Microwave-assisted synthesis of mGluR1 ligands: carbon, nitrogen and oxygen linked derivatives of pyrido[3,4-d]pyrimidin-4-ylamines

Article abstract of DOI:10.1016/j.tetlet.2007.04.035

The syntheses of 6-fluoropyrido[3,4-d]pyrimidin-4-ylamine derivatives is reported herein. Methods for generating C, N and O linked analogues under microwave irradiation are described.

Full text of DOI:10.1016/j.tetlet.2007.04.035

Tetrahedron Letters 48 (2007) 4293–4296
Microwave-assisted synthesis of mGluR1 ligands: carbon,
nitrogen and oxygen linked derivatives of
pyrido[3,4-d]pyrimidin-4-ylamines
Gareth W. Harbottle,* Neil Feeder, Karl R. Gibson, Mel Glossop, Graham N. Maw,
William A. Million, Florence F. Morel, Simon Osborne and Cedric Poinsard
Pfizer Global Research and Development, Sandwich Laboratories, Ramsgate Road, Sandwich, Kent CT13 9NJ, UK
Received 2 March 2007; revised 28 March 2007; accepted 5 April 2007
Available online 14 April 2007
Abstract—The syntheses of 6-fluoropyrido[3,4-d]pyrimidin-4-ylamine derivatives is reported herein. Methods for generating C, N
and O linked analogues under microwave irradiation are described.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Receptor antagonists of the mGluR1 subtype have been
reported to be analgesic.1–3 As part of our investigations
into mGluR1 antagonists, we studied 6-substituted pyr-
ido[3,4-d]pyrimidin-4-ylamines of the general structure
A. Earlier efforts in this direction had allowed us to dis-
cover 1 as an interesting lead.4,5 We thus sought a con-
venient synthetic strategy to enable the preparation of
carbon, nitrogen and oxygen linked compounds. Herein,
we report the microwave-assisted6 synthesis of the afore-
mentioned compounds.
R
N
HN
Cl
N
O
N
F
F
F
ii
i
N
NH
N
N
N
N
3
2
4a-i
N
N
N
O
a, 82%
R =
N
b, 79%
c, 82%
d, 55%
R
HN
X
N
e, 70%
g, 99%
f, 73%
h, 78%
i, 99%
HN
H
N
N
N
N
N
Scheme 1. Reagents and conditions: (i) SOCl2, CH2Cl2, DMF, reflux,
18 h; (ii) RNH2, Pr2NEt, CH2Cl2, rt, 18 h.
i
R = Alkyl, Carbocycle
Heterocycle.
O
N
N
X = N, C and O linked.
amines proceeded rapidly at room temperature in
CH2Cl2 to generate the fluoroheterocyclic advanced
intermediates, 4a–i.
A
1
At the heart of the strategy was 6-fluoro-3H-pyrido[3,4-
d]pyrimidin-4-one, 2, which provides a means of access-
ing common advanced intermediates, 4a–i (Scheme 1).
Pyrimidinone 2 was prepared in five steps from 2-flu-
oro-4-nitropyridine as reported by Rewcastle et al.7
Chlorination with thionyl chloride yielded reactive aryl
chloride 3.8 Nucleophilic aromatic substitution with
The route also provided an opportunity to alkylate the
heterocycle directly with nitroalkanes. Alkylation pro-
ceeded at room temperature with DBU in DMSO to
generate the alkylated intermediates 5a–b (Scheme 2).
However, instead of alkylating at C2 as reported for
similar compounds,5 alkylation proceeded at C8 and
this observation was supported by X-ray crystallo-
graphic data (Fig. 1).9 No reaction was observed with
2-nitropropane or ethyl nitroacetate. The result was in
*
Corresponding author. Tel.: +44 1304 649270; e-mail: gareth.w.
harbottle@pfizer.com
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.04.035

