Journal of the American Chemical Society
COMMUNICATION
Scheme 1. Potential Mechanism of NO2 Migration
supporting the hypothesis that C-N bond formation occurs via
an electrocyclization.
In conclusion, we have demonstrated that rhodium(II) car-
boxylate complexes catalyze the migration of electron-withdraw-
ing groups to enable the selective formation of 3-substituted
indoles from β-substituted styryl azides. Our data allowed for the
construction of a scale that categorizes the aptitudes of migration
for a range of functional groups. Future experiments will be
centered on clarifying the mechanism of this reaction as well as
exploiting these reactivity trends to produce complex, functiona-
lized N-heterocycles from simple, readily accessible styryl azides.
’ ASSOCIATED CONTENT
Scheme 2. Double-Crossover and Relative Rate Experiments
S
Supporting Information. Complete ref 4a, experimental
b
procedures, spectroscopic and analytical data, and crystallo-
graphic data (CIF). This material is available free of charge via
’ AUTHOR INFORMATION
Corresponding Author
’ ACKNOWLEDGMENT
groups but behind hydrogen. The difference in reactivity be-
tween 7a-c (only 3-carbonylindole) and 7f-h (90:10 favoring
3-sulfonylindole) suggests that sulfones should be positioned
between hydrogen and ketones. Finally, because only nitro group
migration was seen for 10f, we rank it ahead of ketones. The
propensity for these electron-withdrawing groups to migrate,
however, hinges on the absence of a second ortho electron-
withdrawing substituent on the aryl azide.
We are grateful to the National Institutes of Health NIGMS
(R01GM084945) and the University of Illinois at Chicago for
their generous financial support. We thank Mr. Furong Sun
(UIUC) for high-resolution mass spectrometry data.
’ REFERENCES
(1) For reviews, see: (a) Sromek, A. W.; Gevorgyan, V. Top. Curr.
Chem. 2007, 274, 77. (b) Snape, T. J. Chem. Soc. Rev. 2007, 36, 1823. (c)
Lang, S.; Murphy, J. A. Chem. Soc. Rev. 2006, 35, 146. (d) ten Brink, G.-J.;
Arends, I. W. C. E.; Sheldon, R. A. Chem. Rev. 2004, 104, 4105. (e)
Overman, L. E.; Pennington, L. D. J. Org. Chem. 2003, 68, 7143.
(2) See: (a) Sulfur groups: Gairns, R. S.; Moody, C. J.; Rees, C. W. J.
Chem. Soc., Chem. Commun. 1985, 1818. (b) Acyl groups: Field, D. J.;
Jones, D. W. J. Chem. Soc., Perkin Trans. 1 1980, 1909. (c) Nitro groups:
Coombes, R. G.; Russell, L. W. J. Chem. Soc. B 1971, 2443.
(3) For examples of 3-nitro-substituted indoles, see: (a) Tang, J.;
Wang, H. Int. J. Antimicrob. Agents 2008, 31, 497. (b) Al-Zereini, W.;
Schuhmann, I.; Laatsch, H.; Helmke, E.; Anke, H. J. Antibiot. 2007,
60, 301.
(4) For recent examples of 3-sulfonyl-substituted indoles, see: (a)
Bernotas, R. C.; et al. Bioorg. Med. Chem. Lett. 2010, 20, 1657. (b)
Samuele, A.; Kataropoulou, A.; Viola, M.; Zanoli, S.; La Regina, G.;
Piscitelli, F.; Silvestri, R.; Maga, G. Antiviral Res. 2009, 81, 47.
(5) For examples of 3-acyl-substituted indoles, see: (a) Kumar, R.;
Balasenthil, S.; Manavathi, B.; Rayala, S. K.; Pakala, S. B. Cancer Res.
2010, 70, 6649. (b) Ramírez, B. G.; Blꢀazquez, C.; del Pulgar, T. G.;
Guzmꢀan, M.; de Ceballos, M. L. J. Neurosci. 2005, 25, 1904.
(6) (a) Bakke, J. M. Pure Appl. Chem. 2003, 75, 1403. (b) Myhre,
P. C. J. Am. Chem. Soc. 1972, 94, 7921. (c) Olah, G. A.; Lin, H. C.; Mo,
Y. K. J. Am. Chem. Soc. 1972, 94, 3667.
alkyl < aryl < amide < H < sulfonyl < ketone < nitro
ð2Þ
migration aptitude :
While a number of mechanisms could explain the reactivity
patterns we observed, we propose that migration occurs from a
common catalytic intermediate, 14 (Scheme 1). Coordination of
the Rh2(II) carboxylate to the R- or γ-nitrogen atom followed by
loss of N2 forms rhodium nitrene 13.18,19 A four-π-electron, five-
atom electrocyclization establishes the C-N bond and generates
a carbocation at C3 in 14.20 From this intermediate, several
different pathways could produce the desired migration. Exam-
ination of 15, a resonance structure of 14, reveals that a [1,5]
sigmatropic shift to form the C3-N bond in 16 could occur.2a,b
Alternatively, the shift could occur stepwise: homolysis of the
C-O bond in 14 could form diradical 17, whose mesomer 18
would place the radical at C3, which could recombine to form the
C-N bond in 16. A similar diradical mechanism was proposed
for the rearrangement of sulfinate ions21 and nitro groups in
electrophilic aromatic substitution.22 Tautomerization of 16
would form the 3-substituted indole.
Several experiments were performed to test our mechanistic
hypothesis (Scheme 2). A double-crossover experiment invol-
ving styryl azides 1-15N and 4a produced only indoles 3-15N and
5a, revealing that no solvent-separated reactive intermediates
were formed in the catalytic cycle. As predicted by our previous
mechanistic study,21 styryl azide 4k reacted 2.1 times faster than
1. This result confirms that the reaction can be accelerated when
an electron-donating group is positioned to assist in N2 loss,
(7) (a) Driver, T. G. Org. Biomol. Chem. 2010, 8, 3831. (b) Shen, M.;
Leslie, B. E.; Driver, T. G. Angew. Chem., Int. Ed. 2008, 47, 5056. (c)
Sundberg, R. J.; Russell, H.; Ligon, W., Jr.; Lin, L.-S. J. Org. Chem. 1972,
37, 719.
(8) Pelkey, E. T.; Gribble, G. W. Tetrahedron Lett. 1997, 38, 5603.
(9) For the reaction conditions surveyed, see the Supporting
Information.
4704
dx.doi.org/10.1021/ja111060q |J. Am. Chem. Soc. 2011, 133, 4702–4705