Development of synthetic strategies for the construction of pyrido[4,3-d]-pyrimidine libraries - The discovery of a new class of PDE-4 inhibitors

Article abstract of DOI:10.1002/ejoc.200600339

The synthesis of a pyrido[4,3-d]pyrimidine library from 4,6-diamino-2-bromonicotinamide and 4,6-diaminonicotinamide is described. A systematic variation of the substituents at positions 2, 4, 5 and 7 of the pyrido[4,3-d]pyrimidine scaffold was carried out

Full text of DOI:10.1002/ejoc.200600339

FULL PAPER
DOI: 10.1002/ejoc.200600339
Development of Synthetic Strategies for the Construction of Pyrido[4,3-d]-
pyrimidine Libraries – the Discovery of a New Class of PDE-4 Inhibitors
Mi-Yeon Jang,[a] Steven De Jonghe,[b] Ling-Jie Gao,[b] Jef Rozenski,[a] and
Piet Herdewijn*[a]
Keywords: Medicinal chemistry / Nitrogen heterocycles / Combinatorial chemistry
The synthesis of a pyrido[4,3-d]pyrimidine library from 4,6-
diamino-2-bromonicotinamide and 4,6-diaminonicotinamide
is described. A systematic variation of the substituents at po-
sitions 2, 4, 5 and 7 of the pyrido[4,3-d]pyrimidine scaffold
was carried out, leading to a wide variety of structural ana-
logues. This strategy led to the discovery of a new structural
class of PDE-4 inhibitors.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
ies. Combinatorial chemistry can be carried out on a solid
support or in solution. Although solid-phase chemistry de-
finitively has some advantages (mainly related to purifica-
tion), we opted for the construction of libraries with the
solution-phase approach. The synthetic schemes described
in the literature for the preparation of pyrido[4,3-d]pyrimi-
dine analogues allow structural variety to be introduced in
only one or two particular positions of the scaffold.[4] To
the best of our knowledge, no systematic studies have been
done on how to elaborate, in a systematic way, the chemis-
try of this compound class. Therefore, the main goal of this
paper is to develop synthetic schemes that can be easily
adapted for use in parallel chemistry, and hence, are suitable
to establish SAR studies. In that respect, we have attempted
to introduce a broad structural variety into the pyrido[4,3-
d]pyrimidine scaffold in which three or more substitution
sites can be varied in one synthetic cycle.
Introduction
Bicyclic heterocycles (such as purines,[1] quinazolines[2]
and pyrido[2,3-d]pyrimidines[3]) are well-known pharmac-
ophores in drug discovery. Examples of marketed drugs
(Figure 1) with a bicyclic core structure include gefitinib (a
quinazoline analogue used for the treatment of non-small-
cell lung cancer), prazosine (an α1-antagonist based on a
quinazoline scaffold, used as a antihypertensive and for the
treatment of benign prostate hypertrophy), theophylline (a
purine analogue used for the treatment of asthma), and tri-
amterene (a pteridine derivative, used for the treatment of
hypertension).
As part of an ongoing medicinal chemistry research pro-
gram to discover anti-inflammatory agents based on TNF-
α inhibition, we became very interested in the synthesis of
pyrido[4,3-d]pyrimidine analogues (Figure 2). These types
of compounds possess five possible substitution sites (R2,
R4, R5, R7, and R8), which means that the number and
combination of substituents that ultimately can lead to a
drug is very high. Therefore, there is a clear need for syn-
thetic schemes that can be used for rapidly exploring the
structure–activity relationship (SAR) of the pyrido[4,3-d]-
pyrimidine scaffold with respect to a well-defined biological
target.
Results and Discussion
Chemistry
It was envisioned that 4,6-diamino-2-bromo-3-cyanopyr-
idine (2) could act as a versatile starting material for the
synthesis of pyrido[4,3-d]pyrimidine libraries. The bromine
atom on the pyridine ring offers the possibility of per-
forming nucleophilic aromatic substitutions as well as Pd-
catalyzed cross coupling reactions to construct C–O, C–N,
C–S and C–C bonds.[5] Moreover, the bromine atom can be
reduced off by catalytic hydrogenation to gain access to 5-
unsubstituted compounds. In this respect, compound 2 was
prepared from malonitrile according to a published patent
procedure.[6]
Combinatorial and parallel chemistry are powerful tools
for medicinal chemists in drug discovery programs. It has
encouraged chemists to work out synthetic strategies and
approaches that can be used for the construction of librar-
[a] REGA Institute, Laboratory for Medicinal Chemistry,
Minderbroedersstraat 10, 3000 Leuven, Belgium
Fax: +32-16-33-73-40
E-mail: piet.herdewijn@rega.kuleuven.be
[b] 4AZA Bioscience, Department of Medicinal Chemistry,
Kapucijnenvoer 33, 3000 Leuven, Belgium
Nicotinamide 3 was synthesized from 4,6-diamino-2-
bromo-3-cyanopyridine (2) by direct hydrolysis of the nitrile
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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Figure 1. Structures of marketed bicyclic drugs.
Nicotinamides 3 and 5 are both valuable starting materi-
als for the construction of the pyrido[4,3-d]pyrimidin-
4(3H)-one scaffold (Scheme 2). Within this context, both
nicotinamides were treated with a set of orthoesters to form
the pyrimidine ring (Entries 1–2 and 4–5 of Table 1). In this
way, hydrogen atoms and methyl groups could be intro-
duced at position 2 of the scaffold. Unfortunately, the
Figure 2. Pyrido[4,3-d]pyrimidine scaffold.
group to form the corresponding carboxamide by treatment number of commercially available orthoesters is limited. Al-
with hydrogen peroxide under aqueous alkaline condi- ternative strategies to introduce structural variety at posi-
tions.[7] Alternatively, 5-unsubstituted compounds could be tion 2 of the pyrido[4,3-d]pyrimidine were considered. An
obtained by hydrogenolysis of compound 2 with 10% Pd/C obvious choice was to effect the ring closure reaction with
in a mixture of THF and MeOH, yielding compound 4, acid chlorides, as a wide range of these building blocks is
which was converted into the corresponding amide 5 with commercially available. As a representative example, we
concentrated sulfuric acid (Scheme 1).[6]
tried a condensation of pyridine analogue 3 with meth-
Scheme 1. Synthesis of nicotinamides 3 and 5. a) HBr (g), 0 °C, 2 h, toluene, then 100 °C, 2 h; b) 10% Pd/C, H2, KOAc, THF/MeOH
(2:1), room temp., 4 h; c) H2O2, NaOH, DMSO, 50 °C, 1 d; d) 90% H2SO4, 80 °C, 3 h.
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Table 1. Synthesis of the pyrido[4,3-d]pyrimidin-4(3H)-one scaffold.
oxyacetyl chloride (Table 1, Entry 3), and the transforma- desired compounds 8a–b in good yields. Methods to pre-
tion consisted of a two-step, one-pot procedure.[8] In the pare alkenylboronic acids from the corresponding acetyl-
first step, the exocyclic amino group was coupled with the enes are well known in the literature,[11] and therefore, this
acid chloride in a mixture of DMF and pyridine. Once the methodology provides a powerful tool to construct double-
amide was formed (which was indicated by a new TLC spot bond-containing analogues.
Sonogashira coupling[12] of 6d with commercially avail-
with a higher Rf value), the formation of the pyrimidine
ring was effected under aqueous alkaline conditions. This
procedure can be easily adopted to a wide range of acid
chlorides, and should make it possible to fully explore
SARs at position 2.
able phenylacetylene did not lead to the formation of the
expected alkyne derivative. Careful analysis of the 13C
NMR spectrum did not reveal any 13C signals between δ
= 70 and 90 ppm, indicating the absence of a triple bond.
1
Moreover, in the H NMR spectrum, three singlets were
observed. If the desired compound had been formed, only
two singlets should be present (from the protons at posi-
tions 2 and 8). The third signal indicated the presence of an
alkene moiety. Therefore, we concluded that a tricyclic by-
product 9a was isolated in 48% yield. These types of side
reactions have been previously observed in the Pd-catalyzed
coupling of terminal alkynes with 5-iodopyrimidine nucleo-
sides, yielding nucleoside analogues with a fluorescent fu-
rano-pyrimidine base and potent antiviral activity.[13] Like-
wise, in our case, the isolated side product had fluorescent
properties according to TLC, which suggested the forma-
tion of compound 9a. As this compound showed interesting
biological activity, we prepared a number of new tricyclic
analogues 9b–9f with commercially available acetylene de-
rivatives. When trimethylsilylacetylene was used as the
coupling partner, in situ deprotection of the silyl group was
observed (Table 3). For the synthesis of compound 9a (En-
try 1), a copper-free version of the Sonogashira reaction
was performed.[14] This might be important for industrial
applications, as copper is very tedious to recycle.
Scheme 2. Synthesis of the pyrido[4,3-d]pyrimidin-4(3H)-one scaf-
fold. a) Triethyl orthoformate, 140 °C, 24 h; b) triethyl orthoace-
tate, 140 °C, 24 h; c) methoxyacetyl chloride, pyridine, DMF, room
temp., 3 h, then 5  NaOH, room temp., 24 h.
The bromine atom at position 5 can act as a versatile
starting material functionality for a wide variety of Pd-cata-
lyzed cross coupling reactions to form new C–C bonds (e.g.