4294
G. W. Harbottle et al. / Tetrahedron Letters 48 (2007) 4293–4296
R'
R'
R
N
NH.HCl
R''
NH
R''
R'
N
HN
i
or ii
R''
HN
N
6a-g
HN
N
N
F
F
a R' = CH3
b R' = CH2CH3
R' = iPr
i
89%
83%
0%
N
N
N
R
N
N
N
HN
R
HN
OH
-
F
R'
5a-b
R'
O
R' = CH2CO2Et 0%
-
4i
R'
N
7a-e
and 9
N
N
iii or iv
N
Scheme 2. Reagents and conditions: (i) R0CH2NO2, DBU, DMSO, rt,
N
4a-i
18 h.
R
HN
N
O
R'
H
N
N
8a-b
N
H
iv
R'
OH
N
Scheme 3. All reactions carried out in NMP under microwave
irradiation.12 Reagents and conditions: (i) method A:14 iPr2NEt,
180 ꢁC, 500–1000 s; (ii) method B:15 KOtBu, Pr2NEt, 200 ꢁC, 1000–
i
2000 s; (iii) method C:16 KOtBu, 180 ꢁC, 400–1000 s; (iv) method D:17
NaH, rt, then 180 ꢁC, 800 s.
absorb and distribute microwave energy were sought.
We wished to avoid N,N-dimethylformamide with bases
at high temperature and dimethylsulfoxide led to com-
plex mixtures.13 These considerations culminated in
the use of N-methylpyrrolidinone as it satisfied our
requirements for a solvent.
Heating amines with 4a–i in the presence of Hunig’s
¨
Base yielded compounds 6a–e (method A). Potassium
tert-butoxide added to ammonium salts (method B)
led to a faster reaction than cases where excess Hunig’s
¨
Base was used, giving compounds 6f–g. As illustrated in
Table 1, the conditions were used to generate reliable
derivatives from a range of amines (entries 1–8), and
deterioration of yields was only observed with sterically
hindered examples.
O-Linked compounds such as 7 were formed in a similar
fashion using stronger bases (Table 1, entries 9–16).
Potassium tert-butoxide (method C) was a suitable base
for the in situ formation of alkoxide nucleophiles and
benefits from being easy to handle. Alternatively, the
sodium alkoxides can be preformed from alcohols and
sodium hydride at room temperature prior to adding
electrophiles, 4a–i, and heating (method D). Sodium
alkoxides reacted more cleanly than potassium salts with
fewer impurities, and reliably generated alkyl ethers,
7a–e.
Figure 1. ORTEP diagram of 5b.
agreement with observations made by Yanai et al. on
the reaction of substituted pyridazines with nitrometh-
ane and nitroethane, in which nucleophilic C-alkylation
occurs.10,11
Fluoride displacements on fluoro-intermediates, 4a–i
were carried out with amines and alcohols. Reactions
performed with conventional heating required a large
excess of amine or alcohol (up to 10 equiv) and pro-
longed heating at 100 ꢁC for 1–3 days in N,N-dimethyl-
acetamide. Careful tuning of reagents and conditions
under microwave12 irradiation resulted in more rapid
and reliable production of analogues.
Acetal protecting groups were tolerated (entry 13) and
allowed scope for further elaboration. As with amines,
sterically hindered secondary alcohols (entry 11) were
slower to react. The method also enabled alcohols to
react selectively over secondary amines resulting in
O-linked compounds featuring NH side chains such as
8a–b (entries 14 and 15).
Reactions were conducted at temperatures between 180
and 200 ꢁC, and as a result, the reaction durations were
reduced to between 10 and 30 min. Scheme 3 summa-
rises the conditions used for N and O derivatives. In
order to achieve the high temperatures that the tech-
nique enables, high boiling solvents with the ability to
When ethylene glycol (entry 16) was subjected to the
same conditions, hydroxylated intermediate 9 (Scheme
4) was formed in good yield via the degradation of the
hydroxyethoxy compound. Compounds such as 9 were

G. W. Harbottle et al. / Tetrahedron Letters 48 (2007) 4293–4296
Table 1. Nucleophilic aromatic substitution of fluoride with alcohols and aminesa
4295
Entry
Amine
Methodb
R
Product
yieldc (%)
Entry
Alcohol
Methodb
R
Product
yieldc (%)
NH2
OH
7a, 74
N
O
N
O
O
1
2
A
A
6a, 41
6b, 95
9
D
C
NH
N
10
7b, 69
7c, 34
7d, 84
7e, 70
N
OH
OH
N
NH
NH
N
O
3
4
5
A
A
A
6c, 18
6d, 93
6e, 8
11
12
13
D
D
D
N
OH
N
N
N
F
F
NH
OH
O
O
O
NH+
OH
2Cl
N
N
N
6
7
8
B
B
B
—, 0
14
15
16
D
D
C
8a, 61
8b, 62
9, 87d
H
NH+
2Cl
OH
OH
N
H
6f, 78
6g, 89
N
NH+
2Cl
HO
a All reactions were performed in NMP under microwave irradiation.
b See Refs. 14–17.
c Isolated yield.
d Product is hydroxyaromatic compound, 9.
was not formed as a result of water since the hydroxy-
ethoxy intermediate could be isolated from the reaction
mixture. Upon further heating the intermediate de-
grades to yield 9. When 4h was heated with potassium
hydroxide in the absence of ethylene glycol, lower yields
were observed. The outcome of the reaction with ethyl-
ene glycol was utilised to prepare the aryl hydroxide,
which was converted to the triflate in moderate yield
to form 10, a precursor enabling C–C cross couplings
to be carried out.
HN
N
HN
N
F
HO
i
N
N
N
N
87%
9
4h
ii
iii
HN
TfO
71%
N
71%
N
A Suzuki–Miyaura cross coupling opened a gateway to
C-linked compounds, incorporating the vinylboronic
anhydride (pyridine complex) developed by O’Shea
and Kerins.18 When heated with 10 in the presence of
potassium carbonate and palladium tetrakis(triphenyl-
phosphine) in 1,2-dimethoxyethane, the coupling gave
11 in good yield (71%).19 The influence of microwave
irradiation again allowed for a shorter reaction time,
but also a marked improvement in yield over a conven-
tionally refluxed procedure, where the product was
obtained in 43% yield only, along with several side
products.
N
10
O
HN
HN
iv
N
N
N
N
96%
N
N
N
11
12
Scheme 4. Reagents and conditions: (i) method C:16 (CH2OH)2
(4.0 equiv), NMP, KOtBu, microwave irradiation, 180 ꢁC, 400–
1000 s; (ii) Tf2O (2.5 equiv), pyridine, 0 ꢁC to rt, 45 min; (iii)
vinylboronic anhydride pyridine complex (1.2 equiv), Pd(PPh3)4,
K2CO3, DME, 150 ꢁC, 1800 s, microwave irradiation; (iv) morpholine
Although alkene 11 could be heated with amines to add
in a Michael fashion to form 12, purifications were often
difficult and yields low. Rhodium catalysts have been
reported by Beller on the anti-Markovnikov addition
of amines to vinylpyridines,20 and more recently,
Hartwig has enhanced the scope towards styrenes.21
i
(4.0 equiv), PrMgCl (3.3 equiv), THF, 0 ꢁC to rt.
often formed as trace side products during reactions
with amines and alcohols due to small amounts of water
present in the solvent. However, in this case the product

