Regioselective cross-coupling reactions and nucleophilic aromatic substitutions on a 5,7-dichloropyrido[4,3-d]pyrimidine scaffold

Article abstract of DOI:10.1016/j.tetlet.2006.10.056

The synthesis of a 5,7-dichloropyrido[4,3-d]pyrimidine scaffold is described. The chlorine at position 5 can selectively be displaced by different palladium-catalyzed cross-coupling reactions and nucleophilic aromatic substitutions. In the subsequent step

Full text of DOI:10.1016/j.tetlet.2006.10.056

Tetrahedron Letters 47 (2006) 8917–8920
Regioselective cross-coupling reactions and
nucleophilic aromatic substitutions on a 5,7-dichloro-
pyrido[4,3-d]pyrimidine scaffold
Mi-Yeon Jang,a Steven De Jonghe,b Ling-Jie Gaob and Piet Herdewijna,*
aREGA Institute, Laboratory of Medicinal Chemistry, Minderbroedersstraat 10, 3000 Leuven, Belgium
b4AZA Bioscience, Department of Medicinal Chemistry, Kapucijnenvoer 33, 3000 Leuven, Belgium
Received 8 August 2006; revised 4 October 2006; accepted 9 October 2006
Available online 31 October 2006
Abstract—The synthesis of a 5,7-dichloropyrido[4,3-d]pyrimidine scaffold is described. The chlorine at position 5 can selectively be
displaced by different palladium-catalyzed cross-coupling reactions and nucleophilic aromatic substitutions. In the subsequent step,
the chlorine at position 7 can be further derivatized. The described synthetic sequence allows for the construction of a diverse pyr-
ido[4,3-d]pyrimidine library with structural variations at positions 5 and 7.
Ó 2006 Elsevier Ltd. All rights reserved.
The pyridopyrimidine scaffold (Fig. 1) is a well-known
pharmacophore in drug design and it is associated with
a wide range of biological properties. Pyrido[3,2-d]-
pyrimidines have been described as tyrosine kinase
inhibitors and as dihydrofolate reductase inhibitors.1
Pyrido[2,3-d]pyrimidines possess dihydrofolate reduc-
tase inhibiting and antitumour activity.2 Pyrido[3,4-d]-
pyrimidines are well known to be potent tyrosine
kinase inhibitors and matrix metalloproteinase-13 inhib-
itors.3 Pyrido[4,3-d]pyrimidines are also known to be
inhibitors of tyrosine kinases of the epidermal growth
factor receptor family.4
key intermediate to elaborate this type of chemistry is
5,7-dichloropyrido[4,3-d]pyrimidine. Both chlorine
atoms are ideal substrates for nucleophilic aromatic sub-
stitutions (SNAr) and palladium-catalyzed cross-cou-
pling reactions. Regioselective cross-coupling reactions
of multiple halogenated heterocycles have recently been
reviewed.5 However, as far as we know, regioselective
cross-coupling reactions on a pyrido[4,3-d]pyrimidine
scaffold have not been reported before.
We envisioned to synthesize the pyrido[4,3-d]pyrimidine
scaffold from an appropriately substituted pyridine
analogue, that is, 4-amino-2,6-dichloronicotinic acid 4.
However, much to our surprise, the synthesis of this
compound is not described in the literature. Therefore,
we worked out the synthesis of compound 4 from the
commercially available 4-amino-2,6-dichloropyridine 1
(Scheme 1). The amino group was protected as a
As part of a structure–activity study on immunosup-
pressive agents, we were interested in synthetic schemes
to introduce a variety of substituents at positions 5 and
7 of the pyrido[4,3-d]pyrimidine scaffold that can be
used in high-throughput medicinal chemistry. An ideal
Figure 1.
Keywords: Pyrido[4,3-d]pyrimidines; Heterocycles; Combinatorial chemistry; Library.
*
Corresponding author. Tel.: +32 16/33 73 87; fax: +32 16/33 73 40; e-mail: piet.herdewijn@rega.kuleuven.be
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.10.056

