The benzyne Fischer-indole reaction

Article abstract of DOI:10.1021/ol201413r

A new approach to the Fischer-indole synthesis is reported that uses the reactive intermediate benzyne. The addition of N-tosyl hydrazones to arynes, generated through fluoride activation of 2-(trimethylsilyl)phenyl triflate precursors, leads to efficient

Full text of DOI:10.1021/ol201413r

ORGANIC
LETTERS
2011
Vol. 13, No. 14
3667–3669
The Benzyne Fischer-Indole Reaction
Donald McAusland,† Sangwon Seo,† Didier G. Pintori,† Jonathan Finlayson,‡ and
Michael F. Greaney*,†
University of Edinburgh, School of Chemistry, Joseph Black Building, King’s Buildings,
West Mains Road, Edinburgh, EH9 3JJ, U.K., and AstraZeneca, Alderley Park,
Macclesfield, SK10 4TG, U.K.
michael.greaney@ed.ac.uk
Received May 25, 2011
ABSTRACT
A new approach to the Fischer-indole synthesis is reported that uses the reactive intermediate benzyne. The addition of N-tosyl hydrazones to
arynes, generated through fluoride activation of 2-(trimethylsilyl)phenyl triflate precursors, leads to efficient N-arylation. Addition of a Lewis acid
to the same reaction pot then affords N-tosylindole products via Fischer cyclization.
The Fischer-indole synthesis, discovered in 1883,1,2 re-
mains one of the most powerful and versatile routes to the
indole heterocycle. Initial observations concerned the acid-
catalyzed rearrangement of enolizable arylhydrazones to
give indoles (Fischer cyclization). It quickly became stan-
dard to form these arylhydrazones in situ, and aryl hydra-
zines and enolizable aldehydes or ketones are now
considered the starting materials for a Fisher-indole synth-
esis (Scheme 1).
available than the aryl hydrazines required in the classic
Fischer.
Scheme 1. Selected Fischer-Indole Syntheses5
The fundamental importance of indoles in the fine
chemical industry has made the Fischer synthesis one of
the most studied of all organic reactions, with a large
number of modifications being reported over the past
century.3 A prominent development in recent times was
Buchwald’s introduction of Pd-catalyzed N-arylation to
access the key N-arylhydrazone intermediate, which then
undergoes a conventional Fischer cyclization on treatment
with acid (Scheme 1).4 By disconnecting across the aniline
CÀN bond, the Buchwald approach harnesses a different
and complementary set of building blocks, inexpensive
aryl halides which are far less toxic and more readily
We were interested in developing an indole synthesis
that uses the same CÀN bond disconnection but em-
ploys the reactive intermediate benzyne as the arene
source in the reaction. The reaction would represent
both a transition-metal-free variant of Buchwald’s ap-
proach and a novel way of capturing the benzyne
† University of Edinburgh.
‡ AstraZeneca.
(1) (a) Fischer, E.; Jourdan, F. Chem. Ber. 1883, 16, 2241. (b) Fischer,
E.; Hess, O. Chem. Ber. 1884, 17, 559.
(2) Reviews: (a) Robinson, B. The Fischer Indole Synthesis;
J. Wiley & Sons: New York, NY, 1982. (b) Hughes, D. L. Org. Prep. Proced.
Int. 1993, 25, 609.
(3) Humphrey, G. R; Kuethe, J. T. Chem. Rev. 2006, 106, 2875.
(4) Wagaw, S.; Yang, B. H.; Buchwald, S. L. J. Am. Chem. Soc. 1999,
121, 10251.
(5) The N-arylhydrazone in Buchwald’s synthesis is usually formed
via Pd-catalyzed N-arylation of benzophenone hydrazone followed by
exchange with the requisite carbonyl component during the Fischer
cyclization step.
r
10.1021/ol201413r
2011 American Chemical Society
Published on Web 06/14/2011

