dioxane (2.0 mL) was heated at 90 °C for 3.5 h under
inert atmosphere. DCM (15 mL) was added to the reaction mixture,
and the mixture was washed with water (10 mL) and brine (10 mL),
dried over Na2SO4, and filtered on Celite. The solvents were removed
under vacuum at 40 °C. The resulting was suspended in MeOH,
filtered, washed twice with MeOH and once with diethyl ether, and
dried under suction to afford derivative 14 as a solid.
2-Methylsulfanyl-4-(4-phenyl)-8-methoxyphenylpyrido[3,2-d]-
pyrimidine-6-carboxylic acid methyl ester (14a): yield = 75%; yellow
solid; mp 168−170 °C; IR νmax 2924, 2845, 1745, 1529, 1256,
1112 cm−1; 1H NMR (400 MHz, CDCl3) δH 2.65 (s, 3H), 3.93
(s, 3H), 4.05 (s, 3H), 7.09−7.06 (d, J = 6.9 Hz, 2H), 7.59−7.57
(m, 3H), 7.94−7.92 (d, J = 6.8 Hz, 2H), 8.50 (s, 1H), 8.56−8.53
(m, 2H); 13C NMR (400 MHz, CDCl3) δC 14.8, 53.1, 55.4, 113.7,
126.5, 127.5, 128.2, 131.3, 132.0, 132.3, 135.4, 136.9, 146.2, 146.2,
146.7, 160.6, 165.3, 167.1, 170.7; HPLC tR = 5.99 min; ES-MS m/z
418 (M + H)+. Anal. Calcd for C23H19N3O3S: C, 66.17; H, 4.59; N,
10.07. Found: C, 66.21; H, 4.63; N, 10.04.
2-Methylsulfanyl-4-(4-methoxyphenyl)-8-phenylpyrido[3,2-d]-
pyrimidine-6-carboxylic acid methyl ester (14b): yield = 82%; yellow
solid; mp 226.0−227.0 °C; IR νmax 1118, 1242, 1439, 1527, 1714, 2361
cm−1; 1H NMR (300 MHz, CDCl3) δH 2.59 (s, 3H), 3.92 (s, 3H), 4.06
(s, 3H), 7.07 (m, 2H), 7.49−7.55 (m, 3H), 7.88−7.91 (m, 2H), 8.49
(s, 1H), 8.70 (m, 2H); 13C NMR (75.47 MHz, CDCl3) δC 14.7, 53.2,
55.5, 113.8, 127.1, 128.0, 128.1, 129.2, 130.6, 134.4, 135.4, 137.0,
145.8, 146.6, 147.0, 162.6, 165.3, 165.8, 170.8; HPLC tR = 5.77 min;
ES-MS m/z 418.30 (M + H)+. Anal. Calcd for C23H19N3O3S: C, 66.17;
H, 4.59; N, 10.06. Found: C, 65.89; H, 4.49; N, 9.80.
General Procedure for SNAr with Sodium Methylthiolate on
Derivatives 7c and 7d. To a solution of derivative 7 (0.21 mmol) in
THF (2.0 mL) was added sodium methylthiolate (14.7 mg, 0.21 mmol).
The reaction mixture was stirred at −10 °C for 4 h. After removal of the
solvents under vacuum, the residue was dissolved in a 1:1 mixture of
DMSO and water (1 mL) and was purified by mass-directed autopuri-
fication system. Derivatives 11d and 11e were isolated.
2-Methylsulfanyl-4-phenyl-8-chloropyrido[3,2-d]pyrimidine-6-
carboxylic acid methyl ester (11d): yield = 60%; beige solid; mp
1
165−166 °C; IR νmax 1721, 1531, 1251 cm−1; H NMR (300 MHz,
CDCl3) δH 2.78 (s, 3H), 4.05 (s, 3H), 7.56−7.58 (m, 3H), 8.52−8.55
(m, 3H); 13C NMR (75.47 MHz, CDCl3) δC 15.3, 53.8, 128.3, 128.7,
132.2, 132.7, 135.2, 137.2, 143.7, 146.2, 146.6, 164.7, 167.2, 173.0;
HPLC tR = 5.16 min; ES-MS m/z 345.99 (M + H)+. Anal. Calcd for
C16H12ClN3O2S: C, 55.57; H, 3.50; N, 12.15. Found: C, 55.15; H,
3.57; N, 11.85.
