Cascade alkenyl amination/heck reaction promoted by a bifunctional palladium catalyst: A novel one-pot synthesis of indoles from o-haloanilines and alkenyl halides

Article abstract of DOI:10.1002/chem.200401274

A novel approach for the synthesis of the important indole ring is described. Indoles are obtained from o-bromoanilines and alkenyl halides in a Pd-catalyzed cascade process that involves an alkenyl amination followed by an intramolecular Heck reaction. The overall process represents the first example of the participation of alkenyl amination reactions in Pd-catalyzed cascade reactions. Initially, the relative reactivity of aryl and alkenyl bromides and chlorides towards Pd-catalyzed amination was investigated. Competition experiments were carried out in the presence of primary and secondary amines, and these revealed the reactivity order alkenyl bromides > aryl bromides > alkenyl chlorides > aryl chlorides, as well as very high chemoselectivity; the more reactive halide was always favored. Thereafter, optimized reaction conditions for the sequential alkenyl amination/Heck cyclization to give indoles were investigated with the model reaction of o-bromoaniline with a-bromostyrene. An extensive screening of ligands, bases, and reaction conditions revealed that the [Pd₂(dba)₃]/ DavePhos, NaOtBu, toluene combination at 100°C were the optimized reaction conditions to carry out the cascade process (dba = dibenzylideneacetone, DavePhos = 2-dicyclohexylphosphino-2'-N,N-dimethylaminobiphenyl). The reaction proceeds with aryl, alkyl, and functionalized substitutents in both starting reactants. The cyclization was also studied with N-substituted o-bromoanilines (which would give rise to N-substituted indoles); however, in this case, indole formation occurred only with 1-substituted-2-bromoalkenes. Finally, the application of this methodology to 0-chloroanilines required further optimization. Although the catalyst based on DavePhos failed to promote the cascade process, a catalytic combination based on [Pd₂(dba)₃]/X-Phos promoted the formation of the indole ring also from the less reactive chloroanilines.

Full text of DOI:10.1002/chem.200401274

Cascade Alkenyl Amination/Heck Reaction Promoted by a Bifunctional
Palladium Catalyst: A Novel One-Pot Synthesis of Indoles from
o-Haloanilines and Alkenyl Halides
Josꢀ Barluenga,* M. Alejandro Fernꢁndez, Fernando Aznar, and Carlos Valdꢀs[a]
Abstract: A novel approach for the
synthesis of the important indole ring
is described. Indoles are obtained from
o-bromoanilines and alkenyl halides in
a Pd-catalyzed cascade process that in-
volves an alkenyl amination followed
by an intramolecular Heck reaction.
The overall process represents the first
example of the participation of alkenyl
amination reactions in Pd-catalyzed
cascade reactions. Initially, the relative
reactivity of aryl and alkenyl bromides
and chlorides towards Pd-catalyzed
amination was investigated. Competi-
tion experiments were carried out in
the presence of primary and secondary
amines, and these revealed the reactivi-
ty order alkenyl bromides > aryl bro-
chlorides, as well as very high chemose-
lectivity; the more reactive halide was
always favored. Thereafter, optimized
reaction conditions for the sequential
alkenyl amination/Heck cyclization to
give indoles were investigated with the
model reaction of o-bromoaniline with
a-bromostyrene. An extensive screen-
ing of ligands, bases, and reaction con-
ditions revealed that the [Pd2(dba)3]/
DavePhos, NaOtBu, toluene combina-
tion at 1008C were the optimized reac-
tion conditions to carry out the cascade
process (dba= dibenzylideneacetone,
DavePhos=2-dicyclohexylphosphino-
2’-N,N-dimethylaminobiphenyl).
The
reaction proceeds with aryl, alkyl, and
functionalized substitutents in both
starting reactants. The cyclization was
also studied with N-substituted o-bro-
moanilines (which would give rise to
N-substituted indoles); however, in this
case, indole formation occurred only
with 1-substituted-2-bromoalkenes. Fi-
nally, the application of this methodol-
ogy to o-chloroanilines required further
optimization. Although the catalyst
based on DavePhos failed to promote
the cascade process, a catalytic combi-
nation based on [Pd2(dba)3]/X-Phos
promoted the formation of the indole
ring also from the less reactive chloro-
anilines.
Keywords: amination · enamines ·
Heck reaction · indoles · nitrogen
heterocycles · palladium
mides
> alkenyl chlorides > aryl
Introduction
the palladium species is used to catalyze one single reaction.
However, those transformations in which the same catalytic
species—a multifunctional catalyst—promotes two or more
distinct reactions in a sequential manner are highly desira-
ble.[2] Such processes make better use of the relatively ex-
pensive catalysts, eliminate the need for the isolation and
purification tasks between steps, and are more atom eco-
nomical, since less waste materials and solvents are pro-
duced.
Palladium-catalyzed cross-coupling reactions are amongst
the more powerful transformations in synthetic organic
chemistry. As a result of the intense effort of many research
groups over the years, a large repertoire of C C and C X
bond-forming reactions, and highly active catalytic combina-
tions are currently available.[1] Nevertheless, in most cases,
À
À
In the recent years, we have been studying the palladium-
catalyzed amination of alkenyl bromides[3] and chlorides.[4,5]
This reaction, which is an extension of the well-developed
Buchwald–Hartwig amination,[6] gives rise to enamines and
imines, versatile intermediates in organic synthesis.[7] In the
course of our investigation, we observed a remarkable selec-
tivity in the amination of alkenyl bromides in the presence
of aryl bromides. For instance, the competition reaction of
4-bromobiphenyl (1) and a-bromostyrene (2) affords exclu-
sively the enamine 3 derived from the amination of the al-
[a] Prof. Dr. J. Barluenga, Dr. M. A. Fernꢀndez, Prof. Dr. F. Aznar,
Dr. C. Valdꢁs
Instituto Universitario de Quꢂmica Organometꢀlica “Enrique Moles”
Universidad de Oviedo
33071 Oviedo (Spain)
Fax : (+34)985-103-450
E-mail: barluenga@uniovi.es
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
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DOI: 10.1002/chem.200401274
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FULL PAPER
kenyl bromide; the aryl bromide is left untouched
(Scheme 1).
