The Neber route to substituted indoles

Article abstract of DOI:10.1021/ja058026j

Two complementary procedures have been developed for the conversion of the oximes of α-aryl ketones to azirines. On heating, the azirines rearrange smoothly to the corresponding indoles. The overall transformation offers a versatile route to indoles, complementary to the Fischer indole synthesis. Copyright

Full text of DOI:10.1021/ja058026j

Published on Web 01/06/2006
The Neber Route to Substituted Indoles
Douglass F. Taber* and Weiwei Tian
Department of Chemistry and Biochemistry, UniVersity of Delaware, Newark, Delaware 19716
Received November 25, 2005; E-mail: taberdf@udel.edu
Table 1. Indoles from R-Aryl Ketones
Indoles are ubiquitous components both of physiologically active
natural products and of important pharmaceuticals.1 Progress in the
development of indole chemistry depends on the development of
efficient synthetic routes to a variety of substitution patterns. We
report what appears to be a general indole synthesis starting from
alkyl-substituted benzene derivatives. This approach is comple-
mentary to the Fischer indole synthesis2 that starts with an aminated
benzene ring and to other existing methods for indole construction
from disubstituted aromatics.3 The reduction to practice of this
route4 to indoles opens a new expanse of pharmaceutical space for
exploration.
We took as our lead the observation that the only existing
approach to the preparation of indoles that started from an alkyl-
substituted benzene, the pyrolysis of R-azido cinnamates (Scheme
1), was known4b to proceed by way of the intermediate azirine 2.
Scheme 1
We reasoned that R-aryl azirines, such as 5a, available by Neber
reaction5,6 of the oximes derived from R-aryl ketones, such as 4a,
could also undergo thermolytic rearrangement to give the indole.4,8
The challenge proved to be the efficient conversion of the oxime
derived from the R-aryl ketone to the azirine.7 Activation of the
oxime OH with a leaving group is an invitation to competing
Beckmann rearrangement and/or Beckmann fragmentation. We
eventually developed two complementary procedures (Table 1) for
effecting this transformation. For monoaryl acyclic ketones, such
as 4a, exposure of the oxime to MsCl and Et3N at 20 °C followed
by the addition of DBU led smoothly to the azirine. For the diaryl
ketone 4c and the cyclic ketone 4e, an alternative procedure,
Mitsunobu cyclization of the oxime with DIAD/Bu3P or Ph3P, was
more satisfactory. We were pleased to observe that each of the
azirines in Table 1 was stable to chromatographic purification and
to storage. The thermal rearrangement to the indole (sealed tube,
o-xylene) worked smoothly for each of the azirines. The temperature
for the rearrangement ranged from 170 °C (entry 1) down to less
than 40 °C (entry 5). In the latter case, the azirine could not be
isolated because it rearranged to the indole as it was formed.
a Yield of azirine from ketone. b Crude oxime to azirine by MsCl; DBU.
c Previously reported in ref 9. d Crude oxime to azirine by DIAD/Bu3P.
e Crude oxime to azirine by DIAD/Ph3P. f Yield of indole from ketone 4e.
We were curious as to the mechanism of the azirine to indole
rearrangement. Following the literature,4a we expected (Scheme 2)
that the rate-determining step would be cleavage of the C-N single
bond. There were, then, two limiting mechanisms: formation of
the nitrene 8 followed by insertion into the Ar-H σ bond to give
9, or π participation from the aromatic ring to give 10, which would
reorganize to 11 and then 9.
To probe this question, we carried out two additional cyclizations,
of 12 and of the intermediate unstable azirine derived from 15
(Scheme 3). We reasoned that the σ insertion (intermediate 8) would
lead to a substantial isotope effect. In fact, there was only a very
9
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J. AM. CHEM. SOC. 2006, 128, 1058-1059
10.1021/ja058026j CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2
Supporting Information Available: Experimental details and
spectra for all new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
References
(1) For leading references to the physiological activity of indole derivatives,
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(4) There have been scattered reports of the rearrangement of aryl azirines to
indoles: (a) Padwa, A.; Smolanoff, J.; Tremper, A. J. Org. Chem. 1976,
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Scheme 3
(5) For the development of the Neber synthesis of azirines, see: (a) Neber,
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P. W.; Huh, G. Justus Liebigs Ann. Chem. 1935, 515, 283.
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(7) For alternative procedures for the preparation of azirines from R-aryl
ketones, see: Barcus, R. L.; Hadel, L. M.; Johnston, L. J.; Platz, M. S.;
Savino, T. G.; Scaiano, J. C. J. Am. Chem. Soc. 1986, 108, 3928. In our
hands, these procedures were not as efficient as those that we report here.
(8) The cyclodehydration of the oxime of an R-aryl ketone to give the indole
is a goal that dates back at least 50 years: Loffler, A.; Ginsburg, D. Nature
1953, 172, 820. Our experience with the oximes of R-aryl ketones that
we have studied is that they sometimes sublime on heating under reduced
pressure, but they do not give even traces of indole.
minor isotope effect (e10%, 1H NMR integration) in the formation
of 13 and 14.10
There was still the formal possibility that the nitrene 8 (Scheme
2) was cyclizing much more quickly than it could rotate. To assess
this, we rearranged the azirine derived from 15. In fact, there was
a significant preference for insertion into the more electron-rich
aromatic ring, to give 17, suggesting that the cyclization is
proceeding by way of the π mechanism. The observed preference
for 17 may be of some preparative utility.
(9) Several of the substances reported here were previously described. (a)
5c: Padwa, A.; Rosenthal, R. J.; Dent, W.; Filho, P.; Turro, N. J.; Hrovat,
D. A.; Gould, I. R. J. Org. Chem. 1984, 49, 3174. (b) 6c: Fuerstner, A.;
Jumbam, D. N. Tetrahedron 1992, 48, 5991. (c) 15: Katritzky, A. R.;
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Dalpozzo, R.; Todesco, P. E. J. Chem. Soc., Perkin Trans. 1 1988, 971.
(e) 17: Ikuta, S.; Shiro, M.; Ogawa, K. U.S. Patent 6,861,444 B2, 2005.
(10) For leading references to primary and secondary kinetic isotope effects,
see: Lykakis, I. N.; Orfanopoulos, M. Tetrahedron Lett. 2005, 46, 7835.
The cyclodehydration of the oximes of R-aryl ketones to indoles,
sought for at least 50 years,8 has now been reduced to practice.
We expect that this approach will be particularly useful for the
preparation of indoles having highly substituted benzene rings.
Acknowledgment. We thank Koichi Narasaka and Gordon W.
Gribble for helpful discussions. This work was supported by the
National Institutes of Health (GM 60287).
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