1978
L. G. Voskressensky et al. / Tetrahedron Letters 46 (2005) 1975–1979
1.DMAD, R2OH
2.H+
10. Voskressensky, L. G.; Borisova, T. N.; Kulikova, L. N.;
Varlamov, A. V.; Catto, M.; Altomare, C.; Carotti, A.
Eur. J. Org. Chem. 2004, 3128.
11. Borisova, T. N.; Voskressensky, L. G.; Kulikova, L. N.;
Soklakova, T. A.; Varlamov, A. V. Mol. Divers. 2003, 6,
207.
12. We used a slightly modified protocol as compared to the
one reported in: Gatto, F.; Rosariadel Giudice, M.;
Mustazza, C. J. Heterocycl. Chem. 1996, 33, 1807. The
main difference is the decrease of the reaction temperature
from 150–160 ꢁC (recommended) to 90–95 ꢁC, which led
to a dramatic increase in yield.
OR2
O
N
O
R
NH
N
NH
N
R1
R1
16
RHN
Scheme 7.
that the enamine bond in compounds 12–14 is cleaved
by any strong acid (e.g., HCl, H2SO4).
13. Cook, A. H.; Reed, K. J. J. Chem. Soc. 1945,
399.
This fact, along with the good yields and the availability
of the starting materials encouraged us to elaborate a
one-pot procedure for the synthesis of substituted pyri-
midinyl-4-ethylamines of general formula 16, having
three points of diversity (hardly available by other syn-
thetic means) (Scheme 7).20
14. General experimental procedure: To a solution of 1 mmol
of the benzonaphthyridine derivative 3, 4 in 10 mL of
methyl alcohol, 1.2 mmol of DMAD was added. The
reaction mixture was stirred for 4–6 h at room tempera-
ture (TLC monitoring). The solvent was evaporated under
reduced pressure. The resulting residue was purified by
column chromatography using 1:2 ethyl acetate–hexane
mixture as eluent. The first fraction provided the corre-
sponding derivatives 8 and 9. Further elution provided
compounds 10 and 11. (In the case of benzonaphthyridine
4, LC–MS analysis of the reaction mass carried out within
2 h after the reaction start showed a small peak (approx.
7–8%) due to a compound with m/z 333, which was neither
isolated nor identified.) Selected physical data for dimethyl
(2Z)-2-(10-cyano-2-isopropyl-1,2,3,4-tetrahydrobenzo[b]-
1,6-naphthyridin-1-yl)but-2-enedioate (8): pale-yellow crys-
In conclusion, we have demonstrated, that 10-cyano tetra-
hydrobenzo[b][1,6]naphthyridines 3, 4 undergo unusual
reactions with DMAD, leading to the formation of
diesters 8–11 having good synthetic potential. We
have also demonstrated, that the readily available tetra-
hydropyrido[4,3-b]pyrimidines react with DMAD
undergoing a tandem cleavage process involving one
molecule of methanol. The resulting enamines are read-
ily cleaved under acidic conditions providing in high
yields the corresponding dihydropyrymidinylethyl-
amines which are hardly available by other synthetic
means. A one-pot protocol for this transformation has
been elaborated.
1
tals, mp 135–137 ꢁC. H NMR (400 MHz, CDCl3): d 8.13
(m, 2H), 7.80 (m, 1H), 7.68 (m, 1H), 5.84 (s, 1H), 5.32 (s,
1H), 3.79 (s, 3H), 3.70 (s, 3H), 3.39 (m, 1H), 3.22–2.90 (m,
4H), 1.14 (d, J = 6.0 Hz, 3H), 1.11 (d, J = 6.0 Hz, 3H). 13
C
NMR (100 MHz, CDCl3): 166.8, 164.5, 157.9, 150.2,
146.5, 131.5, 130.9, 129.2, 128.4, 124.7, 124.6, 122.8, 117.4,
113.9, 61.2, 52.1, 51.8, 50.4, 39.9, 31.2, 20.9, 18.4. EIMS:
m/z (%): 393 (M+, 16), 378 (30), 350 (21), 334 (23), 251
(20), 250 (100), 234 (18), 208 (40), 206 (20), 193 (15).