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M.-Y. Jang et al. / Tetrahedron Letters 47 (2006) 8917–8920
Scheme 1. Reagents and conditions: (a) (Boc)2O, NaHMDS, THF, rt, 3 h; (b) n-BuLi, CO2, diethyl ether, ꢀ78 °C, 4 h then rt overnight; (c) TFA,
CH2Cl2, rt, 12; (d) SOCl2, 1,2-dichloroethane, reflux, 3 h then NH3(aq), diethyl ether, 0 °C, 20 min.
tert-butoxycarbonyl group (Boc). The formation of a
carbanion by treatment with n-butyllithium (n-BuLi),
in the presence of N,N,N0,N0-tetramethylethylenedi-
amine (TMEDA), and quenching by the addition of
anhydrous carbon dioxide gas led to the formation of
the nicotinic acid derivative 3. The Boc group was
cleaved off under acidic conditions, yielding pyridine
analogue 4. By refluxing compound 4 in thionylchloride,
the carboxylic acid was converted to its corresponding
acid chloride, which was subsequently treated with
ammonia, affording amide 5.
Scheme 3. Reagents and conditions: (a) morpholine, NEt3, dioxane,
80 °C, N2, 24 h; (b) propargyl alcohol, NEt3, Pd(OAc)2(PPh3)2,
dioxane, reflux, N2, 24 h; (c) tributylphenyltin, Pd(PPh3)4, dioxane,
reflux, N2, 1 h; (d) 3,4-dimethoxyphenylboronic acid, K2CO3,
Pd(PPh3)4, dioxane/H2O, reflux, N2, 2 h.
In order to construct the pyrido[4,3-d]pyrimidine bi-
cycle, 4-amino-2,6-dichloronicotinamide 5 was condensed
with triethylorthoacetate. Only 4-ethoxy analogue 6
could be isolated in a 38% yield, whereas the 4-hydroxy
derivative could not be detected. However, the 4-ethoxy
congener offers some advantages compared to the
hydroxy compound such as better solubility in common
organic solvents and hence, easier handling and purifica-
tion. In addition, the ethoxy compound could be easily
converted to its 4-hydroxy analogue by acidic or basic
hydrolysis. Alternatively, compound 7 could also be pre-
pared by heating compound 5 in triethylorthoformate
(Scheme 2).
tetrakistriphenylphosphine as the catalyst.6 For the cou-
pling with propargyl alcohol, a copper free version of
the Sonagashira reaction (step (b)) was carried out using
bis(triphenylphosphine)palladium(II)acetate as the cata-
lyst and triethylamine as the base.7 The Stille coupling
(step (c)) was done with tributylphenyl stannane and
tetrakis(triphenylphosphine)palladium(0) as the catalyst.8
For all the above mentioned reactions, only one single
isomer was isolated.9 The regiochemistry of the isolated
compounds could easily be elucidated by 2D NMR
studies (NOESY and HMBC spectra). For compound
2-Methyl-4-ethoxy-5,7-dichloropyrido[4,3-d]pyrimidine
6 was considered as an ideal starting material to study
the regioselectivity of nucleophilic aromatic substitu-
tions and palladium-catalyzed cross-coupling reactions
(Scheme 3). The treatment of compound 6 with 1 equiv
of morpholine leads exclusively to the monosubstituted
compound 8. A Suzuki coupling, a Stille coupling and
a Sonagashira reaction were chosen as representatives
for palladium-catalyzed cross-coupling reactions. The
Suzuki reaction (step (d)) was performed with 3,4-di-
methoxyphenylboronic acid under standard reaction
Scheme 4. Reagents and conditions: (a) H2, KOAc, 10% Pd/ C, THF/
MeOH (2:1), rt, 4 h.
conditions: potassium carbonate as
a base and
Scheme 2. Reagents and conditions: (a) triethyl orthoacetate, reflux, 12 h; (b) triethyl orthoformate, reflux, 3 h.