Results and Discussion
The higher reactivity of alkenyl bromides than aryl bro-
mides in the amination reaction is not surprising, and can be
Relative reactivity of aryl and alkenyl bromides and chlor-
ides in Pd-catalyzed amination reactions: As a continuation
of our studies on the amina-
tion of alkenyl bromides, we
recently reported the Pd-cata-
lyzed amination of alkenyl
chlorides.[4,9] Intrigued by the
remarkable selectivity ob-
served in the amination of al-
Scheme 1. Selectivity in the Pd-catalyzed amination of alkenyl and aryl bromides. RR’=morpholine,
PhMeNH; dba=dibenzylideneacetone, BINAP= 2,2’-bis(diphenylphosphanyl)-1,1’-binaphthyl.
kenyl bromides versus aryl
bromides, we decided to inves-
tigate a broader range of reac-
rationalized in terms of the higher tendency of alkenyl bro-
mides to undergo oxidative addition to Pd.[8] Nevertheless,
the complete chemoselectivity observed is very interesting
indeed. We envisioned that this exquisite selectivity in Pd-
catalyzed aminations could be exploited in sequential pro-
cesses promoted by a single Pd catalyst, and involving con-
secutive reactions of alkenyl and aryl halides. Herein we
report our efforts towards this aim.
tants that can participate in amination processes. According-
ly, we conducted similar competition experiments with dif-
ferent alkenyl and aryl bromides and chlorides and in the
presence of three amines with different steric and electronic
properties: a secondary cyclic amine such as morpholine, a
secondary aromatic amine such as N-methylaniline, and 4-
methoxybenzylamine as a typical primary amine. All the re-
actions were conducted with the [Pd2(dba)3]/DavePhos[10,24]
catalytic system (dba=dibenzylideneacetone) at 908C,
which have been shown to be suitable reaction conditions
for the amination of the less reactive aryl chlorides.[11]
The results represented in Table 1 allowed us to establish
the following relative reactivity order in the Pd-catalyzed
amination reaction: alkenyl bromide > aryl bromide > al-
kenyl chloride > aryl chloride. It is well documented that
vinyl halides are usually more reactive than the correspond-
ing aryl halides, because vinyl halides tend to undergo oxi-
dative addition to Pd more easily.[12,13] However, the high
chemoselectivity observed is remarkable: In all the experi-
ments carried out, the product derived from the amination
of the less reactive halide of each pair was not even detect-
ed.
Abstract in Spanish: Se describe una nueva aproximaciꢀn al
importante anillo de indol a partir de o-bromoanilinas y ha-
luros de alquenilo, en un proceso en cascada catalizado por
Pd, que implica la aminaciꢀn del alquenilo seguida de una
reacciꢀn de Heck intramolecular. El proceso en su conjunto
constituye el primer ejemplo de la participaciꢀn de una ami-
naciꢀn de alquenilo en una secuencia de reacciꢀnes en casca-
da catalizada por Pd. En primer lugar, se estudiꢀ la reactivi-
dad relativa de diferentes halogenuros en reacciones de ami-
naciꢀn catalizadas por Pd. Se llevaron a cabo experimentos
de competencia en presencia de aminas primarias y secunda-
rias que revelaron el orden de reactividad siguiente: bromu-
ros de alquenilo > bromuros de arilo > cloruros de alqueni-
lo > cloruros de arilo, asꢁ como muy alta quimioselectividad
a favor del halogenuro mꢂs reactivo. Seguidamente las condi-
ciones apropiadas para el proceso secuencial aminaciꢀn de
alquenilo/reacciꢀn de Heck, se investigaron con la reacciꢀn
modelo de o-bromoanilina con a-bromostireno. Tras un
amplio estudio de ligandos, bases y condiciones de reacciꢀn
la combinaciꢀn [Pd2(dba)3]/DavePhos, NaOtBu, en tolueno
a 1008C resulto ser la mꢂs adecuada para efectuar el proceso
en cascada. La reacciꢀn transcurre con sustituyentes arilo, al-
quilo y funcionalizados en ambos reactivos de partida. La ci-
claciꢀn tambiꢃn fue estudiada utilizando o-bromoanilinas N-
sustituidas, si bien la formaciꢀn de indol solo tuvo lugar con
2-bromoalquenos monosustituidos en posiciꢀn 1. Finalmente,
la aplicaciꢀn de esta metodologꢁa a o-cloroanilinas requiriꢀ
una optimizaciꢀn adicional. Si bien el catalizador basado en
DavePhos no fue capaz de promover el proceso en cascada,
la utilizaciꢀn de X-Phos como ligando sꢁ permitiꢀ obtener el
anillo de indol a partir de cloroanilinas.
Synthesis of indoles by a cascade alkenyl amination/Heck
cyclization: The interesting observations discussed above,
prompted us to initiate research aimed at developing Pd-cat-
alyzed cascade processes, in which several different alkenyl
and aryl halides may participate in amination and other
cross-coupling reactions, mainly oriented towards the syn-
thesis of heterocycles.
