Cp2Ti[P(OEt)3]2. Takai reagents,4 which are probably 1,1-
bimetallics, have a similar generality but have to be made
from 1,1-dihaloalkanes, which are synthetically less acces-
sible than thioacetals.
affect any unreacted esters 2, thus ensuring high purity of
the compounds released. This “chameleon catch strategy”
was introduced by Barrett and co-workers,14 who used the
Tebbe reagent to methylenate ester links to the resin.
However, their choice of reagent precluded the introduction
of any other functionality in the alkylidenation step. Our
strategy, on the other hand, relies on the introduction of a
masked nucleophile by the titanium reagent. Our solid-phase
synthesis of bicyclic heterocycles would be traceless in that,
theoretically, substituents are allowed at any site and would
be classified as using an Osp2-Csp2 (benzofuran) or Nsp2-
Csp2 (indole) linker.15
We envisaged using Takeda’s method to generate func-
tionalized titanium alkylidene reagents that would allow new
synthetic strategies involving conversion of esters into enol
ethers. Current strategies employ alkylidenation of esters
followed by sigmatropic rearrangement (particularly useful
in the synthesis of macrocycles),8 ring-closing metathesis
(useful in the synthesis of polyethers),9,10 acid-induced
rearrangement,11 or another reaction of the enol ether
moiety.12 However, none of these strategies relies on the
titanium reagent introducing any functionality other than the
enol ether. In their seminal paper,13 Mortimore and Kocienski
used a Takai reagent bearing a masked oxygen nucleophile
in a synthesis of spiroketals. We have designed a similar
strategy for the synthesis of aromatic heterocycles on solid
phase (Scheme 1). Resin-bound esters 2 would be benzylide-
Having successfully used the above route to make ben-
zofurans,16 we now report its application to the solid-phase
synthesis of indoles.17 Readily available ortho-nitrobenzal-
dehydes 8 were converted into thioacetals 9, and the nitro
group was reduced18 to give anilines 10 (Scheme 2).
However, we failed to generate an effective alkylidenating
agent from aniline 10. The key challenge was then to find a
suitable nitrogen protecting group that would be unaffected
(10) Recent examples: (a) Liu, L.; Postema, M. H. D. J. Am. Chem.
Soc. 2001, 123, 8602-8603. (b) Rainier, J. D.; Allwein, S. P.; Cox, J. M.
J. Org. Chem. 2001, 66, 1380-1386. (c) Rainier, J. D.; Allwein, S. P.;
Cox, J. M. Org. Lett. 2000, 2, 231-234. (d) Postema, M. H. D.; Calimente,
D.; Liu, L.; Behrmann, T. L. J. Org. Chem. 2000, 65, 6061-6068. (e) Clark,
J. S.; Kettle, J. G. Tetrahedron 1999, 55, 8231-8248. (f) Hodgson, D. M.;
Foley, A. M.; Boulton, L. T.; Lovell, P. J.; Maw, G. N. J. Chem. Soc.,
Perkin Trans. 1 1999, 2911-2922. (g) Hodgson, D. M.; Foley, A. M.;
Lovell, P. J. Synlett 1999, 744-746. (h) Calimente, D.; Postema, M. H. D.
J. Org. Chem. 1999, 64, 1770-1771. (i) Postema, M. H. D.; Calimente, D.
Tetrahedron Lett. 1999, 40, 4755-4759.
Scheme 1. General Strategy
(11) Recent examples: (a) Dixon, D. J.; Ley, S. V.; Tate, E. W. J. Chem.
Soc., Perkin Trans. 1 2000, 2385-2394. (b) Scheffler, G.; Schmidt, R. R.
J. Org. Chem. 1999, 64, 1319-1325. (c) Smith, A. B., III; Verhoest, P. R.;
Minbiole, K. P.; Lim, J. J. Org. Lett. 1999, 1, 909-912.
(12) Recent examples: (a) Harrowven, D. C.; Lucas, M. C.; Howes, P.
D. Tetrahedron 2001, 57, 791-804. (b) Mu¨ller, M.; Lamottke, K.; Lo¨w,
E.; Magor-Veenstra, E.; Steglich, W. J. Chem. Soc., Perkin Trans. 1 2000,
2483-2489. (c) Fujiwara, K.; Tanaka, H.; Murai, A. Chem. Lett. 2000,
610-611. (d) Clyne, D. S.; Weiler, L. Tetrahedron 1999, 55, 13659-13682.
(e) Kang, K. H.; Cha, M. Y.; Pae, A. N.; Choi, K. I.; Cho, Y. S.; Koh, H.
Y.; Chung, B. Y. Tetrahedron Lett. 2000, 41, 8137-8140. (f) Ennis, S. C.;
Fairbanks, A. J.; Tennant-Eyles, R. J.; Yeates, H. S. Synlett 1999, 1387-
1390.
