ACS Combinatorial Science
Research Article
dimethylpyrimidine-2,4 (1H, 3H)-dione 4{1} (0.55 g, 85%
yield).
was purified by column chromatography to obtain pure product
PPQ 12{1−10,1−22} in 52−98% yield.
1H NMR (300 MHz, CDCl3) δ 7.88 (d, J = 7.4 Hz, 2H), 7.60
(t, J = 7.3 Hz, 1H), 7.48 (d, J = 7.4 Hz, 2H), 3.51 (s, 3H), 3.36
(s, 3H), 2.25 (S, 3H). 13C NMR (75 MHz, CDCl3) δ 193.7,
161.0, 152.1, 152.1, 137.8, 134.2, 129.7, 129.1, 113.5, 32.5, 28.6,
18.1. MS (ESI-MS) m/z: 259 (M+H)+. HRMS: calcd for
C14H14N2O3 m/z: 258.1004; found 259.1082 (M+H)+.
General Procedure for the Synthesis of Compounds
5{1} and 10{1,1−14}. The 5-aryl carbonyl-6-(bromomethyl)-
1,3-dimethylpyrimidine-2,4 (1H, 3H)-dione (0.5 g, 1 equiv)
4{1} and o-amino phenyl methanol (1.2 equiv) or methyl 3-
amino-4-(isobutylamino)benzoate (1.2 equiv) were added to a
15 mL high pressure glass bottle with ethanol (8 mL). Triethyl
amine (1 equiv) was added to the above solution, and the
reaction mixture was exposed to microwave irradiation (180 W,
140 °C) for 15 min. After completion of the reaction, the
organic phase was washed with acetic acid (5 mL) and
concentrated under reduced pressure at 70 °C. Crude product
was further recrystallized with ethyl acetate to obtain
compounds 5{1} (0.41 g, 85% yield) and 10{1,3} (1.01 g,
99% yield).
Methyl-5-isobutyl-7,9-dimethyl-8,10-dioxo-6,11-diphenyl-
5,6,7,8,9,10-hexa-hydropyrimido[4′,5′:3,4] pyrrolo[1,2-a]-
quinoxaline-2-carboxylate 12{2,19}. 1H NMR (300 MHz,
CDCl3) δ 8.08 (d, J = 8.6 Hz, 2H), 7.88 (m, 1H), 7.66 (dd, J =
8.6, 1.7 Hz, 1H), 7.50 (t, J = 7.2 Hz, 1H), 7.36 (d, J = 7.2 Hz,
2H), 7.15 (d, J = 8.6 Hz, 2H), 6.99 (d, J = 8.6 Hz, 1H), 5.97 (s,
1H), 3.65 (s, 3H), 3.57 (s, 3H), 3.43 (dd, J = 13.6, 6.1 Hz, 1H),
3.34 (s, 3H), 2.97 (dd, J = 13.6, 6.1 Hz, 1H), 2.19 (m, 1H),
1.07 (d, J = 6.4 Hz, 3H), 1.02 (d, J = 6.4 Hz, 3H). 13C NMR
(75 MHz, CDCl3) δ 165.9, 159.4, 152.0, 147.7, 145.6, 140.8,
131.1, 130.2, 129.3, 128.7, 128.3, 127.7, 127.7, 125.1, 124.3,
124.3, 123.0, 122.5, 115.2, 111.4, 105.9, 59.8, 58.4, 51.7, 32.6,
27.9, 26.5, 20.6, 20.1. MS (ESI−MS) m/z: 594.2 (M+H+).
HRMS: calcd for C33H31N5O6 m/z: 593.2274; found 594.2342
(M+H+).
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
Methyl-3-(1,3-dimethyl-2,4-dioxo-5-phenyl-3,4-dihydro-
Spectroscopic data (1H and 13C NMR, LRMS, HRMS,
FT-IR) of oxazepines 8{1,1−18}, pyrimido-pyrrolo
amino methyl benzoates 10{1,1−14}, and PPQ 12{1−
1H-pyrrolo[3,4-d]-pyrimidin-6(2H)-yl)-4-(isobutyl amino)-
benzoate 10{1,3}. H NMR (300 MHz, CDCl3) δ 7.87 (d, J
1
= 8.7 Hz, 1H), 7.75 (s, 1H), 7.38−7.29 (m, 2H), 7.25−7.18 (m,
3H), 6.57 (d, J = 8.7 Hz, 1H), 6.43 (s, 1H), 3.82 (s, 3H), 3.40
(s, 3H), 3.38 (s, 3H), 2.94−2.76 (m, 2H), 1.71 (m, 1H), 0.82
(d, J = 6.8 Hz, 3H), 0.80 (d, J = 6.8 Hz, 3H). 13C NMR (75
MHz, CDCl3) δ 166.8, 160.2, 152.1, 148.1, 148.1, 135.3, 132.5,
131.0, 130.6, 129.2, 128.7, 128.1, 123.6, 118.0, 110.6, 104.3,
103.6, 52.2, 51.0, 32.0, 28.5, 28.3, 20.7, 20.6. MS (ESI−MS) m/
z: 461 (M+Na+). HRMS: calcd for C26H28N4O4 m/z:
460.2111; found 483.2005 (M+Na+).