As a simple model system we chose the reaction of a-bro-
mostyrene (2) with o-bromoaniline (4). We anticipated that
the initially formed enamine 5, which is in tautomeric equili-
brium with the more stable imine 6, would undergo an intra-
molecular Heck reaction,[14] catalyzed by the same Pd
system, to produce indole 7 (Scheme 2).[15,16] Although cas-
cade processes involving a cross-coupling reaction followed
by a Heck reaction are known (Suzuki–Heck,[17] Stille–
Heck[18]), this strategy would represent the first example of
a Pd-catalyzed sequential process involving an alkenyl ami-
nation reaction,[19] and would also provide a new approach
to the synthesis of the important indole scaffold.[2–22]
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J. Barluenga et al.
Table 1. Competition experiments in Pd catalyzed amination of aryl and
vinyl bromides and chlorides.[a]
1
2
À
À
Entry
R
X
R
Y
Amine
Ratio
A:B[b]
1
>95: 5
2
3
>95:5
>95:5
Scheme 2. General strategy for the cascade alkenyl amination/Heck reac-
tion.
4
5
6
>95:5
>95:5
>95:5
Table 2. Influence of the ligand and the reaction conditions in the cas-
cade alkenyl amination/Heck reaction.[a]
Entry
[Pd2(dba)3]
[mol%]
Ligand
T [8C]
Conversion[b]
[%] 6/7
7
>95:5
1
2
3
4
5
6
7
8
2
4
4
4
4
4
4
4
2
2
2
4
4
BINAP
BINAP
100
100
100
100
100
100
100
100
90
100
100
120
100
100/0
100/0
100/0
P(o-Tol)3
DavePhos
Xantphos
JohnPhos
X-Phos
0/100 (64)[c]
100/0
8
9
>95:5
100/0
>95:5[c]
0/100 (52)[c]
100/0
NHC
9
DavePhos
DavePhos
X-Phos
DavePhos
DavePhos
50/50
30/70
35/65
10
11
12
13[d]
0/100 (62)[c]
0/100 (50)[c]
10
>95:5
[a] Reaction conditions: 1 equiv of 2, 1 equiv of 4, 3 equiv of NaOtBu,
1:2 Pd/ligand ratio, toluene (4 mLmmolÀ1), 20 h. [b] Determined from
the crude reaction mixture by GC and 1H NMR spectroscopy. [c] Yield
of indole 7. [d] Performed in dioxane.
11
12
>95:5
>95:5
bulky electron-rich biphenyl phosphines (JohnPhos, Dave-
Phos, X-Phos) and a N-heterocyclic carbene (NHC). The
best results in the formation of the indole were observed
1
2
À
[a] Reaction conditions: 1 equiv of R X, 1 equiv of R -Y, 1 equiv of
amine, 1.4 equiv of NaOtBu, 2 mol% of [Pd2(dba)3], 4 mol% of Dave-
Phos, toluene (4 mLmmolÀ1), 908C, 6 h. [b] Determined from the crude
reaction mixture by GC and 1H NMR spectroscopy. [c] 75% conversion.
To optimize the reaction conditions for the overall trans-
formation, we carried out a large array of experiments using
catalytic combinations that had been effective in the amina-
tion of alkenyl bromides, but with larger amounts of
NaOtBu as base,[23] and under various reaction conditions.
Representative results are depicted in Table 2.
The reaction was studied by employing several different
ligands that had been effective the amination of alkenyl bro-
mides: P(o-Tol)3, bidentate ligands (BINAP, Xantphos),
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Cascade Alkenyl Amination/Heck Reaction
FULL PAPER
Table 4. Reaction of alkenyl bromides 8 with o-bromoanilines 9. Synthesis of
1H-indoles 10.[a]
when the reactions were carried out using 4 mol% of Pd
and the bulky biphenylphospane ligands DavePhos[24] and
X-Phos[25] (entries 4 and 7, Table 2), although the former
provided better overall yield. Catalysts based on the other
ligands induced the formation of the imine 6, but failed to
promote the subsequent Heck reaction. The process also
was carried out at higher temperatures and with the more
polar dioxane as solvent (entries 12 and 13, Table 2) but the
yield of the cascade sequence did not improve. Finally, a de-
crease in the Pd loading (entries 9–11, Table 2) resulted in a
decrease in the overall yield.
In an attempt to improve the results of the cascade pro-
cess, the second step in the sequence, the Heck reaction,
was investigated independently. Thus, the Pd-catalyzed cycli-
zation of preformed imine 6 to indole 7 was studied in the
presence of DavePhos and X-Phos as supporting ligands
and by employing different solvents and bases. The results
are shown in Table 3. Under the reaction conditions studied,
Entry[b] Bromide 8
Amine 9
Indole 10
Yield[c]
64
%
a
b
c
62
55
d
e
f
62
61
63
60
Table 3. Optimization of the reaction conditions for the Heck
cyclization.[a]
g
Entry
Ligand
Solvent
Base
Conversion
to 7[b] [%]
h
53
1
2
3
4
5
6
7
8
DavePhos
DavePhos
DavePhos
DavePhos
DavePhos
DavePhos
DavePhos
DavePhos
DavePhos
X-Phos
toluene
toluene
toluene
toluene
toluene
toluene
dioxane
dioxane
dioxane
toluene
toluene
toluene
toluene
NaOtBu
K3PO4
100 (64)[c]
10
Cs2CO3
AgCO3
NaOH
KOtBu
NaOtBu
K3PO4
Cs2CO3
K3PO4
Cs2CO3
NaOH
AgCO3
–
10
10
–
i
j
61
59
100 (50)[c]
20
20
5
–
5
[a] Reaction conditions: 1 equiv of 8, 1 equiv of 9, 3 equiv of NaOtBu, 4 mol%
of Pd, 8 mol% of DavePhos, toluene (4 mLmmolÀ1), 1008C, 20 h. [b] Entry
labels correspond to those of the product 10. [c] Yields after flash chromatog-
raphy.
