Synthesis of a 5-alkoxypyrido[4,3-d]pyrimidin-4(3H)-one derivative via a regioselective Meisenheimer N-oxide rearrangement

Article abstract of DOI:10.1016/j.tetlet.2004.03.088

The synthetic strategy towards a 5-alkoxypyrido[4,3-d]pyrimidin-4(3H)-one is described utilizing a selective N-oxidation and subsequent regioselective Meisenheimer N-oxide rearrangement as key steps.

Full text of DOI:10.1016/j.tetlet.2004.03.088

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3737–3739
Synthesis of a 5-alkoxypyrido[4,3-d]pyrimidin-4(3H)-one derivative
via a regioselective Meisenheimer N-oxide rearrangementq
Emma J. Williams,* Peter W. Kenny, Jason G. Kettle and Paul G. Mwashimba
AstraZeneca, Alderley Park, Macclesfield, Cheshire, England SK10 4TG, UK
Received 23 January 2004; revised 9 March 2004; accepted 16 March 2004
Abstract—The synthetic strategy towards a 5-alkoxypyrido[4,3-d]pyrimidin-4(3H)-one is described utilizing a selective N-oxidation
and subsequent regioselective Meisenheimer N-oxide rearrangement as key steps.
Ó 2004 Elsevier Ltd. All rights reserved.
In the preceding paper1 we outlined a novel synthetic
strategy to a 5-alkoxypyrido[3,4-d]pyrimidin-4(3H)-one
derivative, 2, as part of an investigation into the
structure–activity relationship around a series of 5-
alkoxyquinazolin-4(3H)-one derivatives 1. We sought
to expand these studies by synthesis of the regioiso-
meric 5-alkoxypyrido[4,3-d]pyrimidin-4(3H)-one deriv-
ative 3, where C-6 of the parent quinazoline, 1
is replaced by nitrogen. Our strategy for 3 adopted
similar methodology to that used for 1, namely a
nucleophilic aromatic substitution (SNAr) of a 5-chloro-
pyrido[3,4-d]pyrimidin-4(3H)-one with the requisite
alkoxide nucleophile. Despite extensive interest in the
pyrido[4,3-d]pyrimidin-4(3H)-one core from the medic-
inal and synthetic chemistry communities,2–5 we are not
aware of any routes available that give this specific
(mono)alkoxysubstitution pattern. Herein we report
our preliminary findings on the synthesis of this ring
system.
The retrosynthetic strategy is outlined in Scheme 1.
Displacement of the activated chlorine of compound 4
with an alkoxide nucleophile was expected to proceed
uneventfully. Synthesis of the previously unreported
5-chloropyrido[4,3-d]pyrimidin-4(3H)-one core, as in 4,
depended critically on a regioselective Meisenheimer
N-oxide rearrangement6–9 of a suitably protected pyr-
ido[4,3-d]pyrimidin-4(3H)-one 6-oxide, 5. The synthesis
of this key N-oxide in turn hinged upon a selective
oxidation of a suitably protected analogue of the known
pyrido[4,3-d]pyrimidin-4-one 6, at N-6.
N
O
O
N
Quantum mechanical calculations10 for the model com-
pounds A and B in Figure 1 (in which the N3 protecting
group has been truncated to methyl for simplicity) were
used to predict the regioselectivity of the critical step of
the Meisenheimer rearrangement, namely addition of
chloride to the pyridine ring. The rate determining step of
the reaction was assumed to be the formation of inter-
mediates such as A and B and the Hammond postulate11
is invoked to justify the use of these to model the regio-
selectivity. Model compound A is predicted to be sig-
nificantly lower in energy than B. Calculated values for
the energy difference (BꢀA) at different levels of theory
are 38 kJ molꢀ1 (RHF/6-31Gꢁ12), 28 kJ molꢀ1 (B3LYP/
6-31Gꢁ13) and 43 kJ molꢀ1 (MP2/6-31Gꢁ12). Conse-
quently these theoretical calculations led us to expect
Y
X
NH
1
2
3
X, Y = CH
X = N, Y = CH
X = CH, Y = N
Keywords: Phosphorus oxychloride; Meisenheimer; Pyrido[4,3-d]pyr-
imidin-4(3H)-one.
q Supplementary data associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2004.03.088
* Corresponding author. Tel.: +44-(0)1625-518265; fax: +44-(0)1625-
513910; e-mail: emma.williams@astrazeneca.com
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.03.088

