Standard procedure for the preparation of dispacamide derivatives
11c,d under microwave irradiation
11f, this compound was also dissolved in hot absolute ethanol
(4 ml) and the resulting suspension was submitted to ultrasound
in a Branson 1510 apparatus at 25 ◦C during 1 h. The desired
insoluble product 11f was collected by filtration (108 mg, 34%
yield) and was dried under high vacuum (10-2 Torr) at 25 ◦C for 1
h. The products 11(e,f) were stored at 4 ◦C.
In a 10 ml glass tube were placed successively aldehyde 5a,b
(0.67 mmol), 2-amino-3-methyl-imidazol-4-one hydrochloride 10b
(100 mg, 0.67 mmol), dry piperidine (63 mg, 0.74 mmol, 1.1 equiv.)
and absolute ethanol (6.5 ml). The open glass tube was placed in
(5Z) 4,5-Dibromo-1H-pyrrole-2-carboxylic acid [3-(2-amino-
1-ethyl-4-oxo-1,5-dihydro-i◦midazol-5-ylidene)propyl]amide (11e).
Yellow powder. Mp > 250 C. Yield = 25%. 1H NMR (DMSO-d6)
d: 1.03 (m, 3H, CH3); 2.48 (m, 2H, CH2); 3.30 (m, 4H, CH2); 3.51
(q, J = 7.2 Hz, 2H, CH2); 5.61 (t, J = 7.2 Hz, 1H, CH ); 6.88 (s, 1H,
H-3¢, Ar); 7.26 (br s, 2H, NH2); 8.30 (br s, 1H, NHCO); 11.92 (br s,
1H, H-1¢, Ar). 13C NMR (DMSO-d6) d: 13.90 (CH3); 27.19 (CH2);
33.39 (CH2); 38.07 (CH2); 97.52 (C-5¢, Ar); 104.56 (C-4¢, Ar);
112.52 (C-3¢, Ar); 114.24 (CH ); 128.39 (C-2¢, Ar); 142.63 (C-4);
157.48 (C-2, C N); 158.91 (C O); 167.91 (C O). HRMS m/z:
431.9668 found (calculated for C13H16N5O279Br2 [M+H]+∑ requires
431.9671). Anal. Calc. for C13H15N5O2Br2: C, 36.05; H, 3.49; N,
16.17. Found for C, 36.11; H, 3.51; N, 16.02.
R
the Explorerꢀ 24 CEM microwave cavity (P = 300 W). The stirred
mixture was irradiated at 60 ◦C (with a power of 60 W) for 30 min.
After microwave dielectric heating, the crude reaction mixture was
allowed to cool down at room temperature. The desired insoluble
product 11 was collected by filtration and was washed with cooled
water (2 ¥ 2 ml). The compound 11c,d was dried under high
vacuum (10-2 Torr) at 25 ◦C for 2 h and was stored at 4 ◦C.
(5Z) 4,5-Dibromo-1H-pyrrole-2-carboxylic acid [3-(2-amino-
1-methyl-4-oxo-1,5-dihydro-imidazol-5-ylidene)propyl]amide (11c).
Yellow powder. Mp > 250 ◦C. Yield = 68%. 1H NMR (DMSO-d6)
d: 2.49 (m, 2H, CH2); 2.96 (s, 3H, NCH3); 3.29 (m, 2H, CH2);
5.63 (t, J = 7.4 Hz, 1H, CH ); 6.88 (s, 1H, H-3, Ar); 7.20 (br s,
2H, NH2); 8.24 (br s, 1H, NHCO); 12.38 (br s, 1H, NH, Ar). 13
C
(5Z) 4,5-Dichloro-1H-pyrrole-2-carboxylic acid [3-(2-amino-
1-ethyl-4-oxo-1,5-dihydro-i◦midazol-5-ylidene)propyl]amide (11f).
Yellow powder. Mp > 250 C. Yield = 34%. 1H NMR (DMSO-d6)
d: 1.04 (t, J = 6.9 Hz, 3H, CH3); 2.47 (m, 2H, CH2); 3.29 (m, 2H,
CH2);3.35(m, 2H, CH2);3.53(m, 2H, CH2); 5.62 (t, J = 7.4 Hz, 1H,
CH ); 6.87 (s, 1H, H-3¢, Ar); 7.32 (br s, 2H, NH2); 8.35 (br s, 1H,
NH); 12.51 (br, 1H, NH). 13C NMR (DMSO-d6) d: 13.90 (CH3);
27.19 (CH2); 33.39 (CH2); 38.07 (CH2); 55.96 (C-4, Ar); 97.52 (C-
5¢, Ar); 104.56 (C-4¢, Ar); 112.52 (C-3¢, Ar); 114.24 (CH ); 128.39
(C-24, Ar); 157.48 (C N); 158.91 (C O); 167.91 (C O). HRMS
NMR (DMSO-d6) d: 25.41 (CH3); 27.20 (CH2); 38.11 (CH2); 97.73
(C-4¢, Ar); 104.39 (C-5¢, Ar); 112.42 (CH, Ar); 114.30 (CH );
128.18 (C-2¢, Ar); 142.50 (C-4); 158.12 (C O); 158.78 (C O);
168.06 (C-2, C N). HRMS m/z: 417.9507 found (calculated
∑
for C12H14N5O279Br2 [M+H]+ requires 417.9514). Anal. Calc. for
C12H13N5O2Br2: C, 34.39; H, 3.13; N, 16.71. Found for C, 34.43;
H, 3.21; N, 16.04.
