A novel and direct synthesis of indoles via catalytic reductive annulation of nitroaromatics with alkynes

Article abstract of DOI:10.1039/b110370a

Indoles are produced regioselectively and in moderate yields from the reactions of nitroaromatics with alkynes catalyzed by [CpM(CO)₂]₂ (1; [(η⁵-C₅H₅)Fe(CO)₂] ₂; [(η⁵-C₅Me₅)-Fe(CO)₂] ₂; [(η⁵-C₅Me₅)Ru(CO)₂] ₂) under carbon monoxide.

Full text of DOI:10.1039/b110370a

A novel and direct synthesis of indoles via catalytic reductive annulation
of nitroaromatics with alkynes†
Andrea Penoni and Kenneth M. Nicholas*
Department of Chemistry and Biochemistry, University of Oklahoma, Norman, OK 73019, USA
Received (in Corvallis, OR) 13th November 2001, Accepted 14th January 2002
First published as an Advance Article on the web 7th February 2002
Indoles are produced regioselectively and in moderate yields
from the reactions of nitroaromatics with alkynes catalyzed
30–40% yield). Using the PhNO /PhC·CH reaction for a
2
catalyst survey and optimization study (eqn. (3), X,YNH, ZNCH,
5
5
by [CpM(CO)
2
]
2
(1; [(h -C
5
H
5
)Fe(CO)
2
]
2
; [(h -C
5
Me
5
)-
RNPh, RANH) both Fe- and Ru-cyclopentadienyl derivatives,
5
Fe(CO)
ide.
2
]
2
; [(h -C
5
Me )Ru(CO)
5
2
]
2
) under carbon monox-
10
1
a–c proved to be effective catalysts for the production of
3
-phenylindole. Moderate yields (20–40%) were obtained in
dioxane or benzene operating above 500 psi of CO and 160 °C
with a 2–4+1 PhC·CH+PhNO ratio and 5 mol% catalyst; under
Indoles are among the most abundant and important classes of
N-heterocycles, being present in the form of innumerable
natural products and bioactive compounds. Accordingly, chem-
ists have long sought methods for the preparation of indoles and
numerous approaches continue to be reported toward this end.1
Especially attractive, but rare, are reactions which directly
produce indoles by annulation of commercially available N-
2
these conditions the Ru-complex 1c gave the best yield (39%).
For these reactions the N-mass balance was 80–90%.11 Notably,
several cyclopentadienyl complexes of other metals, non-Cp-
Ru compounds, and various Pd–phosphine complexes, which
are active in other nitroarene reductive reactions, failed to
promote indole formation.12
aromatic precursors, as typified by the Fischer indole synthesis
in which aromatic hydrazines and ketones are condensed.2,3 The
An initial survey of nitroarene and alkyne substrates indicates
that the reaction has significant scope as a method for the
selective preparation of substituted indoles (eqn. (3), Table
need for broad substrate scope, more accessible starting
materials, improved regioselectivity, milder reaction condi-
tions, and functional group tolerance has also stimulated the
development of numerous transition metal-promoted routes to
1
).
4
indoles, most of which, however, are intramolecular cycliza-
tions requiring an ortho-substituted N-aromatic substrate.5
