First heterogeneous ligand- and salt-free larock indole Synthesis

Article abstract of DOI:10.1002/adsc.200900386

A new ligand- and salt-free procedure using heterogeneous palladium catalysts for the Larock indole and benzofuran synthesis is reported. After optimisation of the reaction conditions, good to high isolated yields have been achieved for a variety of structures. Recycling studies have shown that the palladium catalysts can be readily recovered and reused. Reactions and recovery of the palladium catalysts can be carried out in the presence of air, without any particular precaution.

Full text of DOI:10.1002/adsc.200900386

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DOI: 10.1002/adsc.200900386
First Heterogeneous Ligand- and Salt-Free Larock Indole
Synthesis
Nelly Batail,a Anissa Bendjeriou,b Thierry Lomberget,c Roland Barret,c
Vꢀronique Dufaud,b,* and Laurent Djakovitcha,*
a
Universitꢀ de Lyon, CNRS, UMR 5256, IRCELYON, Institut de recherches sur la catalyse et l’environnement de Lyon,
2 avenue Albert Einstein, F-69626 Villeurbanne, France
Fax : (+33)-4-7244-5399; e-mail: Laurent.Djakovitch@ircelyon.univ-lyon1.fr
Universitꢀ de Lyon, CNRS, UMR 5182, Laboratoire de Chimie, Ecole Normale Supꢀrieure de Lyon, 46 Allꢀe d’Italie,
b
F-69364 Lyon Cedex 07, France
E-mail: vdufaud@ens-lyon.fr
ISPB-Facultꢀ de Pharmacie, Laboratoire de Chimie Thꢀrapeutique, INSERM U-863, 8 avenue Rockefeller, F-69373 Lyon,
c
France
Received: June 3, 2009; Revised: July 21, 2009; Published online: September 10, 2009
Dedicated to Prof. K. Kçhler on the occasion of his 50th birthday.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900386.
Abstract: A new ligand- and salt-free procedure
using heterogeneous palladium catalysts for the
Larock indole and benzofuran synthesis is reported.
After optimisation of the reaction conditions, good
to high isolated yields have been achieved for a va-
riety of structures. Recycling studies have shown
that the palladium catalysts can be readily recov-
ered and reused. Reactions and recovery of the pal-
ladium catalysts can be carried out in the presence
of air, without any particular precaution.
of functional indoles is required. Recently, transition
metal-catalysed transformations, and particularly pal-
ladium-catalysed reactions (Figure 1), have been de-
veloped providing increased tolerance towards func-
tional groups, and leading generally to higher reaction
yields.[7–16] Many of these methods have proven to be
most powerful and are currently applied in the target-
or the diversity-oriented synthesis of multifunctional
indoles but, recently, the palladium-catalysed hetero-
annulation of 2-iodoanilines with internal alkynes
known as the Larock indole synthesis (Figure 1, route
1) has emerged as one of the most powerful synthetic
procedures to provide access to 2,3-susbtituted in-
doles.[17–22]
Keywords: benzofurans; heterogeneous catalysis;
indoles; Larock synthesis; palladium catalysts
Benzofurans, isoelectronic to indoles, also show a
variety of pharmacological properties and minor
changes of their structure offer a high degree of diver-
The indole nucleus is an important substructure found sity that has proven useful for the search of new ther-
in numerous natural or synthetic alkaloids.[1,2] The di- apeutic agents.[23–31] Although the benzofuran motif
versity of the structures encountered, as well as their occurs less often in nature and offers less potential
biological and pharmaceutical relevance, have moti- structural multiplicity, the broad spectrum of pharma-
vated research aimed at the development of new eco- cological activity of these heterocycles led neverthe-
nomical, efficient and selective synthetic strategies, less to the elaboration of concise and flexible synthet-
particularly for the synthesis of functional indole ic methods useful in the production of specific struc-
rings.[3–6] Classical methods include the Fischer indole tures.[32] Among all methods reported, again the
synthesis from arylhydrazones, the Batcho–Leimgrub- Larock procedure starting from 2-iodophenols and in-
er synthesis from o-nitrotoluenes and dimethylform- ternal alkynes appeared to be the most versatile pro-
ACHTUNGTRENNUNGamide acetals, the Gassman synthesis from N-haloani- cedure to obtain selectively (2),3-subsituted benzofur-
lines, the Madelung cyclisation of N-acyl-o-toluidines ans.
and the reductive cyclisation of o-nitrobenzyl ketones.
