Thermal and acid-catalyzed Hofmann-Martius rearrangement of 3-N-aryl-2-oxindoles into 3-(arylamino)-2-oxindoles

Article abstract of DOI:10.1021/ol061191z

The Hofmann-Martius rearrangement of 3-N-aryl-2-oxindoles into 3-(arylamino)-2-oxindoles under thermal and acid-catalyzed conditions is described.

Full text of DOI:10.1021/ol061191z

ORGANIC
LETTERS
2006
Vol. 8, No. 16
3497-3499
Thermal and Acid-Catalyzed
Hofmann Martius Rearrangement of
−
3-N-Aryl-2-oxindoles into
3-(Arylamino)-2-oxindoles
Philip Magnus* and Rachel Turnbull
Department of Chemistry and Biochemistry, UniVersity of Texas at Austin,
1 UniVersity Station A5300, Austin, Texas 78712-1167
p.magnus@mail.utexas.edu
Received May 15, 2006
ABSTRACT
The Hofmann−Martius rearrangement of 3-N-aryl-2-oxindoles into 3-(arylamino)-2-oxindoles under thermal and acid-catalyzed conditions is
described.
Recently, we reported the unusual thermal and acid-catalyzed
rearrangement of 3-aryloxy-2-oxindoles into 3-(arylhydroxy)-
2-oxindoles.1 For example, heating 1 at 80 °C resulted in
rearrangement to the ortho isomer 2, Scheme 1, whereas
Since compounds similar to 2 and 3 have found applica-
tions as antiproliferatives2 and calcium-dependent potassium
channel openers,3 we decided to examine the nitrogen
analogue (aniline) version of this rearrangement chemistry.
The conversion of N-alkylanilines into C-alkylanilines under
acidic conditions is known as the Hofmann-Martius re-
arrangement.4,5
Scheme 1. Rearrangement of 3-Phenoxy-2-oxindoles
(1) Goldberg, F. W.; Magnus, P.; Turnbull, R. Org. Lett. 2005, 7, 4531-
4534.
(2) Natarajan, A.; Fan, Y.-H.; Chen, H.; Guo, Y.; Iyasere, J.; Harbinski,
F.; Christ, W. J.; Aktas, H.; Halperin, J. A. J. Med. Chem. 2004, 47, 1882-
1885.
(3) Hewawasam, P.; Erway, M.; Moon, S.; Knipe, J.; Weiner, H.;
Boissard, C. G.; Post-Munson, D. J.; Gao, Q.; Huang, S.; Gribkoff, V. K.;
Meanwell, N. A. J. Med. Chem. 2002, 45, 1487-1499.
(4) Hofmann, A. W.; Martius, C. A. Ber 1871, 4, 742-748. Hofmann,
A. W. Ber 1872, 5, 720-722. Reilly, J.; Hickinbottom, W. J. J. Chem.
Soc. 1920, 103-137. Hickinbottom, W. J. J. Chem. Soc. 1937, 404-406.
Willenz, J. J. Chem. Soc. 1955, 1677-1682. Hart, H.; Kosak, J. R. J. Org.
Chem. 1962, 27, 116-127. For a more recent example of this type of
rearrangement, see: Anderson, L. L.; Arnold, J.; Bergman, R. G. J. Am.
Chem. Soc. 2005, 127, 14542-14543.
treatment of 1 with CF3CO2H (cat.) at 25 °C gave the para
isomer 3. Furthermore, to emphasize the thermodynamic
driving force in these transformations, exposure of 2 to
CF3CO2H (cat.) at 25 °C converted it into 3.
(5) Banthorpe, D. V. Rearrangments involving amino groups. In The
chemistry of the amino group; Patai, S., Ed.; Interscience: New York, 1968;
pp 585-667.
10.1021/ol061191z CCC: $33.50
© 2006 American Chemical Society
Published on Web 07/04/2006

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

Figure 1. ORTEP representation of dimeric 6 X-ray structure.
Figure 2. ORTEP representation of 24 X-ray structure.
of 16 and 17 with Super-Hydride in THF gave the aminals
24 (74%, structure by X-ray, Figure 2) and 25 (63%), Scheme
8.
1), Scheme 7. The dissociated intermediate 23 can form both
16 and 17,11 which is what we observe. The acid-catalyzed
rearrangement gives the same product distribution as the
thermal version and proceeds via 23. The only noticeable
difference between the NH and NMe series is that 7 gave a
mixture of the ortho and para adducts 11 and 12, respectively,
whereas 15 only gave the para adduct 19.
Scheme 8. Formation of the Tetrahydroindolo[2,3-b]indole
Aminal
Scheme 7. Proposed Mechanism of Rearrangement
In conclusion, we have demonstrated the versatility of the
rearrangement reaction and have shown that it has potential
applications in the synthesis of natural product analogues.
Acknowledgment. The NIH (CA RO1 50512) and the
Welch Chair (F-0018) are thanked for their support of this
research. Vince Lynch (The University of Texas at Austin)
is thanked for the X-ray crystallographic structural determi-
nation of 6 and 24.
Because of the structural relationship of these adducts to
the core of diazonamide12 and physostigmine13 analogues,
we attempted to reduce the amide carbonyl group of some
of the rearrangement products. It was found that treatment
Supporting Information Available: Experimental pro-
cedures, spectral data, and characterization of all new
compounds. X-ray crystallographic data for compounds 6
and 24. This material is available free of charge via the
Internet at http://pubs.acs.org.
(11) For structures analogous to 17 see: Fuchs, J. R.; Funk, R. L. Org.
Lett. 2005, 7, 677-680.
(12) Li, J.; Jeong, S.; Esser, L.; Harran, P. G. Angew. Chem., Int. Ed.
2001, 40, 4765-4770. Li, J.; Burgett, A. W. G.; Esser, L.; Amezcua, C.;
Harran, P. G. Angew. Chem., Int. Ed. 2001, 40, 4770-4773.
(13) Stedman, E.; Barger, G. J. Chem. Soc. 1925, 127, 247-258.
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