intermediate for a synthesis of the fundamental indole
heterocycle.
Nucleophilic addition to benzyne is a principal reaction
mode in aryne chemistry.6,7 Nitrogen-based nucleophiles,
in particular, have been widely employed in a host of
recently described transformations that exploit the
strained aryne triple bond.8 For the reaction at hand, we
require the addition of a hydrazone to benzyne as the first
step. This addition has not been widely reported in the
literature,9 so we began work with a simple study of this N-
arylation reaction. Using benzyne precursor 2a, our initial
attempts at arylating unprotected hydrazones led to low
yields of unstable products that were difficult to purify
(Scheme 2). Better results were obtained with hydrazones 1
containing electron-withdrawing groups on the amino
nitrogen atom, with the tosylhydrazone 1b being the best
substrate.
Scheme 2. N-Arylation of Hydrazones with Benzyne
The second step in the reaction, Fischer cyclization of N-
tosylhydrazones 3, has, to the best of our knowledge, not
been reported in the literature.10 In cases where N-protec-
tion is desired for further synthetic transformations, direct
Table 1. N-Arylation and Fischer Cyclization of N-Tosylhydrazones with Benzynea
a Conditions: Hydrazone (1 equiv), aryne precursor (1.5 equiv), CsF (3 equiv), MeCN, rt, 12 h; then BF3 OEt2 (2 equiv), reflux, 5 h. Isolated yields
after SiO2 chromatography.
3
3668
Org. Lett., Vol. 13, No. 14, 2011

