Selective bifunctionalization of pyrido[2,3-d]pyrimidines in positions 2 and 4 by SNAr and palladium-catalyzed coupling reactions

Article abstract of DOI:10.1016/j.tetlet.2005.06.141

Selective disubstitution of 2,4-dichloropyrido[2,3-d]pyrimidine with various nucleophiles was investigated. Suzuki and Stille cross-coupling reactions on monosubstituted compound 4-tert-butylamino-2-chloro-pyrido[2,3-d] pyrimidine were performed in high yields.

Full text of DOI:10.1016/j.tetlet.2005.06.141

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 5851–5855
Selective bifunctionalization of pyrido[2,3-d]pyrimidines in positions
2 and 4 by SNAr and palladium-catalyzed coupling reactions
G. Lavecchia, S. Berteina-Raboin* and G. Guillaumet
Institut de Chimie Organique et Analytique, UMR CNRS 6005, Universite´ d’Orle´ans, BP 6759, 45067 ORLEANS Cedex 2, France
Received 8 March 2005; revised 22 June 2005; accepted 27 June 2005
Available online 14 July 2005
Abstract—Selective disubstitution of 2,4-dichloropyrido[2,3-d]pyrimidine with various nucleophiles was investigated. Suzuki and
Stille cross-coupling reactions on monosubstituted compound 4-tert-butylamino-2-chloro-pyrido[2,3-d]pyrimidine were performed
in high yields.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Pyrido[2,3-d]pyrimidines are known to be pharmacopho-
ric elements in numerous active compounds such as anti-
cancer,1–3 anti-viral,4,5 and anti-inflammatory agents.6
dihydroxypyrido[2,3-d]pyrimidine 2 following Robin
and Hitchings method14 (Scheme 1).
Compound 3 was easily substituted at position 4 with
different nucleophiles15 (Scheme 2). This position was
more reactive than position 2, as in simple pyrimidinic
systems.16 The structures were confirmed by NOESY
studies.
Many publications are devoted to the synthesis of poly-
substituted7,8 and fused pyrido[2,3-d]pyrimidine9,10 sys-
tem, most whose involve substitution on a pyridine
ring.11,12 Prior exploration on the reactivity of pyrim-
idine moiety has shown that substitution essentially
occurred at position 4.13
Aiming to extend pyrido[2,3-d]pyrimidine libraries, a
useful pathway has been developed to obtain pyr-
ido[2,3-d]pyrimidines, that are selectively substituted in
positions 2 and 4 with various nucleophiles.
R1
Cl
Nu1 1 eq.
N
N
N
N
Cl
Base 1.05 eq.
0°C THF
N
N
Cl
We also describe two types of palladium-mediated cross-
coupling reactions (Suzuki and Stille) in position 4, lead-
ing to new dissymmetrical species.
4 R1=NHtBu 85%
5 R1=OBn
6 R1=SPh
73%
69%
Starting material: 2,4-dichloropyrido[2,3-d]pyrimidine 3
was prepared from 2-aminonicotinic acid 1 via 2,4-
Scheme 2.
Cl
N
OH
N
POCl3 reflux
overnight
COOH
NH2
urea 280°C
N
N
N
Cl
N
OH
N
3
65%
2
97%
1
Scheme 1. Previous synthesis of 2,4-dichloropyrido[2,3-d]pyrimidine 3.
Keywords: Suzuki reaction; Stille reaction; Cross-coupling; Palladium; SNAr; Pyrido[2,3-d]pyrimidine.
*
Corresponding author. Tel.: +33 023 849 4856; fax: +33 023 841 7281; e-mail: sabine.berteina@univ-orleans.fr
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.06.141

5852
G. Lavecchia et al. / Tetrahedron Letters 46 (2005) 5851–5855
R1
R1
Nu2
Base
N
N
Conditions A or B
N
N
Cl
N
N
R2
R2=OEt
R2=SEt
R2=OEt
7
8
Cond. A
Cond. A
R1=NHtBu
R1=OBn
R1=SPh
4
5
R1=NHtBu
{
{
{
9
Cond. A
6
R1=OBn
10 Cond. B
R2=NHtBu
R2=OEt
11 Cond. A
12 Cond. B
R1=SPh
R2=NHtBu
Scheme 3. Reagents and conditions: (A) 1 equiv nucleophile, 1.05 equiv NaH, THF, 0 ꢁC; (B) large excess tert-butylamine, THF, reflux overnight.