(13) Mortimore, M.; Kocienski, P. Tetrahedron Lett. 1988, 29, 3357-
3360.
(14) (a) Barrett, A. G. M.; Procopiou, P. A.; Voigtmann, U. Org. Lett.
2001, 3, 3165-3168. (b) Ball, C. P.; Barrett, A. G. M.; Commerc¸on, A.;
Compe`re, D.; Kuhn, C.; Roberts, R. S.; Smith, M. L.; Venier, O. Chem.
Commun. 1998, 2019-2020
nated with titanium benzylidenes 3 having a masked nu-
cleophile in the ortho position. The acid-stable esters 2 would
thus be converted into acid-sensitive enol ethers 4. The
masked nucleophile would then be unmasked to give enol
ethers 5. Treatment with acid should then lead to the
formation of oxonium ion 6 and release from the resin with
concomitant cyclization to give bicyclic heterocycles 7. If
Merrifield resin is used, treatment with mild acid would not
(15) Comely, A. C.; Gibson, S. E. Angew. Chem., Int. Ed. 2001, 40,
1012-1032.
(16) Guthrie, E. J.; Macritchie, J.; Hartley, R. C. Tetrahedron Lett. 2000,
41, 4987-4990.
(17) (a) Zhang, H.-C.; Ye, H.; White, K. B.; Maryanoff, B. E.
Tetrahedron Lett. 2001, 42, 4751-4754. (b) Ketcha, D. M.; Wilson, L. J.;
Portlock, D. E. Tetrahedron Lett. 2000, 41, 6253-6257. (c) Zhang, H.-C.;
Ye, H.; Moretto, A. F.; Brumfield, K. K.; Maryanoff, B. E. Org. Lett. 2000,
2, 89-92. (d) Stephensen, H.; Zaragoza, F. Tetrahedron Lett. 1999, 40,
5799-5802. (e) Zhang, H.-C.; Brumfield, K. K.; Jaroskova, L.; Maryanoff,
B. E. Tetrahedron Lett. 1998, 39, 4449-4452. (f) Collini, M. D.; Ellingboe,
J. W. Tetrahedron Lett. 1997, 38, 7963-7966. (g) Zhang, H.-C.; Brumfield,
K. K.; Maryanoff, B. E. Tetrahedron Lett. 1997, 38, 2439-2442. (h)
Fagnola, M. C.; Candiani, I.; Visentin, G.; Cabri, W.; Zarini, F.; Mongelli,
N.; Bedeschi, A. Tetrahedron Lett. 1997, 38, 2307-2310. (i) Zhang, H.-
C.; Maryanoff, B. E. J. Org. Chem. 1997, 62, 1804-1809. (j) Hughes, I.
Tetrahedron Lett. 1996, 37, 7595-7598. (k) Yun, W.; Mohan, R.
Tetrahedron Lett. 1996, 37, 7189-7192. (l) Hutchins, S. M.; Chapman, K.
T. Tetrahedron Lett. 1996, 37, 4869-4872.
(8) Recent examples: (a) Vedejs, E.; Duncan, S. M. J. Org. Chem. 2000,
65, 6073-6081. (b) Dimartino, G.; Percy, J. M. Chem. Commun. 2000,
2339-2340. (c) Inoue, M.; Frontier, A. J.; Danishefsky, S. J. Angew. Chem.,
Int. Ed. 2000, 39, 761. (d) Godage, H. Y.; Fairbanks, A. J. Tetrahedron
Lett. 2000, 41, 7589-7593. (e) Davidson, J. E. P.; Anderson, E. A.; Buhr,
W.; Harrison, J. R.; O’Sullivan, P. T.; Collins, I.; Green, R. H.; Holmes,
A. B. Chem. Commun. 2000, 629-630. (f) Rutherford, A. P.; Gibb, C. S.;
Hartley, R. C.; Goodman, J. M. J. Chem. Soc., Perkin Trans. 1 2001, 1051-
1061. (g) Rutherford, A. P.; Hartley, R. C. Tetrahedron Lett. 2000, 41,
737-741.
(9) Seminal papers: (a) Fujimura, O.; Fu, G. C.; Grubbs, R. H. J. Org.
Chem. 1994, 59, 4029-4031. (b) Nicolaou, K. C.; Postema, M. H. D.;
Claiborne, C. F. J. Am. Chem. Soc. 1996, 118, 1565-1566.
(18) (a) Petrini, M.; Ballini, R.; Rosini, G. Synthesis 1987, 713-
714. (b) Ramadas, K.; Srinivasan, N. Synth. Commun. 1992, 22, 3189-
3195.
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