synthesis of N-tosyl indoles using Fischer cyclization
would offer an efficient route to these compounds. We
were pleased, therefore, to find that treatment of 3b with
generally more effective than TsOH, and this was adopted
as the standard treatment for the reaction. A range of
ketone-derived hydrazones 1bÀ1i proved effective in the
reaction, affording good yields of N-tosylindoles 4aÀ4l.
The initial N-arylation was generally observed to be very
clean; with erosion of the yield occurring in the Fischer
cyclization. Cyclic (entries 1, 3, and 5), benzylic (entry 4),
and alkyl hydrazones were all productive using benzyne as
the arene source. Aldehyde-derived hydrazones were not
good substrates for the arylation reaction.
either toluenesulfonic acid (TsOH) or BF3 OEt2 in reflux-
3
ing acetonitrile gave a clean conversion to the desired N-
tosyl indole 4a. The use of acetonitrile as solvent in the
Fischer cyclization, which is atypical, was deliberate as it
suggested the possibility of integrating the two steps into a
one pot procedure. Accordingly, we reacted hydrazone 1b
with a slight excess of benzyne precursor 2a and excess CsF
in acetonitrile at room temperature. Arylation was com-
The use of substituted arynes was also successful (entries
9À12) and enabled us to examine the question of regios-
electivity. For naphthyne, both the initial arylation and the
subsequent cyclization were highly selective, in line with
literature precedent,8 to afford the benzannulated indoles
4i and 4j as single regioisomers. 4-Methylbenzyne (from
2c), by contrast, affords little control in both steps, with
indole 4k being isolated as a mixture of three different
isomers. 3-Methoxybenzyne displayed the expected regio-
control in N-arylation, with the nucleophilic hydrazone
adding distally to the OMe group. Cyclization would then
be expected to favor the 7-OMe substituted indole,11 which
was isolated as the major isomer in 61% yield (entry 12).
In conclusion, we have developed a new entry point into
the classic Fischer-indole synthesis using benzyne chemis-
try. The transformation uses an initial N-arylation of
widely available tosylhydrazones with aryne precursors
2, under mild conditions. Subsequent Fischer cyclization,
through a Lewis acid added to the same reaction vessel,
affords a novel one pot synthesis of N-tosyl indoles. The
procedure requires no transition-metal catalysis and will
compliment existing syntheses that form the aniline CÀN
bonds of the indole heterocycle.
plete after 12 h, after which time we added BF3 OEt2 and
3
raisedthe reaction temperature to reflux. Pleasingly, indole
4a was isolated from the reaction in 80% yield (Table 1,
entry 1).
An investigation into the scope of the reaction estab-
lished the transformation to be general for a range of alkyl
hydrazones. The Lewis acid BF3 OEt2 proved to be
3
(6) Hoffman, R. W. Dehydrobenzenes and Cycloalkynes; Academic
Press, NY, 1967.
(7) Selected recent examples: (a) Hwu, J. R.; Hsu, Y. C. Chem.;Eur.
J. 2011, 17, 4727. (b) Truong, T.; Daugulis, O. J. Am. Chem. Soc. 2011,
133, 4243. (c) Bronner, S. M.; Goetz, A. E.; Garg, N. K. J. Am. Chem.
Soc. 2011, 133, 3832. (d) Laczkowski, K. Z.; Garcia, D.; Pena, D.;
Cobas, A.; Perez, D.; Guitian, E. Org. Lett. 2011, 13, 960. (e) Biju, A. T.;
Glorius, F. Angew. Chem., Int. Ed. 2010, 49, 9761. (f) Kirkham, J. D.;
Delaney, P. M.; Ellames, G. J.; Row, E. C.; Harrity, J. P. A. Chem.
Commun. 2010, 46, 5154. (g) Dubrovskiy, A. V.; Larock, R. C. Org. Lett.
2010, 12, 3117. (h) Yoshida, H.; Ohshita, J.; Kunai, A. Bull. Chem. Soc.
Jpn. 2010, 83, 199.
(8) Recent examples: (a) Rogness, D. C.; Larock, R. C. J. Org. Chem.
2011, 76, 4980. (b) Okuma, K.; Matsunaga, N.; Nagahora, N.; Shioji,
K.; Yokomori, Y. Chem. Commun. 2011, 47, 5822. (c) Smith, A. B., III;
Kim, W.-S. Proc. Natl. Acad. Sci. U.S.A. 2011, 108, 6787. (d) Okano, K.;
Fujiwara, H.; Noji, T.; Fukuyama, T.; Tokuyama, H. Angew. Chem.,
Int. Ed. 2010, 49, 5925. (e) Hong, D.; Chen, Z.; Lin, X.; Wang, Y. Org.
Lett. 2010, 12, 4608. (f) Wu, C.; Fang, Y.; Larock, R. C.; Shi, F. Org.
Lett. 2010, 12, 2234. (g) Pintori, D. G.; Greaney, M. F. Org. Lett. 2010,
12, 168. (h) Jeganmohan, M.; Bhuvaneswari, S.; Cheng, C.-H. Chem.;
Asian J. 2009, 5, 153. (i) Cano, R.; Ramon, D. J.; Yus, M. J. Org. Chem.
2010, 76, 654. (j) Cant, A. A.; Bertrand, G. H. V.; Henderson, J. L.;
Roberts, L.; Greaney, M. F. Angew. Chem., Int. Ed. 2009, 48, 5199.
(k) Zhang, F.; Moses, J. E. Org. Lett. 2009, 11, 1587.
(9) Whilst this manuscript was under review, Shi, Larock and co-
workers described the reaction of aldehyde-derived N-tosylhydrazones
with arynes to form indazoles: Li, P.; Zhao, J.; Wu, C.; Larock, R. C.;
Shi, F. Org. Lett. 2011, ASAP DOI: 10.1021/ol201086g.
(10) A conventional Fischer-indole synthesis of N-tosyl indoles
would require uncommon N-tosylsulfonyl-N-arylhydrazines as starting
materials. Examples of N-benzoyl-N-arylhydrazines undergoing
Fischer-indole synthesis to the N-benzoyl indoles are known: (a) Mills,
K.; Al Khawaja, I. K.; Al-Saleh, F. S.; Joule, J. A. J. Chem. Soc., Perkin
Trans. 1 1981, 2, 636. (b) Campos, K. R.; Woo, J. C. S.; Lee, S.; Tillyer,
R. D. Org. Lett. 2004, 6, 79.
Acknowledgment. We thank AstraZeneca and the Uni-
versity of Edinburgh for funding. M.F.G. is an EPSRC
Leadership Fellow.
Supporting Information Available. Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(11) Chalmers, J. R.; Openshaw, H. T.; Smith, G. F. J. Chem. Soc.
1957, 1115.
Org. Lett., Vol. 13, No. 14, 2011
3669