H.A. Ioannidou, P.A. Koutentis / Tetrahedron 67 (2011) 3348e3354
3353
þ
þ
4.1.5. Reactions of 3-bromoisothiazole-4-carbonitrile 3.
159.2, 137.3, 129.6; m/z (EI) 209 (M þ2, 94%), 207 (M , 96), 192
100), 190 (95), 128 (6), 113 (6), 111 (9), 85 (19), 83 (29), 82 (18), 57
(
4.1.5.1. 2-(Morpholinomethylene)malononitrile 15a. Typical pro-
(57), 52 (12), 45 (63).
cedure. A stirred mixture of 3-bromoisothiazole-4-carbonitrile 3
(
(
25 mg, 0.13 mmol) and morpholine (45
1 mL) was heated at ca. 78 C under reflux until no starting ma-
m
L, 0.52 mmol) in EtOH
Acknowledgements
ꢁ
terial remained (TLC). The reaction mixture was adsorbed onto
The authors wish to thank the Cyprus Research Promotion
silica and chromatographed (hexane) to afford elemental sulfur
Foundation [Grant No. PENEK/ENISX/0308/83] and the following
ꢁ
(
3.3 mg, 80%) as yellow needles, mp 114e115 C, R
f
0.76 (hexane).
organizations in Cyprus for generous donations of chemicals and
glassware: the State General Laboratory, the Agricultural Research
Institute, the Ministry of Agriculture and Biotronics Ltd. Further-
more we thank the A.G. Leventis Foundation for helping to establish
the NMR facility in the University of Cyprus.
Further elution (hexane/DCM, 1:4) gave the title compound 15a
ꢁ
(
[
cm
15 mg, 71%) as beige flakes, mp 138e140 C (from EtOH/pentane)
31
ꢁ
lit. 149e150 C (from EtOH)], R
f
0.43 (DCM/t-BuOMe, 9:1); vmax
2982w, 2874w, 2208m and 2197m (C^N), 1632s (C]C),
/
ꢂ1
1
1
466w, 1454m, 1439m, 1375w, 1354m,1310w, 1285w, 1250m, 1119s,
080w, 1026m, 1011m, 974w, 937w, 870s, 779w; (300 MHz;
d
H
Supplementary data
CDCl
OCH
8 (80), 57 (39), 51 (9), 42 (100).
3
) 7.02 (1H, s, C-H), 3.95 (2H, br s, NCH
2
), 3.79 (4H, dd J 4.9, 4.7,
þ
2
), 3.49 (2H, br s, NCH
2
); m/z (EI) 163 (M , 47%), 105 (37), 91 (7),
7
4
.1.5.2. 2-(Piperidin-1-ylmethylene)malononitrile
15b. Similar
(25 mg,
References and notes
treatment of 3-bromoisothiazole-4-carbonitrile
.13 mmol) with piperidine (51
sulfur (3.7 mg, 87%) as yellow needles, mp 114e115 C; R
hexane) and then the title compound 15b (18 mg, 84%) as light
orange needles, mp 85.5e86.5 C (from EtOH/pentane) [lit.
0e91 C (from EtOAc/pentane)], R
max/cm 2947w, 2208m and 2195m (C^N), 1618s (C]C), 1470w,
3
1. (a) Varaprasad, C. V. N. S.; Barawkar, D.; Abdellaoui, H. E.; Chakravarty, S.; Allan,
0
mL, 0.52 mmol) afforded elemental
M.; Chen, H.; Zhang, W.; Wu, J. Z.; Tam, R.; Hamatake, R.; Lang, S.; Hong, Z.
Bioorg. Med. Chem. Lett. 2006, 16, 3975; (b) Abdellaoui, H. E.; Varaprasad, C. V.
N. S.; Barawkar, D.; Chakravarty, S.; Maderna, A.; Tam, R.; Chen, H.; Allan, M.;
Wu, J. Z.; Appleby, T.; Yan, S.; Zhang, W.; Lang, S.; Yao, N.; Hamatake, R.; Hong, Z.
Bioorg. Med. Chem. Lett. 2006, 16, 5561; (c) Melagraki, G.; Afantitis, A.;
Sarimveis, H.; Igglessi-Markopoulou, O.; Koutentis, P. A.; Kollias, G. Chem. Biol.
Drug Des. 2010, 76, 397.
ꢁ
f
0.76
(
ꢁ
32
ꢁ
ꢂ1
9
v
f
0.84 (DCM/t-BuOMe, 9:1);
1
1
441w, 1362m, 1346m, 1269w, 1256w, 1217w, 1179w, 1098w,
024m, 997w, 968w, 945w, 854w, 764m; (300 MHz; CDCl ) 6.96
), 3.43 (2H, br s, NCH ), 1.73 (6H,
2. Larson, E. R.; Noe, M. C.; Gant, T. G. U.S. Patent 6,235,764, 2001.
3. Yan, S.; Appleby, T.; Gunic, E.; Shim, J. H.; Tasu, T.; Kim, H.; Rong, F.; Chen,
d
H
3
H.; Hamatake, R.; Wu, J. Z.; Hong, Z.; Yao, N. Bioorg. Med. Chem. Lett. 2007,
(
1H, s, ]CeH), 3.86 (2H, br s, NCH
2
2
17, 28.
