3426
B. Shao / Tetrahedron Letters 46 (2005) 3423–3427
Y
X
O
N
X
N
Y
Y
EWG
X
O
EWG
EDG
N
EDG
N
N
O
EWG
major component
intermediate
Figure 1. Formation of fused lactones and lactams.
6. Mihovilovic, D.; Leisch, G.; Mereiter, K. Tetrahedron
Lett. 2004, 45, 7087–7090.
7. Karthikeyan, M.; Kamakshi, R.; Sridar, V.; Reddy, B. S.
R. Synth. Commun. 2003, 33, 4199–4204.
1:2. It is most likely that the oxygen in the vessel oxi-
dized the methylene adjacent to nitrogen atom at high
temperature (Scheme 4).
8. Gomtsyan, A.; Didomenico, S.; Lee, C.; Matulenko, M.;
Kim, K.; Kowaluk, E.; Wismer, C.; Mikusa, J.; Yu, H.;
Kohlhass, K.; Jarvis, M.; Shripad, B. J. Med. Chem. 2002,
45, 3639–3648.
9. The microwave-assisted reactions were carried out in a
Microsynth from Milestone with maximum power output
of 1000 W. The reaction temperature profiles used were:
22–280 °C in 1 min, hold at 280 °C for 2.5 min then power
off to cool down to room temperature. For substrate 5
only, 22–265 °C in 1 min, hold at 265 °C for 45 min, then
power off to cool down to room temperature.
We have found that the electronic properties of the
pyrimidine dictate the ratio of the final products. After
cycloaddition occurs across the pyrimidine, the more
electronically rich moiety is selectively extruded from
the intermediate (Fig. 1). This was observed in the
microwave-mediated cycloadditions of both 12 and 14,
where 23 was isolated as the major component and 27
and 28 were minor products, respectively. It was be-
lieved that compounds like 27 and 28 could be accessible
by coupling between 23 and the corresponding amines.
However, several attempts of such direct coupling reac-
tion failed due to the inert characteristic of 23 even at
high temperature under argon. When 22 and 25 were
subjected to the same direct coupling thermally with
an amine under argon, no desired products were ob-
served by LC/MS. Compounds 27 and 28 were eventu-
ally synthesized and isolated in 40% and 69% yields
from 13 and 15, where both chlorine atoms were
replaced with the same amine nucleophile. Similarly,
29 was synthesized and isolated.
10. Satisfactory spectroscopic data (proton NMR, 400 MHz,
MS and elemental analysis) have been obtained for all new
compounds. Compound 20: (CDCl3) d 8.43 (q, 1H, J =
0.8Hz); 5.25 (d, 2H, J = 0.4 Hz); 2.38 (m, 3H). MS: 184
(MH+), 206 (M++Na+). Found: C, 52.23; H, 3.19; N, 7.55.
C8H6ClNO2 requires C, 52.34; H, 3.29; N, 7.63. Com-
pound 21: (CDCl3) d 8.68 (s, 1H); 7.54 (m, 3H); 7.43 (m,
2H); 5.40 (s, 2H). MS: 246 (MH+), 268 (M+Na). Found:
C, 63.16; H, 3.15; N, 5.72. C13H8ClNO2 requires C, 63.56;
H, 3.28; N, 5.70. Compound 22: (CDCl3) d 8.56 (d,
J = 4.8 Hz, 1H); 7.42 (dt, J = 0.4, 5.0 Hz, 1H); 6.82 (br s,
1H); 4.49 (t, J = 0.8 Hz, 2H). MS: 169 (MH+), 191
(M++Na+). Found: C, 49.72; H, 3.01; N, 16.32.
C7H5ClN2O requires C, 49.87; H, 2.99; N, 16.62. Com-
pound 23: (CDCl3) d 8.57 (d, 1H, J = 4.8 Hz); 8.01 (br s,
1H, NH); 7.35 (d, 1H, J = 4.8 Hz); 1.60 (s, 6H). MS: 219
(MH+). Found: C, 54.20; H, 4.58; N, 14.13. C9H9ClN2O
requires C, 54.97; H, 4.61; N, 14.25. Compound 25:
(CDCl3) d 8.51 (d, J = 4.8 Hz, 1H); 7.37 (dt, J = 0.4,
4.8 Hz, 1H); 4.40 (s, 2H); 3.20 (s, 3H). MS: 183.1 (MH+);
205 (M+Na). Found: C, 51.94; H, 3.76; N, 14.99.
C8H7ClN2O requires C, 52.62; H, 3.86; N, 15.34. Com-
pound 26: (CDCl3) d 8.83 (d, J = 4.8 Hz, 1H); 7.73 (d,
J = 4.8 Hz, 1H); 3.23 (s, 3H). MS: 197.0 (MH+). Found:
C, 49.45; H, 2.61; N, 13.90. C8H5ClN2O2 requires C,
48.88; H, 2.56; N, 14.25. Compound 27: (CDCl3) d 8.27 (d,
1H, J = 4.8 Hz); 7.28 (m, 2H); 7.19 (m, 3H); 6.68 (d, 1H,
J = 4.8 Hz); 6.26 (br s, 1H, NH); 4.41 (m, 2H); 2.89 (t, 2H,
J = 12 Hz); 2.60 (d, 2H, J = 6.8 Hz); 1.4–1.8 (m, 5H). MS:
336 (MH+), 358 (M++Na+). Found: C, 74.51; H, 7.51; N,
12.37. C21H25N3O requires C, 75.19; H, 7.51; N, 12.53.
Compound 28: (CDCl3) d 8.28 (d, 1H, J = 4.8 Hz); 6.67 (d,
1H, J = 4.8 Hz); 3.66 (t, 4H, J = 5.2 Hz); 1.73 (m, 4H);
1.62 (m, 2H); 1.48 (s, 6H). MS: 246 (MH+). Found: C,
67.75; H, 7.84; N, 16.90. C14H19N3O requires C, 68.54; H,
7.81; N, 17.13. Compound 29: (CDCl3)d 8.15 (d, 1H,
J = 4.8 Hz); 7.21 (m, 2H); 7.12 (m, 3H); 6.67 (d, 1H,
J = 4.8 Hz); 4.30 (br d, 2H, J = 12 Hz); 4.20 (s, 2H); 3.06
In summary, application of microwave conditions to the
hetero-Diels–Alder cycloaddition reaction of acetylenic
pyrimidines increases yields and broadens the utility to
the preparation of pyrido-fused lactams.
Supplementary data
Proton NMRs of compounds 20, 21, 22, 23, 25, 26, 27,
28, 29, 30. Supplementary data associated with this arti-
References and notes
1. Details will be published elsewhere.
2. Mongin, F.; Trecourt, F.; Queguiner, G. Tetrahedron Lett.
1999, 40, 5483–5486.
3. Tarasov, E. V.; Henckens, A.; Ceulemans, E.; Dehaen, W.
Synlett 2000, 625–626.
4. Keller, E. Schweiz. Laboratoriums-Z. 2004, 61, 162–165.
5. Kartritzky, R.; Singh, K. Arkivoc 2003, 13, 68–86.