Suzuki, Heck and Sonogashira reactions). Standard reac-
tion conditions were used for the Suzuki coupling of com-
pound 6d with a number of (heteroaryl)boronic acids. The
use of tetrakis(triphenylphosphane)palladium(0) as cata-
lyst, aqueous potassium carbonate as base and 1,4-dioxane
as solvent yielded the desired biaryl compounds 7a–e in
good yields (Scheme 3, reaction a).[9] Table 2 gives an over-
view of the compounds synthesized by this procedure.
As the bromine atom is part of a vinylogous acid bro-
mide, it was anticipated that it would undergo substitution
In order to introduce a number of alkenyl substituents, a reactions easily. To that end, the bromine atom at position
Heck reaction was performed with methyl acrylate under 5 of the pyrido[4,3-d]pyrimidine scaffold was subjected to a
standard reaction conditions.[10] However, none of the de- number of nucleophilic aromatic substitutions in order to
sired alkenyl compounds could be isolated. Alternatively, exchange the bromine atom for a nucleophile [e.g. morph-
alkenyl substituents can be introduced with commercially oline, aniline, n-butylamine and (2-thienylmethyl)amine].
available alkenylboronic acids {e.g. [(E)-2-phenylvinyl]- However, it seemed very difficult to displace the bromine
boronic acid and [(E)-1-propenyl]boronic acid}, yielding the atom, as only starting material could be recovered. The
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Scheme 3. a) Boronic acid, K2CO3, Pd(PPh3)4, dioxane/H2O (3:1), reflux, 2 h; b) alkyne, (PPh3)2Pd(OAc)2, CuI, triethylamine, DMF, 60–
70 °C, 3 h–1 d; c) boronic acid, K2CO3, Pd(PPh3)4, dioxane/H2O (3:1), reflux, 2 h; d) n-butylamine, KOtBu, Pd(PPh)4, dioxane, reflux,
1 d.
Table 2. Suzuki reactions of compounds 6d and 6e.
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Table 3. Sonogashira reactions of compounds 6d and 6e.
weak leaving-group capacity of the bromine atom might be well known in the nucleoside field,[16] but, to the best of our
attributed to the electron-donating effect of the amino knowledge, has never been applied in pyrido[4,3-d]pyrimi-
group at position 7. Since SNAr was cumbersome, we dine chemistry. Therefore, compound 6a was heated in
switched our attention to Pd-catalyzed chemistry, as in re- 5 equiv. of 1,1,1,3,3,3-hexamethyldisilazane (HMDS) and
cent years plenty of research had been done to construct C– an appropriate amine with ammonium sulfate as catalyst.[17]
N bonds.[15] n-Butylamine could be introduced at position 5 The reaction turned out to be successful only for primary
by subjecting compound 6d to Buchwald–Hartwig reaction amines, such as benzylamine and (2-thienylmethyl)amine,
conditions with n-butylamine, potassium tert-butoxide as a yielding the final compounds 11a–b.
strong base and tetrakis(triphenylphosphane)palladium(0)
As the silylation/amination approach seemed to be re-
as a catalyst, yielding compound 10 (Scheme 3, reaction d). stricted to primary amines, we have been investigating two-
In order to introduce structural variety at position 4, se- step procedures in which a good leaving group was first
veral possibilities were considered (Scheme 4). The easiest introduced at position 4 and then be exchanged for nucleo-
and fastest approach to introduce nucleophiles at position philes in a second step. The carbonyl group at position 4 of
4 would be a one-step procedure. This was possible through compound 6a was activated as its 4-thio counterpart (see
silylation/amination of the lactam moiety. This method is compound 12) by heating with phosphorus pentasulfide in
Scheme 4. a) 1,1,1,3,3,3-Hexamethyldisilazane, amine, ammonium sulfate, 120 °C, 1–3 d; b) phosphorus pentasulfide, pyridine, reflux,
5 h; c) MeI, triethylamine, DMSO, room temp., 12 h; d) morpholine, ethanol, reflux, 24 h.
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pyridine, followed by methylation with iodomethane under 6b was protected as an acetyl group by reaction with acetic
alkaline conditions.[6] The thiomethyl group of compound anhydride in pyridine (Scheme 5). Introduction of the 1,2,4-
13 can be exchanged for morpholine (as a representative for triazole group was achieved by reaction of compound 15
a wide range of nucleophiles), affording the final compound with POCl3, triethylamine and 1,2,4-triazole in a mixture of
14. In case of less reactive nucleophiles (e.g. aniline), it acetonitrile and dichloromethane. The triazole group
might be anticipated that it would be necessary to oxidize seemed to be sufficiently reactive to be displaced by a
the thiomethyl group to the corresponding sulfoxide or sul- number of neutral alcohols (even without preparing first
fone prior to a nucleophilic displacement reaction.
the sodium alkoxides from the corresponding alcohols by
Alternatively, activation of the 4-oxo group for nucleo- treatment with sodium or sodium hydride). Therefore, treat-
philic displacement reactions as a 1,2,4-triazole is a well- ment of compound 16 with a number of neutral alcohols
known procedure to convert uridine into cytidine.[18] It has (either in the alcohol itself or in DMF as solvent) yielded
also been applied to activate position 4 of pyrido[2,3-d]pyr- compounds 17a–e, which could easily be purified by silica
imidines for nucleophilic displacement reactions.[19] How- gel column chromatography (Table 4). Compound 15 was
ever, this methodology has never been applied to pyr- also used as a starting material for the one-step silylation/
ido[4,3-d]pyrimidines. Prior to introduction of the 1,2,4-tri- amination approach (as described in Scheme 4) with (2-
azole at position 4, the exocyclic amino group of compound methoxyethyl)amine and (3-methoxypropyl)amine as nu-
Scheme 5. a) Acetic anhydride, pyridine, reflux, 30 min; b) phosphorus oxychloride, triethylamine, 1,2,4-triazole, CH3CN/CH2Cl2 (2:1),
room temp., 24 h; c) alcohol, reflux, 12 h; d) alcohol, K2CO3, DMF, 120 °C, 6–12 h; e) 1,1,1,3,3,3-hexamethyldisilazane, amine, ammo-
nium sulfate, 120 °C, 2 d.
Table 4. Synthesis of 4-alkoxypyrido[4,3-d]pyrimidine analogues.
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cleophiles. The vigorous reaction conditions led to cleavage
of the acetyl group, affording compounds 18a–b
(Scheme 5).
Regioselective N-alkylation of the lactam moiety of the
pyrimidine ring could easily be achieved by stirring the re-
action mixtures under alkaline conditions in DMF
(Scheme 6).[20] Potassium carbonate as a base seemed to
work better than sodium hydride (Table 5, Entries 1 and 2).
Therefore, for the synthesis of compounds 20–24, potas-
Scheme 6. a) Alkyl halide, NaH, DMF, 60–80 °C, 3 h; b) alkyl ha-
lide, K2CO3, DMF, room temp., 24 h; c) alkyl halide, K2CO3,
DMF, 80 °C, 24 h.
sium carbonate was used as a base and the desired com- a compound in 68% yield, the 1H NMR spectrum of which
pounds could be isolated in good yields (see Table 5). In was identical with that of compound 24, indicating that a
order to prove that selective N-alkylation was obtained, Mitsunobu reaction on this class of heterocycle leads pref-
compound 24 was prepared. The corresponding 4-methoxy erentially to N-alkylation.
derivative 17a had been prepared before through the 1,2,4-
The aniline group at position 7 can be converted into
triazole approach. Comparison of the 1H NMR spectro- halogens by a diazotization procedure. A chlorine or bro-
scopic data of derivatives 17a and 24 showed that the meth- mine atom would be a useful starting material functionality
oxy signals appeared at δ = 4.18 ppm, whereas the methyl- for further Pd-catalyzed cross coupling reactions. On the
amino signals of compound 24 appeared at δ = 3.61 ppm. other hand, a fluorine atom on an aromatic ring can easily
The downfield shift of the signal of the methyl protons of be displaced by a wide variety of nucleophiles.
17a to a lower field is in complete accordance with the pres-
As a representative example, compound 7e was treated
ence of a methoxy group.
with sodium nitrite and tetrafluoroboric acid to give the
An alternative approach for alkylation is a Mitsunobu diazonium fluoroborate salt, which was converted into the
reaction.[21] Mitsunobu reactions have the disadvantage of 7-fluoro compound 25 in situ (Schiemann reaction).[6] In
leading to mixtures of O- and N-alkylated products, and diethyl ether as solvent, no reaction took place, probably
the outcome is sometimes difficult to predict. Treatment of because of the poor solubility of compound 7e. Therefore,
compound 15 with triphenylphosphane, diisopropyl azo- we switched to a mixture of diethyl ether, DMF and water.
dicarboxylate (DIAD) and methanol in dioxane furnished In this case, the fluoro compound could be isolated by flash
Table 5. N-Alkylation of pyrido[4,3-d]pyrimidin-4(3H)-one analogues.
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Scheme 7. a) 60% HBF4, NaNO2, DMF, 0 °C to room temp., 3 h; b) NaH, ROH, reflux, 4 h.
