SCHEME 1. Ugi-Smiles Couplings with Substituted Nitro Phenol
SCHEME 2. Synthesis of Olefin-Substituted Pyrimidines
Experimental Section
General Procedure for Pyrimidine-Induced Ugi-4CR. To a 3
M solution of the aldehyde in toluene were added successively 1.0
equiv. of allylamine 2a-b, 1.0 equiv. of isocyanide, and 1.0 equiv.
of pyrimidine 5a-d under inert atmosphere. The resulting mixture
was stirred at 110 °C until completion (TLC). It was then
concentrated in vacuo, and the crude product was purified by flash
chromatography on silica gel.
2-[Allyl-(5-but-3-enyl-6-methyl-2-phenyl-pyrimidin-4-yl)-
amino]-4-methyl-pentanoic Acid Benzylamide 6a. The typical
procedure was followed employing the allyl-substituted pyrimidine
5a (70 mg, 0.3 mmol) to afford compound 6a (100 mg, 71%, 4
days) as a yellow oil by flash chromatography on silica gel
(petroleum ether/diethyl ether: 95/5). 1H NMR (CDCl3, 400 MHz)
δ 8.64 (t, 1H, J ) 5.6 Hz), 8.22 (dd, 2H, J ) 7.8, 2.6 Hz), 7.49-
7.34 (m, 4H), 7.21-7.08 (m, 4H), 5.80 (ddt, 1H, J ) 17.1, 10.2,
6.6 Hz), 5.65 (ddt, 1H, J ) 17.3, 10.3, 5.9 Hz), 5.13 (dd, 1H, J )
17.1, 1.2 Hz), 5.04 (dd, 1H, J ) 17.3, 1.2 Hz), 5.05 (dd, 1H, J )
10.3, 1.2 Hz), 5.01 (dd, 1H, J ) 10.2, 1.2 Hz), 4.73 (dd, 1H, J )
9.1, 6.1 Hz), 4.47 (dd, 1H, J ) 14.6, 6.0 Hz), 4.33 (dd, 1H, J )
14.6, 5.4 Hz), 4.10 (dd, 1H, J ) 16.4, 5.9 Hz), 3.87 (dd, 1H, J )
16.4, 5.9 Hz), 2.82-2.62 (m, 2H), 2.57 (s, 3H), 2.26-2.20 (m,
1H), 2.01-1.84 (m, 2H), 1.66 (d, 2H, J ) 5.6 Hz), 0.92 (d, 3H, J
) 6.6 Hz), 0.81 (d, 3H, J ) 6.8 Hz). 13C NMR (CDCl3, 100.6
MHz) δ 173.0, 167.3, 164.7, 160.2, 138.7, 138.0, 137.5, 134.4,
130.5, 129.0, 128.3, 128.0, 127.7, 119.8, 118.3, 116.1, 62.0, 51.4,
43.9, 38.6, 32.8, 27.6, 25.3, 23.7, 23.4, 22.1. IR (thin film) 3401,
2942, 1666, 1542, 1454, 1161 cm-1. MS (DI, CI NH3) m/z 483.
HRMS Calcd for C31H38N4O482.3046, Found 482.3055.
General Procedure for Metathesis Reaction. To a 0.3 M
solution of diene 6a-g in toluene were added 10% mol of
Hoveyda-Grubbs second generation catalyst under inert atmo-
sphere. The resulting mixture was stirred at the given temperature
until completion (TLC). It was then concentrated in vacuo, and
the crude product was purified with preparative chromatography.
4-Methyl-2-(4-methyl-2-phenyl-7,8-dihydro-pyrimido[4,5-b]-
azepin-9-yl)-pentanoic Acid Cyclohexylamide 7b. The typical
procedure employing the diene 6b (92 mg, 0.20 mmol) under
heating at 110 °C to afford compound 7b (58 mg, 67%, 1 day) as
a white solid was followed with preparative chromatography
(petroleum ether/diethyl ether: 50/50). 1H NMR (CDCl3, 400 MHz)
δ 8.43-8.38 (m, 2H), 7.55-7.47 (m, 4H), 6.58 (dt, 1H, J ) 12.1,
1.9 Hz), 6.14 (dt, 1H, J ) 12.1, 3.6 Hz), 5.46 (br s, 1H), 3.79-
3.68 (m, 2H), 3.00-2.91 (m, 1H), 2.66 (s, 3H), 2.56-2.51 (m,
2H), 1.87-1.71 (m, 3H), 1.68-1.59 (m, 2H), 1.54-1.15 (m, 8H),
0.98 (d, 3H, J ) 6.8 Hz), 0.89 (d, 3H, J ) 6.8 Hz). 13C NMR
(CDCl3, 100.6 MHz) δ 171.6, 166.6, 163.6, 159.2, 137.9, 132.5,
130.7, 128.9, 128.1, 122.6, 113.3, 58.2, 47.8, 45.3, 36.5, 33.5, 33.1,
33.0, 25.8, 25.1, 24.7, 24.6, 24.2, 23.7, 22.6. IR (thin film) 3319,
probably because of the degradation of the ruthenium carbene
by the residual isocyanide.9
Pyrimidine derivatives and its fused heterocycles such as
purines, pyrrolopyrimidines, pyrazolopyrimidines, etc., constitute
the backbone of several biologically active compounds. For
example, 4H-pyrido[1,2-a]pyrimidin-4-ones have been used as
anticancer agents,10 HIV-integrase inhibitors;11 pteridines are
potent antitumor agents.12 Therefore, novel methodologies for
the synthesis of pyrimidine scaffolds are of particular interest
in medicinal chemistry. To the best of our knowledge, this is
the first report of the synthesis of 8,9-dihydro-5H-pyrimido-
[4,5-b]azepine. This sequence affords a very short synthesis of
those derivatives and provides an easy access to libraries for
medicinal and pharmaceutical applications.
In conclusion, this study gives further evidence on the
beneficial effect of heteroatoms on the scope of Ugi-Smiles
couplings. Pyrimidines are valuable partners for this reaction,
giving access to biologically relevant scaffolds with a high
structural tolerance toward the Ugi-Smiles couplings. We are
currently further exploring the use of uracil and purine deriva-
tives in these 4-CC.
(9) For a recent report, see: Galan, B. R.; Kalbarczyk, K. P.; Szczepank-
iewicz, S.; Keister, J. B.; Diver, S. T. Org. Lett. 2007, 9, 1203-1206.
(10) Wang, W.; Constantine, R. N.; Lagniton, L. M.; Pecchi, S.; Burger,
M. T.; Desai, M. C. WO2004113335, 2004. Chem. Abstr. 2005, 142, 93843.
Hu, J.-F.; Wunderlich, D.; Thiericke, R.; Dahse, H.-M.; Grabley, S.; Feng,
X.-Z.; Sattler, I. J. Antibiot. 2003, 56, 747-754.
(11) Crescenzi, B.; Kinzel, O.; Muraglia, E.; Orvieto, F.; Pescatore, G.;
Rowley, M.; Summa, V. WO 2004058757, 2004. Chem. Abstr. 2004, 141,
123648.
(12) Bertino, J. R. J. Clin. Oncol. 1993, 11, 5-14.
5836 J. Org. Chem., Vol. 72, No. 15, 2007