Scheme 1
Scheme 2a
a (a) (1) NH2NH2, MeOH, reflux, (2) NaOEt, EtOH, reflux, 98%;
(b) POCl3, DMF, pyridine, CHCl3, 0 °C to rt, 76%; (c) NaH, KH,
MeI, THF, reflux, 97%; (d) (1) MeMgBr, THF, (2) TPAP, NMO,
96%; (e) (1) Tl(TFA)3, TFA, (2) I2, CuI, DMF, 78%; (f) Sn2Me6,
toluene, PdCl2(PPh3)2, reflux, 50%; (g) Pb(OAc)4, Hg(OAc)2,
CHCl3, 40 °C.
been completed.4 It arises from simple â-ketoester 4 and
requires two successive conjugate additions to the intermedi-
ate R,â-unsaturated ketoesters to afford the desired C12
center. â-Ketoester 4 is prepared from 1,4-cyclohexanediol
5. The plan for synthesis of the unprecedented indole lead-
(IV) reagent 3 was envisioned to proceed from 4-iodo-3-
acetylindole 6 which, in turn, comes from 3-acetylindole 7.5
The use of a 2-chloro substituent on the indole ring allows
for easy hydrolysis to the oxindole in the latter stages of the
synthesis.6
The key reaction in this sequence would be the coupling
of organolead compound 3 with â-ketoester 2 to form the
C11 quaternary center. Aryllead(IV) reagents are an excellent
choice for establishment of a quaternary center,5,7,8 and access
to an indole-based reagent would expand the chemistry of
these aryl cation equivalents to this class of medicinally
important compounds. The reactions proceed under very mild
conditions, and yields tend to be very high. Our group, as
well as others, has applied this methodology toward the total
synthesis of natural products.9,10
Our approach to indole fragment 3 is illustrated below
(Scheme 2) and is based on our previous published work
directed toward the total synthesis of the marine natural
product diazonamide A.9 Isatin 8 was treated with hydrazine
to form the corresponding hydrazone, followed by Wolff-
Kishner reduction to give oxindole 9 in 95% yield.11
Vilsmeier chloroformylation with POCl3, DMF, and pyridine
provided 2-chloro-3-formylindole 10.12 Methylation with
NaH/KH/MeI furnished compound 11.13 Treating 11 with
MeMgBr followed by immediate oxidation with TPAP/NMO
yields N-methyl-2-chloro-3-acetylindole 7 in 96% yield.
Oxidation utilizing DDQ gave the same product but required
longer reaction time and led to more difficult product
purification. This four-step procedure affords 7 in much
greater overall yield than does the more direct two-step
method.14
All attempts to obtain the desired lead reagent at the
4-position of the indole nucleus by a direct plumbation
approach failed.15 Therefore, organothallium chemistry was
utilized to functionalize the 4-position of the indole ring
system.16,17 Compound 7 was treated with thallium(III)
trifluoroacetate (TTFA) in TFA, which resulted in efficient
thallation at the C4 position of the indole. After evaporation
of the TFA solvent under vacuum, iodination with iodine
and copper iodide gave the desired N-methyl-3-acetyl-2-
chloro-4-iodoindole 6 in 78% yield for the two steps.
With compound 6 in hand, the conditions for iodo-tin
exchange were investigated. Direct lithium-iodo exchange
with t-BuLi/Bu3SnCl afforded only deiodinated product.
Iodo-tin exchange was achieved to give compound 12 in 50%
yield by refluxing 6 with hexamethylditin in toluene in the
presence of catalytic PdCl2(PPh3)2 or Pd(PPh3)4.18 The
reaction did not proceed as well with Pd(OAc)2. The final
step to the desired indole lead(IV) reagent was the transfor-
(4) Konopelski, J. P.; Deng, H.; Schieman, K.; Keane, J. M.; Olmstead,
M. M. Synlett 1998, 1105.
(5) Pinhey, J. T. Aust. J. Chem. 1991, 44, 1353.
(6) Phillips, R. S.; Cohen, L. A. J. Am. Chem. Soc. 1986, 108, 2023.
(7) Finet, J. P. Ligand Coupling Reactions with Heteroatomic Com-
pounds; Pergamon Press: Oxford, 1998.
(8) Elliott, G. I.; Konopelski, J. P. Tetrahedron 2001, 57, 5683.
(9) Konopelski, J. P.; Hottenroth, J. M.; Monzo´-Oltra, H.; Veliz, E. A.;
Yang, Z. C. Synlett 1996, 609.
(10) Donnelly, D. M. X.; Finet, J. P.; Kiety, J. M. Tetrahedron Lett.
1991, 32, 3835.
(11) Soriano, D. S. J. Chem. Educ. 1993, 70, 332.
(12) Andreani, A.; Bonazzi, D.; Rambaldi, M.; Guarnieri, A.; Andreani,
F.; Strocchi, P.; Montanaro, N. J. Med. Chem. 1977, 20, 1344.
(13) Showalter, H. D. H.; Sercel, A. D.; Leja, B. M.; Wolfangel, C. D.;
Ambroso, L. A.; Wlliott, W. L.; Fry, D. W.; Kraker, A. J.; Howard, C. T.;
Lu, G. H.; Moore, C. W.; Nelson, J. M.; Roberts, B. J.; Vincent, P. W.;
Denny, W. A.; Thompson, A. M. J. Med. Chem. 1997, 40, 413.
(14) Coppola, G. M.; Hardtmann, G. E. J. Heterocycl. Chem. 1977, 14,
1117.
(15) Kozyrod, R. P.; Pinhey, J. T. Org. Synth. 1984, 62, 24.
(16) Hollins, R. A.; Colnago, L. A.; Salin, V. M.; Seidl, M. C. J.
Heterocycl. Chem. 1979, 16, 993.
(17) Somei, M.; Yamada, F.; Kunimoto, M.; Kaneko, C. Heterocycles
1984, 22, 797.
(18) Tueting, D. R.; Echavarren, A. M.; Stille, J. K. Tetrahedron 1989,
45, 979.
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Org. Lett., Vol. 3, No. 19, 2001