triazenyl arenes,11 to internal alkynes (path B). Herein we
describe a new strategy based on Rh-catalyzed tandem
allylation and oxidative cyclization12,13 of anilides14 with
allyl carbonates. This approach allows the synthesis of
indoles with substituents at position 2 but not position 3
and is, thus, equivalent to an oxidative cyclization with
terminal alkynes (path C, Scheme 1).
the catalyst system (entry 9).16 By contrast, replacement
of Cu(OAc)2 H2O by AgOAc as the oxidant prevented
3
the reaction (entry 10). Although allyl alcohol and allyl
chloride showed no reactivity, allyl tert-butyl carbonate,
allyl diethyl phosphate, allyl acetate, and allyl benzoate all
afforded 3a, albeit in lower yields than allyl methyl carbo-
nate (entries 11ꢀ14). Interestingly, as the R group of 1
increased in size from methyl to tert-butyl, the yield of 3
decreased and that of 4 increased (entries 7 and 15ꢀ17).
More expected was the detrimental effect of attenuating
the Lewis basicity of the amide oxygen with a strongly
electron-withdrawing group (entry 18). Rather surpris-
ingly, increasing the starting concentration of 1a to 0.2 M,
as appears to be standard for similar RhIII-catalyzed
reactions,9,12 reduced the yield of indole 3a to ∼50%
(entry 19), which may perhaps indicate partial inhibition
of the catalyst by the product.17
Scheme 1. General Catalytic Synthetic Strategies to Indoles
Based on CꢀH Functionalization
With the optimized procedure in hand, our attention
turned to evaluating the scope and limitations of the
reaction. Given the importance of the 2-methyl substituent
in bioactive indoles,18 we initially assessed the reactions
of variously substituted acetanilides with allyl carbonate
2a (Table 2). The reaction conditions optimized for 1a
also supported the tandem CꢀH allylation and oxidative
cyclization of a variety of para-substituted acetanilides,
affording N-acetyl-2-methylindoles 3bꢀh in yields of
40ꢀ76%. Notably, better indole yields were found when
electron-rich (1b,c) rather than electron-poor anilides
(1dꢀ1h) were employed; the latter substituents were valu-
able functional groups amenable for further decoration of
the corresponding indoles 3dꢀh.
We initiated our study by examining the cyclization of
N-phenylacetamide (1a) withallyl methylcarbonate(2a) in
DCE at 120 °C, using 1:2.5 [{Cp*RhCl2}2]/AgSbF6 as the
catalyst system and Cu(OAc)2 H2O (2.1 equiv) as the
3
oxidant (Table 1). To our delight, N-acetyl-2-methylindole
(3a) was smoothly obtained in 66% yield after 20 h
(entry 1). At 80 °C a lower yield of 3a was obtained with
a longer reaction time (entry 2), but the observation of
a small amount of N-(2-allylphenyl)acetamide (4a)15
(GCMS, 1H NMR) was taken as indicating that the
probable reaction course involves CꢀH bond allylation
followed by oxidative cyclization. Screening of a range of
solvents identified the tertiary alcohols t-BuOH and tert-
amyl alcohol as the most appropriate, with yields of up
to 82% being obtained at 120 °C (entries 3ꢀ7). The yield
was lower using AgBF4 instead of AgSbF6 for chloride
removal (entry 8), but was less sensitive to replacement of
[{Cp*RhCl2}2]/AgSbF6 by [Cp*Rh(CH3CN)3]SbF6 as
The reaction of the benzannulated anilide 1i was regio-
selective, affording the linear naphthylindole 3i in fairly
good yield. The regioselectivity for the less-hindered CꢀH
bond was also excellent with meta-substituted anilides
when electron-poor (1jꢀl), or when the substituent lacked
a coordinating atom (1m), but not when the meta-
substituent of an electron-rich anilide did contain a co-
ordinating atom (1n). However, activation of the less-
hindered CꢀH was reinforced by the additional presence
of a second methoxy group in the para position, with
acetanilide 1o giving indole 3o as the sole product.