However, these Larock procedures rely on the use
While these procedures have contributed to this im- of soluble palladium catalysts, thus involve significant
portant area, some remain limited when the synthesis difficulties including the separation of the catalytic
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Nelly Batail et al.
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Figure 1. Retro-synthetic approaches toward the synthesis of indole nucleus catalysed by palladium.
material from the reaction mixture, lack of adequate lower catalyst loadings (2 mol%) compared to those
catalyst recycling methods and relatively high palladi- reported for homogeneous methods for such synthe-
um and ligand contamination of the products. The ses. The resulting protocol features reasonably priced
latter problems are intolerable in the context of bio- reagents and solvents rendering the method environ-
logical applications. Obviously, an analogous catalytic mentally benign, very practicable, and scalable. Fur-
heterogeneous method would eliminate any of these thermore, we show evidence for the high recyclability
drawbacks but, to the best of our knowledge, there of the catalytic materials.
have been no reports on the use of heterogeneous
Initially, we adapted the existing homogeneous pro-
palladium catalysts for the Larock synthesis of indoles cedures in order to fit the requirements of heteroge-
and benzofurans while supported palladium was ap- neous catalysis (i.e., ligand- and salt-free) for this
plied to fine chemical syntheses.[33–36]
kind of reaction. Following the original procedure re-
With the aim of resolving this issue we report, in ported by Larock, a methodology intensively devel-
this paper, the successful use of various heterogene- oped since this time, we evaluated various homogene-
ous palladium catalysts (Pd/C, [Pd]/NaY) for indole ous catalytic systems under relatively common reac-
and benzofuran syntheses in technical grade solvent tion conditions (1 equiv. 2-iodoaniline, 3 equiv. diphe-
under ligand- and salt-free reaction conditions. More- nylacetylene, 2–5 mol% [Pd], 3 equiv. base, 0–1 equiv.
over, we demonstrate that our procedure tolerates LiCl, DMF, 80–1208C, 24–48 h) (Table 1).
Table 1. Influence of the catalyst nature on the Larock indole synthesis.[a]
Entry
Catalyst
Pd(OAc)2 (5 mol%)
LiCl
T [8C]
Time [h]
Conversion [%][b]
Yield [%][c]
1
2
3
4
5
6
7
G
1 equiv.
1 equiv.
80
48
14
14
24
24
24
14
100
100
100
100
100
100
100
67
15
28
40
73
74
70
Pd(OAc)2 (5 mol%)
Pd(OAc)2 (5 mol%)
Pd(OAc)2 (2 mol%)
T
120
120
120
120
120
120
E
ACHTUNGTRENNUNG
–
–
–
–
–
PdCl
PdCl
2A
CHTUNGTRENNUNG
Pd/C(EVO) (2 mol%)
[a]
Reaction conditions: 2-iodoaniline (1.0 mmol), diphenylacetylene (3.0 mmol), Na2CO3 (3 mmol), [Pd] catalyst (2–
5 mol%), DMF (4.0 mL), T 8C, time.
[b]
[c]
Conversions based on unreacted 2-iodoaniline were determined by GC with an internal standard (biphenyl) (Drel=
Æ5%).
Isolated yields after flash chromatography on silica (purity: ꢀ97%).
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Whatever the catalyst used, all reactions led exclu- reported procedures as generally under homogeneous
sively to the formation of the expected 2,3-diphenylin- conditions in the absence of bulky ligands the diphe-
dole 1. Under the original Larock conditions (Table 1, nylacetylene tends to give side products due to di- or
entry 1) the expected compound was isolated in 67% oligomerisation decreasing thus the yield.[37–39]
yield. Under these conditions, increasing the reaction
Attempting to further improve the reaction condi-
temperature to 1208C, working in the presence or not tions towards more economical procedures by de-
of LiCl, resulted almost always in the formation of creasing the excess of alkyne used (i.e., 3.0 equiv.)
degradation products from starting materials leading failed as using 1.5–2.0 equiv. led to dramatically de-
to poor product yields (Table 1, entries 2 and 3). Im- creased yields (i.e., 42% to compare to 73%, Table 1,
provement was achieved by decreasing the palladium entry 5).