9
10
11
12
13
X-Phos
X-Phos
X-Phos
–
[a] Reaction conditions: 0.5 mmol 6, 3 equiv of Base, 4 mol% of Pd, 1:2
Pd/ligand ratio, solvent (4 mLmmolÀ1), 20 h. [b] Determined by GC.
[c] Yield of indole 7.
h, Table 4), an interesting feature that may allow the intro-
duction of further substitution in the resulting indole.
Noteworthy are the relatively mild conditions and low
catalyst loading required for the sequential transformation.
Previously reported intramolecular Heck cyclizations of en-
amines usually require at least 10 mol% of Pd.[11,12] How-
ever, in these examples, the reactions proceed with only
4 mol% of a Pd catalyst that plays two different roles: to
promote both the amination reaction and the subsequent
Heck cyclization.
To test the scope of this novel method for the synthesis of
indoles, we next examined the reactions of N-substituted o-
bromoanilines 11 (Scheme 3). However, when alkenyl bro-
mides 8 were treated with o-bromo-N-methylanilines 11
under several different reaction conditions, the intermediate
enamine 12 was the only product isolated together with un-
reacted materials, and indole formation was not observed.
Apparently, the increased steric hindrance prevented the
NaOtBu provided the best results. Inorganic bases such as
K3PO4 and CsCO3 in dioxane, also promoted the Heck cycli-
zation, although to a much lesser extent.
The optimized reaction conditions were then applied to a
variety of alkenyl bromides 8 and bromoanilines 9 to give
the corresponding 1H-indoles 10 in good yields (Table 4).
Bromoalkenes with aryl, alkyl, and functionalized substi-
tutents were effective substrates for the tandem process.
Noteworthy, the cyclization with alkyl-substituted bromo-
alkenes occurred with total regioselectivity; only the indole
originating from the cyclization at the terminal position is
isolated (entries f–j, Table 4). As expected from our prelimi-
nary results on the differential reactivity of halides in amina-
tion reactions, the reaction is compatible with the presence
of a chloride substituent on the aromatic system (entries c,
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J. Barluenga et al.
Table 5. Reaction of alkenyl bromides 13 with o-bromoanilines 12. Synthe-
sis of indoles 14.[a]
Scheme 3. General reaction between alkenyl bromides 8 and N-substitut-
ed o-bromoanilines 11.
Entry[b] Bromide 13
Aniline 11
Indole 14
Yield[c] [%]
70
a
progress of the reaction. Nevertheless, it was possible to
achieve the amination/Heck tandem process when the less
sterically hindered trans-1,2-disubstituted bromoalkenes 13
were employed. The results are represented in Table 5.
Again, the reaction is compatible with aryl, alkyl, and func-
tionalyzed bromoalkenes and tolerates several substitutents
on the nitrogen atom of the aniline.
Finally, we wanted to investigate if the less reactive o-
chloroanilines 15 were appropriate substrates for the se-
quential reaction. As represented in Table 6, the reaction of
o-chloroaniline (15) with a-bromostyrene 2 with the opti-
mized catalytic system developed for the reactions with o-
bromoanilines 9—[Pd2(dba)3], DavePhos, NaOtBu—afford-
ed exclusively the intermediate imine 16 (entry 1, Table 6),
even at higher temperatures (entries 2 and 3), higher load-
ings of Pd and ligand (entry 4), different solvents (entry 5),
and bases (entries 6 and 7). However, the indole formation
could be achieved efficiently by using X-Phos as supporting
ligand, and NaOtBu as a base, at 1108C (entry 10). These re-
action conditions were used with different alkenyl bromides
8 to give the indoles 10 in good yields (Table 7).
b
c
72
69
64
d
e
f
63
61
64
It is worth noting the high sensitivity of the reaction to
the structure of the supporting ligand. DavePhos was the
best ligand for the cascade process with o-bromoanilines but
failed completely in the second step with chloroanilines. On
the other hand, X-Phos provided better results for o-chloro-
anilines than for the more reactive bromo analogues, show-
ing that very fine tuning of the catalytic systems is recom-
mended for this type of transformation.
g
h
i
49
68
52
Summary
In summary, we have reported the interesting high chemo-
selectivity of the Pd-catalyzed amination of aryl and alkenyl
halides. More interestingly, the potential application of this
differential reactivity has been demonstrated by the first ex-
amples of cascade processes involving a Pd-catalyzed alken-
yl amination, followed by an intramolecular Heck reaction.
The overall transformation represents a new approach for
the synthesis of substituted indoles in a single step, from
very simple starting materials. Moreover, the incorporation
j
[a] Reaction conditions: 1 equiv of 13, 1 equiv of 11, 3 equiv of NaOtBu,
4 mol% of Pd, 8 mol% of DavePhos, toluene (4 mLmmolÀ1), 1008C, 20 h.
[b] Entry labels correspond to those of the product 14. [c] Yields after flash
chromatography.
