A palladium-catalyzed strategy for the preparation of indoles: A novel entry into the Fischer indole synthesis

Full text of DOI:10.1021/ja981045r

J. Am. Chem. Soc. 1998, 120, 6621-6622
6621
Scheme 1
A Palladium-Catalyzed Strategy for the Preparation
of Indoles: A Novel Entry into the Fischer Indole
Synthesis
Seble Wagaw, Bryant H. Yang, and Stephen L. Buchwald*
Department of Chemistry
Massachusetts Institute of Technology
Cambridge, Massachusetts 02139
Table 1. Synthesis of N-Aryl Hydrazones and Indoles
ReceiVed March 30, 1998
The indole nucleus is an important element in many pharma-
cologically active compounds.1 Of the many methods developed
for indole synthesis, the oldest and most widely used is the Fischer
indole synthesis,1,2 in which an N-aryl hydrazone undergoes acid-
catalyzed or thermal sigmatropic rearrangement to generate, after
elimination of ammonia, the indole skeleton. Although a number
of methods exist for the preparation of N-aryl hydrazones,3 the
most common is the condensation of an aldehyde or ketone with
an N-aryl hydrazine. The N-aryl hydrazine, in turn, is typically
prepared via reduction of the corresponding aryl diazonium
species.1,2
The palladium-catalyzed cross coupling of amines with aryl
halides has proven to be general in substrate scope with respect
to both the amine component and the aryl halide.4 Due to the
success of this reaction, we hoped that this methodology could
provide a complementary synthesis of N-aryl hydrazones as
substrates for Fischer indolizations. In an initial experiment, we
found that the palladium-catalyzed coupling of cyclohexanone
hydrazone with 4-bromobiphenyl proceeded as evidenced by GC/
MS. We found, however, that a more convenient means to access
the desired N-aryl hydrazones was via the intermediacy of the
N-aryl hydrazones of benzophenone (Scheme 1). These N-aryl
benzophenone hydrazones could be prepared by the coupling
reaction of benzophenone hydrazone and an aryl bromide with a
Pd(OAc)2/BINAP catalyst system.5 Both electron-rich and electron-
poor aryl bromides of a variety of substitution patterns were
successfully employed (Table 1, N-aryl hydrazones 1-7).
In contrast to simple hydrazones derived from nonaromatic
ketones, benzophenone hydrazones could typically be stored for
weeks on the benchtop without significant decomposition.6
Attempts to effect the hydrolysis of these compounds afforded
the desired N-aryl hydrazine in low yield, along with the
corresponding aniline side-product resulting from N-N bond
cleavage of the aryl hydrazine. Since we were less interested in
the liberated hydrazines than in the hydrazones which could be
Yields refer to the average of two isolated yields of >95% purity as
determined by GC, 1H NMR and, for new compounds, elemental
analysis. aReactions were run with 1 equiv of aryl bromide, 1-1.1
equiv of benzophenone hydrazone, 1-1.5 mol % Pd(OAc)2, 1-2.3 mol
% (S)- or (()-BINAP, 1.4 equiv of NaOt-Bu, and 0.5-1 M toluene
with respect to benzophenone hydrazone, at 80 °C. bReactions were
run at 100 °C, otherwise following reaction conditions described in
footnote a. cThe reaction was run with 2.5 mol % Pd(OAc)2, 3.75
mol % (()-BINAP, and 1.4 equiv of Cs2CO3 at reflux, otherwise
following reaction conditions previously described in footnote a.
dReactions were run with 1 equiv of N-aryl benzophenone hydrazone,
1.5 equiv of ketone, and 2.0-5.0 equiv of TsOH•H2O in refluxing
EtOH. eThe intermediate N-aryl benzophenone hydrazone was not
isolated prior to indolization. fThe yield refers only to the isolated
6-methoxy indole regioisomer. gIndolization was conducted in refluxing
THF otherwise following reaction conditions described in footnote d.
(1) For a description of the biological activity of indoles, see: Sundberg,
R. J. Indoles; Academic Press: London, 1996, and references therein.
(2) For a recent review on the Fischer indole synthesis, see: Hughes, D.
