An annulative approach to highly substituted indoles: Unusual effect of phenolic additives on the success of the arylation of ketone enolates

Article abstract of DOI:10.1021/ja0288993

A novel palladium-catalyzed arylation of ketone enolates with o-nitrohaloarenes was achieved through the addition of phenol additives. The mild reaction conditions employed allowed for the inclusion of a wide variety of functional groups in both substrates to be tolerated. The products of this reaction were then readily reductively cyclized to give highly substituted indoles in moderate to excellent overall yields. Copyright

Full text of DOI:10.1021/ja0288993

Published on Web 11/28/2002
An Annulative Approach to Highly Substituted Indoles: Unusual Effect of
Phenolic Additives on the Success of the Arylation of Ketone Enolates
Jennifer L. Rutherford, Matthew P. Rainka, and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
Received October 10, 2002
Table 1. Synthesis of 2,n-Substituted Indolesa
The synthesis of indoles has occupied organic chemists for well
over a century.1 The combination of traditional and modern methods
has provided accessibility to a wide variety of structural variations
of this important class of heterocycles.2-9 Still, a general, mild,
and efficient method to access 4-, 5-, 6- as well as 5,6- and other
polysubstituted indoles from simple and readily accessible (non-
aryl iodide) precursors has proved elusive. Herein we disclose a
method, based on the Pd-catalyzed arylation of ketone enolates,
that concatenates simple ketones with widely available chloro- and
bromoaromatics,10 to provide a wide range of polysubstituted indole
derivatives. The success of the method is due to an unexpected
effect of an additive in the ketone arylation process: the inclusion
of a catalytic quantity of a phenol in the enolate arylation of
o-halonitroarenes effects a remarkable increase in the efficiency
of the transformation.
The Pd-catalyzed arylation of ketone enolates has recently
emerged as a useful method in organic synthesis.11 However, to
our knowledge, o-halonitroarenes have never appeared as coupling
partners in this reaction. In our preliminary studies toward this goal,
we found that along with trace product, we observed the persistent
formation of 2-nitrophenol. Any attempts to lessen the quantity of
this phenolic impurity also resulted in suppression of product
formation, indicating that the phenol might be performing a
beneficial role. In fact, we found that addition of 20 mol % phenol,
in combination with phosphine 1a, led to the development of a
highly efficient process. With the ability to couple ketones with
o-halonitroarenes, we were then able to synthesize substituted
indoles in a straightforward manner following previously described
reductive cyclization procedures.9,12 The substrate scope of this
reaction was found to be quite broad, as is depicted in Table 1.
Both electron-rich and -deficient o-bromo or o-chloro nitroarenes
were effective coupling partners under mild reaction conditions.
The reactions were carried out at 35-50 °C (save entry 9) in toluene
using K3PO4 as the base in the presence of 20 mol % of a phenol
(4-methoxyphenol was found to be optimum in most cases).
Acetophenone derivatives, as well as alkyl methyl ketones, including
a Reaction conditions: 1.0 equiv of ArX, 2.2 equiv of ketone, 0.2 equiv
acetone, were viable substrates in this process. However, the current
of phenol (see Supporting Information for exact phenol used), 2.5 equiv of
reaction conditions are successful only when arylating either methyl
or cyclic ketones. Mitigating this limitation was that the arylated
ketones I could be deprotonated and efficiently alkylated with
several electrophiles, and subsequently reductively cyclized to give
2,3-substituted indoles in moderate to excellent yields (Table 2).
In our first alkylation protocol, the ketone arylation process was
K3PO4, 1 mol % Pd2(dba)3, 4 mol % 1a, toluene. Isolated yields (average
of two runs) of compounds estimated to be >95% pure as determined by
1H NMR and GC or combustion analysis. b 4 mol % Pd, 8 mol % 1a. c 2.0
equiv of ketone. d 6 equiv of ketone. e 1.2 equiv of ketone. f 1c used as
ligand.
carried out followed by aqueous workup and isolation of the crude
product. Without purification, this was alkylated with the electro-
phile (1.1 equiv) using NaH (1.2 equiv) as the base in THF.
* To whom correspondence should be addressed. E-mail: sbuchwal@mit.edu.
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10.1021/ja0288993 CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Synthesis of 2,3,n-Substituted Indolesa
Figure 1. Role of the phenol additive.
type III, as a dramatic decrease in efficiency is seen as more
