References and Notes
1
Verma S.
Mishra AK.
Kumar J.
Acc.
Chem. Res.
2010,
43:
79
2a
Legraverend M.
Grierson DS.
Bioorg.
Med. Chem.
2006,
14:
3987 ;
and references therein
2b
Legraverend M.
Tetrahedron
2008,
64:
8585 ; and references therein
3
Baraldi PG.
Tabrizi MA.
Gessi S.
Borea PA.
Chem. Rev.
2008,
108:
238
4a
Zhang C.
Shokat KM.
Tetrahedron
2007,
63:
5832
4b
Huang H.
Mab J.
Shi J.
Meng L.
Jiang H.
Ding J.
Liu H.
Bioorg. Med. Chem.
2010,
18:
4615
5
Zacharie B.
Fortin D.
Wilb N.
Bienvenu J.-F.
Asselin M.
Grouix B.
Penney C.
Bioorg. Med.
Chem. Lett.
2009,
19:
242
6
Tang Y.-b.
Peng Z.-g.
Liu Z.-y.
Li Y.-p.
Jiang J.-d.
Li Z.-r.
Bioorg. Med. Chem. Lett.
2007,
17:
6350
7a
Tunçbilek M.
Ates-Alagöz Z.
Altanlar N.
Karayel A.
Özbey S.
Bioorg.
Med. Chem.
2009,
17:
1693
7b
Geng B.
Breault G.
Comita-Prevoir J.
Petrichko R.
Eyermann C.
Lundqvist T.
Doig P.
Gorseth E.
Noonan B.
Bioorg.
Med. Chem. Lett.
2008,
18:
4368
8
Goswami P.
Das B.
Tetrahedron Lett.
2009,
50:
2384
9a
Mitsunobu O.
Synthesis
1981,
1
9b
Rad M.
Khalafi-Nezhad A.
Behrouz S.
Faghihi M.
Zare Parhami A.
Tetrahedron
2008,
64:
1778
9c
Aguado L.
Thibaut HJ.
Priego E.-M.
Jimeno M.-L.
Camarasa M.-J.
Neyts J.
Perez-Perez M.-J.
J.
Med. Chem.
2010,
53:
316
9d
Giorgi I.
Biagi G.
Livi O.
Leonardi M.
Scartoni V.
Pietra D.
Arch. Pharm. Chem. Life Sci.
2007,
340:
81
10a
Montgomery JA.
Thomas HJ.
J. Med. Chem.
1972,
15:
182
10b
Kadir K.
Shaw G.
Wright D.
J.
Chem. Soc. Perkin Trans. 1
1980,
2728
11a
Alves MJ.
Booth BL.
Freitas AP.
Proença MF.
J. Chem. Soc., Perkin Trans. 1
1992,
913
11b
Booth BL.
Dias AM.
Proença MF.
J. Chem. Soc., Perkin Trans. 1
1992,
2119
11c
Alves MJ.
Booth BL.
Proença MF.
J. Heterocycl. Chem.
1994,
31:
345
11d
Booth BL.
Coster RD.
Proença MF.
Synthesis
1988,
389
11e
Alves MJ.
Booth BL.
Carvalho MA.
Pritchard RG.
Proença MF.
J. Heterocycl.
Chem.
1997,
739
11f
Al-Azmi A.
Booth BL.
Carpenter RA.
Carvalho MA.
Marrelec E.
Pritchard RG.
Proença MF.
J. Chem. Soc., Perkin Trans. 1
2001,
2532
11g
Booth BL.
Cabral IM.
Dias AM.
Freitas AP.
Matos-Beja AM.
Proença MF.
Ramos-Silva M.
J.
Chem Soc., Perkin Trans. 1
2001,
1241
11h
Carvalho MA.
Esteves TM.
Proença MF.
Booth BL.
Org.
Biomol. Chem.
2004,
2:
1019
11i
Carvalho MA.
Álvares Y.
Zaki ME.
Proença MF.
Booth BL.
Org. Biomol. Chem.
2004,
2:
2340
11j
Carvalho MA.
Esperança S.
Esteves T.
Proença MF.
Eur.
J. Org. Chem.
2007,
1324
11k
Dias AM.
Cabral I.
Vila-Chã AS.
Costa DS.
Proença MF.
Eur. J.
Org. Chem.
2007,
1925
11l
Alves MJ.
Carvalho MA.
Carvalho S.