Single X-ray crystallographic data of compound 8{1,12}
Single X-ray crystallographic data of compound 12{2,19}
AUTHOR INFORMATION
Corresponding Authors
■
General Procedure for the Synthesis of Oxazepine
8{1,1−18}. To the solution of compound 5{1} (0.5 g, 1 equiv)
in chloroform (12 mL), aldehyde (1.2 equiv) and a catalytic
amount of trifluoroacetic acid (0.05 equiv) were added. The
reaction mixture was refluxed for 6 h, and reaction progress was
monitored by TLC. After completion of the reaction, the
solvent was concentrated under reduced pressure at 55 °C.
Crude product was purified by column chromatography to
obtain pure product 8{1,1−18} (68−82% yield).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors wish to thank the National Science Council of
Taiwan for financial support and the authorities of the National
Chiao Tung University for providing laboratory facilities. This
study was particularly supported by the “Centre for
bioinformatics research of aiming for the Top University
Plan” of the National Chiao Tung University and Ministry of
Education, Taiwan.
7-(Furan-2-yl)-8,10-dimethyl-12-phenyl-8,10-
dihydrobenzo[e]pyrimido[4′,5′:3,4]pyrrolo[2,1-c][1,4]-
1
oxazepine-9,11(5H,7H)-dione 8{1,12}. H NMR (300 MHz,
CDCl3) δ 7.34 (d, J = 7.5 Hz, 1H), 7.17−7.32 (m, 5H), 7.13 (t,
J = 7.5 Hz, 1H), 7.01 (s, 1H), 6.87 (t, J = 7.8 Hz, 1H), 6.65 (s,
1H), 6.40 (d, J = 8.0 Hz, 1H), 5.91 (m, 1H), 5.43 (d, J = 2.4
Hz, 1H), 4.90 (d, J = 11.9 Hz, 1H), 4.70 (d, J = 11.9 Hz, 1H),
3.74 (s, 3H), 3.39 (s, 3H). 13C NMR (75 MHz, CDCl3) δ
159.5, 152.9, 152.3, 141.2, 137.5, 134.6, 132.2, 131.0, 129.8,
128.9, 128.8, 128.7 127.9, 127.6, 126.2, 112.1, 110.3, 106.5,
104.5, 67.4, 66.6, 33.1, 28.1. MS (ESI−MS) m/z: 440 (M+H+).
HRMS: calcd for C26H21N3O4 m/z 439.1532; found 440.1605
(M+H+). IR (cm−1, neat): 3069, 2954, 2865, 1700, 1658.
General Procedure for the Synthesis of PPQ 12{1−
10,1−22}. To the solution of compound 5{1} (0.5 g, 1 equiv)
in chloroform (12 mL), aldehyde (1.2 equiv) and a catalytic
amount of trifluoroacetic acid (0.05 equiv) were added. The
reaction mixture was refluxed for 8 h, and reaction progress was
monitored by TLC. After completion of the reaction, the
solvent was removed under reduced pressure. Crude product
REFERENCES
■
(1) (a) Liu, X. H.; Jia, Y. M.; Song, B. A.; Pang, Z. X.; Yang, S. Design
and synthesis of novel 2-methyl-4,5-substitutedbenzo[f]-3,3a,4,5-
tetrahydro-pyrazolo[1,5-d][1,4]oxazepin-8(7H)-one derivatives as te-
lomerase inhibitors. Bioorg. Med. Chem. Lett. 2013, 23, 720−723.
(b) Agirbas, H.; Kemal, B.; Budak, F. Synthesis and structure−
antibacterial activity relationship studies of 4-substituted phenyl-4,5-
dihydrobenzo[f][1,4]oxazepin-3(2H)-thiones. Med. Chem. Res. 2011,
20, 1170−1180. (c) Kubota, K.; Kurebayashi, H.; Miyachi, H.; Tobe,
M.; Onishi, M.; Isobe, Y. Synthesis and structure-activity relationship
of tricyclic carboxylic acids as novel anti-histamines. Bioorg. Med. Chem.
2011, 19, 3005−3021.
(2) (a) Blass, B. 5-Amino-oxazepine and 5-amino-thiazepine
compounds as β-secretase antagonists and methods of use. ACS
Med. Chem. Lett. 2012, 3, 873−874. (b) Smits, R. A.; Lim, H. D.;
G
ACS Comb. Sci. XXXX, XXX, XXX−XXX