2-Methylsulfanyl-4-(4-methoxyphenyl)-8-chloropyrido[3,2-d]-
pyrimidine-6-carboxylic acid methyl ester (11e): yield = 57%; yellow
solid; mp 197−198; °C; IR νmax 2821, 1722, 1525 cm−1; 1H NMR
(300 MHz, DMSO-d6), δH 2.77 (s, 3H), 3.92 (s, 3H), 4.05 (s, 3H),
7.06−7.09 (m, 2H), 8.52 (s, 1H), 8.68−8.72 (m, 2H); 13C NMR
(75.47 MHz, DMSO-d6), δC 14.9, 53.4, 55.5, 113.9, 127.4,
127.7, 134.5, 136.9, 143.2, 145.3, 146.2, 162.9, 164.3, 165.4, 172.4;
HPLC tR = 5.15 min; ES-MS m/z 376.0 (M + H)+; HRMS (ESI) m/z
calcd for C17H14ClN3O3S [M + 1]+ 376.0517, found 376.0523. Anal.
Calcd for C17H14ClN3O3S·0.26H2O: C, 53.66; H, 3.85; N, 11.04; Cl,
9.32. Found: C, 53.93; H, 3.75; N, 10.64; Cl, 9.59.
General Procedure for Synthesis of Derivative 13. To a
solution of 11d (100 mg, 0.29 mmol) in MeCN (4 mL) was added the
amine (1.44 mmol) in presence of Hunig’s base (0.151 mL, 0.87 mmol).
The reaction was heated at 90 °C for 2 h. Solvents were removed
General Procedure for Synthesis of Derivatives 15 and 16.
Boronic acid derivative (0.21 mmol), derivative 13a, 13c, or 14a,b
̈
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(0.14 mmol), copper(I) thiophene-2-carboxylate (40.0 mg, 0.21 mmol),
and Pd(PPh3)4 (23.1 mg, 0.02 mmol) were added to dioxane (3.0 mL)
under inert atmosphere. The reaction was stirred at 90 °C. After 3.5 h,
NaHCO3 saturated solution (10 mL) was added, and the resulting
mixture was extracted with DCM (2 × 15 mL). Combined organic
layers were washed with brine (15 mL), dried over Na2SO4, and
filtered through Celite. After having removed solvents under vacuum
at 40 °C, the resulting solid was triturated in MeOH, filtered, and dried
under vacuum to afford derivatives 15 and 16.
8-Benzylamino-2-(4-chlorophenyl)-4-phenylpyrido[3,2-d]-
pyrimidine-6-carboxylic acid methyl ester (15a). yield = 71%; pale
yellow solid; mp 210−212 °C; IR νmax 3388, 3051, 1719, 1531, 1241
cm−1; 1H NMR (400 MHz, CDCl3) δH 4.01 (s, 3H), 4.73−4.71 (d, J =
5.9 Hz, 2H), 7.24−7.20 (t, J = 7.4 Hz, 1H), 7.41−7.35 (m, 1H), 7.45−
7.42 (m, 4H), 7.52−7.49 (m, 3H), 7.61−7.57 (m, 3H), 8.63−8.60
(m, 2H), 8.75−8.72 (m, 2H); 13C NMR (400 MHz, CDCl3) δC 46.9,
53.0, 102.4, 127.3, 127.9, 128.2, 128.8, 129.0, 130.0, 131.1, 132.1,
135.9, 136.2, 136.4, 136.9, 137.1, 139.8, 148.6, 150.5, 158.0, 166.1,
166.1; HPLC tR = 6.68 min; ES-MS m/z 481 (M + H)+. Anal. Calcd
for C28H21ClN4O2: C, 69.92; H, 4.40; N, 11.65. Found: C, 69.93; H,
4.48; N, 11.49.
2-(4-Chlorophenyl)-8-diethylamino-4-phenylpyrido[3,2-d]-
pyrimidine-6-carboxylic acid methyl ester (15b): yield = 76%; yellow
solid; mp 183−185 °C; IR νmax 2953, 2925, 1746, 1536, 1117 cm−1;
1H NMR (400 MHz, CDCl3) δH 1.49−1.45 (t, J = 6.9 Hz, 6H), 4.03
(s, 3H), 4.09−4.05 (m, 4H), 7.51−7.49 (d, J = 8.6 Hz, 2H), 7.57−7.50
(m, 4H), 8.55−8.53 (d, J = 8.48 Hz, 2H), 8.63−8.61 (m, 2H); 13C
NMR (400 MHz, CDCl3) δC 12.8, 47.2, 53.0, 107.5, 128.0, 128.7,
129.7, 130.6, 132.1, 136.5, 136.7, 137.0, 138.7, 142.0, 147.5, 151.3,
156.2, 166.5, 166.9; HPLC tR = 6.02 min; ES-MS m/z 447 (M + H)+.