The reactions proceeded in good yield with high selectiv-
ity for position 4, without an isomer in position 2.
noted that compound 7 (tert-butylamino-group in posi-
tion 4) did not react even under stringent conditions.
The chlorine at position 2 of monosubstituted com-
pounds 4–6 could be substituted with several other nucleo-
philes17 to give products 7–12 as shown in Scheme 3.
A similar reactivity was already observed with the
pyrido[4,3-d]pyrimidine system, as methylsulfanyl- or
anilino-groups in position
4 were also displaced
by nucleophiles.13
The introduction of a tert-butylamino-group required
harsher conditions than for other nucleophiles such as
sodium ethoxide or sodium ethanethiolate, although
expected products were obtained in high yield (Table 1).
Position 2 was also functionalized using palladium-pro-
moted cross-coupling reactions performed on com-
pound 4. Suzuki19 and Stille20 conditions were applied
(Scheme 5). Unfortunately, the chlorine in position
We also found that compounds 9 and 11 were easily
substituted at position 4 by sodium ethoxide under very
mild conditions, affording 1318 (Scheme 4). It should be
HN
HN
N
Table 1. Nucleophilic substitutions at position 4
"Pd"
N
N
R1
R2
Yield (%)
N
N
R3
N
Cl
NH-t-Bu
OEt
SEt
NH-t-Bu
OEt
NH-t-Bu
OEt
78
75
81
72
83
77
14-26
4
OBn
SPh
Scheme 5. Suzuki conditions: boronic acid 1.05 equiv, Pd(PPh3)4
5 mol%, Na2CO3 2 equiv, DME/H2O, 75 ꢁC. Stille conditions: tin
derivative 1.25 equiv, Pd(PPh3)4 5 mol%, toluene reflux then TBAF
1 M/THF.
OEt
Cl
EtONa 2 eq.
THF
3
7
13 98%
N
N
13
R.T. overnight
OEt
N
N
N
Cl
N
9
13 79%
13 80%
13
3
11
EtONa 1 eq.
THF
R.T. overnight
R1
N
OEt
N
N
7
R1=NHtBu
9
R1=OBn
11 R1=SPh
Scheme 4.

G. Lavecchia et al. / Tetrahedron Letters 46 (2005) 5851–5855
5853
Table 2. Cross-coupling yields
Reaction type
R3
Ph
Reaction time
10 min
Yield (%)
Compd
Suzuki coupling
92
90
89
88
86
90
80
84
14
15
16
17
18
19
20
21
o-MeOPh
1 h
1 h
1 h
12 h
2 h
4 h
4 h
m-MeCOPh
1-Naphtyl
4-Pyridyl
2-Furyl
2-Thiophenyl
3-Thiophenyl
Stille coupling
Ph
1 h
1 h
6 h
80
70
68
14
19
20
2-Furyl
2-Thiophenyl
HCl 10%
OEt
Coupling: 1 h
71
22
O
Deprotection: 5 min
1 h
100
82
23
24
SnBu3
3 h
1 h
72
78
25
26
via
Me
2 did not react under the Sonogashira or Heck
protocols.
The Suzuki and Stille coupling for different R3 groups
are summarized in Table 2. Interestingly, Stille coupling
with allenic tin derivatives afforded alkyne 25, which is
unreachable by the Sonogashira method in the present
case. Formation of 25 could be explained by a rapid
thermal isomerization of allenic intermediate 250 pro-
duced just after the cross-coupling. The possibility of a
base-catalyzed isomerization of 250 with fluoride anion
The transformation proceeded under quite mild
conditions and reaction times were often short. The
experiments led to the expected compounds in excellent
yields (Table 2) even for ethoxyvinyl product 22, of
which derivatives are usually sensitive.