Scheme 8. a) 6  HCl, CuCl, NaNO2, –15 °C to room temp., 1 h then 60 °C, 1 h; b) (3,4-dimethoxyphenyl)boronic acid, K2CO3, Pd-
(PPh3)4, dioxane/H2O (3:1), reflux, 2 h.
chromatography on silica in fairly good yields. Nucleophilic cytes, stimulated by a bacterial lipopolysacharide (LPS).[23]
substitution of the fluorine atom by sodium alkoxides fur- None of the compounds was able to block the production
nished the final compounds 26a–b (Scheme 7).
of TNF-α, as they all displayed an IC50 Ͼ 10 µ. Interest-
In order to introduce a chlorine atom at position 7, com- ingly, the side products (compounds 9a–9f) isolated from
pound 14 was chosen as a representative example. Diazoti- the Sonogashira coupling showed biological activity
zation of 14 in 6  HCl with sodium nitrite, followed by (Table 6). The most active compounds contained either a
decomposition of the diazonium salt with cuprous chloride phenyl (compound 9a) or a cyclohexene (compound 9b)
(Sandmeyer reaction) gave access to the 7-chloro derivative ring. Introduction of a heteroaromatic ring (such as the
27 in a low yield (34%).[6,19] Sufficient material could be imidazole-containing compound 9c) led to a 10-fold loss
isolated to conduct a Suzuki-type reaction with (3,4-di- in activity. The unsubstituted compound 9f completely lost
methoxphenyl)boronic acid, leading to the formation of biological activity, and compounds containing more polar
compound 28 (Scheme 8). However, the low yield of the substituents [such as (dimethylamino)methyl in 9e and hy-
Sandmeyer reaction prevents us from using this approach droxymethyl in 9d] were devoid of biological activity, indi-
for parallel chemistry purposes, and studies are currently cating that a neutral and rather large substituent was neces-
conducted in order to obtain easier access to 7-chloro-sub- sary in order to obtain biologically active compounds.
stituted pyrido[4,3-d]pyrimidine compounds and will be re-
ported in due course.
Table 6. TNF-α inhibition by compounds 9a–9f.
All isolated compounds submitted for biological testing
were more than 95% pure, based on LC/MS or HPLC-UV
analysis (Table S1 in the Supporting Information).
Compound
TNF-α
IC50 [µ]
9a
9b
9c
9d
9e
9f
0.9
0.6
8.6
Ͼ10
3.2
Ͼ10
Biological Evaluation
Tumor necrosis factor alpha (TNF-α) overexpression is
associated with a number of diseases, such as rheumatoid
arthritis and Crohn’s disease. Inhibition of TNF-α pro-
duction has been shown to be beneficial in preclinical mod-
The molecular target of compounds 9a and 9b could not
els of rheumatoid arthritis, which makes inhibition of TNF- be determined with a cell-based assay. By employing a
α production an attractive target for the treatment of vari- broad target-based screening, it was discovered that cyclic
ous inflammatory and autoimmune diseases.[22] As part of AMP-specific phosphodiesterase type 4 (PDE-4) turned out
an ongoing drug discovery program dedicated to finding to be the molecular target. Compound 9a gave 90% PDE-
new small-molecule TNF-α inhibitors, the compounds dis- 4 inhibition at 10 µ. It is well known from the literature
closed above were evaluated for their ability to block the that there is a correlation between PDE-4 inhibition and
production of TNF-α in human peripheral blood mono- inhibition of TNF-α release from monocytes.[24]
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tate (60 mL) was refluxed under N2 for 24 h. After removing the
solvent, the residue was dissolved in hot 2  NaOH (20 mL) for
30 min and neutralized with 6  HCl (6–7 mL). On cooling, 7-
amino-2-methylpyrido[4,3-d]pyrimidin-4(3H)-one precipitated. The
yellow solid was filtered off and dried in a vacuum oven, affording
the pure title compound 6b (2.4 g, 72%). M.p. Ͼ 290 °C. 1H NMR
(200 MHz, [D6]DMSO, 25 °C): δ = 11.79 (br. s, 1 H, NH), 8.68 (s,
1 H, 5-H), 6.68 (br. s, 2 H, NH2), 6.28 (s, 1 H, 8-H), 2.25 (s, 3 H,
2-CH3) ppm. 13C NMR (50 MHz, [D6]DMSO, 25 °C): δ = 163.8,
161.3, 158.4, 155.1, 150.0, 107.4, 98.3, 21.6 ppm. MS: m/z (%) =
177.30 (100) [M+H]+.
Different structural classes of compounds are known as
PDE-4 inhibitors.[25] However, PDE-4 inhibitors based on
a pyrido[4,3-d]pyrimidine scaffold are not known, and
therefore, compounds 9a and 9b represent new lead struc-
tures in the design of new PDE-4 inhibitors useful for the
treatment of a wide range of inflammatory and autoim-
mune disorders.
Conclusions
7-Amino-2-(methoxymethyl)pyrido[4,3-d]pyrimidin-4(3H)-one (6c):
To a solution of 4,6-diaminonicotinamide (4, 0.395 g, 2.6 mmol)
in DMF (12 mL) were added methoxyacetyl chloride (0.498 mL,
5.45 mmol) and pyridine (0.525 mL, 6.46 mmol). The reaction mix-
ture was stirred at room temperature under N2. After 3 h, 5 
NaOH (8 mL) was added, and the reaction mixture was stirred for
an additional 18 h. The reaction mixture was concentrated in vacuo
and acidified with a concentrated HCl solution. On cooling, 7-
Considering the synthetic approaches described above, it
is possible to vary, in one synthetic cycle, up to 5 substitu-
tion sites of the pyrido[4,3-d]pyrimidine template. Position
2 can be diversified by reaction with different orthoesters
or acid chlorides. Position 3 can be N-alkylated with dif-
ferent alkyl halides, and at position 4, different N-, O- or
S-nucleophiles can be incorporated. The bromine atom at
position 5 can be hydrogenated or can be used for Pd-cata-
lyzed chemistry. An amino group is present at position 7,
which can be easily converted into different halogens by
diazotization procedures, and the resulting halides are use-
ful starting materials for further derivatisations.
We have demonstrated that a new series of pyrido[4,5-d]-
pyrimidine analogues can be prepared, and that this type
of chemistry is useful for parallel synthesis. The full exploi-
tation of the discussed strategy would allow for the prepara-
tion of highly diverse libraries based on the pyrido[4,3-d]-
pyrimidine scaffold. In addition, the application of this
strategy led to the discovery of a new structural class of
PDE-4 inhibitors.
amino-2-(methoxymethyl)pyrido[4,3-d]pyrimidin-4(3H)-one
(6c)
precipitated. The pale yellow solid was collected by filtration and
dried in a vacuum oven, furnishing the pure title compound (0.27 g,
1
50%). M.p. 272–273 °C. H NMR (200 MHz, [D6]DMSO, 25 °C):
δ = 11.70 (br. s, 1 H, NH), 8.71 (s, 1 H, 5-H), 6.74 (s, 2 H, NH2),
6.35 (s, 1 H, 8-H), 4.24 (s, 2 H, 2-CH2), 3.33 (s, 3 H, OCH3) ppm.
13C NMR (50 MHz, [D6]DMSO, 25 °C): δ = 164.0, 161.2, 157.9,
154.7, 150.4, 108.0, 99.0, 71.6, 58.7 ppm. IR (KBr): ν = 3407, 3328,
˜
3201, 2826, 1697, 1655, 1598, 1486, 1261, 1115 cm–1. MS: m/z (%)
= 207.21 (100) [M+H]+.
7-Amino-5-bromopyrido[4,3-d]pyrimidin-4(3H)-one (6d): A mixture
of 4,6-diamino-2-bromonicotinamide (3, 2.1 g, 9.09 mmol) in tri-
ethyl orthoformate (45 mL) was refluxed under N2 for 24 h. The
solvent was removed under reduced pressure, and the residue was
redissolved in hot 2  NaOH (20 mL) for 30 min and neutralized
with 6  HCl (6–7 mL). On cooling, 7-amino-5-bromopyrido[4,3-
d]pyrimidin-4(3H)-one (6d) precipitated. The precipitate was fil-
tered off and dried in a vacuum oven, yielding the title compound
as a yellow solid (1.95 g, 88%). M.p. Ͼ 290 °C. 1H NMR
(200 MHz, [D6]DMSO, 25 °C): δ = 11.86 (br. s, 1 H, NH), 7.94 (s,
1 H, 2-H), 7.06 (br. s, 2 H, NH2), 6.33 (s, 1 H, 8-H) ppm. 13C
NMR (50 MHz, [D6]DMSO, 25 °C): δ = 161.6, 158.2, 157.3, 149.2,
Experimental Section
General: For all reactions, analytical-grade solvents were used. All
moisture-sensitive reactions were carried out in oven-dried (135 °C)
1
glassware. H and 13C NMR spectra were recorded with a Varian
Gemini 200 (1H NMR: 200 MHz, 13C NMR: 50 MHz) or a Bruker
Avance 300 (1H NMR: 300 MHz, 13C NMR: 75 MHz) spectrome-
ter, with tetramethylsilane as an internal standard for 1H NMR
spectra and [D6]DMSO (δ = 39.5 ppm) or CDCl3 (δ = 77.2 ppm)
for 13C NMR spectra. Abbreviations used are: s = singlet, d =
doublet, t = triplet, q = quartet, m = multiplet, br. s = broad signal.
Coupling constants are expressed in Hz. Mass spectra were ob-
tained with a Finnigan LCQ advantage Max (ion trap) mass spec-
trophotometer from Thermo Finnigan, San Jose, CA, USA. Exact
mass measurements were performed with a quadrupole time-of-
flight mass spectrometer (Q-tof-2, Micromass, Manchester, UK)
equipped with a standard electrospray-ionization (ESI) interface.