Anal. Calcd for C25H23ClN4O2: C, 67.18; H, 5.19; N, 12.54. Found: C,
67.19; H, 5.21; N, 12.49
2-(4-Chlorophenyl)-8-(4-methoxyphenyl)-4-phenylpyrido[3,2-d]-
pyrimidine-6-carboxylic acid methyl ester (16a). yield = 80%; yellow
solid; mp 236−239 °C; IR νmax 3060, 2955, 1726, 1250 cm−1;
1H NMR (400 MHz, CDCl3) δH 3.98 (s, 3H), 4.10 (s, 3H), 7.17−7.5
(d, J = 8.7 Hz, 2H), 7.52−7.50 (d, J = 8.6 Hz, 2H), 7.65−7.64
(m, 3H), 8.01−7.99 (d, J = 8.7 Hz, 2H), 8.58 (s, 1H), 8.65−8.62
(d, J = 8.6 Hz, 2H), 8.71−8.69 (m, 2H) ; 13C NMR (400 MHz,
CDCl3) δC 53.2, 55.4, 113.8, 126.2, 127.7, 128.2, 128.9, 130.4, 131.2,
132.3, 132.4, 136.0, 136.2, 137.5, 137.8, 146.8, 147.6, 148.4, 160.2,
160.8, 165.3, 167.4; HPLC tR = 6.97 min; ES-MS m/z 482.0
(M + H)+. Anal. Calcd for C28H20ClN3O3: C, 69.78; H, 4.18; N, 8.72.
Found: C, 69.82; H, 4.22; N, 8.60.
2-(4-Chlorophenyl)-4-(4-methoxyphenyl)-8-phenylpyrido[3,2-d]-
pyrimidine-6-carboxylic acid methyl ester (16b): yield = 69%; yellow
solid; mp 217−219 °C; IR νmax 2949, 2921, 1716, 1536, 1252, cm−1;
1H NMR (400 MHz, CDCl3) δH 3.96 (s, 3H), 4.10 (s, 3H), 7.16−7.14
(d, J = 7.0 Hz, 2H), 7.49−7.47 (d, J = 6.9 Hz, 2H), 7.64−7.58
(m, 3H), 7.98−7.95 (m, 2H), 8.57 (s, 1H), 8.61−8.58 (d, J = 6.8 Hz,
2H), 8.85−8.83 (d, J = 7.0 Hz, 2H) ; 13C NMR (400 MHz, CDCl3) δC
53.2, 55.4, 113.8, 126.8, 128.2, 128.7, 128.8, 129.3, 130.4, 130.8, 134.3,
135.5, 136.1, 137.4, 137.7, 146.7, 147.1, 148.8, 160.3, 162.5, 165.2,
166.2; HPLC tR = 7.06 min; ES-MS m/z 482.2 (M + H)+. Anal. Calcd
for C28H20ClN3O3: C, 69.78; H, 4.18; N, 8.72. Found: C, 69.85; H,
4.28; N, 8.61.
ACKNOWLEDGMENTS
■
We thank Prof. Lanny Liebeskind from Emory University as
well as Prof. Jer me Lacour, Prof. Alexandre Alexakis from
́ ̂
o
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 the manuscript.
REFERENCES
■
(1) Pozharskii, A. F.; Soldatenkov, A. T.; Katrizky, A. R. Heterocycles
in Life and Society; Wiley: New York, 1997.
(2) Lipinski, C.; Hopkins, A. Nature 2004, 432, 855−861.
(3) Bouscary-Desforges, G.; Bombrun, A.; Augustine, J. K.;
Bernardinelli, G.; Quattropani, A. J. Org. Chem. 2012, 77, 243−252.
(4) Irwin, W. J.; Wibberly, D. G. J. Chem. Soc. C 1967, 1745−1750.
(5) Srinivasan, A.; Broom, A. D. J. Org. Chem. 1979, 44, 435−440.
(6) (a) Katritzky, A. R.; Ramsden, C. A.; Joule, J. A.; Zhdankin, V. V.
Handbook of Heterocyclic Chemistry, 3rd ed.; Elsevier: New York, 2010.
(b) Crampton, M. R. Organic Reaction Mechanisms−2006; Wiley: New
York, 2010; pp 175−186.
(7) Schroter, S.; Stock., C.; Bach, T. Tetrahedron 2005, 61, 2245−
̈
2267.