3738
E. J. Williams et al. / Tetrahedron Letters 45 (2004) 3737–3739
N
O
O
N
Cl
O
N
O
N
R
O
N
NH
N
NH
N+
N
3
4
5
O
N
CO2H
NH2
N
N
NH
7
6
Scheme 1. Retrosynthetic strategy for assembly of the 5-alkoxypyridopyrimidinone core.
rearrangement of 5 to furnish the requisite 5-substituted
product in preference to the alternative 7-substituted
isomer (quinazoline ring numbering).
The sequence started with esterification of the trifluo-
roacetate (TFA) salt of 4-aminonicotinic acid 714 (con-
centrated sulfuric acid, 10% (v/v)/EtOH/85 °C/18 h) to
give the ethyl ester 8 in 91% yield (Scheme 2). Cycliza-
tion was achieved by heating the ester in neat formamide
(170 °C/16 h) to give the pyrido[4,3-d]pyrimidin-4(3H)-
one core 6 in 75% yield on a multigram scale, using an
acidic ion-exchange resin catch-and-release strategy to
isolate the compound from the solvent. The direct
conversion of 7 to 6 with formamide was successful, but
a considerable exotherm and gas evolution was noted at
150 °C that was speculated to be due to thermal
decomposition of the TFA salt. Thus the two-step
strategy described above was adopted. Pivaloyloxy-
Figure 1. Lowest energy conformations of intermediates A (chloride
addition to C5) and B (chloride addition to C7) energy-minimized at
RHF/6-31Gꢁ level.
O
c.H2SO4 / EtOH
85oC / 91%
formamide
chloromethyl pivalate
NaH/ DMF/ 63%
CO2H
NH2
CO2Et
NH2
N
N
NH
N
170oC / 75%
N
TFA Salt
6
8
7
O
O
N
N
O
Cl
O
N
POM
POM
m-CPBA
DCM / 50%
O
POCl3
100oC / 66%
O
N
N
N
N+
N
N
11
10
9
N
N
Cl
O
N
7N NH3 in MeOH
RT/ 18 h / 94%
OH
O
O
NH
N
NaH/ DMF
80oC/ 65%
NH
N
N
4
3
Scheme 2. Synthesis of 5-alkoxypyrido[4,3-d]pyrimidin-4(3H)-one from 4-aminonicotinic acid.

E. J. Williams et al. / Tetrahedron Letters 45 (2004) 3737–3739
3739
methyl (POM) protection at N3 was introduced by
References and notes
formation of the anion with sodium hydride (1.2 equiv/
DMF/0 °C) and a subsequent quench with chloromethyl
pivalate (1.2 equiv/0 °C to rt/1 h) to give 9 in 63% yield.
Selective oxidation of the pyridine ring nitrogen with
m-CPBA (1.25 equiv/0 °C to rt/16 h) gave the N-oxide 10
in 50% yield. This reaction appeared to give cleanly a
single regioisomer, with no evidence of oxidation at N-1
of the pyrimidone ring. Despite this, we were unable to
improve the isolated yield beyond that reported here. As
anticipated, the crucial Meisenheimer N-oxide rear-
rangement was accomplished in a regioselective manner
with phosphorus oxychloride as solvent (100 °C/2 h) to
give 11, after work up with ice-cold saturated sodium
carbonate solution, in 66% yield. The structure of 11
was confirmed by NMR studies.15 Removal of the POM
protecting group proceeded uneventfully by treatment
with a solution of 7 N ammonia in methanol to give 4 in
94% yield. Finally, displacement of the chlorine was
accomplished by in situ generation of the alkoxide
nucleophile in 65% yield, in a manner analogous to that
used for synthesis of 1.1
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In conclusion we have described the first synthesis of the
5-alkoxypyrido[4,3-d]pyrimidin-4(3H)-one ring system
in seven steps from the TFA salt of 4-aminonicotinic
acid in 9% overall yield. It is anticipated that a range of
alkoxides and other nucleophiles could be used to
introduce diversity at C-5 and that a subsequent chlo-
rination-displacement strategy at C-4 would introduce
further complexity to the molecule.
13. Koch, W.; Holthausen, M. C. A Chemist’s Guide to Density
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15. NMR spectrum of compound 11 (DMSO-d6); 1.10 (s, 9H),
5.85 (s, 2H), 7.60 (d, 1H), 8.60 (d, 1H), 8.70 (s, 1H); MS:
MHþ 296.