J. A. Pfefferkorn, C. Choi / Tetrahedron Letters 49 (2008) 4372–4373
4373
O
O
O
NH
Br
a
b
N
OtBu
+
N
R
N
OtBu
NH2
Br
CO2Et
CO2Et
7: R = H
8: R = PMB
c
4
5
6
d
O
OtBu
O
N
N
OtBu
NH
O
e
f
N
N
N
H
( ) 3
10
9
MeO
MeO
Scheme 1. Synthesis of ( ) spiro[indoline-3,30-piperidine] 3. Reagents and conditions: (a) Boc2O, Et3N, CH2Cl2, 25 °C, 18 h, 38%; (b) AlMe3, CH2Cl2, 40 °C, 16 h, 68%; (c) PMB–
Cl, NaH, DMF, 0 ? 25 °C, 4 h, 100%; (d) Pd(OAc)2, (C6H11)3P; KOtBu, Dioxane/THF (10:1), 85 °C, 54%; (e) BH3ꢀSMe2, THF, 60 °C, 4 h, 90%; (f) (i) 1-chloroethyl chloroformate,
CH2Cl2, 0 °C, 1 h; (ii) MeOH, 60 °C, 1 h, 49% (2 steps).
5. (a) Patchett, A. A.; Nargund, R. P.; Tata, J. R.; Chen, M. H.; Barakat, K. J.; Johnston,
and PMB–Cl to afford tertiary amide 8 as the desired cyclization
precursor. In the palladium-catalyzed cyclization event, 8 was
D. B. R.; Cheng, K.; Chan, W. W. S.; Butler, B.; Hickey, G.; Jacks, T.; Schleim, K.;
Pong, S. S.; Chaung, L. Y. P.; Chen, H. Y.; Frazier, E.; Leung, K. H.; Chiu, S. H. L.;
treated with Pd(OAc)2, (C6H11)3P and KOtBu at elevated tempera-
ture to provide oxindole 9 in 54% yield. Separate attempts to
cyclize precursor 7 directly (without PMB protection) were not
successful and resulted only in debromination. The synthesis was
then completed by reduction of oxindole 9 to indoline 10 with
BH3ꢀSMe2 followed by exhaustive deprotection with 1-chloroethyl
chloroformate to provide racemic 1,10-H-spiro[indoline-3,30-piper-
idine] (3) in 49% yield.12
Smith, R. G. Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 7001–7005; (b) Bondensgaard,
K.; Ankersen, M.; Thogersen, H.; Hansen, B. S.; Wulff, B. S.; Bywater, R. P. J. Med.
Chem. 2004, 47, 888–899.
6. Xie, J.-S.; Huang, C. Q.; Fang, Y.-Y.; Zhu, Y.-F. Tetrahedron 2004, 60, 4875.
7. (a) Grigg, R.; Köppen, I.; Rasparini, M.; Sridharan, V. Chem. Commun. 2001, 964–
965; (b) Grigg, R.; Sansano, J. M.; Santhakumar, V.; Sridharan, V.;
Thangavelanthum, T.; Thorton-Pett, M.; Wilson, D. Tetrahedron 1997, 53,
11803–11826; (c) Grigg, R.; Teasdale, A.; Sridharan, V. Tetrahedron Lett. 1991,
32, 3859–3862.
8. A report of the synthesis of a 30-N-Boc spiro[indoline-3,30-piperidine] system
via an intramolecular Heck reaction has appeared in the patent literature, see:
Cassayre, J.; Molleyres, L.-P.; Maienfisch, P.; Cederbaum, F. WO 2005061512.
9. For a review of palladium-catalyzed a-arylation reactions of enolates, see:
Clukin, D. A.; Hartwig, J. F. Acc. Chem. Res. 2003, 36, 234–245.
In conclusion, we have described a convenient synthesis of the
spiro[indoline-3,30-piperidine] ring system utilizing an intramole-
cular palladium-catalyzed a-arylation reaction.
10. For recent progress on the palladium-catalyzed intermolecular a-arylation of
zinc amide enolates, see: Hama, T.; Culkin, D. A.; Hartwig, J. F. J. Am. Chem. Soc.
2006, 128, 4976–4985.
11. (a) Shaughnessy, K. H.; Hamann, B. C.; Hartwig, J. F. J. Org. Chem. 1998, 63,
6546–6553; (b) Lee, S.; Hartwig, J. F. J. Org. Chem. 2001, 66, 3402–3415; (c)
Honda, T.; Namiki, H.; Satoh, F. Org. Lett. 2001, 3, 631–633; (d) Zhang, T. Y.;
Zhang, H. Tetrahedron Lett. 2002, 43, 193–195; (e) Zhang, T. Y.; Zhang, H.
Tetrahedron Lett. 2002, 43, 1363–1365.
References and notes
1. Hershenson, F. M.; Prodan, K. A.; Kochman, R. L.; Bloss, J. L.; Mackerer, C. R. J.
Med. Chem. 1977, 20, 1448–1451.
2. (a) Maligres, P. E.; Houpis, I.; Rossen, K.; Molina, A.; Sager, J.; Upadhyay, V.;
Wells, K. M.; Reamer, R. A.; Lynch, J. E.; Askin, D.; Volante, R. P.; Reider, P. J.
Tetrahedron 1997, 53, 10983–10992; (b) Palucki, B. L.; Feighner, S. D.; Pong, S.-
S.; McKee, K. K.; Hrenuik, D. L.; Tan, C.; Howard, A. D.; Van der Ploeg, L. H. Y.;
Patchett, A. A.; Nargund, R. P. Bioorg. Med. Chem. Lett. 2001, 11, 1955–1957.
3. Elliott, J. M.; Broughton, H.; Cascieri, M. A.; Chicchi, G.; Huscroft, I. T.; Kurtz, M.;
MacLeod, A. M.; Sadowski, S.; Stevenson, G. I. Bioorg. Med. Chem. Lett. 1998, 8,
1851–1856.
12. Analytical data for 1,10-H-spiro[indoline-3,30-piperidine] (3): 1H NMR (CDCl3) d
7.03 (dd, J = 7.6, 1.2 Hz, 1H), 6.95 (d, J = 7.2 Hz, 1H), 6.70 (dd, J = 7.2, 1.2 Hz, 1H),
6.59 (d, J = 7.6 Hz, 1H), 4.05 (d, J = 9.6 Hz, 1H), 3.43–3.37 (m, 4H), 2.91–2.83 (m,
2H), 1.97–1.78 (m, 4H); 13C NMR (CDCl3) d 151.0, 131.8, 129.3, 122.8, 119.0,
110.3, 56.3, 50.0, 44.6, 43.4, 32.6, 20.0; MS(APCI+): m/z 189.1 (M+H). These data
were consistent with previously reported derivatives of the 1,10-H-
spiro[indoline-3,30-piperidine] ring system, see Ref. 8.
4. Makings, L. R.; Garcia-Guzman Blanco, M.; Hurley, D. J.; Drutu, I.; Raffai, G.;
Bergeron, D. M.; Nakatani, A.; Termin, A. P.; Silina, A. WO 2007100670.