J 7.9), 7.56 (2 H, d, J 8.3), 7.27–7.18 (7 H, m), 5.76 (1 H, ddd, J
10.1, 5.6, 2.6), 5.30 (1 H, s), 4.94 (1 H, dd, J 10.3, 1.6), 3.81 (1 H,
dd, J 7.1, 5.3), 3.58 (1 H, dd, J 7.1, 2.2), 2.64–2.56 (1 H, m), 2.43 (3
H, s), 1.92–1.82 (1 H, m), 1.73–1.59 (2 H, m), 1.47–1.37 (1 H, m);
dC (50 MHz) 145.1, 138.0, 135.6, 134.5, 133.0, 131.8, 130.7, 128.9,
128.8, 128.4, 128.2, 127.9, 127.6, 122.2, 77.2, 66.5, 54.0, 38.0, 24.8,
22.0, 21.6; (m/z,%) 338 (11), 155 (43), 91 (47), 77 (100). Exact
mass found: 338.1216. Calc for C20H20NO2S: 338.1215 (M+ - Ts).
The preparations of 11b–11i were performed similarly and their
characterization data are provided in the ESI.† All of the above
products except 11e were obtained as single diastereomers.
IMDA reactions of N-propargyl derivatives 9d–9f and 9i
were performed similarly and afforded ca. 1 : 1 mixtures of
diastereomers of the cycloadducts 12d–12f and 12i. The IMDA
reaction of the butynyl derivative 10d required refluxing in anisole
for 24 h and afforded a similar mixture of diastereomers of 13d.
These products were used in subsequent aromatizations without
separation of isomers.28
(75), 219 (100), 208 (71), 130 (74). Exact mass found: 208.0760.
Calc for C14H10NO (M+ - SO2Ph): 208.0762.
Products 16f, 16i and 17d were prepared similarly (see ESI†).
Acknowledgements
We thank the Natural Sciences and Engineering Research Council
of Canada (NSERC) for financial support. K.N.C. thanks NSERC
and the Alberta Ingenuity Fund for postgraduate scholarships.
References
1 (a) W.-T. Jiaang, Y.-S. Chen, T. Hsu, S.-H. Wu, C.-H. Chien, C.-N.
Chang, S.-P. Chang, S.-J. Lee and X. Chen, Bioorg. Med. Chem. Lett.,
2005, 15, 687–691; (b) S. Van Goethem, P. Van der Veken, V. Dubois,
A. Soroka, A.-M. Lambeir, X. Chen, A. Haemers, S. Scharpe´, I. De
Meester and K. Augustyns, Bioorg. Med. Chem. Lett., 2008, 18, 4159–
4162.
2 (a) B. Portevin, C. Tordjman, P. Pastoureau, J. Bonnet and G. De
Nanteuil, J. Med. Chem., 2000, 43, 4582–4593; (b) T. Mancilla, J.
Correa-Basurto, K. S. Alaves Carbajal, E. T. J. Sanchez Escalante and
J. T. Ferrara, J. Mex. Chem. Soc., 2007, 51, 96–102.
3 (a) P. J. Kukkola, N. A. Bilci and T. J. Ikeler, Tetrahedron Lett., 1996,
37, 5065–5068; (b) P. J. Kukkola, N. A. Bilci, T. Ikler, P. Savage, S. S.
Shetty, D. DelGrande and A. Y. Jeng, Bioorg. Med. Chem. Lett., 2001,
11, 1737–1740.
4 (a) T. M. Bare, C. W. Draper, C. D. McLaren, L. M. Pullan, J. Patel and
J. B. Patel, Bioorg. Med. Chem. Lett., 1993, 3, 55–60; (b) A. Alanine, S.
Burner, B. Buettelmann, N. M. Heitz, G. Jaeschke, E. Pinard, and R.
Wyler, Eur. Pat. 1090917, 2001, Chem. Abs., 134, 280719.
5 (a) D. Hamprecht, F. Micheli, G. Tedesco, A. Checchia, D. Donati, M.
Petrone, S. Terreni and M. Wood, Bioorg. Med. Chem. Lett., 2007, 17,
428–433; (b) G. A. Cain, and J. F. McElroy, PCT Int., WO 0000472,
2000,Chem. Abs., 132, 64183; (c) P. George, M. Sevrin, M. Mangane,
J. P. Merly and D. Bigg, Eur. Pat., 351283, 1990,Chem. Abs., 113, 58970.
6 (a) S. S. Bhagwat, L. M. Gayo-Fung, B. M. Stein, Q. Chao, A. R.
Gangloff, J. A. McKie, and K. D. Rice, PCT Int., WO 02024653,
2002,Chem. Abs., 136, 279351; (b) B. Barlaam and C. Dantzman, PCT
Int., WO 02046164, 2002,Chem. Abs., 137, 47127.
7 (a) C. N. Johnson and G. Stemp, PCT Int., WO 00021950, 2000,Chem.
Abs., 132, 279110; (b) H. B. Broughton, J. J. Kulagowski, P. D. Leeson
and I. M. Mawer, PCT Int. Appl., WO 9421628, 1994,Chem. Abs., 122,
9863.
8 B. Van Wagenen, R. Ukkiramapandian, J. Clayton, I. Egle, J. Empfield,
M. Isaac, F. Ma, A. Slassi, G. Steelman, R. Urbanek and S. Walsh, PCT
Int., WO 07021309, 2007,Chem. Abs., 146, 274221.