The ability of metal complexes to induce C–N bond
formation by the reduction of nitroaromatic compounds with
6
carbon monoxide and our continuing goal to develop direct
7
nitrogenation reactions of hydrocarbons, led us recently to
develop a novel and regioselective, iron-catalyzed synthesis of
allyl amines by the reductive amination of olefins with
nitroaromatics (eqn. (1)).8
(
3)
Although electron-neutral or -deficient nitroarenes react more
rapidly, both electron rich and electron deficient substrates gave
comparable yields of indoles in their reactions with phenyl-
3
acetylene (entries 1,6–10). The unsymmetrical m-CF -deriva-
(
1)
tive (entry 9) reacted with phenylacetylene to give a (3+2)
Anticipating a new route to propargyl- and/or allenylamines, we
began to examine the corresponding reactions of nitroaromatics
and alkynes but have found, remarkably, that indoles are the
major products of these reactions.
mixture of 3-phenyl-4-CF - and 3-phenyl-6-CF -indoles but the
3
3
3-aryl specificity was preserved. The electron poor nitropyr-
idine derivative (entry 10) is an especially effective substrate for
annulation, illustrating direct access to azaindoles which are of
considerable importance as clinical, fluorescent and metal-
In our initial experiments 1-phenylpropyne and nitrobenzene
2 2
were heated together with [CpFe(CO) ] (1a) under CO pres-
sure (dioxane, 170 °C, 750 psi, 24 h); GC/MS monitoring
indicated the formation of a major product (ca. 20%) with the
mass of the expected amine (m/e 207) as well as lesser quantities
of aniline (12%), azo- (15%) and azoxybenzene (8%). Isolation
2 2
Table 1 Preparation of indoles by [Cp*Ru(CO) ] -catalyzed reductive
annulation (eqn. 3)a
b
Entry
ArNO2
R
RA
Yield (%)
of this material in fact showed it to be 2-methyl-3-phenylindole
9
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
Ph
p-OCH
p-Cl-C
p-CN-C
m-CF
2-Cl-C
Ph
Ph
Ph
Ph
CH
Ph
Ph
Ph
Ph
Ph
H
39c,d
34
(
(
2a) rather than the isomeric propargyl- or allenylamine (eqn.
c
Me
Et
CO
CH
H
H
H
H
H
2)).
24
24
e
2
Et
3
(CH )
3 2 4
Traces
f
3
-C
6
H
4
38
6
H
4
23
31
H
6 4
(
2)
g
3
6
-C H
4
44
h
1
0
5
3
H N-4-NO
2
53
5 5 2 2
Under similar conditions with [(C Me )Fe(CO) ] (1b) or
a
5
mol% 1c, benzene, 750 psi CO, 170 °C, 48 h (see ref. 11 for procedure).
[
(C
5 5 2 2
Me )Ru(CO) ] (1c) as the catalyst phenyl acetylene and
b
c
Isolated, after chromatography. GC yield, naphthalene internal refer-
nitrobenzene afforded 3-phenylindole regiospecifically (2b,
d
e
ence. Reaction carried out in dioxane. 2+1 mixture of 2,3-regioisomers.
f
5% conversion after 120 h. g 3+2 mixture of 4,6-regioisomers. h 3.5+1
4
†
Electronic supplementary information (ESI) available: analytical data for
mixture of 4- and 6-azaindoles.
the product indoles. See http://www.rsc.org/suppdata/cc/b1/b110370a/
4
84
CHEM. COMMUN., 2002, 484–485
This journal is © The Royal Society of Chemistry 2002