Samples were infused in iPrOH/H2O (1:1) at 3 µL/min. Melting
points were determined with a Büchi SMP-20 apparatus and are
uncorrected. Infrared spectra were recorded with a Perkin–Elmer
Spectrum RX I FT-IR System in KBr. Vibration frequencies in IR
spectra are expressed in cm–1. Precoated aluminum sheets (Fluka
Silica gel/TLC cards, 254 nm) were used for TLC. Column
chromatography was performed on ICN silica gel (63–200 mesh,
60 Å). Compounds 2, 4 and 5 were synthesized according to litera-
ture protocols.[6] Compound 6a is also a known compound.[4b]
140.8, 107.4, 99.4 ppm. IR (KBr): ν = 3436, 3317, 3171, 3067, 2925,
˜
2854, 1683, 1623, 1585, 1522, 1466, 1382, 1299, 1240, 1214, 1133,
1091 cm–1. MS: m/z (%) = 240.9 (80) [M+H]+, 242.9 (100)
[M+H]+.
7-Amino-5-(3,4-dimethoxyphenyl)pyrido[4,3-d]pyrimidin-4(3H)-one
(7a): To a solution of 7-amino-5-bromopyrido[4,3-d]pyrimidin-
4(3H)-one (6d, 0.33 g, 1.37 mmol) in dioxane/H2O (3:1, 14 mL),
were added (3,4-dimethoxyphenyl)boronic acid (0.299 g,
1.64 mmol), K2CO3 (0.757 g, 5.48 mmol) and Pd(PPh3)4 (0.158 g,
0.14 mmol). The reaction mixture was refluxed under N2 for 2 h.
After cooling to room temperature, 1  HCl was added slowly to
neutralize the mixture to pH = 7–8. The solvents were removed
under reduced pressure. The residue was diluted with H2O (10 mL)
and filtered. The crude solid was redissolved in MeOH, pre-ad-
sorbed on silica gel and purified by chromatography on silica gel
(CH2Cl2/MeOH, 30:1), yielding 7-amino-5-(3,4-dimethoxyphenyl)-
pyrido[4,3-d]pyrimidin-4(3H)-one (7a) as a pale yellow solid
1
(0.383 g, 94%). M.p. Ͼ 290 °C. H NMR (200 MHz, [D6]DMSO,
25 °C): δ = 11.55 (br. s, 1 H, NH), 7.92 (s, 1 H, 2-H), 7.00–6.88
(m, 3 H, ArH), 6.70 (br. s, 2 H, NH2), 6.36 (s, 1 H, 8-H), 3.79 (s,
3 H, OCH3), 3.72 (s, 3 H, OCH3) ppm. 13C NMR (50 MHz, [D6]-
7-Amino-2-methylpyrido[4,3-d]pyrimidin-4(3H)-one (6b): A solution
of 4,6-diaminonicotinamide (4, 3 g, 13 mmol) in triethyl orthoace-
Eur. J. Org. Chem. 2006, 4257–4269
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4265

M.-Y. Jang, S. De Jonghe, L.-J. Gao, J. Rozenski, P. Herdewijn
FULL PAPER
DMSO, 25 °C): δ = 161.9, 161.1, 159.3, 157.0, 148.8, 148.6, 147.3,
1.39–1.28 (m, 2 H, 3Ј-CH2), 0.89 (t, 3J = 7.4 Hz, 3 H, 4Ј-CH3) ppm.
13C NMR (75 MHz, [D6]DMSO, 25 °C): δ = 162.5, 162.3, 159.7,
134.0, 122.0, 113.6, 110.3, 106.4, 98.6, 55.5 ppm. IR (KBr): ν =
˜
3438, 3327, 3210, 3068, 2842, 1678, 1651, 1582, 1519, 1387, 1257,
1225, 1160, 1140 cm–1. HRMS: calcd. for C15H15N4O3 299.1144;
found 299.1148.
156.6, 90.7, 88.1, 31.2, 21.2, 19.7, 13.7 ppm. IR (KBr): ν = 3470,
˜
3323, 3165, 2951, 2923, 2870, 1656, 1612, 1567, 1476, 1374, 1339,
1283, 1210, 1147, 1130, 1091, 1057 cm–1. HRMS: calcd. for
C12H18N5O 248.1511; found 248.1516.
7-Amino-2-methyl-5-[(E)-prop-1-enyl]pyrido[4,3-d]pyrimidin-4(3H)-
one (8a): To a solution of 7-amino-5-bromo-2-methylpyrido[4,3-d]-
pyrimidin-4(3H)-one (6e, 0.1 g, 0.39 mmol) in dioxane/H2O (3:1,
4 mL) were added (E)-propenylboronic acid (40 mg, 0.47 mmol),
K2CO3 (0.217 g, 1.57 mmol) and Pd(PPh3)4 (45 mg, 0.04 mmol).
The reaction mixture was refluxed under N2 for 1 h. After cooling
to room temperature, 1  HCl was added slowly to neutralize the
mixture to pH = 7–8. The solvents were removed under reduced
pressure. The residue was diluted with H2O (5 mL) and filtered.
The crude solid was redissolved in MeOH, pre-adsorbed on silica
gel and purified by chromatography on silica gel (CH2Cl2/MeOH,
30:1) affording 7-amino-2-methyl-5-[(E)-prop-1-enyl]pyrido[4,3-d]-
pyrimidin-4(3H)-one (8a) as a pale yellow solid (67 mg, 55%). M.p.
N4-Benzylpyrido[4,3-d]pyrimidine-4,7-diamine (11a): A reaction
mixture consisting of 7-aminopyrido[4,3-d]pyrimidin-4(3H)-one
(6a, 0.1 g, 0.62 mmol), 1,1,1,3,3,3-hexamethyldisilazane (0.386 mL,
1.85 mmol), benzylamine (0.202 mL, 1.85 mmol) and ammonium
sulfate (8 mg, 0.006 mmol) was heated at 120 °C for 3 d. After cool-
ing to room temperature, ethanol (10 mL) was added, and the reac-
tion mixture was concentrated in vacuo. The residue was purified
by column chromatography on silica gel (CH2Cl2/MeOH, 40:1),
yielding N4-benzylpyrido[4,3-d]pyrimidine-4,7-diamine (11a,
30 mg, 20 %) as a light brown solid. M.p. 236 °C. 1H NMR
3
(200 MHz, [D6]DMSO, 25 °C): δ = 9.10 (s, 1 H, 5-H), 8.85 (t, J =
5.4 Hz, 1 H, NH), 8.24 (s, 1 H, 2-H), 7.34–7.24 (m, 5 H, ArH),
3
1
6.45 (br. s, 2 H, NH2), 6.35 (s, 1 H, 8-H), 4.73 (d, J = 5.4 Hz, 2
263 °C. H NMR (200 MHz, [D6]DMSO, 25 °C): δ = 11.59 (br. s,
H, NCH2) ppm. 13C NMR (50 MHz, [D6]DMSO, 25 °C): δ =
1 H, NH), 7.94 (d, 3J = 15.4 Hz, 1 H, vinyl-H), 6.96–6.81 (m, 1 H,
161.7, 159.3, 158.4, 154.3, 147.8, 139.3, 128.2, 127.1, 126.7, 103.8,
vinyl-H), 6.47 (br. s, 2 H, NH2), 6.19 (s, 1 H, 8-H), 2.19 (s, 3 H, 2-
3
CH3), 1.88 (d, J = 7 Hz, 3 H, 3Ј-CH3) ppm. 13C NMR (50 MHz,
96.9, 43.1 ppm. IR (KBr): ν = 3455, 3262, 3123, 2923, 1651, 1593,
˜
1543, 1497, 1466, 1420, 1370, 1337, 1260, 1209, 1159, 1136, 1077,
[D6]DMSO, 25 °C): δ = 161.6, 161.4, 157.2, 157.0, 157.0, 133.1,
1010 cm–1. HRMS: calcd. for C14H14N5 252.1249; found 252.1238.
129.6, 103.8, 98.6, 21.1, 18.2 ppm. IR (KBr): ν = 3420, 3294, 3167,
˜
3056, 2922, 1675, 1618, 1575, 1457, 1437, 1288, 1199, 1139 cm–1.
HRMS: calcd. for C11H13N4O 217.1089; found 217.1083.
7-Aminopyrido[4,3-d]pyrimidine-4(3H)-thione (12): Phosphorus
pentasulfide (0.754 g, 3.39 mmol) was added to a solution of 7-
aminopyrido[4,3-d]pyrimidine-4(3H)-one (6a, 0.5 g, 3.08 mmol) in
pyridine (16 mL). The mixture was refluxed for 5 h. On cooling, a
precipitate formed, and the supernatant was decanted. The solid
was suspended in H2O and filtered to yield 7-aminopyrido[4,3-d]-
pyrimidine-4(3H)-thione (12, 0.465 g, 85%) as a brown solid. M.p.