loading to 2 mol% which considerably reduced side
Further developments concerned the evaluation of
product formation and reaction time, leading to a various heterogeneous palladium catalysts for the syn-
moderate 40% yield (Table 1, entry 4). The other thesis of different indole nuclei by varying either the
evaluated catalysts (Table 1, entries 5 and 6) gave nature of 2-the iodoanilines or the alkynes. Addition-
slightly better results (i.e., ca 73% yield) under these ally, the reaction conditions were applied to the
conditions (Table 1, entries 5 and 6) that could be at- Larock synthesis of benzofurans. As commercial cata-
tributed to the presence of ligands (i.e., PPh3 or lysts, the palladium supported on active carbon De-
PhCN).
gussa type E101 NE/W from Aldrich [Pd/C 10% wt
Having thus adapted the reactions conditions, we on dry basis, 52% water; labelled herein as Pd/C(ALD)
]
next evaluated a Pd/C catalyst provided by Evonik and a palladium supported on active carbon type
(see below) for that reaction (Table 1, entry 7). Unex- E105 CA/W available at Evonik [Pd/C 5% wt, 55%
pectedly, using this heterogeneous catalyst resulted in water; labelled Pd/C(EVO)] were evaluated. The nature
increased performances: the reaction was complete of the two catalysts is different: Pd/C(ALD) is character-
after only 14 h, giving an isolated yield 70%, which ised by a low degree of reduction and high water con-
corresponds to 24–48 h of reaction under homogene- tent (52%) while Pd/C(EVO), fully described by Kçhler
ous conditions. This result is rather competitive with and co-workers, is characterised by high Pd dispersion
Table 2. Heteroannulation of various 2-iodoaryls with diphenylacetylene.[a]
Entry
Ar(I)NH2
Catalyst
Base
Time
Conversion [%][b]
Product
Yield [%][c]
1
2
3
Pd/C(ALD)
[Pd]/NaY
Pd/C(EVO)
Na2CO3
Na2CO3
Na2CO3
9 h
2 h
14 h
100
100
100
40
20
70
1
4
4
5
6
7
Pd/C(ALD)
[Pd]/NaY
[Pd]/NaY
Pd/C(EVO)
Na2CO3
Na2CO3
K2CO3
6 d
100
0[d]
0[d]
0[d]
70
–
–
12 d
12 d
9 d
2
3
Na2CO3
–
8
9
Pd/C(ALD)
[Pd]/NaY
Na2CO3
Na2CO3
6 d
4 h
0[d]
100
–
43
5
6
10
11
Pd/C(ALD)
[Pd]/NaY
Na2CO3
Na2CO3
5 d
5 d
0[d]
0[d]
–
–
[a]
Reaction conditions: 2-iodoaryl (1.0 mmol), diphenylacetylene (3.0 mmol), base (3 mmol), [Pd] catalyst (2 mol%), DMF
(4.0 mL), 1208C, time.
[b]
[c]
[d]
Conversions based on unreacted 2-iodoaryle were determined by GC with an internal standard (biphenyl) (Drel=Æ5%).
Isolated yields after flash chromatography on silica (purity: ꢀ97%).
The starting 2-iodoaryl was fully recovered.
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(36%), very low reduction degree [no Pd(0) was de- tion of the target molecule. Unexpectedly, with other
tected by TPR measurements] and high water content iodoanilines, only one catalyst was found to be active
(55%).[40,41] Another catalyst prepared in our labora- for the given reaction. Thus using 4-nitro-2-iodoani-
tory following procedures previously reported was in- line 2, only the Pd/C(ALD) gave in good yield the ex-
volved in this study: [PdACTHNUTRGNEUNG(NH3)4]/NaY (1% wt), la- pected indole 4. All other evaluated catalysts general-
belled [Pd]/NaY in following tables, was obtained by ly led only to di- or oligomerisation of diphenylacety-
ion exchange of a NaY zeolite using a 0.1M aqueous lene; generally as observed by GC the iodoaniline
solution of [Pd
Using diphenylacetylene as coupling partner the re- more electron-rich 3,5-dimethoxy-2-iodoaniline 3,
sults appeared to be strongly dependant on the nature only the [Pd(NH3)4]/NaY gave the expected com-
A
was not consumed (Table 2, entries 5–7). With the
AHCTUNGTRENNUNG
of the iodoaniline (Table 2). While with 2-iodoaniline pound 5 in moderate yield due to the formation of di-
full conversions were generally achieved whatever the phenylacetylene oligomers while full conversion was
catalyst, other anilines showed strong dependencies observed (Table 2, entries 8 and 9). Unfortunately, all
on the catalystꢂs nature. In more detail, it appeared attempts to get benzofurans 6 failed under these con-
that in the case of 2-iodoaniline the nature of the cat- ditions.
