Month 2019
Metal-free Indolines Synthesis
N , the o-allylamine (0.5 g, 3.7 mmol, 1.0 equiv) was
[2] Rakhit, A.; Hurley, M. E.; Tipnis, V.; Coleman, J.; Rommel,
A.; Brunner, H. R. J Clin Pharmacol 1986, 26, 156.
2
added. The reaction was allowed to warm to room
temperature and stirred for 4 h in the presence of pre-dried
silica gel (500 mg). The reaction mixture was then diluted
with CH Cl , washed with water, HCl (1 N), NaHCO
3
[
3] (a) Kunz, R. K.; MacMillan, D. W. C. J Am Chem Soc 2005,
27, 3240; (b) Andersson, F.; Hedenstrçm, E. Tetrahedron Asymmetry
2006, 17, 1952; (c) Hartikka, A.; Arvidsson, P. I. J Org Chem 2007, 72,
874; (d) Pietruszka, J.; Simon, R. C. ChemCatChem 2010, 2, 505.
4] (a) Bermudez, J.; Dabbs, S.; Joiner, K. A.; King, F. D. J Med
1
5
2
2
[
(
sat.) and brine, and dried with anhydrous MgSO . The
4
Chem 1990, 33, 1929; (b) Adachi, S.; Koike, K.; Takayanagi, I. Pharma-
cology 1996, 53, 250; (c) Horton, D. A.; Bourne, G. T.; Smythe, M. L.
Chem Rev 2003, 103, 893.
mixture was filtered, and the filtrate was concentrated
under vacuum. The residue was purified through silica gel
[5] Chang, L.; Podoll, J. D.; Wang, W.; Walls, S.; Orourke, C. P.;
flash chromatography (eluents: hexanes and ethyl acetate).
Wang, X. J Med Chem 2014, 57, 3803.
1
8
9% yield; yellow crystalline solid, mp = 157–159°C; H
[6] Danilenko, V. N.; Simonov, A. Y.; Lakatosh, S. A.; Kubbutat,
M. H. G.; Totzke, F.; Schachtele, C.; Elizarov, S. M.; Bekker, O. B.;
Printsevskaya, S. S.; Luzikov, Y. N.; Reznikova, M. I. J Med Chem
NMR (300 MHz, acetone) δ 8.58 (s, 1H), 8.29–8.13 (m,
2
7
H), 7.99 (d, J = 7.7 Hz, 1H), 7.97–7.89 (m, 2H), 7.32–
.09 (m, 2H), 6.99 (td, J = 7.4, 1.0 Hz, 1H), 4.88 (dqd,
2008, 51, 7731.
[7] Chessari, G.; Buck, I. M.; Day, J. E. H.; Day, P. J.; Iqbal, A.;
Johnson, C. N.; Lewis, E. J.; Martins, V.; Miller, D.; Reader, M.; Rees, D.
C. J Med Chem 2015, 58, 6574.
J = 11.0, 6.3, 1.8 Hz, 1H), 3.46 (dd, J = 15.9, 9.1 Hz,
1
H), 2.76 (d, J = 15.9 Hz, 1H), 1.35 (d, J = 6.3 Hz, 3H);
C NMR (126 MHz, acetone) δ 151.32, 146.46, 142.25,
42.22, 130.20, 127.19, 125.08, 124.51, 122.64, 118.94,
15.98, 55.04, 35.98, 20.40; ESI HRMS m/z: Calcd
97.1113 g/mol; observed 298.1188 g/mol.
[8] Sato, K.; Takahagi, H.; Yoshikawa, T.; Morimoto, S.; Takai,
1
3
T.; Hidaka, K.; Kamaura, M.; Kubo, O.; Adachi, R.; Ishii, T.; Maki, T.
J Med Chem 2015, 58, 3892.
1
1
2
[9] (a) Bergmeier, S. C. Tetrahedron 2000, 56, 2561; (b) Lyons, T.
W.; Sanford, M. S. Chem Rev 2007, 110, 1147; (c) Donohoe, T. J.;
Callens, C. K. A.; Flores, A.; Lacy, A. R.; Rathi, A. H. Chem A Eur J
2011, 17, 58; (d) Ye, K.-Y.; Pombar, G.; Fu, N.; Sauer, G. S.; Keresztes,
I.; Lin, S. J Am Chem Soc 2018, 140, 2438; (e) Ahmed, N.; Khatoon,
S.; Shirinfar, B. ChemElectroChem 2018, 5, 1245; (f) Triandafillidi, I.;
Tzaras, D. I.; Kokotos, C. G. ChemCatChem 2018, 10, 2521; (g)
Triandafillidi, I.; Kokotos, C. G. Org Lett 2017, 19, 106; (h) Theodorou,
A.; Kokotos, C. G. Adv Synth Catal 2017, 359, 1577; (i) Theodorou, A.;
Triandafillidi, I.; Kokotos, C. G. Adv Synth Catal 2018, 360, 951; (j) Is-
ChemistryOpen 2018, 7, 576.