(5-Phenyl-4-oxa-1,3,7-triazaphenalen-8-yl)amine (9a): To a mixture
of bis(triphenylphosphane)palladium(II) acetate (6 mg,
0.01 mmol), 7-amino-5-bromopyrido[4,3-d]pyrimidin-4(3H)-one
(6d, 0.1 g, 0.41 mmol) and triethylamine (0.415 mL) in DMF
(8 mL) was added a solution of phenylacetylene (0.091 mL,
0.83 mmol) in DMF (0.3 mL) over a period of 30 min. The reaction
mixture was refluxed under N2 for 1 h and cooled to room tem-
perature. The volatiles were removed under reduced pressure. The
crude residue was diluted with CH2Cl2 and washed with H2O. The
combined organic layers were dried with MgSO4 and concentrated
in vacuo. The crude residue was purified by chromatography on
silica gel (CH2Cl2/MeOH, 30:1), yielding the pure title compound
9a as a yellowish green solid (52 mg, 48%). M.p. 276 °C. 1H NMR
(200 MHz, [D6]DMSO, 25 °C): δ = 8.50 (s, 1 H, 2-H), 8.03–7.99
(m, 2 H, ArH), 7.59–7.54 (m, 3 H, ArH), 7.31 (s, 1 H, 6-H), 6.98
(br. s, 2 H, NH2), 6.27 (s, 1 H, 9-H) ppm. 13C NMR (50 MHz,
[D6]DMSO, 25 °C): δ = 165.7, 164.3, 160.0, 157.6, 155.9, 153.4,
1
245 °C. H NMR (200 MHz, [D6]DMSO, 25 °C): δ = 13.14 (br. s,
1 H, NH), 9.17 (s, 1 H, 5-H), 7.97 (s, 1 H, 2-H), 7.10 (br. s, 2 H,
NH2), 6.34 (s, 1 H, 8-H) ppm. 13C NMR (50 MHz, [D6]DMSO,
25 °C): δ = 184.1, 164.0, 154.0, 150.6, 146.9, 116.7, 98.2 ppm. IR
(KBr): ν = 3446, 3306, 3123, 2924, 2853, 1653, 1594, 1479, 1393,
˜
1356, 1323, 1252, 1162 cm–1. MS: m/z (%) = 179.1 (100) [M+H]+.
4-(Methylthio)pyrido[4,3-d]pyrimidin-7-amine (13): To a solution of
7-aminopyrido[4,3-d]pyrimidine-4(3H)-thione (12, 0.437 g,
2.45 mmol) in DMSO (12 mL) were added triethylamine
(0.854 mL, 6.13 mmol) and iodomethane (0.305 mL, 4.90 mmol).
The reaction mixture was stirred at room temperature under N2 for
12 h. The mixture was poured into H2O and extracted with EtOAc.
The combined organic layers were dried with MgSO4 and concen-
trated in vacuo to yield 4-(methylthio)pyrido[4,3-d]pyrimidin-7-
131.2, 131.8, 129.2, 128.7, 125.7, 106.2, 93.4 ppm. IR (KBr): ν =
˜
3318, 3167, 1645, 1590, 1565, 1464, 1451, 1428, 1375, 1335, 1270,
1191, 1211, 1077, 1003 cm–1. HRMS: calcd. for C15H11N4O
263.0932; found 263.0930.
1
amine (13, 0.345 g, 73%) as a brown solid. M.p. 186 °C. H NMR
(200 MHz, [D6]DMSO, 25 °C): δ = 8.98 (s, 1 H, 5-H), 8.71 (s, 1 H,
2-H), 6.93 (s, 2 H, NH2), 6.49 (s, 1 H, 8-H), 2.63 (s, 3 H, SCH3)
ppm. 13C NMR (50 MHz, [D6]DMSO, 25 °C): δ = 171.1, 162.6,
156.6, 152.5, 149.3, 112.5, 96.5, 11.4 ppm. MS: m/z (%) = 193.1
(100) [M+H]+.
7-Amino-5-(butylamino)-2-methylpyrido[4,3-d]pyrimidin-4(3H)-one
(10): To a solution of 7-amino-5-bromo-2-methylpyrido[4,3-d]pyri-
midin-4(3H)-one (6e, 50 mg, 0.20 mmol) in dioxane (1.5 mL) were
added n-butylamine (0.039 g, 0.39 mmol), potassium tert-butoxide
(31 mg, 0.27 mmol) and Pd(PPh3)4 (9 mg, 0.01 mmol). The reaction
mixture was refluxed under N2 for 24 h and cooled to room tem-
perature. The solvents were removed under reduced pressure. The
crude residue was diluted with MeOH and pre-adsorbed onto silica
gel. After removing the solvent, the residue was purified by
chromatography on silica gel (CH2Cl2/MeOH, 30:1), yielding 7-
amino-5-(butylamino)-2-methylpyrido[4,3-d]pyrimidin-4(3H)-one
(10) as a light brown solid (20 mg, 41%). M.p. 270–272 °C. 1H
4-Morpholinopyrido[4,3-d]pyrimidin-7-amine (14): A mixture of 4-
(methylthio)pyrido[4,3-d]pyrimidin-7-amine (13, 260 mg,
1.35 mmol) and morpholine (0.237 mL, 2.27 mmol) in ethanol
(6 mL) was refluxed for 24 h. The volatiles were removed by evapo-
ration in vacuo. The crude residue was purified by chromatography
on silica gel (CH2Cl2/MeOH, 30:1), yielding 4-morpholinopyr-
ido[4,3-d]pyrimidin-7-amine (14) as a light brown solid (225 mg,
1
72%). M.p. 154–156 °C. H NMR (200 MHz, [D6]DMSO, 25 °C):
NMR (200 MHz, [D6]DMSO, 25 °C): δ = 11.44 (s, 1 H, NH), 8.66 δ = 8.85 (s, 1 H, 5-H), 8.34 (s, 1 H, 2-H), 6.58 (br. s, 2 H, NH2),
(t, 3J = 5.8 Hz, 1 H, 5-NH), 6.24 (s, 2 H, NH2), 5.52 (s, 1 H, 8-H), 6.41 (s, 1 H, 8-H), 3.78 (br. s, 4 H, morpholinyl 3-H), 3.75 (br. s, 4
3.35 (q, 3J = 5.8 Hz, 2 H, 1Ј-CH2), 1.55–1.44 (m, 2 H, 2Ј-CH2),
H, morpholinyl 2-H) ppm. 13C NMR (50 MHz, [D6]DMSO,
4266
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 4257–4269

Pyrido[4,3-d]pyrimidine Libraries
FULL PAPER
25 °C): δ = 162.7, 161.2, 157.0, 156.5, 150.2, 104.4, 96.7, 66.1, chromatography on silica gel (acetone/MeOH, 50:1), yielding N4-
49.3 ppm. IR (KBr): ν = 3430, 3338, 3227, 2925, 1640, 1605, 1565, (2-methoxyethyl)-2-methylpyrido[4,3-d]pyrimidine-4,7-diamine
˜
1
1528, 1498, 1464, 1384, 1358, 1331, 1269, 1224, 1109, 1066, (18a) as a pale yellow solid (74 mg, 69%). M.p. 268 °C. H NMR
1031 cm–1. HRMS: calcd. for C11H14N5O 232.1198; found
232.1192.
(300 MHz, [D6]DMSO, 25 °C): δ = 9.00 (s, 1 H, 5-H), 8.23 (br. s,
1 H, 4-NH), 6.33 (s, 2 H, 7-NH2), 6.27 (s, 1 H, 8-H), 3.64 (t, J =
3
3
5.3 Hz, 2 H, 2Ј-CH2), 3.54 (t, J = 5.3 Hz, 2 H, 1Ј-CH2), 3.29 (s, 3
N-(2-Methyl-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-7-yl)acet-
amide (15): A mixture of 7-amino-2-methylpyrido[4,3-d]pyrimidin-
4(3H)-one (6b, 700 mg, 3.97 mmol) in acetic anhydride/pyridine
(1:1, 20 mL) was refluxed for 30 min. The solvents were removed
in vacuo, and the residue was purified by chromatography on silica
gel (CH2Cl2/MeOH, 30:1), yielding N-(2-methyl-4-oxo-3,4-dihy-
dropyrido[4,3-d]pyrimidin-7-yl)acetamide (15, 0.75 g, 86%) as a
pale yellow solid. M.p. Ͼ 290 °C. 1H NMR (200 MHz, [D6]DMSO,
25 °C): δ = 12.33 (br. s, 1 H, 3-NH), 10.84 (s, 1 H, 7-NH), 8.98 (s,
1 H, 5-H), 8.10 (s, 1 H, 8-H), 2.35 (s, 3 H, 2-CH3), 2.13 (s, 3 H,
COCH3) ppm. 13C NMR (50 MHz, [D6]DMSO, 25 °C): δ = 170.0,
160.8, 159.7, 155.6, 148.8, 112.8, 106.7, 24.0, 21.8 ppm. IR (KBr):
H, OCH3), 2.33 (s, 3 H, 2-CH3) ppm. 13C NMR (75 MHz, [D6]-
DMSO, 25 °C): δ = 167.0, 161.6, 159.4, 155.1, 147.5, 102.4, 96.6,
70.2, 57.9, 39.7, 26.7 ppm. IR (KBr): ν = 3416, 3262, 3142, 2974,
2932, 1655, 1601, 1561, 1501, 1459, 1397, 1343, 1267, 1204,
1120 cm–1. HRMS: calcd. for C11H16N5O 234.1355; found
234.1370.
˜
7-Amino-5-(3,4-dimethoxyphenyl)-3-methylpyrido[4,3-d]pyrimidin-
4(3H)-one (19): To a solution of 7-amino-5-(3,4-dimethoxyphenyl)-
pyrido[4,3-d]pyrimidin-4(3H)-one (7a, 0.11 g, 0.37 mmol) in DMF
(4 mL) was added NaH (60% in mineral oil, 10 mg, 0.41 mmol).