alyst influenced strongly the formation of side prod-
With triethyl[4-(triethylsilyl)but-3-ynyloxy]silane 7
ucts from diphenylacetylene (Table 2, entry 1) result- (Table 3) or triethyl(phenylethynyl)silane 12 (Table 4)
ing, in extreme cases, in low product yields (Table 2, as alkyne partner no important catalyst performance
entry 2) together with degradation of the starting ma- differences were shown under the conditions tested.
terial. Furthermore, these side reactions decreased Generally full conversions and selectivities were ach-
dramatically the yield, mainly due to tedious separa- ieved leading to good to high isolated yields. Noticea-
Table 3. Heteroannulation of various 2-iodoaryls with triethyl[4-(triethylsilyl)but-3-ynyloxy]silane.[a]
Entry
Ar(I)NH2
Catalyst
Base
Time
Conversion [%][b]
Product
Yield [%][c]
1
2
3
Pd/C(ALD)
Pd/C(ALD)
[Pd]/NaY
K2CO3
Na2CO3
Na2CO3
14 h
14 h
14 h
100
100
100
8
48
62
98
4
5
2
3
Pd/C(ALD)
[Pd]/NaY
Na2CO3
Na2CO3
9 d
6 d
100
100
9
60
70
6
7
Pd/C(ALD)
[Pd]/NaY
K2CO3
K2CO3
14 h
14 h
100
100
10
11
70
81
8
9
Pd/C(ALD)
[Pd]/NaY
Na2CO3
Na2CO3
14 h
14 h
100
100
60
65
[a]
Reaction conditions: 2-iodoaryl (1.0 mmol), diphenylacetylene (3.0 mmol), base (3 mmol), [Pd] catalyst (2 mol%), DMF
(4.0 mL), 1208C, time.
[b]
[c]
Conversions based on unreacted 2-iodoaryl were determined by GC with an internal standard (biphenyl) (Drel=Æ5%).
Isolated yields after flash chromatography on silica (purity: ꢀ97%).
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First Heterogeneous Ligand- and Salt-Free Larock Indole Synthesis
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Table 4. Heteroannulation of various 2- iodoaryls with triethyl(phenylethynyl)silane.[a]
Entry
Ar(I)NH2
Catalyst
Base
Time
Conversion (%)[b]
Product
Yield [%][c]
1
2
Pd/C(ALD)
[Pd]/NaY
Na2CO3
Na2CO3
24 h
24 h
100
100
13
14
15
80
70
3
4
2
3
Pd/C(ALD)
[Pd]/NaY
Na2CO3
Na2CO3
12 d
7 d
100
100
42
80
5
6
Pd/C(ALD)
[Pd]/NaY
K2CO3
K2CO3
14 h
14 h
100
100
83
88
7
8
Pd/C(ALD)
[Pd]/NaY
Na2CO3
Na2CO3
14 h
14 h
100
100
16
67
80
[a]
Reaction conditions: 2-iodoaryl (1.0 mmol), diphenylacetylene (3.0 mmol), base (3 mmol), [Pd] catalyst (2 mol%), DMF
(4.0 mL), 1208C, time.
[b]
[c]
Conversions based on unreacted 2-iodoaryl were determined by GC with an internal standard (biphenyl) (Drel=Æ5%).
Isolated yields after flash chromatography on silica (purity: ꢀ97%).
bly, 4-nitro-2-iodoaniline 2 and 3,5-dimethoxy-2-io- version under acceptable conditions (short reaction
doaniline 3, while sometimes unreactive with diphen- time, higher yields). Applied to the corresponding
ACHTUNGTRENNUNG
K2CO3 was required as base, as otherwise only a very
ACHTUNGTRENNUNG
poor conversion was achieved (ca. <30%). When
triethyl[4-(triethylsilyl)but-3-ynyloxy]silane 7 was em- neous catalysts for the Larock synthesis of indoles
ployed using the heterogeneous [Pd(NH3)4]/NaY cata- and benzofurans, we addressed the recycling of the
AHCTUNGTRENNUNG
lyst, it leads to generally better isolated yields toward catalyst. The benchmark reaction chosen for the recy-
the expected indole, up to 98% in the case of 2-iodo- cling study was the heteroannulation of 2-iodoaniline
A
7
(ca. 60–65%; Table 3 entries 8 and 9).