HN
N
Thermal
isomerisation
H
N
N
Coupling
reaction
H
H
25'
HN
HN
N
N
N
N
N
Cl
N
25
4
Base-catalysed
isomerisation
Coupling
reaction
HN
N
N
H
N
H
H
25'
F
Scheme 6.

5854
G. Lavecchia et al. / Tetrahedron Letters 46 (2005) 5851–5855
NHCCH3); 2.04 (s; 3H; CCH3); 6.05 (sl; 1H; NH); 7.28
(dd; 1H; H6; J = 4.4 Hz; J = 7.8 Hz); 8.21 (dd; 1H; H5;
J = 1.5 Hz; J = 7.8 Hz); 8.95 (dd; 1H; H7; J = 1.5 Hz;
J = 4.4 Hz); 13C NMR (CDCl3) dppm: 28.0 (CH3); 53.4
(CCH3); 109.0 (C4a); 121.3 (C6); 133.7 (C5); 155.9 (C7);
158.7; 159.2; 161.3 (C8a); MS: m/z = 235 (M+H; 35Cl)+;
237 (M+H; 37Cl)+.
Compound 5: 4-benzyloxy-2-chloro-pyrido[2,3-d]pyrim-
idine: 1H NMR (CDCl3) dppm: 5.65 (s; 2H; OCH2Ph);
7.35–7.52 (m; 6H; Harom and H6); 8.50 (dd; 1H; H5;
J = 2.0 Hz; J = 8.1 Hz); 9.12 (dd; 1H; H7; J = 2.0 Hz;
J = 4.4 Hz); 13C NMR dppm: 70.6 (OCH2Ph); 110.2 (C4a);
122.8 (C6); 128.5; 128.8; 128.9; 133.7; 134.7; 157.9 (C7);
159.6; 160.3; 168.4 (C4); MS: m/z = 272 (M+H; 35Cl)+;
274 (M+H; 37Cl)+.
from TBAF workup is less likely since compound 25
was also observed without this workup (Scheme 6).
To resume, disubstituted-pyrido[2,3-d]pyrimidines were
prepared by the means of easy and clean reactions. Posi-
tions 2 and 4 were diversified by introduction of various
nucleophiles. Two typical cross-coupling palladium-
mediated reactions were successfully investigated from
4-tert-butylamino-2-chloro-pyrido[2,3-d]pyrimidine. In
this way, a new alkyne species 25 was obtained.
Acknowledgment
Compound
6:
2-chloro-4-phenylsulfanyl-pyrido[2,3-
The authors gratefully acknowledge Laboratoires SER-
VIER (Courbevoie FRANCE) for financial support.
1
d]pyrimidine: H NMR (CDCl3) dppm: 7.48–7.63 (m; 6H;
Harom and H6); 8.55 (dd; 1H; H5; J = 1.8 Hz; J = 8.3 Hz);
9.19 (dd; 1H; H7; J = 1.8 Hz; J = 4.4 Hz); 13C NMR dppm
:
118.2(C4a); 124.6 (C6); 127.0 (Carom); 131.2 (Carom); 132.0
(C5); 134.9 (Carom); 137.1 (Carom); 159.4; 160.1 (C7); 161.3;
MS: m/z = 274 (M+H; 35Cl)+; 276 (M+H; 37Cl)+.
16. Chung, M.; Harris, P. A.; Lackey, K. E. Tetrahedron Lett.
2001, 42, 999–1001.
References and notes
1. Gangjee, A.; Adair, O.; Queener, S. F. Bioorg. Med.
Chem. 2001, 9, 2929–2935.
17. Experimental details of conditions A: 0.35 mmol (1 equiv)
of 2-chloro-4-substituted-pyrido[2,3-d]pyrimidine were
dissolved in THF (20 mL) then cooled at 0 ꢁC. A solution
of 1 equiv nucleophile and 1.05 equiv of sodium hydride in
THF (5 mL) was added dropwise at 0 ꢁC. The mixture was
stirred overnight then the solvents were removed under
vacuum. The crude residue was purified by silica gel
column chromatography.