4296
G. W. Harbottle et al. / Tetrahedron Letters 48 (2007) 4293–4296
12. ‘EmrysTM Creator’ and ‘EmrysTM Liberator’ microwave
systems were used.
13. Urben, P. G.; Pitt, M. J. In Bretherick’s Handbook of
Reactive Chemical Hazards, 6th ed; Butterworth Heine-
mann: Oxford, 1999; Vol. 1, p 1604.
Compound 11 was reacted with morpholine (4.0 equiv)
and [Rh(COD)2]BF4:PPh3 (1:2, 5 mol %) in refluxing
THF. After 3 h no reaction was observed. Remarkably,
pre-forming the magnesium amide with isopropylmag-
nesium chloride at 0 ꢁC in THF, then adding the vinyl
substrate and warming to room temperature, the addi-
tion proceeded to give 12 in excellent yield. To the best
14. General method for substitution of fluoride with amines,
method A: 6-fluoropyrido[3,4-d]pyrimidin-4-ylamine,
4a–i, (0.2 mmol), amine (2.5 equiv, 0.5 mmol) and
diisopropylethylamine (2.5 equiv, 0.5 mmol) were heated
in N-methylpyrrolidinone (2 mL) at 180 ꢁC for 500–1000 s
using microwave irradiation. Water (5 mL) was added and
the precipitate was collected by filtration. Compounds
which did not precipitate upon the addition of water were
extracted with ethyl acetate (3 · 5 mL). The combined
organic extracts were washed with brine, dried (MgSO4)
and concentrated. Silica gel chromatography yielded the
pure compounds.
15. General method for substitution of fluoride with amine
hydrochloride salts, method B: 6-fluoropyrido[3,4-d]pyr-
imidin-4-ylamine, 4a–i, (0.2 mmol), amine (2.5 equiv,
0.5 mmol), potassium tert-butoxide (2.5 equiv, 0.5 mmol)
and diisopropylethylamine (2.5 equiv, 0.5 mmol) were
heated in N-methylpyrrolidinone (2 mL) at 200 ꢁC for
1000–2000 s using microwave irradiation. Workup as in
method A.
i
of our knowledge, the use of PrMgCl to facilitate the
anti-Markovnikov addition of amines to vinylarenes
has not been reported. Further findings associated with
this reaction will be published.
In summary, we have demonstrated how microwave
irradiation can shorten reaction times by providing a
practical means of heating reactions above their normal
i
reflux temperatures, and how PrMgCl can be used to
generate magnesium amides that react more favourably
than the corresponding amines. In addition, we have re-
ported some remarkable observations around the regio-
selectivity of the aromatic substitution of nitroethane
and nitromethane.
16. General method for substitution of fluoride with alcohols,
method C: 6-fluoropyrido[3,4-d]pyrimidin-4-ylamine, 4a–i,
(0.2 mmol), alcohol (4.0 equiv, 0.8 mmol) and potassium
tert-butoxide (4.0 equiv, 0.8 mmol) were heated in N-
methylpyrrolidinone (2 mL) at 180 ꢁC for 400–1000 s
using microwave irradiation. Workup as in method A.
17. General method for substitution of fluoride with alcohols,
method D: An EmrysTM Process Vial was charged with
NaH (3 equiv, 0.6 mmol) under a flow of N2. The relevant
alcohol (3 equiv, 0.6 mmol) in N-methyl pyrrolidinone
(2 mL) was added and the mixture was stirred at room
temperature for 5 min. 6-Fluoro-pyrido[3,4-d]pyrimidin-4-
ylamine, 4a–i, (0.2 mmol) was added and the mixture was
heated to 180 ꢁC for 800 s using microwave irradiation.
Workup as in method A.
Acknowledgements
Thanks to Thomas Ryckmans and Dafydd Owen for
helpful discussions.
References and notes
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tetrakis(triphenylphosphino)palladium (89 mg, 0.077
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using microwave irradiation. The mixture was diluted with
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(d, J = 10.53 Hz, 1H), 6.39 (d, J = 17.16 Hz, 1H), 6.89 (dd,
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}
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