(9) (a) Stuart, D. R.; Bertrand-Laperle, M.; Burgess, K. M. N.;
Fagnou, K. J. Am. Chem. Soc. 2008, 130, 16474–16475. (b) Stuart,
D. R.; Alsabeh, P.; Kuhn, M.; Fagnou, K. J. Am. Chem. Soc. 2010, 132,
18326–18339.
Gratifyingly, dicyclization of the meta-diacetanilide 1p
(R2 = NHCOMe) readily provided the fused bis-indole
3p in 42% yield with excellent regioselectivity for the
linear product. No conventional method affords the cor-
responding bis-indoles with such ease. Interestingly, this
(10) Ackermann, L.; Lygin, A. V. Org. Lett. 2012, 14, 764–767.
(11) Wang, C.; Sun, H.; Fang, Y.; Huang, Y. Angew. Chem., Int. Ed.
2013, 52, 5795–5798.
(12) For Rh(III)-catalyzed direct CꢀH allylation of arenes with
€
allylic carbonates, see: Wang, H.; Schroder, N.; Glorius, F. Angew.
Chem., Int. Ed. 2013, 52, 5386–5389.
(13) (a) For indoline synthesis by Pd(II)-catalyzed coupling of
N-arylureas with activated dienes, see: Houlden, C. E.; Bailey, C. D.;
ꢀ
Ford, J. G.; Gagne, M. R.; Lloyd-Jones, G. C.; Booker-Milburn, K. I.
J. Am. Chem. Soc. 2008, 130, 10066–10067. (b) For indoline synthesis by
Rh(III)-catalyzed oxidative alkylation of acetanilides with allylic alco-
hols, see: Huang, L.; Wang, Q.; Qi, J.; Wu, X.; Huang, K.; Jiang, H.
Chem. Sci. 2013, 4, 2665–2669.
(14) Substrates other than secondary amides (tosylamide, urethane,
urea, and several tertiary amides) all failed to produce appreciable yields
of indole under presumably favorable conditions (see SI for details).
(15) For CꢀH allylation of acetanilides using Pd and allylic deriva-
tives, see: (a) Zhang, Z.; Lu, X.; Xu, Z.; Zhang, Q.; Han, X. Organome-
tallics 2001, 20, 3724–3728. (b) Song, J.; Shen, Q.; Xu, F.; Lu, X.
Tetrahedron 2007, 63, 5148–5153. For Pd-catalyzed cyclization of
2-allylacetanilides, see: (c) Yip, K.-T.; Yang, D. Chem.;Asian J.
(16) Reactions at lower temperature using O2 as the oxidant gave
incomplete transformations. See ref 9.
(17) A small amount (< 3%) of starting acetanilide 1a was observed
at the end of the reaction. For a related inhibition by a substrate, see:
Tauchert, M. E.; Incarvito, C. D.; Rheingold, A. L.; Bergman, R. G.;
Ellman, J. A. J. Am. Chem. Soc. 2012, 134, 1482–1485.
(18) (a) Pan, S.; Ryu, N.; Shibata, T. J. Am. Chem. Soc. 2012, 134,
17474–17477and references therein. (b) Hill, T. A.; Gordon, C. P.;
McGeachie, A. B.; Venn-Brown, B.; Odell, L. R.; Chau, N.; Quan, A.;
Mariana, A.; Sakoff, J. A.; Chircop (nee Fabbro), M.; Robinson, P. J.;
McCluskey, A. J. Med. Chem. 2009, 52, 3762–3773. (c) Bell, M. R.;
D’Ambra, T. E.; Kumar, V.; Eissenstat, M. A.; Herrmann, J. L.; Wetzel,
J. R.; Rosi, D.; Philion, R. E.; Daum, S. J. J. Med. Chem. 1991, 34, 1099–
1110.
~
2011, 6, 2166–2175. For preparation of 2-allylaniline, see: (d) Muniz,
€
K.; Hovelmann, C. H.; Streuff, J. J. Am. Chem. Soc. 2008, 130, 763–773.
B
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