M.-Y. Jang et al. / Tetrahedron Letters 47 (2006) 8917–8920
8919
Scheme 5. Reagents and conditions: (a) morpholine, NEt3, dioxane, 80 °C, N2, 24 h; (b) H2, KOAc, Pd/C, THF/MeOH (2:1), rt; (c) 3,4-
dimethoxyphenylboronic acid, K2CO3, Pd(PPh3)4, dioxane/H2O, reflux, N2, 2 h.
8, a clear NOE contact was observed between the ethoxy
protons and the protons on the morpholino ring. In
addition, a clear HMBC cross-peak was seen between
C(5) of the pyrido[4,3-d]pyrimidine scaffold and the
morpholino protons. For compounds 10 and 11, we
observed clear HMBC correlations between the protons
on the phenyl ring and C(5) of the pyrido[4,3-d]pyrimi-
dine moiety, whereas no HMBC cross-peak was
detected between the proton on C(8) and the phenyl
protons. For the Sonogashira derived coupling product
9, a clear HMBC connectivity was observed between the
CH2 protons adjacent to the triple bond and C(5) of the
pyrido[4,3-d]pyrimidine core structure. All these findings
indicate that the chlorine at position 5 was displaced,
whereas the chlorine at position 7 was still intact.
References and notes
1. (a) Smaill, J. B.; Palmer, B. D.; Rewcastle, G. R.; Denny,
W. A.; McNamara, D. J.; Dobrusin, E. M.; Bridges, A. J.;
Zhou, H.; Hollis Showalter, H. D.; Winters, R. T.;
Leopold, W. R.; Fry, D. W.; Nelson, J. M.; Slintak, V.;
Elliott, W. L.; Roberts, B. J.; Vincent, P. W.; Patmore, S.
J. J. Med. Chem. 1999, 42, 1803–1815; (b) Gangjee, A.;
Zhu, Y.; Queener, S. F. J. Med. Chem. 1998, 41, 4533–
4541.
2. Gangjee, A.; Adair, O.; Queener, S. F. J. Med. Chem.
1999, 42, 2447–2455.
3. (a) Rewcastle, G. W.; Murray, D. K.; Elliott, W. L.; Fry,
D. W.; Howard, C. T.; Nelson, J. M.; Roberts, B. J.;
Vincent, P. W.; Showalter, H. D. H.; Winters, R. T.;
Denny, W. A. J. Med. Chem. 1998, 41, 742–751; (b)
Bunker, A.; Picard, J.; Lodaya, R.; Waldo, M.; Marlatt,
M. WO 2005/016926.
Alternatively, the regiochemistry could also be proven
unambiguously through chemical conversion (Scheme
4).10 The remaining chlorine of compounds 8 and 10
was reduced off by catalytic hydrogenation over palla-
dium, giving rise in the 1H NMR spectrum to two doub-
lets, arising from the protons at positions 7 and 8. If
the remaining chlorine would be present at position 5,
only a singlet (from the proton at position 5) would be
observed in the 1H NMR spectrum, after reductive
removal of the chlorine.
4. Bridges, A. J.; Denny, W. A.; Fry, D.; Kraker, A.; Meyer,
R. F.; Rewcastle, G. W.; Thompson, A. M. US 5654307.
5. Schro¨ter, S.; Stock, C.; Bach, T. Tetrahedron 2005, 61,
2245–2267.
6. Schomaker, J. M.; Delia, T. J. J. Org. Chem. 2001, 66,
7125–7128.
7. Li, J.; Zhang, X.; Xie, Y. Eur. J. Org. Chem. 2005, 20,
4256–4259.
8. Schnute, M. E.; Cudahy, M. M.; Brideau, R. J.; Homa, F.
L.; Hopkins, T. A.; Knechtel, M. L.; Oien, N. L.; Pitts, T.
W.; Poorman, R. A.; Wathen, M. W.; Wieber, J. L. J.
Med. Chem. 1999, 42, 2447–2455.
The remaining chlorine at position 7 can be used for a
subsequent SNAr or palladium-catalyzed cross-coupling
reaction, as exemplified in Scheme 5. The treatment of
compound 7 with morpholine furnished 5-morpholino
derivative 14. The regiochemistry of this compound
was proven by the reductive dehalogenation of chlorine,
yielding compound 15. In the subsequent step, chlorine
at position 7 was used for a Suzuki-type of coupling with
3,4-dimethoxyphenyl boronic acid, yielding the 5,7-
disubstituted pyrido[4,3-d]pyrimidine analogue 16.
1
9. Compound 8: H NMR (500 MHz, CDCl3): d = 7.06 (s,
1H, H-8), 4.63 (q, J = 7.15 Hz, 2H, OCH2CH3), 3.86 (t,
J = 4.55 Hz, 4H, O(CH2)2), 3.51 (t, J = 4.55 Hz, 4H,
N(CH2)2), 2.62 (s, 3H, 2-CH3), 1.50 (t, J = 7.15 Hz, 3H,
1
OCH2CH3). Compound 9: H NMR (500 MHz, CDCl3):
d = 7.62 (s, 1H, H-8), 4.63 (q, J = 7.1 Hz, 2H, OCH2CH3),
4.62 (s, 2H, CH2OH), 2.69 (s, 3H, 2-CH3), 1.55 (t,
J = 7.1 Hz, 3H, OCH2CH3). Compound 10: 1H NMR
(500 MHz, CDCl3): d = 7.67 (s, 1H, H-8), 7.46–7.42 (m,
5H, ArH), 4.31 (q, J = 6.9 Hz, 2H, OCH2CH3), 2.70 (s,
3H, 2-CH31), 0.96 (t, J = 6.9 Hz, 3H, OCH2CH3). Com-
pound 11: H NMR (500 MHz, CDCl3): d = 7.64 (s, 1H,
H-8), 7.06–7.04 (m, 2H, ArH), 6.93 (d, J = 8.75 Hz, 1H,
ArH), 4.36 (q, J = 7.1 Hz, 2H, OCH2CH3), 3.95 (s, 3H,
OCH3), 3.91 (s, 3H, OCH3), 2.70 (s, 3H, 2-CH3), 1.05 (t,
J = 7.1 Hz, 3H, OCH2CH3).
In summary, we developed an efficient approach which
makes sequential palladium-catalyzed cross-coupling
reactions or nucleophilic aromatic substitutions possible
and will allow for the construction of a diverse pyr-
ido[4,3-d]pyrimidine library, with structural variations
at positions 5 and 7 of the scaffold.
10. General procedure for the reductive removal of chlorine: A
solution of compound 8 or 10 (0.04 mmol), KOAc (6 mg)

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M.-Y. Jang et al. / Tetrahedron Letters 47 (2006) 8917–8920
and 10% Pd/C (2 mg) in THF/MeOH (2:1, 1 ml) was
extracted with CH2Cl2, washed with water and brine and
dried over MgSO4. After concentration under reduced
pressure, the crude residue was purified by chromatogra-
phy on silica gel (CH2Cl2/MeOH 30:1), yielding the pure
compounds 12 and 13 (in yields varying from 45% to
60%).
stirred for 4 h at room temperature under a H2 atmo-
sphere. The mixture was filtered over Celite and the
solvents were evaporated in vacuo. The solid was redis-
solved in dilute HCl and the pH was adjusted to 10, by the
addition of a 2 M NaOH solution. The mixture was