(8) Compound 3a was obtained from a commercial source;
compound 3b was synthesized according to the literature procedure
reported in: Green, N. J.; Xiang, J.; Chen, J.; Chen, L.; Davies, A. M.;
Erbe, D.; Tama, S.; Tobinb, J. F. Bioorg. Med. Chem. 2003, 11, 2991−
3013.
(9) Kappe, C. O.; Stadler, A. Microwaves in Organic and Medicinal
Chemistry; Wiley-VCH: Weinheim, 2005.
(10) Suzuki cross-coupling reaction was attempted to introduce
selectively a phenyl group at the C-4 position to derivative 1c. Multiple
combinations of solvents (DME/H2O/TBAB, dioxane/MeOH, or
pure dioxane), bases (K2CO3 or Cs2CO3), and catalysts (Pd(PPh3)4 or
Pd(OAc)2 with 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride as
ligand) were tried. Unfortunately, all combinations yielded a mixture
of byproducts, such as chlorine hydrolysis or multiple-coupling
product, in addition to 7c (if present). For derivatives 1a and 1b,
the use of Pd(PPh3)4 as catalyst and K2CO3 as base in toluene at 100
°C yielded only 21 and 27% conversion, respectively. These same
reaction conditions applied to 1c yielded a mixture of mono- and
multiple cross-coupling products (unpublished results). Stille cross-
coupling reaction was used for 1c arylation. With Pd(OAc)2 as catalyst
and 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride as ligand, only
traces of 7c were formed, contaminated with several byproducts, such
as multiple cross-coupling products and diverse chlorine hydrolysis
products (unpublished results).
́
(11) (a) Tikad, A.; Routier, S.; Akssira, M.; Leger, J.-M.; Jarry, C.;
Guillaumet, G. Synthesis 2009, 2379−2384. (b) Tikad, A.; Routier, S.;
Akssira, M.; Guillaumet, G. Org. Biomol. Chem. 2009, 7, 5113−5118.
(c) Tikad, A.; Routier, S.; Akssira, M.; Leger, J.-M.; Jarry, C.;
Guillaumet, G. Org. Lett. 2007, 9, 4673−4676. (d) Tikad, A.; Routier,
S.; Akssira, M.; Leger, J.-M.; Jarry, C.; Guillaumet, G. Synlett 2006,
1938−1942.
ASSOCIATED CONTENT
■
(12) (a) Liebeskind, L. S.; Srogl, J. Org. Lett. 2002, 4, 979−981.
(b) Alphonse, F.-A.; Suzenet, F.; Keromnes, A.; Lebret, B.; Guillaumet,
G. Synlett 2002, 447−450.
(13) Addition of sodium methylthiolate to scaffold 1 at rt in THF
gave a mixture of mono, bis, and tris methylsulfanyl addition products
(unpublished results).
(14) The use of microwave irradiation in Liebeskind−Srogl cross-
coupling reactions was already reported: Lengar, A.; Kappe, C. O. Org.
Lett. 2004, 6, 771−774.
(15) Kusturin, C.; Liebeskind, L. S.; Rahman, H.; Sample, K.;
Schweitzer, B.; Srogl, J.; Neumann, W. L. Org. Lett. 2003, 5, 4349−
4352.
S
* Supporting Information
1H and 13C NMR spectra of the synthesized compounds and
ORTEP representation and cif file of 13b. 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.
Notes
The authors declare no competing financial interest.
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The Journal of Organic Chemistry
Article
(16) (a) Cho, K.; Ando, M.; Kobayashi, K.; Miyazoe, H.; Tsujino, T.;
Ito, S.; Suzuki, T.; Tanaka, T.; Tokita, S.; Sato, N. Bioorg. Med. Chem.
Lett. 2009, 19, 4781−4785. (b) Jones, R. V.; Godorhazy, L.; Varga, N.;
Szalay, D.; Urge, L.; Darvas, F. J. Comb. Chem. 2006, 8, 110−116.
(17) Semiempirical calculations of 7a−c; minimization, followed by
conformational search (60° steps) around five rotatable bonds (i.e.,
7776 points each) using MM3. All local minima (94 and 106,
respectively) extracted and minimized with PM5. All calculations done
with Scigress Explorer 7.7 (Fujitsu Ltd.).
7
C-2 partial C-2 LUMO C-8 partial C-8 LUMO
charge
0.124
0.125
0.135
density
0.06
0.072
0.101
charge
0.024
0.019
0.002
density
0.149
0.15
7a
7b
7c
0.15
(18) Comparison between (Table 7, entry 3) and (Table 3, entry 1)
of ref 3.
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dx.doi.org/10.1021/jo300189q | J. Org. Chem. 2012, 77, 4586−4595