2. Toogood, P. L. Med. Chem. Rev. 2001, 21, 487–498.
3. Pietrzkowski, Z.; Girardet, J.-L.; Esler, C.; Wang, G.
Nucleosides Nucleotides Nucleic Acids 2001, 20, 323–328.
4. Singh, Gi; Singh, Ga; Yadav, A. K.; Mishra, A. K. Indian
J. Chem., Sect. B 2002, 41B, 430–432.
5. Kumar, N.; Singh, G.; Yadav, A. K. Heteroat. Chem.
2001, 12, 52–56.
6. Ghilsoo, N.; Cheol, M. Y.; Euikyung, K.; Chung, K. R.;
Joong, H. K.; Jung, H. S.; Sung, H. K. Bioorg. Med.
Chem. Lett. 2001, 11, 611–614.
7. Bae, J. W.; Lee, S. H.; Cho, Y. J.; Jung, Y. J.; Hwang,
H.-J.; Yoon, C. M. Tetrahedron Lett. 2000, 41, 5899–5902.
8. Wardakhan, W. W.; Agami, S. M. Egyptian J. Chem.
2001, 9, 2929–2935.
9. Oganisyan, A. S.; Noravyan, A. S.; Grigoryan, M. Z.
Chem. Heterocycl. Comp. 2001, 37, 763–765.
10. Booth, B. L.; Carpenter, R. A.; Morlock, G.; Mahmood,
Z.; Pritchard, R. B. Synthesis 2001, 16, 2393–2396.
11. Saoud, M.; Benabdelouahab, F. B.; El Guemmout, F.;
Romerosa, A. Chem. Heterocycl. Comp. 2002, 38, 306–
309.
12. Quiroga, J.; Insuasty, H.; Insuasty, B.; Abonia, R.; Cobo,
J.; Sanchez, A.; Nogeras, M. Tetrahedron 2002, 58, 4873–
4877.
13. Rewcastle, G. W.; Palmer, B. D.; Thompson, A. M.;
Bridges, A. J.; Cody, D. R.; Zhou, H.; Fry, D. W.;
McMichael, A.; Denny, W. A. J. Med. Chem. 1996, 39,
1823–1835.
14. Robins, R. K.; Hitchings, G. H. J. Am. Chem. Soc. 1954,
77, 2256–2260.
15. General procedure for synthesis of 4-chloro-2-substituted-
pyrido[2,3-d]pyrimidines 4–6: 5 mmol (1 equiv) of 2,4-
dichloropyrido[2,3-d]pyrimidine 3 were dissolved in THF
(50 mL) then cooled at 0 ꢁC. A solution of 1 equiv
nucleophile and 1.05 equiv of sodium hydride (for thio-
phenol or benzyl alcohol as nucleophile) or 1.05 equiv of
triethylamine (for tert-butylamine as nucleophile) in THF
(15 mL) was added dropwise at 0 ꢁC. The mixture was
stirred overnight then 10 mL of cold water was poured
onto, and then extracted with ethylacetate. The organic
phase wad dried on MgSO4 and finally evaporated under
reduced pressure. The crude residue was purified by silica
gel column chromatography.
Compound 11: 2-ethoxy-4-phenylsulfanyl-pyrido[2,3-
d]pyrimidine: 1H NMR (CDCl3) dppm: 1.36 (t; 3H;
CH2CH3; J = 7.0 Hz); 4.41 (q; 2H; CH2CH3; J =
7.0 Hz); 7.31 (dd; 1H; H6; J = 4.6 Hz; J = 8.2 Hz); 7.40–
7.43 (m; 3H; Harom); 7.67–7.72 (m; 2H; Harom); 8.35 (dd;
1H; H5; J = 2.0 Hz; J = 8.2 Hz); 8.98 (dd; 1H; H7; J =
2.0 Hz; J = 4.6 Hz); 13C NMR (CDCl3) dppm
: 12.0
(CH2CH3); 62.0 (CH2CH3); 107.3 (C4a); 119.0 (C6);
126.9 (Carom); 127.1 (Carom); 127.5 (Carom); 131.3 (C5);
133.4 (Carom); 154.8 (C7); 158.0 (C4); 164.5 (C8a); 169.6
(C2); MS: m/z = 284 (M+H)+.
