two-fold addition of ACCN in dry, degassed refluxing decane
(entry 5).
of TTMSS was slowly added to a mixture of 4e and AIBN in
boiling toluene. These conditions enabled to increase to 40%
the chemical yield of tricyclic products 7e (entry 15).
These optimised conditions were then successfully applied to
2-tolyl 4b and 2-chlorophenyl 4c sulfonamide-type precursors
leading to the corresponding oxindoles 5b and 5c in 62% and
59% yields, respectively (entries 6 and 7). In both cases a third
portion of ACCN (0.2 equiv.) was needed to complete the reaction.
We were pleased to find that p-methyl 4d or p-chloro 4e substituted
sulfonamide analogs under the same conditions gave oxindoles 5d
or 5e in 64 and 68% yields, respectively (entries 8 and 9). Under
these conditions, only a few amount of tricyclic product 7e was
isolated. 4-Pyrazolo substituted derivative 4g afforded the
prospected oxindole 5g in a slightly lower yield (51%) probably
due to the lower migration ability of the diaryl group (entry 11).
Next we examined the influence of R1 and R2 groups on the
radical domino process. An N-isopropyl group containing
analog 4f led to an almost equimolar syn–anti mixture of 5f
in 54% yield along with some starting material (entry 10).
Treatment of p-toluidine analog 4i gave a complex mixture of
products (entry 13), while the p-chloro counterpart 4j
smoothly afforded the expected 5j in 55% yield together with
monocyclic 6j (8%) and tricyclic 7j (5%) products (entry 14).
In connection with optimisation studies we focused our
attention on the so-called tricyclic products 7a and 7e obtained
as an unseparable mixture (4 : 1). Spectroscopic analyses
(MS, NMR) evidenced a partially reduced oxindole moiety.
Fortunately in the 4-chlorophenyl series the major derivative 7e1
was isolated in a pure crystalline form (entry 9). X-Ray analysis of
7e1 confirmed its unique tricyclic structure with a tetrahydro-
oxindole skeleton bearing an additional pyrrolidone moiety with a
cis relative configuration between the ring junction and aryl
substituted carbon (Fig. 1). Minor compounds (7a2 and 7e2)
could be identified as dihydrooxindole analogs by comparison of
NMR and MS data. These results supported that only one of the
two intermediate diastereomers (30 : 70 to 50 : 50 ratio,
1H NMR determination) cyclised16 by addition of the amidyl
radical on the ring junction of the oxindole moiety.17
A tricyclic radical intermediate underwent successive reductions
affording the tetrahydro-oxindole derivative as the major product
(Scheme 3, path c).18 Minor dihydro compounds may result from
the reduction at C6 of the indolinone ring probably owing to the
steric hindrance of TTMSS. In the series of substituted iodoanilines
the exclusive formation of dihydro derivatives 7i and 7j may also be
explained by the more accessible C6 carbon to reducing agents. In
order to promote the final stages of our domino process a solution
With the aim to extend our domino process to the synthesis of
complex indole-heterocycles, we were pleased to find that the ester
containing precursor 4h gave exclusively the corresponding oxindole
derivative 5h in very good yield (entry 12). This compound could be
considered as a useful intermediate toward indolo[2,3-b]quinoline-
type derivatives by simple functional group transformations.
In conclusion, these preliminary results demonstrated the
efficiency and potentiality of our original domino radical
cyclisation–Smiles rearrangement approach and could open
an access toward various azaheterocycles of biological interest.
Moreover, we observed an unprecedented domino radical
cyclisation–Smiles rearrangement–radical cyclisation sequence
affording tricyclic di(tetrahydro)oxindoles 7. Optimisation and
mechanistic studies of this procedure are in due course.
Financial support of the ‘‘Region Champagne-Ardenne’’
´
(PhD fellowship for I.A.-S.) and of EU (‘‘Fonds FEDER’’) is
gratefully acknowledged.
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Fig. 1 ORTEP view and atom labeling of 7e1.
c
2444 Chem. Commun., 2012, 48, 2442–2444
This journal is The Royal Society of Chemistry 2012