Dias AM.
Fernandes FH.
Proença MF.
Eur.
J. Org. Chem.
2007,
4881
11m
Correia C.
Carvalho MA.
Proença MF.
Tetrahedron
2009,
65:
6903
11n
Ribeiro A.
Carvalho MA.
Proença MF.
Eur. J. Org. Chem.
2009,
4867
11o
Bacelar AH.
Carvalho MA.
Proença MF.
Eur. J. Org. Chem.
2010,
3234
12a
Dias AM.
Cabral IM.
Vila-Chã AS.
Proença MF.
Synlett
2007,
1231
12b
Dias AM.
Cabral IM.
Vila-Chã AS.
Cunha D.
Senhorães N.
Nobre S.
Sousa C.
Proença MF.
Synlett
2010,
2792
13
General Procedure
for the Synthesis of 4a-d
Benzylamine (1.1
equiv for 4a,b),
methylamine (for 4c), or isopropylamine
(for 4d) was added to a suspension of the acylated
imidazole 2 (0.59-2.82 mmol) in
MeCN (0.5 mL), and the mixture turned immediately into a beige solution. The
mixture was stirred at 0 ˚C (20 min for 4a,
10 min for 4b, and 5 min for 4c) or at r.t. (10 min for 4d).
Bright white solids precipitated and were filtered and washed with
MeCN and Et2O to give compounds 4a-d (44-63%). The structure of
the products was confirmed by elemental analysis, ¹H NMR,
and ¹³C NMR spectroscopy.
Characterization of
N
-[(5-Amino-1-phenyl-1
H
-imidazol-4-yl)benzylaminomethylene]acetamide
(4a)
Mp 159.1-160.2 ˚C. ¹H
NMR (300 MHz, DMSO-d
6): δ = 11.69
(br s, 1 H), 7.58 (m, 2 H), 7.52-7.47 (m, 3 H), 7.49 (s,
1 H), 7.40-7.30 (m, 5 H), 7.30 (br s, 2 H), 5.32 (br s,
2 H), 1.98 (s, 3 H). ¹³C NMR (75 MHz,
DMSO-d
6): δ = 182.93, 161.94,
147.19, 139.09, 131.30, 129.91, 129.05, 128.51, 128.28, 127.23,
126.19, 124.97, 111.32, 47.41, 28.19. Anal. Calcd for C19H19N5O:
C, 68.45; H, 5.74; N, 21.01. Found: C, 68.51; H, 5.61; N, 21.41.
IR (mull): 3374, 3256, 1620, 1549, 1455 cm-¹.
14
General Procedure
for the Synthesis of 7c
Method
B
A beige suspension of the imidazole 3 (0.82
mmol) in MeCN (2 mL) stirred at r.t. was combined with benzylamine
(1.2 equiv). After 2 h, the mixture turned to an orange solution and
was heated under reflux for 7 h. After cooling, the product precipitated
out of solution, and the solid was filtered and washed with MeCN
and Et2O to give compound 7c (50% yield).
Method C
Benzoic anhydride (2
equiv) was added to a beige suspension of imidazole 1 in
MeCN (4 mL), and the mixture was stirred at r.t. for 5 h, when the
mixture turned into an orange suspension. Benzylamine (1.2 equiv)
and EtOH (4 mL) were added, and the mixture was heated under reflux
for 5 h. After cooling, a solid precipitated out of solution and was
filtered and washed with MeCN, EtOH, and Et2O to give
compound 7c (63%).
Characterization of
N
-Benzyl-2-phenyl-9-(
p
-tolyl)-9
H
-purin-6-amine (7c)
Mp 199.8-200.7 ˚C. ¹H
NMR (300 MHz, DMSO-d
6): δ = 8.57
(s, 1 H), 8.56 (br s, 1 H), 8.34 (d, J = 7.2
Hz, 2 H), 7.93 (d, J = 8.4
Hz, 2 H), 7.83 (d, J = 8.4
Hz, 2 H), 7.47-7.41 (m, 3 H), 7.38 (d, J = 7.6
Hz, 2 H), 7.30 (t, J = 7.6
Hz, 2 H), 7.20 (t, J = 7.6
Hz, 1 H), 4.85 (br s, 2 H), 2.39 (s, 3 H). ¹³C NMR
(75 MHz, DMSO-d
6): δ = 158.00,
154.29, 149.49, 140.35, 139.96, 138.38, 136.85, 132.73, 129.66,
129.14, 128.19, 128.12, 127.64, 127.39, 126.62, 122.84, 118.73, 43.17,
20.57. Anal. Calcd for C25H21N5:
C, 76.70; H, 5.41; N, 17.89. Found: C, 76.70; H, 5.24; N, 17.64.
