Scheme 1
energetically preferred reactions, aryl radicals are well known
be rather low yielding, and so 15 was converted to the acid
chloride 16 by careful reaction with oxalyl chloride in THF
at 0 °C. Reaction with 2-bromobenzylamine as its hydro-
chloride salt using an excess of diisopropylethylamine in
dichloromethane gave the primary amide 17 in 94% yield.
Unfortunately, it proved impossible to alkylate 17 on the
amide nitrogen using base and alkyl halide owing to what
appears to be a cyclization onto the nitrile. Consequently,
acid chloride 16 was reacted with N-methyl-2-bromobenzyl-
amine and N-ethyl-2-bromobenzylamine14 to give the desired
radical precursors 5a and 5b, respectively, in 84% and 90%
yields.
With these two substrates in hand, we were in a position
to study the radical sequence. However, NMR studies of 5a
and 5b clearly demonstrated that two amide rotamers were
present in each case in approximately equal amounts. It is
well established that the lifetime of radicals is generally
insufficient to allow amide bond rotation to occur.15 In the
case of 5, one of the two rotamers would be unable to cyclize
onto the indole-3-position owing to its geometry and would
undergo reduction leading to a maximum yield for the
sequence of 50%. To aid rotamer interconversion, we carried
out the radical reactions in high-boiling solvents, although
the results indicate this has little beneficial effect. Reaction
of 5a in tert-butylbenzene at 170 °C with TBTH using AIBN
as initiator and syringe pump delivery gave a 30% yield of
the spirocyclic indolenine 9a as a 1:1 mixture of diastere-
omers. The proton NMR of the individual diastereomers of
9a showed three AB quartets for the three methylene groups
and a singlet for the proton adjacent to the nitrile. Along
with the desired product, some 60% of reduced product was
isolated, mainly arising from the “wrong” amide rotamer,
and a small amount of starting material was recovered,
to undergo [1,5]-hydrogen atom abstraction10 which in this
case should generate the R-amido radical 7. A report by
Fang11 has shown that alkyl radicals will add intramolecularly
to the 3-position of 2-cyanoindoles which in our case will
generate spiropyrrolidinyl indolenine radical 8. Reduction
of this stabilized radical with tributyltin hydride (TBTH) will
generate cyanoindolenine 9 and more tributylstannyl radical.
Transformation of the cyanoindolenine to the oxindole by
oxidative decyanation is well precedented.12
The synthesis of cyclization precursors 5 commenced with
indole-3-acetic acid 10 (Scheme 2). Formation of the methyl
ester using thionyl chloride in methanol at -78 °C followed
by N-methylation using sodium hydride and methyl iodide
gave the N-methylindole 11 in 91% overall yield. Vilsmeier
formylation of 11 proceeded in some 67% yield on a small
scale, but on a larger scale the yield of 2-formylindole 12
was consistently around 50%. Formation of the oxime 13
using hydroxylamine hydrochloride in ethanol containing
pyridine was uneventful, and elimination in refluxing acetic
anhydride using triethylamine gave the 2-cyanoindole 14 in
69% yield from the aldehyde 12. Hydrolysis of the ester to
enable elaboration to the required amide proved to be rather
troublesome. Most of the base-promoted conditions explored
led to concomitant hydrolysis of the nitrile to the primary
amide possibly via a mechanism involving intramolecular
catalysis by the ester group. However, the very mild
conditions reported by Boger13 involving lithium hydroxide
in a tert-butyl alcohol/water mixture at room temperature
proved successful and gave the acid 15 in 97% yield.
Coupling of the acid 15 with amines using DCC proved to
(10) Curran, D. P.; Xu, J. Y. J. Am. Chem. Soc. 1996, 118, 3142.
Beckwith, A. L. J.; Storey, J. M. D. J. Chem. Soc., Chem. Commun. 1995,
977.
(11) Yang, C. C.; Chang, H. T.; Fang, J. J. Org. Chem. 1993, 58, 3100.
(12) Fang, J. M.; Chuang, T. H.; Yang, C. C.; Chang, C. J. Synlett 1990,
733
(14) These secondary amines were prepared by the procedure reported
by Fukuyama: Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett.
1995, 36, 6373. See also: Bowman, W. R.; Coghlan, D. R. Tetrahedron
1997, 53, 15787.
(13) Boger, D. L.; Borzilleri, R. M.; Nukui, S.; Beresis, R. T. J. Org.
Chem. 1997, 62, 4721.
(15) Jones, K.; McCarthy, C. Tetrahedron Lett. 1989, 30, 2657. Musa,
O. M.; Horner, J. H.; Newcomb, M. J. Org. Chem. 1999, 64, 1022.
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Org. Lett., Vol. 2, No. 17, 2000