L. Org. Prep. Proced. Int. 1993, 25, 607.
derived from them, we pursued a modified approach. The
hydrolysis of hydrazones can generally be promoted by trapping
the liberated hydrazine with an excess of an aldehyde or ketone.3b
In the case of N-aryl benzophenone hydrazones, we felt that
conducting the hydrolysis in the presence of a ketone could
produce an enolizable hydrazone that would undergo Fischer
indolization under the acidic reaction conditions.7 This would
be advantageous from two perspectives. First, it would obviate
the need to prepare or isolate potentially sensitive aryl hydrazines.
Second, it would provide a potentially very general means to the
requisite N-aryl hydrazones for Fischer indolization from a single,
(3) For preparative routes to N-aryl hydrazones, see: (a) Robinson, B. The
Fischer Indole Synthesis; John Wiley & Sons: Chichester, 1982; pp 48-59.
(b) Smith, P. A. S. DeriVatiVes of Hydrazine and Other Hydronitrogens HaVing
N-N Bonds, 2nd ed.; The Benjamin/Cummings Publishing Company:
Reading, MA, 1983; Chapter 2.
(4) For lead references on the palladium-catalyzed coupling of amines with
aryl halides see: (a) Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S.
L. Acc. Chem. Res. Submitted for publication. (b) Hartwig, J. F. Synlett 1997,
329. (c) Wolfe, J. P.; Wagaw, S.; Buchwald, S. L. J. Am. Chem. Soc. 1996,
118, 7215. (d) Driver, M. S.; Hartwig, J. F. J. Am. Chem. Soc. 1996, 118,
7217.
(5) In a related process, benzophenone imine undergoes palladium-catalyzed
cross-coupling with aryl halides: (a) Wolfe, J. P.; Åhman J.; Sadighi, J. P.;
Singer, R. A.; Buchwald, S. L. Tetrahedron Lett. 1997, 38, 6367. (b) Mann,
G.; Hartwig, J. F.; Driver, M. S.; Ferna´ndez-Rivas, C. J. Am. Chem. Soc.
1998, 120, 827.
(6) Hydrazones of aromatic ketones are more resistant to azine formation
as compared to hydrazones derived from aliphatic ketones: Szmant, H. H.;
McGinnis, C. J. Am. Chem. Soc. 1950, 72, 2890. Additionally, crystalline
hydrazones may be stored for longer periods of time without decomposition
than undiluted liquid hydrazones.10
(7) It has been reported that heating an acetic acid solution of acetophenone
phenylhydrazone or benzaldehyde phenylhydrazone in the presence of
cyclohexanone results in the formation of tetrahydrocarbazole in 50% and
5% yield, respectively. This was ascribed to have resulted from transhydra-
zonation followed by Fischer cyclization: Gore, P. H.; Hughes, G. K.; Ritchie,
E. Nature 1949, 164, 835.
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6622 J. Am. Chem. Soc., Vol. 120, No. 26, 1998
Communications to the Editor
Scheme 2
consistent with previous findings that such hydrazones do not
readily undergo Fischer indolization even under forcing condi-
tions.9
The regioselectivity of the indolization with respect to the
N-aryl group was as expected.2 In the case of meta-substituted
hydrazone 5, indolization gave a 4:1 mixture of the 6-methoxy-
and the 4-methoxyindole regioisomers, with the 6-substituted
isomer predominating. In the case of dimethoxy hydrazone 6,
only the product resulting from indolization at the less hindered
site of the aryl group was observed. Regioselectivity with respect
to the ketone component was consistent with rate-limiting
sigmatropic rearrangement of the more substituted ene-hydrazine.
Thus, indolization of dimethoxyhydrazone 6 with 2-hexanone
provided the corresponding 2-methyl-3-propyl indole (14). In
all cases where unsymmetrical ketones were employed, only one
regioisomer of the product was observed.
Scheme 3
While the palladium-catalyzed N-arylation of nonbenzophe-
none-derived simple hydrazones does proceed, this method is less
convenient. Preparation of these simple hydrazones requires the
use of anhydrous hydrazine.10,11 Moreover, decomposition of the
hydrazones was apparent under the conditions of the palladium-
catalyzed coupling reaction, leading to variable yields (see Scheme
3).12 N-Aryl hydrazones formed from these coupling reactions
were not stable to chromatography, though the crude product
could be directly subjected to Fischer indolization. Yields of
indoles derived from these nonbenzophenone simple hydrazones
were lower compared to those derived from the benzophenone
hydrazone protocol under otherwise identical reaction conditions.