À
of C N bond-forming reactions, and in particular alkenyl
Experimental Section
amination reactions, in sequential processes promoted by
multifunctional Pd catalysts, represents a general strategy
that may be of great use in the synthesis of more complex
heterocycles.
General considerations: All reactions were carried out under a nitrogen
atmosphere in a RR98030 12 place Carousel Reaction Station from Rad-
leys Discovery Technologies, equipped with gas-tight threaded caps with
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Cascade Alkenyl Amination/Heck Reaction
FULL PAPER
Table 6. Optimization of the reaction conditions with o-chloroanilines
15.[a]
movinyl)-4-methylbenzene,[26] 1-bromodec-1-ene,[28] 1-bromo-3-benzyl-
oxy-1-propene,[29] 1-(2-bromovinyl)-4-methylbenzene.[29] Non-commercial
N-substituted o-bromoanilines 12 were prepared by a two-step reductive
amination sequence: condensation of the unsubstituted bromoanilines
with the appropriate aldehydes in the presence of methyl orthoformate
followed by reduction of the corresponding imines with NaBH4 in metha-
nol.
General procedure for the study of the relative reactivity of aryl and al-
kenyl bromides and chlorides in Pd-catalyzed amination reactions: A re-
action tube under a nitrogen atmosphere was charged with the ligand
DavePhos (15.5 mg, 0.04 mmol, 4 mol%), tris(dibenzylideneacetone)di-
palladium(0) (9.15 mg, 0.001 mmol, 2 mol%), sodium tert-butoxide
(134 mg, 1.4 equiv), and toluene (4 mL). After 1 min, the two halides
(1 mmol each) and the amine (1 mmol) were added under nitrogen and
the tube was placed in the carousel block and heated to 908C with stir-
ring for 6 h. The mixture was allowed to cool to room temperature, taken
up in hexanes (15 mL), and filtered through Celite. The solvents were
evaporated under reduced pressure.
Entry [Pd2(dba)3]
[mol%]
Ligand
Base
T [8C] Conversion[b] [%]
16/7
1
2
3
4
4
4
4
5
4
4
4
4
4
4
4
4
DavePhos NaOtBu 100
DavePhos NaOtBu 110
DavePhos NaOtBu 120
DavePhos NaOtBu 100
DavePhos NaOtBu 100
DavePhos KOtBu 100
DavePhos LHMDS 100
NHC
NHC
X-Phos
X-Phos
X-Phos
100/0
100/0
100/0
100/0
100/0
100/0
100/0
100/0
5[c]
6
7
8
9
10
11
12
NaOtBu 100
LHMDS 100
NaOtBu 110
NaOtBu 100
KOtBu 110
100/0
0/100 (65)[d]
0/100 (50)[d]
100/0
General procedure for the synthesis of 1H-indoles 10 by palladium-cata-
lyzed cascade reactions of alkenyl bromides 8 with o-bromoanilines 9: A
reaction tube under a nitrogen atmosphere was charged with DavePhos
(31 mg, 0.08 mmol, 8 mol%), tris(dibenzylideneacetone)dipalladium(0)
(18.3 mg, 0.002 mmol, 4 mol%), sodium tert-butoxide (288 mg, 3 mmol,
[a] Reaction conditions: 1 equiv of 2, 1 equiv of 15, 3 equiv of Base, 1:2
Pd/ligand ratio, toluene (4 mLmmolÀ1), 20 h. [b] Determined from the
crude reaction mixture by GC and 1H NMR spectroscopy. [c] Performed
in dioxane. [d] Yield of indole 7.
3 equiv), and toluene (4 mL). After 1 min, the alkenyl bromide
8
(1 mmol) and the bromoaniline 9 (1 mmol) were added under nitrogen
and the tube was placed in the carousel block and heated to 1008C with
stirring for 20 h. The mixture was allowed to cool to room temperature,
taken up in hexanes (15 mL), and filtered through Celite. The solvents
were evaporated under reduced pressure. Purification by flash chroma-
tography (SiO2, Hex/EtOAc, 20:1) afforded indoles 10.
Table 7. Reaction of alkenyl bromides 8 with o-chloroanilines 16. Synthe-
sis of 1H-indoles 10.[a]
Spectroscopic data of known indoles 10a and 10b,[30] 10c,[31] 10d,[32]
10e,[33] 10 f,[34] 14a,[35] and 14 f[36] were in complete agreement with litera-
ture values.
2-Phenyl-1H-indole 10a: The general procedure gave 10a in 64% yield.
5-Methyl-2-phenyl-1H-indole 10b: The general procedure gave 10b in
62% yield.
Entry[b] Bromide 8
Amine 16
Indole 10
Yield[c] [%]
65
5-Chloro-2-phenyl-1H-indole 10c: The general procedure gave 10c in
55% yield.
a
2-p-Tolyl-1H-indole 10d: The general procedure gave 10d in 62% yield.
5-Methyl-2-p-tolyl-1H-indole 10e: The general procedure gave 10e in
61% yield.
b
c
58
60
55
2-Octyl-1H-indole 10 f: The general procedure gave 10 f in 63% yield.