IR (mull): 3270, 3084, 1623, 1571, 1529, 1519, 1496 cm-¹.
15
General Procedure
for the Synthesis of 8a
A yellow suspension of imidazole 2 (1.82 mmol) in EtOH (50 mL) was stirred
at r.t. for 50 min. Benzylamine (1.1 equiv) was added to this solution
and 10 min later, the mixture was evaporated in vacuum (30 ˚C).
The residual oil was cooled and a solid precipitated by addition
of acetone. The solid was filtered and washed with EtOH and Et2O
to give compound 8a (91%).
Characterization of
N
-{4-[(benzylamino)(imino)methyl]-1-phenyl-1
H
-imidazol-5-yl}acetamide
(8a)
Mp 160.6-161.5 ˚C. ¹H
NMR (300 MHz, DMSO-d
6): δ = 7.81
(s, 1 H), 7.46-7.43 (m, 5 H), 7.43-7.34 (m, 5
H), 4.50 (s, 2 H), 1.72 (s, 3 H). ¹³C
NMR (75 MHz, DMSO-d
6): δ = 171.83,
155.80, 148.66, 138.73, 136.01, 134.17, 129.08, 128.32, 127.44,
126.92, 124.09, 115.21, 45.52, 24.78. Anal. Calcd for C19H19N5O:
C, 68.45; H, 5.74; N, 21.01. Found: C, 68.41; H, 5.75; N, 20.86.
IR (mull) 3370, 3251, 1631, 1551 cm-¹.
General Procedure
for the Synthesis of 6a
16a
Method
A
A white suspension of 4a (1.75
mmol) in EtOH (2 mL) was heated at reflux for 5 min. The solution
was evaporated in vacuum and after cooling, a white solid precipitated
out of solution. The bright white solid was filtered and washed
with EtOH and Et2O to give compound 6a (92%).
16b A suspension of imidazole 8a in EtOH (2 mL) was heated under reflux
for 5 min. After that, the solution was evaporated in vacuum and,
after cooling, a solid precipitated out of solution. The bright
white solid was filtered and washed with EtOH and Et2O
to give compound 6a (87% yield).
The structure of the product obtained was confirmed by elemental
analysis, ¹H NMR and ¹³C
NMR spectroscopy.
Method D
Acetic
anhydride (1.2 equiv) and DMAP (1.5 equiv) were added to a beige
suspension of 1 (1.80 mmol) in MeCN (1 mL)
at 0 ˚C. The mixture immediately turned in an orange solution
and 3 min later, a white solid precipitated out of solution. The
solid was filtered and benzylamine (1.2 equiv) and EtOH (2 mL) were
added, and the mixture was heated under reflux for 1 h. After cooling,
a white solid precipitated out of solution and it was filtered and
washed with EtOH and Et2O to give compound 6a (76% yield).
Characterization of
N
-Benzyl-2-methyl-9-phenyl-9
H
-purin-6-amine
(6a)
Mp 175.6-176.7 ˚C. ¹H
NMR (300 MHz, DMSO-d
6):
δ = 8.48
(s, 1 H), 8.30 (br s, 1 H), 7.85 (d, J = 7.8
Hz, 2 H), 7.57 (t, J = 7.8
Hz, 2 H), 7.43 (t, J = 7.8
Hz, 1 H), 7.38 (d, J = 6.9
Hz, 2 H), 7.30 (t, J = 6.9
Hz, 2 H), 7.20 (t, J = 6.9
Hz, 1 H), 4.80 (br s, 2 H)), 2.42 (s, 3 H). ¹³C
NMR (75 MHz, DMSO-d
6): δ = 161.84,
154.32, 149.39, 140.21, 139.11, 135.15, 129.46, 128.19, 127.61,
127.60, 126.19, 123.15, 117.95, 42.60, 26.11. Anal. Calcd for C19H17N5:
C, 72.36; H, 5.43; N, 22.21. Found: C, 72.21; H, 5.28; N, 22.06.
IR (mull): 3270, 3223, 3063, 1617, 1598, 1581, 1530 cm-¹.