J. Kasparec et al. / Tetrahedron Letters 44 (2003) 4567–4570
4569
Table 3. Introduction of amine side chain
M.; Trumpp-Kallmeyer, S.; Toogood, P.; Wu, Z.; Zhang,
E. J. Med. Chem. 2000, 43, 4606–4616.
2. Klutchko, S. R.; Hamby, J. M.; Boschelli, D. H.; Wu, Z.;
Kraker, A. J.; Amar, A. M.; Hartl, B. G.; Shen, C.;
Klohs, W. D.; Steinkampf, R. W.; Driscoll, D. L.; Nel-
son, J. M.; Elliott, W. L.; Roberts, B. J.; Stoner, C. L.;
Vincent, P. W.; Dykes, D. J.; Panek, R. L.; Lu, G. H.;
Major, T. C.; Dahring, T. K.; Hallak, H.; Bradford, L.
A.; Showalter, H. D. H.; Doherty, A. M. J. Med. Chem.
1998, 41, 3276–3292.
3. Boschelli, D. H.; Wu, Z.; Klutchko, S. R.; Showalter, H.
D. H.; Hamby, J. M.; Lu, G. H.; Major, T. C.; Dahring,
T. K.; Batley, B.; Panek, R. L.; Keiser, J.; Hartl, B. G.;
Kraker, A. J.; Klohs, W. D.; Roberts, B. J.; Patmore, S.;
Elliott, W. L.; Steinkampf, R.; Bradford, L. A.; Hallak,
H.; Doherty, M. J. Med. Chem. 1998, 41, 4365–4377.
4. Aldehyde 5 is available from Maybridge but may also be
easily prepared in one step from the more readily avail-
able 4,6-dihydroxy-2-methylsulfanylpyrimidine using the
procedure described in: (a) Santilli, A. A.; Dong, H. K.;
Wander, S. K. J. Heterocyclic Chem. 1971, 8, 445–453.
For other examples of previously described pyrimidines
which could be used to assemble a heavily derivatized
bicyclic system, see: (b) Taylor, E. C.; Gillespie, P. J. Org.
Chem. 1992, 57, 5757–5761; (c) Wormstadt, F.; Brinck-
man, U.; Gutschow, M.; Eger, K. J. Heterocyclic Chem.
2000, 37, 1187–1191.
Sulfoxide used
R3 group, derived from
amine R3NH2
Isolated yield (%)
11a
11a
11b
11b
11b
11b
-CH2CH2OH
-CH2CH2NH2
-CH2CH2OH
-CH2CH2N(CH2CH3)2
1-Methylpiperidin-4-yl
-CH2CH2NH2
1a (94)
1b (78)
1c (96)
1d (92)
1e (85)
1f (82)
chlorophenyl but not for R1=3-pentyl (only 10% yield
after 48 h).
As shown above, the optimal method for the conver-
sion of 7 to 8 is highly dependent on the nature of R1,
i.e. whether R1 is alkyl or aryl. Our studies indicated
that, when R1=alkyl, 7 is cleanly converted to 8 in one
step using the Horner-Emmons reaction (Table 1, entry
II). When R1=aryl, the conversion of 7 to 8 is most
efficiently performed by reflux with acetic anhydride
and pyridine (Table 1, entry III). These procedures
have worked well for all examples of R1 used so far in
this research.
5. Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24,
4405–4408.
6. Jacobsen, E. N.; Deng, L.; Furukawa, Y.; Martinez, L.
E. Tetrahedron 1994, 50, 4323–4334.
7. Under the reaction conditions, the weak base used (excess
alkylamine or aniline added) plays a key role in ensuring
that no imine is formed. When the reaction was run in
DMSO using 1 equiv. of NaH, up to 50% yield of the
corresponding imine was observed. 4-Chloro-6-(1-ethyl-
propylamino)-2-methylsulfanylpyrimidine-5-carboxalde-
1
hyde (6a): H NMR (CDCl3): l 0.92 (t, 6H, J=7.3 Hz),
As part of the final derivatization step in this synthesis,
oxidation of sulfide 8 with mCPBA afforded sulfone
11,11 which was then reacted with a wide range of
amine nucleophiles under mild conditions to afford the
desired product 112 (Table 3). The final trisubstituted
pyrido[2,3-d]pyrimidin-7-ones were easily purified by a
combination of aqueous work-up and column
chromatography.
1.50–1.74 (m, 4H), 2.52 (s, 3H), 4.22 (m, 1H), 9.21 (br s,
1H), 10.33 (s, 1H). LC MS (m/e)=274 (MH+). 4-Chloro-
6-(2-chlorophenylamino)-2-methylsulfanylpyrimidine-5-
1
carboxaldehyde (6b): H NMR (CDCl3): l 2.55 (s, 3H),
7.17 (m, 1H), 7.29 (m, 2H), 7.44 (m, 1H), 10.37 (s, 1H),
11.49 (br s, 1H). LC MS (m/e)=315 (MH+).
8. 4-(2-Chlorophenyl)-6-(1-ethylpropylamino)-2-methylsul-
fanylpyrimidine-5-carboxaldehyde (7a): 1H NMR
(CDCl3): l 0.91 (m, 6H), 1.42–1.60 (m, 4H), 2.45 (s, 3H),
4.21 (m, 1H), 7.32 (m, 4H), 8.96 (br s, 1H), 9.44 (s, 1H).
LC MS (m/e)=350.2 (MH+). 4-(2-Chlorophenyl)-6-(2-
chlorophenylamino)-2-methylsulfanylpyrimidine-5-carb-
oxaldehyde (7b): 1H NMR (CDCl3): l 2.58 (s, 3H),
7.01–7.59 (m, 7H), 8.61 (d, 1H, J=4.7 Hz), 9.65 (s, 1H),
11.48 (br s, 1H). LC MS (m/e)=390 (MH+).
Conclusion
A novel, highly efficient and scalable route to trisubsti-
tuted pyrido[2,3-d]pyrimidin-7-ones was developed.
Readily available starting material 5 was converted into
the desired pyrimidinones 1 in five steps in about 40%
overall yield.
9. 4-(2-Chlorophenyl)-8-(1-ethylpropyl)-2-methylsulfanyl-
8H-pyrido[2,3-d]pyrimidin-7-one
(8a):
1H
NMR
(CDCl3): l 0.85 (m, 6H), 2.01 (m, 2H), 2.26–2.44 (m,
2H), 2.63 (s, 3H), 5.39 (m, 0.5H), 5.75 (m, 0.5H), 6.62 (br
d, 1H, J=9.6), 7.31–7.60 (m, 5H). LC MS (m/e)=374.2
(MH+). 4-(2-Chlorophenyl)-8-(2-chlorophenyl)-2-methyl-
sulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (8b): H NMR
(CDCl3): l 1.99 (s, 3H), 6.50 (d, 1H, J=9.7 Hz), 7.11–
7.48 (m, 9H). LC MS (m/e)=414 (MH+).
References
1
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