(5Z) 4,5-Dichloro-1H-pyrrole-2-carboxylic acid [3-(2-amino-1-
methyl-4-oxo-1,5-dihydro-imidazol-5-ylidene)-propyl]-amide (11d).
Yellow powder. Mp > 250 ◦C. Yield = 69%. 1H NMR (DMSO-d6)
d: 2.45 (m, 2H, CH2); 2.96 (s, 3H, CH3); 3.41 (m, 2H, CH2); 5.63
(t, J = 7.5 Hz, 1H, CH ); 6.86 (s, 1H, H-3, Ar); 7.19 (br s, 2H,
NH2); 8.27 (br s, 1H, NHCO). 12.31 (br s, 1H, NH, Ar). 13C NMR
(DMSO-d6) d: 25.42 (CH3); 27.20 (CH2); 38.11 (CH2); 107.81
(C-4¢, Ar); 109.57 (CH ); 114.25 (C-5¢, Ar); 114.68 (C-3¢, Ar);
124.97 (C-2, Ar); 142.47 (C-4); 158.15 (C O); 158.93 (C O);
168.06 (C-2, C N). HRMS m/z: 330.0522 found (calculated
∑
m/z: 344.0678 found (calculated for C13H16N5O235Cl2 [M+H]+
requires 344.0681). Anal. Calc. for C13H15N5O2Cl2: C, 45.36; H,
4.39; N, 20.35. Found for C, 45.47; H, 4.43; N, 20.02.
Acknowledgements
One of us (S.G.) wishes to thank the “Ministe`re de la Recherche et
de l’Enseignement Supe´rieur” for research fellowships. Financial
support of this program carried out under the French National
Cancer Institute “Cance´ropoˆle Grand Ouest” by contracts PRIR
04-8390 and ACI 04-2254, is gratefully acknowledged.
∑
for C12H14N5O235Cl2 [M+H]+ requires 330.0525). Anal. Calc. for
C12H13N5O2Cl2: C, 43.65; H, 3.97; N, 21.21. Found for C, 43.71;
H, 4.09; N, 20.94.
Standard procedure for the preparation of dispacamide derivatives
11e,f under microwave irradiation
Notes and references
1 F. Scala, E. Fattorusso, M. Menna, O. Taglialatela-Scafati, M. Tierney,
M. Kaiser and D. Tasdemir, Mar. Drugs, 2010, 8, 2162–2174.
2 D. Tasdemir, R. Mallon, M. Greenstein, L. R. Feldberg, S. C. Kim, K.
Collin, D. Wojciechowiecz, G. C. Mangalindan, G. P. Concepcion, M.
K. Harper and G. M. Ireland, J. Med. Chem., 2002, 45, 529–532.
3 L. Meijer, A. M. W. H. Thunnissen, A. White, M. Garnier, M. Nikolic,
L. H. Tsai, J. Walter, K. E. Cleverley, P. C. Salinas, Y. Z. Wu, J. Biernat,
E. M. Mandelkow, S.-H. Kim and G. R. Pettit, Chem. Biol., 2000, 7,
51–63.
4 (a) P. Sauleau, P. Retailleau, S. Nogues, I. Carletti, L. Marcourt,
R. Roux, A. Al-Mourabit and C. Debitus, Tetrahedron Lett., 2011,
52, 2676–2678. See also the following reference for the synthesis of
hymenialdisine analogs as inhibitors of CHK1: (b) J. G. Parmentier, B.
Portevin, R. H. Golsteyn, A. Pierre´, C. Hickman, P. Gloanec and G.
de Nanteuil, Bioorg. Med. Chem. Lett., 2009, 19, 841–844.
In a 10 ml glass tube were placed successively aldehyde 5(b,c)
(0.93 mmol), 2-amino-3-ethyl-imidazol-4-one hydrochloride 10c
(152 mg, 0.93 mmol, 1 equiv.), dry piperidine (86 mg, 1.02 mmol,
1.1 equiv.) and absolute ethanol (6 ml). The open glass tube was
R
placed in the Explorerꢀ 24 CEM microwave cavity (P = 300 W).
The stirred mixture was irradiated at 60 ◦C (with a power of 60 W)
for 30 min. After microwave dielectric heating, the crude reaction
mixture was allowed to cool down at room temperature and the
desired insoluble product 11e,f, was collected by filtration and was
dried under high vacuum (10-2 Torr) at 25 ◦C for 1 h. For 11e this
compound was dissolved in hot absolute ethanol (4 ml) and to this
solution was added at 0 ◦C dry diethyl ether (4 ml). The insoluble
product 11e was submitted to filtration (109 mg, 25% yield) and
5 (a) M. Debdab, S. Renault, F. Carreaux, M. Soundararajan, O. Federov,
O. Lozach, L. Babault, B. Baratte, Y. Ogawa, M. Hagiwara, A.
Einsenreich, U. Rauch, S. Knapp, L. Meijer and J. P. Bazureau, J.
Med. Chem., 2011, 54, 4172–4186; (b) S. Renault, O. Lozach, L. Meijer,
◦
was dried under high vacuum (10-2 Torr) at 25 C for 0.5 h. For
986 | Org. Biomol. Chem., 2012, 10, 978–987
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The Royal Society of Chemistry 2012
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