Experimental details of conditions B: 0.37 mmol (1 equiv)
of 2-chloro-4-substituted-pyrido[2,3-d]pyrimidine were
dissolved in THF (20 mL) then excess of tert-butylamine
(2 mL) was added, and the mixture was refluxed overnight.
After cooling, the solvents were evaporated under
vacuum. The crude residue was purified by silica gel
column chromatography. Compound 12: 2-tert-butyl-
1
amino-4-phenylsulfanyl-pyrido[2,3-d]pyrimidine: H NMR
(CDCl3) dppm: 1.57 (s; 9H; CCH3); 7.08 (dd; 1H; H6;
J = 4.4 Hz; J = 8.1 Hz); 7.44–7.46 (m; 3H; Harom); 7.57–
7.60 (m; 2H; Harom); 8.26 (dd; 1H; H5; J = 1.8 Hz;
J = 8.1 Hz); 8.86 (dd; 1H; H7; J = 1.8 Hz; J = 4.4 Hz);
13C NMR dppm: 28.9 (CCH3); 51.2 (CCH3); 117.2 (C4a);
120.8 (C6); 127.3; 129.2; 129.5; 129.8; 133.2; 156.0 (C7);
157.3; MS: m/z = 311 (M+H)+.
18. Preparation of 13. 0.5 mmol (1 equiv) of 9 or 11 were
dissolved in THF (20 mL), then a solution of ethanol
(1 equiv), and sodium hydride (1.05 equiv) in THF (5 mL)
was added. The mixture was stirred overnight, then the
solvents were removed under reduced pressure. The crude
residue was purified by silica gel column chromatography
(dichloromethane/ethylacetate 5/5).
Compound 13: 2,4-diethoxy-pyrido[2,3-d]pyrimidine: 1H
NMR (CDCl3) dppm: 1.47–1.54 (m; 6H; CH2CH3); 4.60–
4.70 (m; 4H; CH2CH3); 7.31 (dd; 1H; H6; J = 4.4 Hz;
J = 7.9 Hz); 8.40 (dd; 1H; H5; J = 2.2 Hz; J = 7.9 Hz);
Compound 4: 4-tert-butylamino-2-chloropyrido[2,3-d]-
pyrimidine: 1H NMR (CDCl3) dppm
: 1.59 (s; 9H;

G. Lavecchia et al. / Tetrahedron Letters 46 (2005) 5851–5855
5855
8.98 (dd; 1H; H7; J = 2.2 Hz; J = 4.4 Hz); 13C NMR dppm
:
14.2 (CH2CH3); 14.4 (CH2CH3); 64.1 (2 · CH2CH3);
108.4 (C4a); 119.8 (C6); 133.5 (C5); 156.6 (C7); 161.0
(C8a); 164.2 (C2 or C4); 169.4 (C2 or C4); MS: m/z = 220
(M+H)+.
J = 8.1 Hz); 8.93 (dd; 1H; H7; J = 1.8 Hz; J = 4.4 Hz); 13
C
NMR (CDCl3) dppm: 28.8 (CCH3); 53.3 (CCH3); 109.0
(C4a); 112.0 (Cfur); 114.1 (Cfur); 120.3 (C6); 130.6 (C5); 145.0
(Cfur); 153.3 (Cfur); 155.6 (C7); 156.4 (C4); 159.4 (C2 or C8a);
160.1 (C2 or C8a); MS: m/z = 213 (M+Hꢀt-Bu)+, 269
(M+H)+.
19. See experimental section for Suzuki coupling: Enguehard,
C.; Renou, J. L.; Allouchi, H.; Leger, J. M.; Gueiffier, A.
Chem. Pharm. Bull. 2000, 48, 935–940.