5-Methyl-2-octyl-1H-indole 10g: The general procedure gave 10g in
1
60% yield as an orange syrup. Rf: 0.40 (SiO2, Hex/AcOEt, 9/1); H NMR
(CDCl3, 300 MHz): d=0.96 (t, 3J=6.2 Hz, 3H), 1.38–1.28 (m, 10H),
1.77–1.72 (m, 2H), 2.49 (s, 3H), 2.74 (t, 3J=7.6 Hz, 2H), 6.20 (s, 1H),
6.99 (d, 3J=7.9 Hz, 1H), 7.19 (d, 3J=7.9 Hz, 1H), 7.37 (s, 1H), 7.82 ppm
(s, 1H); 13C NMR (CDCl3, 75 MHz): d=13.9 (CH3), 21.3 (CH3), 22.5
(CH2), 28.1 (CH2), 29.0 (CH2), 29.1 (CH2), 29.2 (CH2), 29.3 (CH2), 31.7
(CH2), 98.7 (CH), 109.8 (CH), 119.3 (CH), 122.2 (CH), 128.4 (C), 129.1
(C), 134.0 (C), 140.0 ppm (C); HRMS calcd for C17H25N: 243.19815;
found: 243.19804.
d
[a] Reaction conditions: 1 equiv of 8, 1 equiv of 16, 3 equiv of NaOtBu,
4 mol% of Pd, 8 mol% of X-Phos, toluene (4 mLmmolÀ1), 1108C, 20 h.
[b] Entry labels correspond to those of the product 10. [c] Yields after
flash chromatography.
5-Chloro-2-octyl-1H-indole 10h: The general procedure gave 10h in
1
53% yield as an orange syrup. Rf: 0.40 (SiO2, Hex/AcOEt, 9/1); H NMR
a valve, cooling reflux head system, and digital temperature controller.
Toluene and hexane solvents were refluxed and freshly distilled from
sodium/benzophenone under nitrogen. NMR spectra were recorded at
300 or 200 MHz for 1H and 75 or 50.3 MHz for 13C, with tetramethylsi-
lane as internal standard for 1H and the residual solvent signals as stan-
dard for 13C. Chemical shifts are given in ppm. Mass spectra were ob-
tained by EI (70 eV). Pd(OAc)2 and [Pd2(dba)3] were purchased from
Strem Chemical Co. and used without further purification. All phosphine
ligands used are commercially available from Strem or Aldrich and were
used without further purification. NaOtBu was purchased from Aldrich,
stored in a flask purged with nitrogen and weighed in the air. Non-com-
mercial alkenyl bromides were prepared according to literature proce-
dures: 2-bromodec-1-ene,[26] 2-bromo-3-benzyloxy-1-propene,[27] 1-(1-bro-
(CDCl3, 300 MHz): d=0.91 (t, 3J=6.2 Hz, 3H), 1.35–1.28 (m, 10H),
1.74–1.70 (m, 2H), 2.74 (t, 3J=7.6 Hz, 2H), 6.20 (s, 1H), 7.07 (d, 3J=
8.5 Hz, 1H), 7.20 (d, 3J=8.5 Hz, 1H), 7.50 (s, 1H), 7.98 ppm (s, 1H);
13C NMR (CDCl3, 75 MHz): d=14.0 (CH3), 22.5 (CH2), 28.1 (CH2), 28.9
(CH2), 29.1 (CH2), 29.2 (CH2), 29.3 (CH2), 31.7 (CH2), 99.1 (CH), 111.1
(CH), 119.0 (CH), 120.9 (CH), 125.0 (C), 129.8 (C), 134.0 (C), 141.6 ppm
(C); HRMS calcd for C16H22ClN: 263.14352; found: 263.14348.
2-Benzyloxymethyl-1H-indole 10i: The general procedure gave 10i in
1
61% yield as an orange syrup. Rf: 0.14 (SiO2, Hex/AcOEt, 9/1); H NMR
(CDCl3, 300 MHz): d=4.63 (s, 2H), 4.79 (s, 2H), 6.55 (s, 1H), 7.31–7.19
(m, 2H), 7.45–7.38 (m, 6H), 7.71 (d, 3J=7.7 Hz, 1H), 8.62 ppm (s, 1H);
13C NMR (CDCl3, 75 MHz): d=64.9 (CH2), 71.5 (CH2), 101.8 (CH),
Chem. Eur. J. 2005, 11, 2276 – 2283
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ꢃ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2281

J. Barluenga et al.
110.8 (CH), 119.6 (CH), 120.4 (CH), 121.9 (CH), 127.7 (CH), 127.9
(2CH), 128.0 (C), 128.3 (2CH), 134.8 (C), 136.4 (C), 137.6 ppm (C);
HRMS calcd for C16H15NO: 237.11481; found: 237.11503.
127.1 (2CH), 127.5 (C), 128.6 (2CH), 129.3 (2CH), 132.4 (C), 135.3 (C),
136.9 (C), 137.1 ppm (C); HRMS calcd for C22H19N: 297.15120; found:
297.15151.
1-Benzyl-3-benzyloxymethyl-1H-indole 14h: The general procedure gave
14h in 49% yield as an orange syrup. Rf: 0.21 (SiO2, Hex/AcOEt 9/1);
1H NMR (CDCl3, 200 MHz): d=4.66 (s, 2H), 4.84 (s, 2H), 5.34 (s, 2H),
7.18–7.30 (m, 4H), 7.45–7.32 (m, 10H), 7.83–7.79 ppm (m, 1H);
13C NMR (CDCl3, 50.4 MHz): d=49.8 (CH2), 63.9 (CH2), 71.4 (CH2),
109.6 (CH), 112.2 (C), 119.4 (CH), 119.5 (CH), 121.9 (CH), 126.7 (2CH),
127.4 (CH), 127.5 (CH), 127.7 (CH), 127.8 (2CH), 127.9 (C), 128.2
(2CH), 128.6 (2CH), 136.8 (C), 137.2 (C), 138.5 ppm (C); HRMS calcd
for C23H21NO: 327.16171; found: 327.16194.