CRYSTAL STRUCTURE DETERMINATION
Single-crystal X-ray diffraction data were recorded at
ambient temperature using an Agilent SuperNova Dual
Atlas diffractometer equipped with mirror
a
monochromator using Mo Kα (λ = 0.71073 Å) radiation.
Generally, H atoms were inserted in idealized positions
and refined using a riding model, with Uiso(H) values
equal to 1.2 or 1.5 times the Ueq value of the atom to
which it is bonded and with methyl groups allowed to
rotate about the C─C bond. Structure solution and
refinement were performed using SHELXS-2013 and
SHEXL-2018, respectively.
[10] (a) Lira, R.; Wolfe, J. P. J Am Chem Soc 2004, 126, 13906; (b)
Alexanian, E. J.; Lee, C.; Sorensen, E. J Am Chem Soc 2005, 127, 7690;
(c) Sherman, E. S.; Chemler, S. R.; Tan, T. B.; Gerlits, O. Org Lett 2004, 6,
1573; (d) Zabawa, T. P.; Kasi, D.; Chemler, S. R. J Am Chem Soc 2005,
127, 11250; (e) Nicolaou, K. C.; Roecker, A. J.; Pfefferkorn, J. A.; Cao,
G.-Q. J Am Chem Soc 2000, 122, 2966; (f) Yin, Y.; Zhao, G. Heterocycles
2006, 68, 23; (g) Gleave, D. M.; Brickner, S. J.; Manninen, P. R.; Allwine,
D. A.; Lovasz, K. D.; Rohrer, D. C.; Tucker, J. A.; Zurenko, G. E.; Ford, C.
W. Bioorg Med Chem Lett 1998, 8, 1231; (h) Gleave, D. M.; Brickner, S. J
Org Chem 1996, 61, 6470; (i) Liu, D.; Zhao, G.; Xiang, L. Eur J Org Chem
2
010, 2010, 3975.
11] (a) Correa, A.; Tellilu, I.; Dominguez, E.; SanMartin, R. J Org
Chem 2006, 71, 8316; (b) Lovick, H. M.; Michael, F. E. J Am Chem Soc
010, 132, 1249; (c) Mizar, P.; Burelli, A.; Gunther, E.; Softje, M.;
Acknowledgments. Marie Skłodowska-Curie Actions COFUND
[
(
grant no. 663830) to Dr. Nisar Ahmed is gratefully
acknowledged. We thank the Cardiff Chemistry and Welsh
Govt for their generous funding to COFUND Fellow (N. A.).
We thank the EPSRC National Mass Spectrometry Facility,
Swansea, for mass spectrometric data. We thank the Higher
Education Commission (HEC) Pakistan for IRSIP Fellowship to
S. K. We also thank the Erasmus program to A. V. We also thank
Mr. M. Islam for technical support.
2
Farooq, U.; Wirth, T. Chem A Eur J 2014, 20, 13113; (d) Moriyama,
K.; Izumisawa, Y.; Togo, H. J Org Chem 2012, 77, 9846.
[12] (a) Banerjee, A. K.; Mimo’, M. S. L.; Vegas, W. J. V. Russ
Chem Rev 2001, 70, 971; (b) Clive, D. L. J.; Farina, V.; Singh, A.; Wong,
C. K.; Kiel, W. A.; Menchen, S. M. J Org Chem 1980, 45, 2120.
[13] Beckett, N. S.; Peters, R.; Fletcher, A. E.; Staessen, J. A.; Liu,
L.; Dumitrascu, D.; Stoyanovsky, V.; Antikainen, R. L.; Nikitin, Y.; An-
derson, C.; Belhani, A. N Engl J Med 2008, 358, 1887.
[14] CCDC 1877878 (4a), 1877879 (4b) contain the supplementary
crystallographic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre.
REFERENCES AND NOTES
[1] (a) Kuehne, M. E.; Bornmann, W. G.; Marko, I.; Qin, Y.; Le-
Boulluec, K. L.; Frasier, D. A.; Xu, F.; Mulamba, T.; Ensinger, C. L.;
Borman, L. S.; Huot, A. E.; Exon, C.; Bizzarro, F. T.; Cheung, J. B.;
Bane, S. L. Org Biomol Chem 2003, 1, 2120; (b) Zhang, H.; Boonsombat,
J.; Padwa, A. Org Lett 2007, 9, 279; (c) Bui, T.; Syed, S.; Barbas, C. F. III
J Am Chem Soc 2009, 131, 8758; (d) Wang, T.; Xu, Q.; Yu, P.; Liu, X.;
Cook, J. M. Org Lett 2001, 3, 345; (e) Iyengar, R.; Schildknegt, K.; Mor-
ton, M.; Aube, J. J Org Chem 2005, 70, 10645.
SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of the
article.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet