2350
R. E. Conrow et al. / Tetrahedron Letters 49 (2008) 2348–2350
Treatment of 12 with Et3SiH or n-BuMe2SiH17,18 and BF3
etherate (2 equiv of each) in CH2Cl2 at 23 °C then gave 13,
mp 119.5–122.5 °C, in 60% yield from 11 after crystalliza-
tion from n-BuCl–hexane. The enantiomeric excess of such
material was determined to be 97%, corresponding to that
of the L-Ala component used to prepare 10. Notably, acyl-
indazole 11 proved inert to reduction under these
conditions.
8. For example, see: (a) Saenz, J.; Mitchell, M.; Bahmanyar, S.;
Stankovic, N.; Perry, M.; Craig-Woods, B.; Kline, B.; Yu, S.;
Albizati, K. Org. Process Res. Dev. 2007, 11, 30; (b) Batt, D. G.;
Petraitis, J. J.; Houghton, G. C.; Modi, D. P.; Cain, G. A.; Corjay, M.
H.; Mousa, S. A.; Bouchard, P. J.; Fortsythe, M. S.; Harlow, P. P.;
Barbera, F. A.; Spitz, S. M.; Wexler, R. R.; Jadhav, P. K. J. Med.
Chem. 2000, 43, 41; (c) Seela, F.; Peng, X. Nucleosides, Nucleotides
Nucleic Acids 2004, 23, 227; (d) Lo´pez, M. C.; Claramunt, R. M.;
Ballesteros, P. J. Org. Chem. 1992, 57, 5240.
9. Elguero, J. In Comprehensive Heterocyclic Chemistry; Katritzky, A.
R., Rees, C. M., Eds.; Pergamon: Oxford, 1984; Vol. 5, pp 167–303.
cf. pp 212, 232.
10. (a) The pKa of indazole in DMSO is estimated to be 17.7 by
interpolation from pKa values of azoles and their benzo derivatives
in Ref. 10d; (b) pKa of indole = 20.95;10d (c) pKa of carbazole =
19.9;10d (d) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456.
11. Jackson, M. B.; Mander, L. N.; Spotswood, T. M. Aust. J. Chem.
1983, 36, 779.
12. (a) Biswas, K. M.; Dhara, R.; Roy, S.; Mallik, H. Tetrahedron 1984,
40, 4351; (b) Biswas, K. M.; Dhara, R. N.; Mallik, H.; Halder, S.;
Sinha-Chaudhuri, A.; De, P.; Brahmachari, A. S. Indian J. Chem.
1991, 30B, 906.
13. Carey, D. T.; Mair, F. S.; Pritchard, R. G.; Warren, J. E.; Woods, R.
J. Dalton Trans. 2003, 3792.
14. (a) Kopecky, D. J.; Rychnovsky, S. D. J. Org. Chem. 2000, 65, 191;
(b) Kopecky, D. J.; Rychnovsky, S. D. In Organic Syntheses; Wiley:
Hoboken, N.J., 2003; Vol. 80, pp 177–183.
General precedent for this deacetoxylation step can be
discerned in a report by Mayr of the conversion of N-(1-
acetoxyethyl)carbazole to N-ethylcarbazole by treatment
with Et3SiH and TMSOTf.19 The former substance was
obtained by the addition of carbazole10c to vinyl acetate,20
a method that in several variants has yielded other simple
racemic azole adducts.21 Silane deoxygenation of hemi-
aminal structures is more typically practiced in the non-
aromatic domain, exemplified by 2-hydroxy- and 2-
acyloxypyrrolidines and the corresponding piperidines.22
The synthesis of 1 was completed by hydrogenolysis of
13. Alternatively, exposure of 13 to 3.5 mol equiv of boron
trichloride in CH2Cl2 at À45 °C selectively cleaved the aryl
benzyl ether to provide the monoprotected derivative 14.
In summary, the new route shown in Scheme 3 redresses
prior issues related to alkylation regiochemistry and amino
group emplacement, without recourse to chromatography
and with no increase in step count from Scheme 1 common
intermediate 2. The scope and scale of hemiaminal ester
formation and deoxygenation have been enlarged to
encompass an indazole-derived substrate bearing an adja-
cent stereocenter. Refinements and scaleup studies are
ongoing and will be reported in due course.
15. Yin, J.; Huffman, M. A.; Conrad, K. M.; Armstrong, J. D., III. J.
Org. Chem. 2006, 71, 840.
16. For a discussion of the workup of i-Bu2AlH reductions on large scale,
see: Perrault, W. R.; Shephard, K. P.; LaPean, L. A.; Krook, M. A.;
Dobrowolski, P. J.; Lyster, M. A.; McMillan, M. W.; Knoechel, D. J.;
Evenson, G. N.; Watt, W.; Pearlman, B. A. Org. Process Res. Dev.
1997, 1, 106.
17. n-BuMe2SiH is prepared more economically than Et3SiH on com-
mercial scale, that is, n-BuMgX + ClSiMe2H versus 3EtMgX +
Cl3SiH: G. L. Larson, Gelest Inc., personal communication.
18. For acetal reduction with various silanes, see: Federspiel, M.; Fischer,
R.; Hennig, M.; Mair, H.-J.; Oberhauser, T.; Rimmler, G.; Albiez, T.;
Bruhin, J.; Estermann, H.; Gandert, C.; Go¨ckel, V.; Go¨tzo¨, S.;
Hoffmann, U.; Huber, G.; Janatsch, G.; Lauper, S.; Ro¨ckel-Sta¨bler,
O.; Trussardi, R.; Zwahlen, A. G. Org. Process Res. Dev. 1999, 3,
266.
19. Schimmel, H.; Ofial, A. R.; Mayr, H. Macromolecules 2002, 35, 5454.
20. Kricka, L. J.; Ledwith, A. J. Org. Chem. 1973, 38, 2240.
21. (a) Smith, K.; Hammond, M. E. W.; James, D. M.; Ellison, I. J.;
Hutchings, M. G. Chem. Lett. 1990, 351; (b) Katritzky, A. R.;
Rachwal, S.; Hitchings, G. J. Tetrahedron 1991, 47, 2683; (c) Xu,
J.-M.; Liu, B.-K.; Wu, W.-B.; Qian, C.; Wu, Q.; Lin, X.-F. J. Org.
Chem. 2006, 71, 3991.
References and notes
1. (a) May, J. A.; Dantanarayana, A.; Zinke, P. W.; McLaughlin, M. A.;
Sharif, N. A. J. Med. Chem. 2006, 49, 318; (b) Sharif, N. A.;
McLaughlin, M. A.; Kelly, C. R. J. Ocul. Pharmacol. Ther. 2007, 23,
1.
2. (a) For details see the examples and relevant discussion in: Conrow,
R. E.; Delgado, P.; Dean, W. D.; Pierce, D. R.; Gaines, M. S. U.S.
Patent 6,998,489B1; (b) Delgado, P.; Conrow, R. E.; Dean, W. D.
PCT WO2004/058725A1.
3. Ref. 2a also details the synthesis of ( )-8 from 6-benzyloxyindole by
the sequence: propylene oxide/NaH, O3/Me2S, NaOH.
´
4. East, S. P.; Joullie, M. M. Tetrahedron Lett. 1998, 39, 7211.
´
22. (a) Pedregal, C.; Ezquerra, J.; Escribano, A.; Carreno, M. C.; Garcıa
˜
5. Caution: This common method for converting alcohols to azides
carries the risk of diazidomethane formation, to be discussed in a
future publication.
6. Schlessinger, R. H.; Iwanowicz, E. J. Tetrahedron Lett. 1987, 28, 2083.
7. Posakony, J. J.; Grierson, J. R.; Tewson, T. J. J. Org. Chem. 2002, 67,
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Ruano, J. L. Tetrahedron Lett. 1994, 35, 2053; (b) Hwang, D. J.; Kim,
S. N.; Choi, J. H.; Lee, Y. S. Bioorg. Med. Chem. 2001, 9, 1429; (c)
Furukubo, S.; Moriyama, N.; Onomura, O.; Matsumura, Y. Tetra-
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Reactions; Wiley: Hoboken, N.J., 2008; Vol. 71, pp 1–735.