Treatment of 46 with aniline, p-toluidine, and o-toluidine,
respectively, in CH2Cl2 at 25 °C in the presence of Cs2CO3
gave 5 (87%), 6 (62%), and 7 (59%), Scheme 2.
Scheme 5. Thermal and Acid-Catalyzed Rearrangement
Scheme 2. 3-NHAr-2-oxindoles
Somewhat surprisingly, the adduct 5 did not rearrange to
either 8 or 9 (Scheme 3) under thermal reaction conditions
and 17 (37%), Scheme 5. Likewise, heating 14 gave 18
(55%), and 15 gave only the para isomer 19 (71%).
The acid-catalyzed rearrangement of the N-methyl series
using CF3CO2H (cat.) in benzene at 25 °C for 18 h converted
13 into 16 (55%) and 17 (25%), 14 into 18 (75%), and 15
into 19 (82%), Scheme 5.
Scheme 3. Acid-Catalyzed Rearrangement
To demonstrate the dissociative10 reversible nature of these
rearrangements we conducted two crossover experiments.
Treatment of 14 with phenol (1.0 equiv) in toluene at 80 °C
gave 2 (20%), 3 (26%), and 18 (43%) along with N-methyl
p-toluididne and phenol, Scheme 6. Conducting the same
Scheme 6. Crossover Experiments
(80 °C/PhH, sealed tube) that had sufficed for the phenoxy
adduct 1. Heating 5 in o-dichlorobenzene at 180 °C resulted
in decomposition with no trace of 8 or 9.7 It is speculated
that at higher temperatures the compounds 5-7 undergo
homolysis8 to an N-centered aniline radical and a 2-oxindole
radical.9 Indeed, melting 5 and heating neat at 220 °C for 2
h resulted in a complex mixture of products derived from
homolysis. Consequently, we examined acidic reaction
conditions to effect the rearrangement. Treatment of 5 with
CF3CO2H (cat.) in benzene at 25 °C for 18 h produced the
ortho product 8 and para product 9 in 35% and 30% yield,
respectively, Scheme 3. Similarly, under the acidic reaction
conditions, 6 was converted into 10 (68%), and 7 gave 11
(40%) and 12 (36%).
experiment under the acidic reaction conditions of CF3CO2H
(cat.) in benzene at 25 °C for 18 h gave 3 (39%) and 18
(46%). The ortho product 2 was not detected. This informa-
tion is consistent with the mechanism suggested for the
phenol rearrangement,1 Scheme 1.
We attribute the thermal stability of the NH series (5-7)
to the presence of intramolecular hydrogen bonds: X-ray
crystallography shows intermolecular H-bonding in a dimeric
fashion between the NH (aniline) and the amide carbonyl
groups (Figure 1).
The NMe series behaves “normally” and thermally ionizes
in the same manner as the phenolic ethers. The thermal
rearrangement of 13 proceeds to the ion pair 20 which
appears to dissociate to 23 rather than form the π-complex
21 which would lead exclusively to 16 via 22 (cf. Scheme
The N-methyl analogues 13-15 were made from 4 and
the corresponding N-methylanilines using Cs2CO3 as the
base, Scheme 4. These compounds were thermally labile and
rearranged under the same conditions as the phenolic ethers.
For example, heating 13 in toluene at 80 °C gave 16 (30%)
(6) Bruce, J. M.; Sutcliffe, F. K. J. Chem. Soc. 1957, 4789-4798.
(7) If 8 and/or 9 had been formed they would have been stable to the
reaction conditions.
Scheme 4. 3-NMeAr-2-oxindoles
(8) Magnus, P.; Venable, J. D.; Shen, L.; Lynch, V. Tetrahedron Lett.
2005, 46, 707-710.
(9) Akira. I.; Yutaka, M. Heterocycles 1982, 19, 2139-2142.
(10) Alder, R. W.; Baker, R.; Brown, J. M. Dissociative Processes. In
Mechanisms in Organic Chemistry; Wiley-Interscience: New York, 1971;
pp 78-179.
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Org. Lett., Vol. 8, No. 16, 2006