2-Benzyloxymethyl-5-methyl-1H-indol 10j: The general procedure gave
10j in 59% yield as an orange syrup. Rf: 0.15 (SiO2, Hex/AcOEt, 9/1);
1H NMR (CDCl3, 300 MHz): d=2.53 (s, 3H), 4.59 (s, 2H), 4.75 (s, 2H),
6.44 (s, 1H), 7.09 (d, 3J=8.2 Hz, 1H), 7.27 (d, 3J=8.2 Hz, 1H), 7.46–7.41
(m, 6H), 8.40 ppm (s, 1H); 13C NMR (CDCl3, 75 MHz): d=21.3 (CH3),
65.0 (CH2), 71.5 (CH2), 101.5 (CH), 110.5 (CH), 120.1 (CH), 123.5 (CH),
127.7 (CH), 127.9 (2CH), 128.1 (C), 128.4 (2CH), 128.8 (C), 134.6 (C),
134.9 (C), 137.6 ppm (C); HRMS calcd for C17H17NO: 251.13046; found:
251.13063.
1-Octyl-3-phenyl-1H-indole 14i: The general procedure gave 14i in 68%
yield as an orange syrup. Rf: 0.56 (SiO2, Hex/AcOEt 9/1); 1H NMR
(CDCl3, 300 MHz): d=1.06 (t, 3J=5.9 Hz, 3H), 1.54–1.43 (m, 10H),
2.03–1.98 (m, 2H), 4.25 (t, 3J=7.1 Hz, 2H), 7.42–7.35 (m, 4H), 7.62–7.52
(m, 3H), 7.96–7.83 (m, 2H), 8.14 ppm (t, 3J=5.9 Hz, 1H); 13C NMR
(CDCl3, 75 MHz): d=13.9 (CH3), 22.5 (CH2), 26.9 (CH2), 29.0 (CH2),
29.1 (CH2), 30.1 (CH2), 31.7 (CH2), 46.3 (CH2), 109.6 (CH), 116.4 (C),
119.6 (CH), 119.8 (CH), 121.6 (CH), 125.4 (CH), 125.5 (CH), 126.1 (C),
127.2 (2CH), 128.6 (2CH), 135.7 (C), 136.6 ppm (C); HRMS calcd for
C22H27N: 305.21380; found: 305.21412.
General procedure for the synthesis of 1R-indoles 14 by palladium-cata-
lyzed cascade reactions of alkenyl bromides 13 with o-bromoanilines 11:
A reaction tube under a nitrogen atmosphere was charged with Dave-
Phos (31 mg, 0.08 mmol, 8 mol%), tris(dibenzylideneacetone)dipalladi-
um(0) (18.3 mg, 0.002 mmol, 4 mol%), sodium tert-butoxide (288 mg,
3 mmol, 3 equiv), and toluene (4 mL). After 1 min, the alkenyl bromide 8
(1 mmol) and the bromoaniline 11 (1 mmol) were added under nitrogen
and the tube was placed in the carousel block and heated to 1008C with
stirring for 20 h. The mixture was allowed to cool to room temperature,
taken up in hexanes (15 mL), and filtered through Celite. The solvents
were evaporated under reduced pressure. Purification by flash chroma-
tography (SiO2, Hex/EtOAc, 20:1) afforded indoles 14.
3-Benzyloxymethyl-1-octyl-1H-indol 14j: The general procedure gave
14j in 52% yield as an orange syrup. Rf: 0.35 (SiO2, Hex/AcOEt 9/1);
1H NMR (CDCl3, 300 MHz): d=0.91 (t, 3J=5.9 Hz, 3H), 1.34–1.29 (m,
10H), 1.88–1.84 (m, 2H), 4.11 (t, 3J=7.1 Hz, 2H), 4.61 (s, 2H), 4.79 (s,
1-Methyl-3-phenyl-1H-indole 14a: The general procedure gave 14a in
70% yield.
3
2H), 7.40–7.14 (m, 9H), 7.73 ppm (d, J=7.6 Hz, 1H); 13C NMR (CDCl3,
1,5-Dimethyl-3-phenyl-1H-indole 14b: The general procedure gave 14b
in 72% yield as an orange syrup. Rf: 0.33 (SiO2, Hex/AcOEt 9/1);
1H NMR (CDCl3, 300 MHz): d=2.56 (s, 3H), 3.84 (s, 3H), 7.18 (dd, 3J=
1.4 y 8.2 Hz, 1H), 7.23 (s, 1H), 7.35–7.30 (m, 2H), 7.50 (t, 3J=7.7 Hz,
75 MHz): d=13.9 (CH3), 22.5 (CH2), 26.9 (CH2), 29.0 (CH2), 29.1 (CH2),
30.1 (CH2), 31.7 (CH2), 46.2 (CH2), 63.9 (CH2), 71.3 (CH2), 109.3 (CH),
111.4 (C), 119.2 (CH), 119.4 (CH), 121.5 (CH), 127.4 (CH), 127.5 (CH),
127.7 (C), 127.8 (2CH), 128.2 (2CH), 136.5 (C), 138.6 ppm (C); HRMS
calcd for C24H31NO: 349.24001; found: 349.24007.
3
2H), 7.72 (dd, J=1.4 y 8.2 Hz, 2H), 7.81 ppm (s, 1H); 13C NMR (CDCl3,
75 MHz): d=21.5 (CH3), 32.8 (CH3), 109.1 (CH), 115.9 (C), 119.4 (CH),
123.4 (CH), 125.4 (CH), 126.2 (C), 126.5 (CH), 127.2 (2CH), 128.6
(2CH), 129.1 (C), 135.7 (C), 135.8 ppm (C); HMRS calcd for C16H15N:
221.11990; found: 221.11979.