Selected physical data for dimethyl (2Z)-2-[amino(2-
isopropyl-1-oxo-1,2,3,4-tetrahydrobenzo[b]-1,6-naphthyri-
din-10-yl)methylene]succinate (10): yellow crystals, mp
205–207 ꢁC. 1H NMR (400 MHz, CDCl3): d 8.14 (d,
J = 8.1 Hz, 1H), 8.00 (d, J = 8.1 Hz, 1H), 7.80 (t,
J = 8.1 Hz, 1H), 7.61 (t, J = 8.1 Hz, 1H), 6.60 (br s, 2H),
5.10 (spt, J = 6.8 Hz, 1H), 3.80 (s, 3H), 3.60–3.40 (m, 2H),
3.35 (s, 3H), 3.31–3.22 (m, 2H), 2.80 (d, J = 17.1 Hz, 1H),
2.60 (d, J = 17.1 Hz, 1H), 1.22 (d, J = 6.8 Hz, 3H), 1.20 (d,
J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3): d 167.3,
164.4, 156.1, 152.6, 152.1, 143.1, 138.6, 126.5, 123.2, 122.0,
121.9, 119.7, 115.2, 85.2, 46.2, 45.7, 38.8, 32.5, 28.4, 28.2,
14.6, 14.2. EIMS: m/z (%): 411 (M+, 55), 379 (15), 352
(100), 337 (75), 320 (20), 306 (60), 292 (25), 278 (30), 250
(30), 235 (25), 224 (25), 206 (22), 192 (15).
Acknowledgements
This work was supported by the Russian Foundation
for Basic Research (Grant # 05-03-32211) and the
ÔRussian UniversitiesÕ federal program (Grant # UR
05.01.254). The authors want to thank Dr. G. G.
Alexandrov (RAS Kurnakov Institute) for the X-ray
analyses.
References and notes
1. Siener, T.; Mueller, U.; Jansen, M.; Holzgrabe, U.
Pharmazie 1998, 53, 442.
2. Boiteau, L.; Boivin, J.; Liard, A.; Quiclet-Sire, B.; Zard, S.
Z. Angew. Chem., Int. Ed. 1998, 37, 1128.
3. Li, X.; Schenkel, L. B.; Kozlowski, M. C. Org. Lett. 2000,
2, 875.
4. Li, X.; Yang, J.; Kozlowski, M. C. Org. Lett. 2001, 3,
1137.
5. Xie, X.; Phuan, P.-W.; Kozlowski, M. C. Angew. Chem.,
Int. Ed. 2003, 42, 2168.
15. Crystal structure analysis for 8: C22H23N3O4,
Mr = 393.43 g molꢀ1
, monoclinic, space group P21/c,
˚
a = 9.784(3),
100.01(3)ꢁ, V = 2067.4(9) A , Z = 4, q = 1.264 g cm , l =
0.088 cmꢀ1
b = 17.546(4),
c = 12.229(3) A,
b =
3
3
˚
,
F(000) = 832, crystal size: 0.12 · 0.06 ·
0.02 mm. Crystal data was collected on a Cad-4 diffrac-
tometer (k Mo Ka radiation, graphite monochromator; x
6. Vasse, J.-L.; Levacher, V.; Bourguignon, J.; Dupas, G.
Tetrahedron 2003, 59, 4911.
7. Rosovsky, A.; Mota, C. E.; Queener, S. F. J. Heterocycl.
Chem. 1995, 32, 335.
8. Huber, I.; Fulop, F.; Bernath, G.; Hermecz, I. J. Hetero-
cycl. Chem. 1987, 24, 1473.
9. Victory, P.; Crespo, A.; Garriga, M.; Nomen, R. J.
Heterocycl. Chem. 1988, 25, 245.
scaning, 2hmakc. = 50ꢁ).
A total of 3860 reflections
(2.05 < h < 24.97ꢁ) were collected of which 3610 were
unique (R(int) = 0.0958). The structure was solved with
the program SHELXS-9721 and refined using SHELXL-9722 to
R1 = 0.0520 and wR(F2) = 0.1450 for 2377 reflections with
I > 2r(I); max.nmin. residual electron density 0.262 and
–0.249 e Aꢀ3. All atoms were refined with anisotropic
˚
thermal parameters. Crystallographic data (excluding