20. See experimental section for Stille coupling: Aboul-Fadl,
T.; Lo¨ber, S.; Gmeiner, P. Synthesis 2000, 1727–1732Com-
pound 24: 4-tert-butylamino-2-vinyl-pyrido[2,3-d]pyrim-
idine: 1H NMR (CDCl3) dppm: 1.62 (s; 9H; CH3); 5.71–
5.81 (m; 2H; CH@CH2); 6.66–6.95 (m; 2H; CH@CH2 and
H6); 8.10 (sl; 1H; H5); 8.93 (sl; 1H; H7); 13C NMR
(CDCl3) dppm: 29.1 (CH3); 53.6 (CCH3); 109.4 (C4a); 120.9
(C6); 124.4 (CH@CH2); 130.7 (C5); 138.5 (CH@CH2);
155.8 (C7); 159.7 (C2 or C4); 160.0 (C2 or C4); 163.7 (C8a);
MS: m/z = 173 (M+Hꢀt-Bu)+, 229 (M+H)+.
Compound 16: 4-tert-butylamino-2-(m-methylcarbonyl-
1
phenyl)-pyrido[2,3-d]pyrimidine: H NMR (CDCl3) dppm
:
1.70 (s; 9H; NHCCH3); 2.70 (s; 3H; COCH3); 6.45 (sl; 1H;
NH); 7.28 (dd; 1H; H6; J = 4.2 Hz; J = 8.0 Hz); 7.45–7.70
(m; 2H; Harom); 8.09–8.12 (m; 1H; Harom); 8.38 (dd; 1H; H5;
J = 1.6 Hz; J = 8.0 Hz); 8.84–8.87 (m; 1H; Harom); 8.98 (dd;
1H; H7; J = 1.6 Hz; J = 4.2 Hz); 13C NMR dppm: 26.8
(COCH3); 28.8 (NHCCH3); 53.3 (NHCCH3); 109.2 (C4a);
120.7 (C6); 128.6; 129.3; 129.9; 131.1; 133.4; 137.2; 139.0;
155.6 (C7); 159.4; 160.2; 162.3; 198.5 (C@O); MS: m/
z = 265 (M+Hꢀt-Bu)+, 321 (M+H)+; IR (cmꢀ1, KBr):
1685 (C@O).
Compound 25: 4-tert-butylamino-2-(methylethynyl)-pyr-
ido[2,3-d]pyrimidine: 1H NMR (CDCl3) dppm: 1.59 (s; 9H;
NHCCH3); 2.04 (s; 3H; C„CCH3); 6.05 (sl; 1H; NH);
7.28 (dd; 1H; H6; J = 4.4 Hz; J = 7.8 Hz); 8.21 (dd; 1H;
H5; J = 1.5 Hz; J = 7.8 Hz); 8.95 (dd; 1H; H7; J = 1.5 Hz;
J = 4.4 Hz); 13C NMR (CDCl3) dppm: 4.5 (C„CCH3);
28.8 (NCCH3); 53.5 (NHCCH3); 81.0 (C„CCH3); 84.4
(C„CCH3); 109.3 (C4a); 120.9 (C6); 130.7 (C5); 151.3 (C7);
152.1; 158.9; 160.1; MS: m/z = 185 (M+Hꢀt-Bu)+, 241
(M+H)+.
Compound 19: 4-tert-butylamino-2-(furan-2-yl)-pyr-
ido[2,3-d]pyrimidine: 1H NMR (CDCl3) dppm: 1.59 (s; 9H;
CH3); 6.01 (sl; 1H; NH); 6.54 (dd; 1H; Hfur; J = 1.8 Hz;
3
3
J = 3.4 Hz); 7.25 (dd; 1H; H6; J = 4.4 Hz; J = 8.1 Hz);
7.39 (dd; 1H; Hfur; J = 0.8 Hz; J = 3.4 Hz); 7.60 (dd; 1H;
H
fur; J = 0.8 Hz; J = 1.8 Hz); 8.18 (dd; 1H; H5; J = 1.8 Hz;