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complexing agents.13 The most effective reactions occur with
alkynes possessing at least one aryl or carboalkoxy group
Org. Chem., 1997, 62, 5838; S. Tollari, S. Cenini, C. Crotti and E.
Gianella, J. Mol. Catal., 1994, 87, 203; M. Akazome, T. Kondo and Y.
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40, 5717.
(
entries 1–4 vs. 5). As above, phenylacetylene and arylalkyl
alkynes reacted with complete regioselectivity ( > 99%), plac-
ing the aryl substituent at the 3-position (entries 1–3, 6–10),
while ethyl phenylpropiolate afforded a 2:1 mixture of
6 S. Cenini and F. Ragaini Catalytic Reductive Carbonylation of Organic
Nitro Compounds, Kluwer Academic, Dordrecht, Netherlands, 1997.
3
-phenyl/2-phenyl regioisomers.
7
A. Srivastava, Y. Ma, R. Pankayatselvan, W. Dinges and K. M.
Nicholas, J. Chem. Soc., Chem. Commun., 1992, 853; R. S. Srivastava
and K.M. Nicholas, Tetrahedron Lett., 1994, 8739; R. S. Srivastava and
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2335; R. S. Srivastava and K. M. Nicholas, J. Am. Chem. Soc., 1997,
119, 3302.
The mechanistic pathway for this remarkable transformation,
which involves N-centered reduction, C–H activation, and the
formation of both C–N and C–C bonds is presently unknown
but the following initial observations are informative. No
reaction occurs in the absence of either catalyst or carbon
monoxide, consistent with the precedented ability of metal
carbonyl complexes to promote deoxygenation of nitro com-
3
pounds. Under the same conditions employed for the nitroar-
8 R. S. Srivastava and K. M. Nicholas, J. Chem. Soc., Chem. Commun.,
1998, 2705; M. K. Kolel-Veetil, M. A. Khan and K. M. Nicholas,
Organometallics, 2000, 19, 3754.
ene/alkyne reactions, a mixture of nitrosobenzene, phenyl-
acetylene and 1c also was converted to 3-phenylindole, faster
and in greater yield (18 h, 53% yield),14 suggesting the
9 Product characterization details are available in the ESI†.
1
0 [CpFe(CO)
2
]
2
2
and [Cp*Fe(CO)
2
]
2
are commercially available;
(CO)12 with Cp*-H
intermediacy of the nitrosoarene (free or coordinated) in the
nitroarene reactions. On the other hand no carbazole was
detected in the reaction of o-nitrobiphenyl with PhC·CH (1c,
benzene, 170 °C, 750 psi), rendering unlikely the intermediacy
of a free aryl nitrene.15 Similarly, possible formation of the
indoles by metal-promoted heterocyclization of azobenzene16
[Cp*Ru(CO)
]
2
was prepared by the reaction of Ru
3
according to R. B. King, M. Z. Iqbal and A. D. King, J. Organomet.
Chem., 1979, 171, 53.
11 The following procedure was used for all the catalytic reactions. A
stainless steel autoclave fitted with a glass liner was charged with
catalyst (0.15 mmol), nitro compound (3 mmol), alkyne (12 mmol), a
spatula of 4 Å molecular sieves, and distilled solvent (dioxane or
benzene, 10 ml). In a well-ventilated fume hood the autoclave was
purged with CO three times and then pressurized to 750 psi. The vessel
was then heated to 170° C for 48–72 h. After cooling, the autoclave was
vented in the fume hood. Partial recovery of the catalyst (20–30%) can
be achieved by precipitation with excess hexane. The solvent was
removed by rotary evaporation and the products were isolated by flash
(
present as a by-product) was excluded by the failure of the
latter to be converted to 3-phenylindole under the catalytic
reaction conditions. It is also noteworthy, both mechanistically
and synthetically, that complex 1c is largely recovered
following catalytic runs. The unique activity of the dinuclear
[
2 2
CpM(CO) ] complexes 1 to catalyze the reductive aminations
of alkenes and alkynes by nitroarenes is extraordinary,
considering their stable, eighteen electron count and very
limited catalytic history.17 The ability of 1 to dissociate to
2 2
chromatography over silica gel. Elution with 4+1 CH Cl –pet. ether
afforded the products (yield, R ): azoarene (5–15%, 0.7), azoxyarene
f
(4–22 %, 0.5), indole (20–50%, ca. 0.3), arylamine (7–20%, 0.1).
12 Representatives of the following classes of complexes failed to catalyze
18
seventeen electron organometallic radicals and/or to undergo
facile redox reactions19 may be relevant to their special catalytic
activity.
indole formation: PdX
2
L
2
,
PdL
3
4
,
RuCl
2
(C
6
H
6
)/L, Ru
3
(CO)12/L;
2
Rh(CO) I
2 2
active.
, (Me-Cp)Mn(CO) and [Cp*Cr(CO) ]
3 3
were also in-
The presently disclosed novel annulation reaction provides a
direct and regioselective route to indoles from nitroaromatics,
the most readily available of N-functionalized aromatic com-
pounds, and alkynes. Although the indole yields presently are
only moderate, the directness, regioselectivity and neutral
reaction conditions of this annulation route portend its wide
synthetic utility. Our current efforts are centered on identifying
more active and efficient catalyst systems and on exploring the
synthetic scope and the mechanism of this remarkable trans-
formation.
1
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National Science Foundation and the Ministero dell’Universita’
e della Ricerca Scientifica e Tecnologica (Italy).
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