þ
br s, 3ꢃCH
2
); m/z (EI) 161 (M , 100%), 146 (13), 132 (32), 120 (26),
4. (a) Pain, D. L.; Peart, B. J.; Wooldridge, K. R. H. In Comprehensive Heterocyclic
Chemistry I; Potts, K. T., Chief Katritzky, A. R., Rees, C. W., Eds.; Pergamon:
Oxford, 1984; Vol. 6; Chapter 4.17, p 131; (b) Chapman, R. F.; Peart, B. J. In
Comprehensive Heterocyclic Chemistry II; Shinkai, I., Chief Katritzky, A. R., Rees,
C. W., Scriven, E. F. V., Eds.; Pergamon: Oxford, 1996; Vol. 3; Chapter 3.05, p 319;
106 (32), 94 (11), 83 (73), 78 (43), 67 (13), 57 (29), 41 (65).
4.1.5.3. 3-Bromoisothiazole-4-carboxamide 19. A mixture of 3-
(c) Clerici, F.; Gelmi, M. L.; Pellegrino, S. In Comprehensive Heterocyclic Chemistry
bromoisothiazole-4-carbonitrile 3 (25 mg, 0.13 mmol) in c. H
2
SO
4
III; Joule, J., Chief Katritzky, A. R., Ramsden, C. A., Scriven, E. F. V., Taylor, R. J. K.,
Eds.; Elsevier: Oxford, 2008; Vol. 4; Chapter 4.05, p 545; (d) Kaberdin, R. V.;
Potkin, V. I. Russ. Chem. Rev. 2002, 71, 673; (e) Brown, D. W.; Sainsbury, M. In
Isothiazoles in Science of Synthesis, Product Class 15; Schaumann, E., Ed.; Georg
Thieme: Stuttgart, 2002; Vol. 11; Chapter 11.15, p 507; (f) Elgazwy, A.-S. S. H.
Tetrahedron 2003, 59, 7445.
ꢁ
(
1 mL) was stirred at ca. 20 C for 2 h until no starting material
remained (TLC). After the reaction was finished, the reaction mix-
ture was poured onto crushed ice and extracted with t-BuOMe
(
2ꢃ50 mL). The organic layers were combined, dried (Na
2 4
SO ), and
evaporated in vacuo to afford the title compound 19 (15 mg, 70%) as
5. Morton, B. U.S. Patent 3,057,875, 1962.
6. (a) Hatchard, W. R. J. Org. Chem. 1964, 29, 660; (b) Hatchard, W. R. U.S. Patent
ꢁ
colorless needles, mp 138e141 C (from PhH), R
f
0.47 (t-BuOMe);
3,155,679, 1964.
(
found: C, 23.3; H, 1.4; N, 13.4. C
4
H
3
BrN
2
OS requires C, 23.2; H, 1.5;
7. (a) Lee, F. T.; Li, B. W.; Volpp, G. P. J. Heterocycl. Chem. 1970, 7, 941; (b) Walsh, R.
ꢂ1
N, 13.5%); max (DCM)/nm 228 (log
l
3 3.44), 258 (3.96); vmax/cm
J. A.; Wooldridge, K. R. H. J. Chem. Soc., Perkin Trans. 1 1972, 1247; (c) Clarke, K.;
Fox, W. R.; Scrowston, R. M. J. Chem. Soc., Perkin Trans. 11980, 1029; (d) Turnbull,
M. D.; Smith, A. M.; Salmon, R. U.S. Patent 5,705,516, 1998. (e) Ioannidou, H. A.;
Koutentis, P. A. Tetrahedron 2009, 65, 7023.
3
1
7
7
381w (NH), 3289w, 3188w, 3102w, 1655s (C]O), 1612m, 1506m,
406m, 1344w, 1294m, 1140w, 1120m, 1003m, 864w, 822w, 812w,
79w; (300 MHz; DMSO-d ) 9.32 (1H, s, H-5), 7.96 (1H, br s, NH),
.59 (1H, br s, NH);
d
H
6
8. (a) Christoforou, I. C.; Koutentis, P. A.; Rees, C. W. Org. Biomol. Chem. 2003, 1,
d
C
(75 MHz; DMSO-d
6
) 162.4 (C]O), 153.4 (C-5),
2900; (b) Christoforou, I. C.; Koutentis, P. A. Org. Biomol. Chem. 2006, 4, 3681.