hindered phenols are used with the same substrate combination. In
summary, we have described a procedure for the arylation of methyl
and cyclic ketone enolates with o-halonitroarenes. This process has
provided for the regioselective synthesis of a wide variety of
substituted indoles from commercially available materials.
Acknowledgment. We thank the National Institutes of Health
(GM 46059) for funding, as well as Pfizer, Merck, and Bristol-
Myers Squibb for additional unrestricted support. J.L.R. thanks the
NIH for a Postdoctoral Fellowship (F32GM20826).
a Reaction conditions: 1.0 equiv of ArX, 2.0 equiv of ketone, 2.5 equiv
of K3PO4, 0.2 equiv of 4-methoxyphenol, 1 mol % Pd2(dba)3, 4 mol % 1a,
1 mL of toluene, 22 h. Isolated yields (average of two runs) of compounds
estimated to be >95% pure as determined by 1H NMR and GC or
combustion analysis. b 1.1 equiv of ketone, 2.0 equiv of K3PO4. c 6.0 equiv
of ketone. d 1.5 equiv of iodomethane, 1 mL of THF added upon completion
of ketone arylation.
Supporting Information Available: Preparation and characteriza-
tion of all substrates and products (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
References
Alternatively, we found that upon completion of the ketone
arylation, addition of iodomethane and THF (as a cosolvent) to
the crude reaction mixture and then heating at 50 °C provided the
same intermediate as obtained above. In both cases, the alkylated
material was carried on crude to the reductive cyclization step. This
method allows for the independent variation of the three substrate
components, providing a route to numerous indoles not previously
readily available.
(1) For a recent review on indoles: Saxton, J. E. Nat. Prod. Rep. 1997, 559.
(2) For reviews on indole syntheses: (a) Sundberg, R. J. Indoles; Academic
Press: San Diego, 1996. (b) Gribble, G. W. J. Chem. Soc., Perkin Trans.
1 2000, 1045. (c) Gilchrist, T. L. J. Chem. Soc., Perkin Trans. 1 2001,
2491.
(3) Larock, R. C. J. Organomet. Chem. 1999, 576, 111 and references therein.
(4) Chen, C.; Lieberman, D. R.; Larsen, R. D.; Verhoeven, T. R.; Reider, P.
J. J. Org. Chem. 1997, 62, 2676.
(5) Tokuyama, H.; Fukuyama, T. Chem. Rec. 2002, 2, 37 and references
therein.
To date, we have only seen such a remarkable effect of the added
phenol in the case of electron-deficient aryl halide substrates.
Moreover, its magnitude is significantly larger for o-halonitro-
benzene derivatives than for other substrates. To delineate the reason
for the effect of the added phenol, a series of experiments were
performed as outlined in Figure 1. From these, we found that no
desired product was formed in the presence of an excess of the
phenolic addititive or in its absence. However, good results were
obtained when the reaction was performed in the presence of a
catalytic quantity of a phenol. Several explanations are plausible.
The simplest of these is that the formation of an intermediate
palladium phenoxide (e.g., III) stabilizes an otherwise unstable
intermediate preventing catalyst decomposition.13 A second is that
intermediate II serves as a Lewis acid, while the phenoxide serves
as a base to deprotonate the coordinated ketone. A third explanation
is that III can coordinate to the ketone, facilitating deprotonation
with concomitant formation of a Pd-O bond. At present, we have
been unable to differentiate between the possibilities discussed
above. However, we favor the third, intermediacy of a complex of
(6) Battistuzzi, G.; Cacchi, S.; Fabrizi, G. Eur. J. Org. Chem. 2002, 2671
and references therein.
(7) Rodriguez, A. L.; Koradin, C.; Dohle, W.; Knochel, P. Angew. Chem.,
Int. Ed. 2000, 39, 2488.
(8) Takeda, A.; Kamijo, S.; Yamamoto, Y. J. Am. Chem. Soc. 2000, 122,
5662.
(9) (a) Iwama, T.; Birman, V. B.; Kozmin, S. A.; Rawal, V. H. Org. Lett.
1999, 1, 673. (b) Kozmin, S. A.; Iwama, T.; Huang, Y.; Rawal, V. H. J.
Am. Chem. Soc. 2002, 124, 4628.
(10) For other syntheses of intermediates of type I, see ref 9 and: (a) Kuehne,
M. E. J. Am. Chem. Soc. 1962, 84, 837. (b) Kuwajima, I.; Urabe, H. J.
Am. Chem. Soc. 1982, 104, 6831. (c) RajanBabu, T. V.; Chenard, B. L.;
Petti, M. A. J. Org. Chem. 1986, 51, 1704. (d) Gassman, P. G.; Van
Bergen, T. J. Org. Synth.; Wiley: New York, 1988; Collect. Vol. 6, p
601.
(11) (a) Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 1999, 121, 1473. (b)
Fox, J. M.; Huang, X.; Chieffi, A.; Buchwald, S. L. J. Am. Chem. Soc.
2000, 122, 1360.
(12) (a) Ho, T. L.; Wong, C. M. Synthesis 1974, 45. (b) Moody, C. J.;
Rahimtoola, K. F. J. Chem. Soc., Perkin Trans. 1 1990, 673.
(13) A similar concept has been proposed in the Pd-catalyzed amination of
aryl halides: Mann, G.; Hartwig, J. F. J. Am. Chem. Soc. 1996, 118, 13109.
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