Typical aromatization procedure: preparation of
2-benzenesulfonyl-1-phenyl-2,3-dihydro-1H-isoindole (14d)
A mixture of both diastereomers of 12d (82.6 mg, 0.228 mmol)
was dissolved in toluene (20 mL). DBU was added (36 mg, 0.23
mmol) and the solution was refluxed until TLC analysis indicated
completion of the reaction (9 h). The mixture was poured into
water and extracted 3 times with ethyl acetate. The combined
organic fractions were dried (MgSO4), filtered and concentrated.
The product was chromatographed (toluene : ethyl acetate, 16 : 1)
to afford 68.4 mg (89%) of 14d: white solid, mp 155–157 ◦C (from
ethyl acetate); nmax/cm-1(film) 1350, 1164, 1101; dH (300 MHz)
7.62–7.59 (2 H, m), 7.45 (1 H, tt, J 8.4, 1.2), 7.34 (2 H, t, J 8.4),
7.24–7.13 (8 H, m), 6.88 (1 H, d, J 7.5), 5.94 (1 H, s), 4.90–4.80
(2 H, m); dC (75 MHz) 141.6, 140.9, 138.5, 135.0, 132.4, 128.8,
128.5, 128.0, 127.97, 127.87, 127.7, 127.2, 123.7, 122.4, 69.5, 54.0;
(m/z,%) 335 (4), 258 (67), 194 (100). Exact mass found: 334.0964.
Calc for C20H17NO2S: 335.0980.
Products 14e, 14f, 14i and 15d were prepared similarly (see
ESI†).
9 C. E. Augelli-Szafran, Y. Lai, A. T. Sakkab and L. C. Walker, PCT Int.,
WO 0076969, 2000,Chem. Abs., 134, 56565.
10 K. J. Kapples and G. M. Shutske, J. Heterocycl. Chem., 1997, 34, 1335–
1338.
11 M. Yamada, S. Hamamoto, K. Hayashi, K. Takaoka, H. Matsukura,
M. Yotsuji, K. Yonezawa, K. Ojima, T. Takamatsu, K. Taya, H.
Yamamoto, T. Kiyoto and H. Kotsubo, PCT Int., WO 9921849,
1999,Chem. Abs., 130, 311706.
Typical procedure for benzylic oxidation: preparation of
2-benzenesulfonyl-3-phenyl-2,3-dihydroisoindol-1-one (16d)
Potassium permanganate (200 mg) and copper sulfate pentahy-
drate (200 mg) were combined and crushed into a fine powder.
This was added to a solution of 14d (59.1 mg, 0.176 mmol)
in dichloromethane (8 mL). The reaction was refluxed until
TLC showed completion of the reaction (3 d). The solution was
filtered through a pad of Celite, which was washed thoroughly
with dichloromethane. The filtrate was concentrated and chro-
matographed (toluene : ethyl acetate, 16 : 1) to provide 46.3 mg
(75%) of 16d: colourless needles, mp 176–178 ◦C (from ethyl
acetate). Found: C, 68.45; H, 4.3; N, 4.0%. Calc for C20H15NO3S:
C, 68.75; H, 4.3; N, 4.0%. nmax/cm-1(film) 1733, 1367, 1280, 1181,
1090; dH (300 MHz) 7.85 (1 H, d, J 7.5), 7.61–7.46 (5 H, m), 7.33–
7.19 (5 H, m), 7.14 (1 H, d, J 7.6), 7.03 (2 H, d, J 7.0), 6.21 (1 H, s);
dC (50 MHz) 166.4, 146.4, 138.9, 136.7, 134.4, 133.6, 129.0, 128.8,
128.7, 128.6, 128.5, 128.1, 127.9, 124.8, 123.7, 65.6; (m/z,%) 284
12 (a) D. Berger, R. Citarella, M. Dutia, L. Greenberger, W. Hallett, R.
Paul and D. Powell, J. Med. Chem., 1999, 42, 2145–2161; (b) G. W.
Muller, and H.-W. Man, PCT Int., WO 06025991, 2006,Chem. Abs.,
144, 369911; (c) C. Murakata, N. Amishiro, T. Atsumi, Y. Yamashita,
T. Takahashi, R. Nakai, H. Tagaya, H. Takahashi, J. Funahashi, J.
Yamamoto and Y. Fukuda, PCT Int., WO 06112479, 2006,Chem. Abs.,
145, 454932; (d) L. A. Funk, M. C. Johnson, P.-P. Kung, J. J. Meng and
J. Z. Zhou, PCT Int., WO 06117669, 2006,Chem. Abs., 145, 489014.
13 E. J. Cornish, G. E. Lee and W. R. Wragg, Nature, 1963, 197, 1296–1297.
14 M.-Z. Huang, K.-L. Huang, Y.-G. Ren, M.-X. Lei, L. Huang, Z.-K.
Hou, A.-P. Liu and X.-M. Ou, J. Agric. Food Chem., 2005, 53, 7908–
7914.
15 A. Bjoere, J. Bostroem, O. Davidsson, H. Emtenaes, U. Gran, T. Iliefski,
J. Kajanus, R. Olsson, L. Sandberg, G. Strandlund, J. Sundell and Z.-Q.
Yuan, PCT Int., WO 08008022, 2008,Chem. Abs., 148, 168577.
16 N. Harada, M. Yato, H. Kamaya, K. Nagata and H. Iwai, PCT Int.,
WO 02098872, 2002,Chem. Abs., 138, 24729.
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