General procedure for the synthesis of 1H-indoles 10 by palladium-cata-
lyzed cascade reactions of alkenyl bromides 8 with o-chloroanilines 15: A
reaction tube under nitrogen atmosphere was charged with X-Phos
(38.1 mg, 0.08 mmol), tris(dibenzylideneacetone)dipalladium(0) (18.3 mg,
0.002 mmol, 4 mol%), sodium tert-butoxide (288 mg, 3 mmol, 3 equiv),
and toluene (4 mL). After 1 min, the alkenyl bromide 8 (1 mmol) and the
chloroaniline 15 (1 mmol) were added under nitrogen and the tube was
placed in the carousel block and heated to 1108C with stirring for 20 h.
The mixture was allowed to cool to room temperature, taken up in hex-
anes (15 mL), and filtered through Celite. The solvents were evaporated
under reduced pressure. Purification by flash chromatography (SiO2,
Hex/EtOAc, 20:1) afforded indoles 10.
1-Methyl-3-p-tolyl-1H-indole 14c: The general procedure gave 14c in
1
69% yield as an orange syrup. Rf: 0.32 (SiO2, Hex/AcOEt 9/1); H NMR
(CDCl3, 300 MHz): d=2.50 (s, 3H), 3.88 (s, 3H), 7.46–7.26 (m, 6H), 7.65
(d, 3J=7.3 Hz, 2H), 8.04 ppm (d, 3J=7.8 Hz, 1H); 13C NMR (CDCl3,
75 MHz): d 21.1 (CH3), 32.7 (CH3), 109.4 (CH), 116.5 (C), 119.6 (CH),
119.8 (CH), 121.8 (CH), 126.2 (CH), 127.1 (2CH), 128.9 (C), 129.3
(2CH), 132.6 (C), 135.7 (C), 137.3 ppm (C); HRMS calcd for C16H15N:
221.11990; found: 221.11959.
1-Methyl-3-octyl-1H-indole 14d: The general procedure gave 14d in
2-Phenyl-1H-indole 10a: The general procedure gave 10a in 65% yield.
2-p-Tolyl-1H-indole 10d: The general procedure gave 10d in 58% yield.
2-Octyl-1H-indole 10 f: The general procedure gave 10 f in 60% yield.
1
64% yield as an orange syrup. Rf: 0.40 (SiO2, Hex/AcOEt 9/1); H NMR
(CDCl3, 300 MHz): d=0.94 (t, 3J=6.2 Hz, 3H), 1.40–1.25 (m, 14H), 2.94
(s, 3H), 6.69–6.60 (m, 3H), 7.29–7.24 (m, 1H), 7.48 ppm (d, 3J=7.8 Hz,
1H); 13C NMR (CDCl3, 75 MHz): d=14.0 (CH3), 22.6 (CH2), 29.5–29.3
(5CH2), 30.4 (CH3), 31.8 (CH2), 109.4 (C), 110.6 (CH), 117.5 (CH), 128.4
(2CH), 128.5 (C), 132.1 (CH), 145.8 ppm (C); HRMS calcd for C17H25N:
243.19815; found: 243.19850.
2-Benzyloxymethyl-1H-indole 10i: The general procedure gave 10i in
55% yield.
3-Benzyloxymethyl-1-methyl-1H-indole 14e: The general procedure gave
14e in 63% yield as an orange syrup. Rf: 0.22 (SiO2, Hex/AcOEt 9/1);
1H NMR (CDCl3, 300 MHz): d=3.81 (s, 3H), 4.66 (s, 2H), 4.84 (s, 2H),
7.13 (s, 1H), 7.24 (t, 3J=6.8 Hz, 1H), 7.45–7.31 (m, 7H), 7.80 ppm (d, 3J
=7.7 Hz, 1H); 13C NMR (CDCl3, 75 MHz): d=32.6 (CH3), 63.7 (CH2),
71.3 (CH2), 109.1 (CH), 111.4 (C), 119.2 (2CH), 121.7 (CH), 127.3 (CH),
127.5 (C), 127.7 (2CH), 128.2 (2CH), 128.4 (CH), 137.1 (C), 138.6 ppm
(C); HRMS calcd for C17H17NO: 251.13046; found: 251.13057.
Acknowledgements
This research was supported by DGI (Grant BQU-2001–3853) and
FYCYT (Grant PR-01-GE-09).
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2282
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Chem. Eur. J. 2005, 11, 2276 – 2283

Cascade Alkenyl Amination/Heck Reaction
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[13] The Suzuki reaction catalyzed by the Pd0/PtBu3 system represents
an exception to the rule as it reacts more readily with aryl chlorides
than with vinyl chorides, although with low selectivity: A. F. Littke,
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[14] For a recent review on the Heck reaction: I. P. Beletskaya, A. V.
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[15] For intramolecular Heck reactions of enamines leading to indoles
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Bull. Chem. Soc. Jpn. 1986, 59, 927–928. A. Kasahara, T. Izumi, T.
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[36] S. Wattanasin, P. G. Kathawala, Synth. Commun. 1989, 19, 2659–
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[16] While preparing this manuscript a paper describing the intramolecu-
lar Heck reaction of enamines, generated in situ from ketones and
o-chloroanilines, oriented toward the synthesis of indoles was pub-
Received: December 10, 2004
Published online: February 1, 2005
Chem. Eur. J. 2005, 11, 2276 – 2283
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