The resulting slurry was heated at 65 °C for 30 min, at which time
a solution was obtained. It was cooled to 50 °C, and a solution of
iodomethane (0.028 mL, 0.44 mmol) in DMF (0.3 mL) was added
dropwise to the mixture. The mixture was maintained at 60–80 °C
for 3 h and cooled to room temperature. The reaction mixture was
concentrated in vacuo, and the residue was purified by chromatog-
raphy on silica gel (CH2Cl2/MeOH, 50:1), yielding 7-amino-5-(3,4-
dimethoxyphenyl)-3-methylpyrido[4,3-d]pyrimidin-4(3H)-one (19)
as a pale yellow solid (40 mg, 35%). M.p. 231–233 °C. 1H NMR
(200 MHz, [D6]DMSO, 25 °C): δ = 8.23 (s, 1 H, 2-H), 6.96 (s, 1 H,
ArH), 6.90 (s, 2 H, ArH), 6.70 (br. s, 2 H, NH2), 6.35 (s, 1 H, 8-
H), 3.79 (s, 3 H, OCH3), 3.72 (s, 3 H, OCH3), 3.26 (s, 3 H, 3-CH3)
ppm. 13C NMR (75 MHz, [D6]DMSO, 25 °C): δ = 161.8, 161.0,
159.1, 156.4, 151.4, 148.6, 147.3, 134.1, 121.7, 113.3, 110.3, 105.5,
ν = 3335, 3127, 3074, 2926, 2789, 1702, 1606, 1564, 1524, 1431,
˜
1374, 1256, 1173, 1133, 1040 cm–1. MS: m/z (%) = 177.1 (100)
[M+H]+.
N-{2-Methyl-4-(1H-1,2,4-triazol-1-yl)pyrido[4,3-d]pyrimidin-7-
yl}acetamide (16): To a solution of N-(2-methyl-4-oxo-3,4-dihy-
dropyrido[4,3-d]pyrimidin-7-yl)acetamide (15, 0.595 g, 2.73 mmol)
in acetonitrile/CH2Cl2 (2:1, 27 mL) were added phosphorus oxy-
chloride (0.762 mL, 8.18 mmol) and triethylamine (1.14 mL,
8.18 mmol). The reaction mixture was stirred at room temperature
for 24 h. The solvents were removed in vacuo, and the residue was
redissolved in CH2Cl2 and washed with iced H2O until pH = 6–7.
The residue was dried with MgSO4 and concentrated to yield N-
{2-methyl-4-(1H-1,2,4-triazol-1-yl)pyrido[4,3-d]pyrimidin-7-
yl}acetamide (16) as a crude product (0.464 g, 77 %). M.p. Ͼ
290 °C. 1H NMR (200 MHz, [D6]DMSO, 25 °C): δ = 11.23 (s, 1 H,
NH), 10.16 (s, 1 H, 5Ј-H), 9.65 (s, 1 H, 5-H), 8.59 (s, 1 H, 3Ј-H),
8.40 (s, 1 H, 8-H), 2.77 (s, 3 H, 2-CH3), 2.19 (s, 3 H, COCH3) ppm.
13C NMR (50 MHz, [D6]DMSO, 25 °C): δ = 170.3, 167.3, 157.8,
154.7, 153.6, 153.3, 152.7, 145.7, 106.8, 105.2, 26.1, 24.1 ppm. MS:
m/z (%) = 270.16 (100) [M+H]+.
98.3, 55.52, 55.48, 33.2 ppm. IR (KBr): ν = 3424, 3181, 2924, 2853,
1687, 1634, 1589, 1513, 1465, 1419, 1327, 1256, 1187, 1137,
˜
1025 cm–1. MS: m/z (%) = 313.1 (100) [M+H]+.
7-Amino-5-(3,4-dimethoxyphenyl)-2,3-dimethylpyrido[4,3-d]pyrimi-
din-4(3H)-one (20): To a solution of 7-amino-5-(3,4-dimeth-
oxyphenyl)-2-methylpyrido[4,3-d]pyrimidin-4(3H)-one (7e, 50 mg,
0.16 mmol) in DMF (1 mL) were added K2 CO3 (27 mg,
0.19 mmol) and iodomethane (0.012 mL, 0.19 mmol). The resulting
slurry was stirred at room temperature for 24 h. After removing the
volatiles, the residue was diluted with H2O and extracted with
EtOAc. The combined organic phases were dried with MgSO4 and
concentrated in vacuo. The crude residue was purified by
chromatography on silica gel (CH2Cl2/MeOH, 50:1), yielding 7-
amino-5-(3,4-dimethoxyphenyl)-2,3-dimethylpyrido[4,3-d]pyrimi-
din-4(3H)-one (20) as a pale yellow solid (26 mg, 50 %). M.p.
N-(4-Methoxy-2-methylpyrido[4,3-d]pyrimidin-7-yl)acetamide (17a):
A mixture of N-{2-methyl-4-(1H-1,2,4-triazol-1-yl)pyrido[4,3-d]py-
rimidin-7-yl}acetamide (16, 45 mg, 0.17 mmol) in MeOH (1.6 mL)
was refluxed for 12 h. The solvents were evaporated in vacuo. The
residue was redissolved in CH2Cl2 and washed with H2O. The com-
bined organic layers were dried with MgSO4 and concentrated in
vacuo. The crude residue was purified by chromatography on silica
gel (CH2Cl2/MeOH, 20:1), yielding N-(4-methoxy-2-methylpyr-
ido[4,3-d]pyrimidin-7-yl)acetamide (17a) as a pale yellow solid
(22 mg, 57%). M.p. 210 °C. 1H NMR (200 MHz, CDCl3, 25 °C): δ
= 9.16 (s, 1 H, 5-H), 8.52 (s, 1 H, 8-H), 8.18 (br. s, 1 H, NH), 4.18
(s, 3 H, 4-OCH3), 2.72 (s, 3 H, 2-CH3), 2.27 (s, 3 H, COCH3) ppm.
13C NMR (50 MHz, CDCl3, 25 °C): δ = 168.6, 167.9, 166.5, 156.3,
1
290 °C. H NMR (200 MHz, CDCl3, 25 °C): δ = 7.05–6.91 (m, 3
H, ArH), 6.45 (s, 1 H, 8-H), 4.89 (br. s, 2 H, NH2), 3.92 (s, 3 H,
OCH3), 3.90 (s, 3 H, OCH3), 3.45 (s, 3 H, 3-CH3), 2.56 (s, 3 H, 2-
CH3) ppm. 13C NMR (50 MHz, [D6]DMSO, 25 °C): δ = 161.1,
159.1, 158.9, 158.1, 154.4, 147.7, 146.5, 133.4, 120.9, 112.4, 109.6,
103.4, 96.6, 54.6, 29.1, 22.4 ppm. IR (KBr): ν = 3424, 3310, 3192,
˜
152.1, 147.2, 107.3, 106.2, 53.6, 26.1, 24.1 ppm. IR (KBr): ν = 3447,
˜
2924, 2853, 1681, 1635, 1577, 1513, 1466, 1420, 1373, 1338, 1259,
1155, 1136, 1025 cm–1. HRMS: calcd. for C17H19N4O3 327.1457;
found 327.1458.
3266, 2926, 1686, 1624, 1570, 1475, 1400, 1361, 1243, 1186, 1127,
1019 cm–1. HRMS: calcd. for C11H13N4O2 233.1038; found
233.1030.
N4-(2-Methoxyethyl)-2-methylpyrido[4,3-d]pyrimidine-4,7-diamine N-(2,3-Dimethyl-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-7-yl)acet-
(18a): A reaction mixture consisting of 7-amino-2-methylpyr-
ido[4,3-d]pyrimidin-4(3H)-one (15, 0.10 g, 0.46 mmol), 1,1,1,3,3,3-
hexamethyldisilazane (0.382 mL, 1.83 mmol), (2-methoxyethyl)-
amine (0.159 mL, 1.83 mmol) and ammonium sulfate (6 mg,
0.005 mmol) was heated at 120 °C for 2 d. After cooling to room
temperature, ethanol (10 mL) was added, and the reaction mixture
was concentrated in vacuo. The residue was purified by column
amide (24). Method A: To a solution of N-(2-methyl-4-oxo-3,4-dihy-
dropyrido[4,3-d]pyrimidin-7-yl)acetamide (15, 34 mg, 0.16 mmol)
in DMF (2 mL) were added K2CO3 (26 mg, 0.19 mmol) and benzyl
bromide (0.012 mL, 0.19 mmol). The resulting slurry was stirred at
room temperature for 24 h. The solvents were removed under re-
duced pressure. The residue was diluted with CH2Cl2 and washed
with H2O. The combined organic layers were dried with MgSO4
Eur. J. Org. Chem. 2006, 4257–4269
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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4267

M.-Y. Jang, S. De Jonghe, L.-J. Gao, J. Rozenski, P. Herdewijn
FULL PAPER
and concentrated in vacuo. The crude residue was purified by
chromatography on silica gel (CH2Cl2/MeOH, 30:1) to give N-(2,3-
dimethyl-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-7-yl)acetamide
(24) as a pale yellow solid (19 mg, 53%). Method B: To a mixture
of N-(2-methyl-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-7-yl)acet-
amide (15, 0.10 g, 0.46 mmol), triphenylphosphane (0.18 g,
0.69 mmol) and MeOH (0.028 mL, 0.69 mmol) in dioxane (4.5 mL)
was added DIAD (0.135 mL, 0.69 mmol). The reaction mixture
was stirred at room temperature for 1 d, after which the same
amounts of triphenylphosphane, MeOH and dioxane were added.
The resulting reaction mixture was stirred for an additional 1 d.
After removing the volatiles, the residue was purified by column
chromatography on silica gel (CH2Cl2/MeOH, 50:1) to give N-(2,3-
dimethyl-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-7-yl)acetamide
(24, 73 mg, 68%) as a pale yellow solid. M.p. 237–239 °C. 1H NMR
(300 MHz, CDCl3, 25 °C): δ = 9.16 (s, 1 H, 5-H), 8.32 (s, 1 H, 8-
H), 8.11 (br. s, 1 H, NH), 3.61 (s, 3 H, 3-CH3), 2.64 (s, 3 H, 2-
CH3), 2.25 (s, 3 H, COCH3) ppm. 13C NMR (75 MHz, CDCl3,
25 °C): δ = 168.8, 161.3, 159.8, 154.7, 154.6, 150.2, 113.0, 107.7,
= 3056, 2926, 1684, 1618, 1587, 1520, 1457, 1420, 1391, 1363, 1252,
1232, 1178, 1137, 1021 cm–1. HRMS: calcd. for C17H18N3O4
328.1297; found 328.1303.
4-(7-Chloropyrido[4,3-d]pyrimidin-4-yl)morpholine (27): A solution
of NaNO2 (54 mg, 0.78 mmol) in H2O (0.2 mL) was added drop-
wise to a solution of 4-morpholinopyrido[4,3-d]pyrimidin-7-amine
(14, 90 mg, 0.39 mmol) in 6  HCl (2 mL) at –15 °C over 20 min.
This reaction mixture was stirred for another 10 min, after which
a cold suspension of CuCl (116 mg, 1.17 mmol) in 6  HCl
(0.2 mL) was added. The temperature of the reaction was gradually
raised to room temperature over 1 h, and the mixture was stirred
at 60 °C for another 1 h. The pH of the mixture was adjusted to
5–6 with a 10  NaOH solution. The mixture was extracted with
CH2Cl2. The combined organic layers were dried with MgSO4 and
concentrated in vacuo. The crude residue was purified by
chromatography on silica gel (CH2Cl2/MeOH, 40:1), yielding pure
4-(7-chloropyrido[4,3-d]pyrimidin-4-yl)morpholine (27) as a solid
(33 mg, 34 %). M.p. 132 °C. 1H NMR (200 MHz, [D6]DMSO,
25 °C): δ = 9.21 (s, 1 H, 5-H), 8.45 (s, 1 H, 2-H), 7.73 (s, 1 H, 8-
H), 3.99 (br. s, 4 H, morpholinyl 3-H), 3.77 (br. s, 4 H, morpholinyl
2-H) ppm. 13C NMR (50 MHz, [D6]DMSO, 25 °C): δ = 161.8,
158.1, 157.2, 150.8, 119.4, 110.8, 66.0, 48.9 ppm. HRMS: calcd. for
C11H12N4OCl 251.0699; found 251.0699.
31.0, 25.0, 24.2 ppm. IR (KBr): ν = 3350, 3178, 2924, 2364, 1676,
˜
1614, 1594, 1522, 1417, 1385, 1260, 1172, 1145, 1032 cm–1. HRMS:
calcd. for C11H13N4O2 233.1039; found 233.1030.
5-(3,4-Dimethoxyphenyl)-7-fluoro-2-methylpyrido[4,3-d]pyrimidin-
4(3H)-one (25): To a solution of 7-amino-5-(3,4-dimethoxyphenyl)-
2-methylpyrido[4,3-d]pyrimidin-4(3H)-one (7e, 0.218 g, 0.70 mmol)
in 60 % HBF4 (in diethyl ether/DMF, 1:1, 4.5 mL) at 0 °C was
added dropwise a solution of NaNO2 (96 mg, 1.40 mmol) in H2O
(0.5 mL). The reaction mixture was stirred at 0 °C for another 1 h
and at room temperature for 3 h. The resulting mixture was ice-
cooled, neutralized with a saturated aqueous sodium carbonate
solution and extracted with EtOAc. The combined organic layers
were dried with MgSO4 and concentrated in vacuo. The crude resi-
due was purified by chromatography on silica gel (CH2Cl2/MeOH,
60:1), yielding 5-(3,4-dimethoxyphenyl)-7-fluoro-2-methylpyr-
ido[4,3-d]pyrimidin-4(3H)-one (25) as a solid (176 mg, 79%). M.p.
240–244 °C. 1H NMR (200 MHz, [D6]DMSO, 25 °C): δ = 12.37
(br. s, 1 H, NH), 7.15–7.09 (m, 3 H, ArH), 7.01 (s, 1 H, 8-H), 3.82
(s, 3 H, OCH3), 3.74 (s, 3 H, OCH3), 2.37 (s, 3 H, 2-CH3) ppm.
4-{7-(3,4-Dimethoxyphenyl)pyrido[4,3-d]pyrimidin-4-yl}morpholine
(28): To a solution of 4-(7-chloropyrido[4,3-d]pyrimidin-4-yl)-
morpholine (27, 34 mg, 0.14 mmol) in dioxane/H2O (3:1, 2 mL),
was added (3,4-dimethoxyphenyl)boronic acid (30 mg, 0.16 mmol),
K2CO3 (75 mg, 0.54 mmol) and Pd(PPh3)4 (16 g, 0.01 mmol). The
reaction mixture was refluxed under N2 for 2 h. After cooling to
room temperature, 1  HCl was added slowly to neutralize the mix-
ture to pH = 7–8. After removing the solvents under reduced pres-
sure, the residue was extracted with CH2Cl2. The combined organic
layers were dried with MgSO4 and concentrated in vacuo. The
crude residue was purified by chromatography on silica gel
(CH2Cl2/MeOH, 40:1), yielding 4-{7-(3,4-dimethoxyphenyl)pyr-
ido[4,3-d]pyrimidin-4-yl}morpholine (28, 40 mg, 83%) as a white
1
solid. M.p. 148 °C. H NMR (300 MHz, CDCl3, 25 °C): δ = 9.32
(s, 1 H, 5-H), 8.75 (s, 1 H, 2-H), 1.05 (s, 1 H, 8-H), 8.00–7.64 (m,
2 H, ArH), 7.01 (d, 3J = 8.5 Hz,1 H, ArH), 4.04–3.99 (m, 7 H,
morpholinyl 3-H, OCH3), 3.97 (s, 3 H, OCH3), 3.92–3.88 (m, 4 H,
morpholinyl 2-H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ =
163.1, 158.0, 157.6, 150.9, 149.5, 149.1, 132.3, 132.2, 132.1, 132.1,
131.0, 128.8, 128.6, 120.2, 115.7, 111.5, 110.1, 66.9, 56.2, 50.0 ppm.
1
13C NMR (50 MHz, CDCl3, 25 °C): δ = 165.0 (d, JC,F = 265 Hz),
3
3
162.4 (d, JC,F = 9 Hz), 162.4, 161.2 (d, JC,F = 13 Hz), 158.8,
2
150.5, 148.5, 131.8, 123.1, 113.2, 110.3, 103.3 (d, JC,F = 36 Hz),
97.1, 56.2, 21.7 ppm. IR (KBr): ν = 3168, 3051, 2944, 1665, 1633,
˜
1593, 1519, 1420, 1410, 1356, 1326, 1261, 1225, 1168, 1128,
1022 cm–1. HRMS: calcd. for C16H15FN3O3 316.1097; found
316.1100.
IR (KBr): ν = 2995, 2924, 2850, 1608, 1560, 1534, 1434, 1405,
˜
1340, 1207, 1149, 1119, 1026 cm–1. HRMS: calcd. for C19H21N4O3
353.1614; found 353.1605.
5-(3,4-Dimethoxyphenyl)-7-methoxy-2-methylpyrido[4,3-d]pyrimi-
din-4(3H)-one (26a): A solution of 5-(3,4-dimethoxyphenyl)-7-
fluoro-2-methylpyrido[4,3-d]pyrimidin-4(3H)-one (25, 70 mg,
0.21 mmol) in sodium methoxide (30 wt.-% solution in MeOH,
3 mL) was stirred at reflux for 4 h. The resulting mixture was con-
centrated under reduced pressure, diluted with H2O, neutralized
with 2  HCl and extracted with CH2Cl2. The combined organic
layers were dried with MgSO4 and concentrated in vacuo. The
crude residue was purified by chromatography on silica gel
(CH2Cl2/MeOH, 30:1), yielding 5-(3,4-dimethoxyphenyl)-7-meth-
oxy-2-methylpyrido[4,3-d]pyrimidin-4(3H)-one (26a, 58 mg, 83%)
as a solid. M.p. 245–248 °C. 1H NMR (200 MHz, [D6]DMSO,
Supporting Information (see footnote on the first page of this arti-
cle): Synthetic procedures and analytical data for 6e, 7b, 7c, 7d, 7e,
8b, 9b, 9c, 9d, 9e, 9f, 11b, 17b, 17c, 17d, 17e, 18b, 21, 22, 23, 26b;
Table S1 with the purity of the final compounds as measured by
LC/MS or LC/UV.
[1] a) S. Ding, N. S. Gray, X. Wu, Q. Ding, P. Schultz, J. Am.
Chem. Soc. 2002, 124, 1594–1596; b) P. Raboisson, C. Lugnier,
C. Muller, J. M. Reimund, D. Schultz, G. Pinna, A. Le Bec, H.
Basaran, L. Desaubry, F. Gaudiot, M. Seloum, J. J. Bourguig-
non, Eur. J. Med. Chem. 2003, 38, 199–214; c) A. Manikowski,
A. Verri, A. Lossani, B. M. Gebhardt, J. Gambino, F. Focher,
S. Spadari, G. E. Wright, J. Med. Chem. 2005, 48, 3919–3929.
[2] a) A. Pandey, D. L. Volkots, J. M. Seroogy, J. W. Rose, J. Yu,
J. L. Lambing, A. Hutchaleelaha, S. J. Hollenbach, K. Abe,
N. A. Giese, R. M. Scarborough, J. Med. Chem. 2002, 45,
3772–3793; b) A. Antonello, P. Hrelia, A. Leonardi, G. Ma-
3
25 °C): δ = 12.00 (br. s, 1 H, NH), 7.14 (s, 1 H, ArH), 7.11 (d, J
= 8.2 Hz, 1 H, ArH), 6.96 (d, 3J = 8.2 Hz, 1 H, ArH), 6.71 (s, 1
H, 8-H), 3.93 (s, 3 H, 7-OCH3), 3.81 (s, 3 H, OCH3), 3.73 (s, 3 H,
OCH3), 2.31 (s, 3 H, 2-CH3) ppm. 13C NMR (50 MHz, [D6]DMSO,
25 °C): δ = 164.9, 160.6, 160.4, 158.8, 149.4, 147.4, 133.0, 122.6,
114.2, 110.5, 109.2, 101.4, 97.8, 55.5, 53.8, 21.3 ppm. IR (KBr): ν
˜
4268
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Eur. J. Org. Chem. 2006, 4257–4269

Pyrido[4,3-d]pyrimidine Libraries
FULL PAPER
rucci, M. Rosini, A. Tarozzi, V. Tumiatti, C. Melchiorre, J.
Med. Chem. 2005, 48, 28–31; c) Y. Bathini, I. Singh, P. J. Har-
vey, P. R. Keller, R. Singh, R. G. Micetich, D. W. Fry, E. M.
Dobrusin, P. L. Toogood, Bioorg. Med. Chem. Lett. 2005, 15,
3881–3885.
[15]
[16]
[17]
a) N. Kataoka, Q. Shelby, J. P. Stambuli, J. F. Hartwig, J. Org.
Chem. 2002, 67, 5553–5566; b) S. Wagaw, S. L. Buchwald, J.
Org. Chem. 1996, 61, 7240–7241.
a) H. Vorbrüggen, K. Krolikiewicz, U. Nieballa, Angew. Chem.
Int. Ed. Engl. 1971, 10, 657; b) H. Vorbrüggen, K. Krolikiew-
icz, U. Nieballa, Justus Liebigs Ann. Chem. 1975, 988.
S. Nishikawa, Z. Kumazawa, N. Kashimura, S. Maki, Y. Nishi-
kimi, Agric. Biol. Chem. 1986, 50, 495.
Y. Z. Xu, P. F. Swann, Nucleic Acids Res. 1990, 18, 4061.
E. C. Taylor, S. R. Otiv, I. Durucasu, Heterocycles 1993, 36,
1883–1895.
[3] a) J. M. Quintela, C. Peinador, L. Botana, M. Estevez, R. Rig-
uera, Bioorg. Med. Chem. 1997, 5, 1543–1553; b) A. Rosowsky,
H. Chen, H. Fu, S. Queener, Bioorg. Med. Chem. 2003, 11, 59–
67; c) K. Lee, M. Jiang, M. Cowart, G. Gfesser, R. Perner,
K. H. Kim, Y. G. Gu, M. Williams, M. F. Jarvis, E. A. Kowa-
luk, A. O. Stewart, S. S. Bhagwat, J. Med. Chem. 2001, 44,
2133–2138.
[18]
[19]
[20]
[4] a) A. M. Thompson, A. J. Bridges, D. W. Fry, A. J. Kraker,
W. A. Denny, J. Med. Chem. 1995, 38, 3780–3788; b) G. W.
Rewcastle, B. D. Palmer, A. M. Thompson, A. J. Bridges, D. R.
Cody, H. Zhou, D. W. Fry, A. McMichael, W. A. Denny, J.
Med. Chem. 1996, 39, 1823–1835; c) A. M. Thompson, D. K.
Murray, W. L. Elliott, D. W. Fry, J. A. Nelson, H. D. Hol-
lis Showalter, B. J. Roberts, P. W. Vincent, W. A. Denny, J. Med.
Chem. 1997, 40, 3915–3925.
a) Q. Chao, L. Deng, H. Shih, L. M. Leoni, D. Genini, D. A.
Carson, H. B. Cottam, J. Med. Chem. 1999, 42, 3860–3873; b)
G. S. Chen, S. Kalchar, C. Kuo, C. Chang, C. O. Usifoh, J.
Chern, J. Org. Chem. 2003, 68, 2502–2505.
[21] a) M. Abarghaz, A. Kerbal, J. Bourguignon, Tetrahedron Lett.
1995, 36, 6463–6466; b) S. Ferrer, D. P. Naughton, I. Parveen,
M. D. Threadgill, J. Chem. Soc., Perkin Trans. 1 2002, 335–
340.
[5] S. V. Ley, A. W. Thomas, Angew. Chem. Int. Ed. 2003, 42,
[22] R. C. Newton, C. P. Decicco, J. Med. Chem. 1999, 42, 2295–
5400–5449.
2314.
[6] A. J. Bridges, W. A. Denny, D. Fry, G. W. Rewcastle, US 6,713, [23] R. Schindler, J. Mancilla, S. Endres, R. Ghorbani, S. C. Clark,
484.
C. A. Dinarello, Blood 1990, 75, 40–47.
[24] S. L. C. Jin, M. Conti, Proc. Natl. Acad. Sci. USA 2002, 99,
7628–7633.
[7] J. S. Buck, W. S. Ide, Org. Synth. Coll. Vol. 1943, 2, 44.
[8] R. J. Griffin, S. Srinivasan, K. Bowman, A. H. Calvert, N. J.
Curtin, D. R. Newell, L. C. Pemberton, B. T. Golding, J. Med. [25] a) G. L. Card, L. Blasdel, B. P. England, C. Zhang, Y. Suzuki,
Chem. 1998, 41, 5247–5256.
[9] J. M. Schomaker, T. J. Delia, J. Org. Chem. 2001, 66, 7125–
7128.
S. Gilette, D. Fong, P. N. Ibrahim, D. R. Artis, G. Bollag, M. V.
Milburn, S. Kim, J. Schlessinger, K. Y. J. Zhang, Nat. Biotech-
nol. 2005, 23, 201–207; b) A. Castro, M. J. Jerez, C. Gil, A.
Martinez, Med. Res. Rev. 2005, 25, 229–244; c) M. Krier, J. X.
de Araujo-Junior, M. Schmitt, J. Duranton, H. Justiano-Basa-
ran, C. Lugnier, J. J. Bourguignon, D. Rognan, J. Med. Chem.
2005, 48, 3816–3822; d) J. I. Andres, J. M. Alonso, A. Diaz, J.
Fernandez, L. Iturrino, P. Martinez, E. Matesanz, E. J. Freyne,
F. Deroose, G. Boeckx, D. Petit, G. Diels, A. Megens, M. So-
mers, J. Van Wauwe, P. Stoppie, M. Cools, F. De Clerck, D.
Peeters, D. de Chaffoy, Bioorg. Med. Chem. Lett. 2002, 12, 653–
658; e) H. Ochiai, T. Ohtani, A. Ishida, K. Kusumi, M. Kato,
H. Kohno, Y. Odagaki, K. Kishikawa, S. Yamamoto, H.
Takeda, T. Obata, H. Nakai, M. Toda, Bioorg. Med. Chem.
Lett. 2004, 14, 207–210; f) D. T. Manallack, R. A. Hughes,
P. E. Thompson, J. Med. Chem. 2005, 48, 3449–3462.
Received: April 18, 2006
[10] C. Wolf, R. Lerebours, J. Org. Chem. 2003, 68, 7077–7084.
[11] R. Perner, C. Lee, M. Jiang, Y. Gu, S. DiDomenico, E. K.
Bayburt, K. M. Alexander, K. L. Kohlhaas, M. F. Jarvis, E. L.
Kowaluk, S. S. Bhagwat, Bioorg. Med. Chem. Lett. 2005, 15,
2803–2807.
[12] a) K. Sonogashira, Y. Tohda, N. Hagihara, Tetrahedron Lett.
1975, 16, 4467–4470; b) R. M. Lester, M. D. Julia, A. Razwan,
J. S. Ian, Tetrahedron Lett. 2002, 43, 8853–8857.
[13] a) C. McGuigan, C. J. Yarnold, G. Jones, S. Velazquez, H. Ba-
rucki, A. Barucki, G. Andrei, R. Snoeck, E. De Clercq, J. Balz-
arini, J. Med. Chem. 1999, 42, 4479–4484; b) C. McGuigan, A.
Brancale, H. Barucki, S. Srinivasan, Antiviral Chem. Chem-
other. 2001, 12, 77–89.
[14] U. S. Sorensen, E. Pombo-Villar, Tetrahedron 2005, 61, 2697–
2703.
Published Online: July 21, 2006
Eur. J. Org. Chem. 2006, 4257–4269
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4269