For example, the combination of cyclohexanone hydrazone with
4-bromobiphenyl gave 16 in an average yield of 36%. A 92%
overall yield was realized by using the procedure via the
intermediacy of the N-aryl benzophenone hydrazone, which was
converted to indole 16 without purification. Likewise, the latter
procedure produced 17 in substantially higher yield (81%) than
when simple hydrazone III was employed (47% average yield).
Reagents and conditions: (i) 4-bromobiphenyl (1.0 equiv), Pd(OAc)2
(5 mol %), (()-BINAP (5 mol %), NaOt-Bu (1.4 equiv), toluene, 100
°C. (ii) TsOH‚H2O (2 equiv), refluxing EtOH. aThe range of yields which
were obtained from four reactions run under identical conditions.
commercially available precursor. In fact, the reaction of N-(4-
chlorophenyl)benzophenone hydrazone 1 with cyclohexanone8 in
the presence of concentrated hydrochloric acid solution in
refluxing THF gave the desired indole 8 in 64% yield. After
examining a number of acids commonly employed in Fischer
indolization procedures,3a we found that the best results were
obtained using p-toluenesulfonic acid monohydrate (p-TsOH‚
H2O). In this way a 95% yield of 8 was realized. We have found
that the p-TsOH‚H2O generally provides a sufficient amount of
water to effect hydrolysis of the N-aryl benzophenone hydrazone.
Although THF was found to be a satisfactory solvent in this
procedure, protocols which utilized ethanol were frequently found
to be preferable.
As shown in Table 1, reaction conditions described above are
applicable to the synthesis of a wide variety of indoles. Note
that a large excess of ketone is not necessary; in general 1.5 equiv
were sufficient. As shown in Scheme 2, I and II are in dynamic
equilibrium. Hydrazone II, however, is irreversibly consumed
in the Fischer indolization process, thus driving the reaction to
completion. We have found that purification of the intermediate
N-aryl benzophenone hydrazone is not required. Filtration of the
crude product from the palladium-catalyzed coupling reaction
through Celite/silica gel followed by the removal of solvent and
subjecting the crude material to Fischer indolization conditions
affords the indole product in overall yields comparable to the
stepwise protocol (see Table 1, entries 1-2 and Scheme 3). In
testing the limits of this methodology, we find that when the
N-aryl group is p-CF3 substituted (hydrazone 7), condensation
of the corresponding N-aryl hydrazine with 2-hexanone occurs
cleanly, but subsequent indolization does not occur. This is
In summary, we have developed a method that provides an
alternative source of substrates for Fischer indolizations. Central
to this strategy was the application of a palladium-catalyzed
coupling procedure to prepare N-aryl benzophenone hydrazones,
and their use as general precursors to intermediates in the classical
Fischer Indole Synthesis. We are currently applying this and
related methodologies toward the preparation of N-alkyl and
N-aryl indoles, pyrroles, furans, and benzofurans, as well as the
synthesis of pharmaceutical targets and indole libraries.
Acknowledgment. This research was funded by the National Science
Foundation. We also thank Pfizer Inc. for additional support. B.H.Y. is
a trainee of the National Cancer Institute (NCI Training Grant NCI No.
5T32CA09112). S.W. gratefully acknowledges the Ford Foundation for
a Predoctoral Fellowship. We thank Professor John Hartwig for informing
us of his work on the coupling reactions of benzophenone hydrazone.
Supporting Information Available: Preparation and characterization
of 1-17 (12 pages, print/PDF). See any current masthead page for
ordering information and Web access instructions.
JA981045R
(9) Troitskaya, V. I.; Oksengendler, I. G.; Pazenok, S. V.; Lyubich, M. S.;
Larina, S. M. Chem. Heterocycl. Compd. 1982, 18, 39.
(10) Newkome, G. R.; Fishel, D. L. J. Org. Chem. 1966, 31, 677.
(11) Day, A. C.; Whiting, M. C. Organic Syntheses; John Wiley & Sons:
New York, 1970; Vol. 50, pp 3-6.
(12) Azine byproducts were irreversibly formed during the coupling reaction
of nonbenzophenone derived simple hydrazones, as determined by GC/MS.
For discussions on the stability of simple hydrazones, see refs 6, 10, and 11.
(8) In this initial experiment, 10 equiv of cyclohexanone were employed.