þ
þ
9. Virgilio, J. A; Manowitz, M.; Heilweil, E. U.S. Patent 4,281,136, 1981.
1
36.1, 133.8; m/z (EI) 208 (M þ2, 58%), 206 (M , 59), 192 (99), 190
ꢀ
ꢀ
1
0. (a) Cutrõ, C. C. C.; Garozzo, A.; Siracusa, M. A.; Sarva, M. C.; Tempera, G.; Ger-
(
(
100), 164 (3), 162 (3), 127 (15), 113 (5), 111 (9), 85 (20), 83 (22), 57
32), 52 (9), 44 (65).
emia, E.; Pinizzotto, M. R.; Guerrera, F. Bioorg. Med. Chem. 1998, 6, 2271; (b)
ꢀ
ꢀ
Cutrõ, C. C. C.; Garozzo, A.; Siracusa, M. A.; Sarva, M. C.; Castro, A.; Geremia, E.;
Pinizzotto, M. R.; Guerrera, F. Bioorg. Med. Chem. 1999, 7, 225; (c) Garozzo, A.;
ꢀ
ꢀ
Cutrõ, C. C. C.; Castro, A.; Tempera, G.; Guerrera, F.; Sarva, M. C.; Geremia, E.
4.1.5.4. 3-Bromoisothiazole-4-carboxylic acid 20. To a stirred
ꢀ
Antiviral Res. 2000, 45, 199; (d) Cutrõ, C. C. C.; Garozzo, A.; Siracusa, M. A.;
solution of 3-bromoisothiazole-4-carboxamide 19 (86 mg,
Castro, A.; Tempera, G.; Sarv aꢀ , M. C.; Guerrera, F. Antiviral Res. 2002, 55, 357.
11. Christoforou, I. C.; Koutentis, P. A. Org. Biomol. Chem. 2007, 5, 1381.
ꢁ
0
.41 mmol) in concentrated H
2
SO
4
(2 mL) at 0 C was added in
1
2. (a) Christoforou, I. C.; Koutentis, P. A.; Rees, C. W. J. Chem. Soc., Perkin Trans. 1
002, 1236; (b) Emayan, K.; English, R. F.; Koutentis, P. A.; Rees, C. W. J. Chem.
Soc., Perkin Trans. 1 1997, 3345.
three equal portions NaNO
mixture was then heated at ca. 100 C until no starting material
remained (TLC). The mixture was allowed to cool to ca. 20 C and
2
(285 mg, 4.1 mmol). The reaction
2
ꢁ
ꢁ
13. (a) Pinder, A. R. Synthesis 1980, 425; (b) Urbano, F. J.; Marinas, J. M. J. Mol. Catal.
A: Chem. 2001, 173, 329; (c) Alonso, F.; Beletskaya, I. P.; Yus, M. Chem. Rev. 2002,
was poured onto crushed ice to afford a colorless precipitate. The
102, 4009.
precipitate was filtered, washed (H
2
O), and dried in vacuo to give
14. (a) Hudlicky, M. In Comprehensive Organic Synthesis; Chief Trost, B. M., Fleming,
I., Eds.; Pergamon: Oxford, 1991; Vol. 8; Chapter 4.5, pp 895e922; (b) Suther-
land, A. G. In Comprehensive Organic Functional Group Transformations; Roberts,
S. M., Chief Katritzky, A. R., Meth-Cohn, O., Rees, C. W., Eds.; Elsevier: Oxford,
the title compound 20 (79.4 mg, 92%) as pale beige plates, mp
ꢁ
1
95e197 C (from PhH), R
f
0.44 (t-BuOMe); (found: C, 23.2; H, 0.7;
N, 6.5. C
4
H
3
2
BrNO
2
S requires C, 23.1; H, 1.0; N, 6.7%);
l
max (DCM)/nm
1
995; Vol. 1, pp 1e11.
15. (a) Zhang, Y.-M.; Gu, M.; Ma, H.; Tang, J.; Lu, W.; Nan, F.-J. Chin. J. Chem. 2008,
6, 962; (b) Libnow, S.; Wille, S.; Christiansen, A.; Hein, M.; Reinke, H.;
ꢂ1
2
2
28 (log
3.49), 260 (3.93); vmax/cm
3113w, 2947w, 2907w,
2
733w, 2602w, 2536w, 1713 (C]O), 1483m, 1435w, 1418w, 1354m,
(300 MHz; DMSO-d
(75 MHz; DMSO-d ) 161.2 (C]O),
K o€ ckerling, M.; Miethchen, R. Synthesis 2006, 496; (c) Wagner, F. F.; Comins, D.
L. Eur. J. Org. Chem. 2006, 3562; (d) Thomsen, B.; Beeley, N.; Sekiguchi, Y. Bioorg.
Med. Chem. Lett. 2005, 15, 2565; (e) Bastos, M. M.; Barbosa, J. P.; Pinto, A. C.;
1333w, 1217s, 1015s, 887m, 849w, 835m;
d
H
6
)
OH missing, 9.60 (1H, s, H-5);
d
C
6