explained elsewhere, was performed as follows: at the
Using triethyl(phenylethynyl)silane 12 as alkyne completion of the 1st run using fresh catalyst, the sus-
partner gave nearly the same tendencies. However, in pension was cooled to room temperature and centri-
that case the heterogeneous catalyst to use depends fuged. The supernatant was decanted and the solid
on the nature of the iodoaniline. The reaction of 2-io- was washed three times with DMF, then twice with di-
doaniline over the Pd/C(ALD) gave the highest isolated ethylether, then allowed to dry at room temperature
yield (Table 4, entry 1 vs. 2). With the other anilines, overnight. It was then engaged in a new catalytic
the PdACHTUNGTRENNUNG(NH3)4]/NaY catalyst gave the best results (i.e., cycle. The procedure was repeated up to a total of 5
Table 4, 80% yield with 4-nitro-2-iodoaniline 2 – runs (Figure 2). Both catalysts showed high recyclabil-
entry 4 vs. 3; 88% yield with 3,5-dimethoxy-2-iodoani- ity under our reaction conditions. However differen-
line 3 – entry 6 vs. 5). Again with 3,5-dimethoxy-2-io- ces were observed: while the Pd/C(ALD) gave full con-
doaniline 3, K2CO3 had to be used to achieve full con- version until the 3rd run before being deactivated, the
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Figure 2. Recyclability of the Pd/C(ALD) and [PdACTHUNTRGNE(UNG NH3)4]/NaY catalysts for the Larock indole synthesis of 2-iodoaniline with
triethyl[4-(triethylsilyl)but-3-ynyloxy]silane 7. Reaction conditions: 1.0 mmol iodoaniline, 3.0 mmol alkyne, 3.0 mmol
Na2CO3, 2.0 mol% [Pd], 4.0 mL DMF, 1208C, 14 h.
[Pd
(NH3)4]/NaY was fully recyclable until the 4th run
The experimental simplicity associated with the rel-
before showing a decreased activity in the 5th run. atively mild conditions renders the reported method
This apparent loss of activity could have several sour- highly competitive with respect to existing proce-
ces, including mechanical mass loss during the recy- dures.
cling protocol (centrifuge, decantation) or real cata-
lytic site deactivation. Nevertheless, the activity of the
recycled catalysts remain excellent, the [PdACHTNUGTRNEG(UN NH3)4]/
NaY showing definitively a higher behaviour for the
potential applications in fine chemical industry.
Experimental Section
All commercial materials were used without further purifi-
cation. Analytical thin layer chromatography (TLC) was
performed on Fluka Silica Gel 60 F254. GC analyses were
performed on an HP 4890 chromatograph equipped with an
FID detector, a HP 6890 autosampler and an HP-5 column
(cross-linked 5% phenyl-methylsiloxane, 30 mꢃ0.25 mm
i.d.ꢃ0.25 mm film thickness) with nitrogen as carrier gas.
In conclusion, heterogeneous palladium catalysts
offer viable alternatives to the use of soluble palladi-
um complexes for the Larock indole and benzofuran
synthesis. Full conversion and relatively high selectivi-
ties were achieved for nearly all of the substrates
evaluated under common reaction conditions, the ex-
ception being the sterically encumbered diphenylace- GC-MS analyses were obtained on a Shimadzu GC-MS-
QP2010S equipped with a Sulpelco SLB-5MS column (95%
methylpolysiloxane+5% phenylpolysiloxane, 30 mꢃ
tylene. To the best of our knowledge, this work repre-
sents the first application of heterogeneous palladium
catalysts in such syntheses. We demonstrated that the
use of an active heterogeneous catalyst allowed prod-
uct yields similar to those observed under homogene-
ous conditions but without requiring the use of extra
salts or ligand.
0.25 mmꢃ0.25 mm) with helium as carrier gas. Conversions
were determined by GC based on the relative area of GC
signals referred to an internal standard (biphenyl) calibrated
to the corresponding pure compounds. The experimental
error was estimated to be Drel =Æ5%. Chemical yields refer
to pure isolated substances. Purification of products was ac-
complished by flash chromatography performed at a pres-
sure slightly greater than atmospheric pressure using silica
In summary, the easily home-made [Pd
ACHTUGNRTNE(NUNG NH3)4]/
NaY catalyst appeared to be the catalyst of choice
both for indoles or benzofurans syntheses, even in re- (Macherey–Nagel Silica Gel 60, 230–400 mesh) with the in-
dicated solvent system. Infrared spectra were recorded on a
Bruker Vector 22 FT-IR spectrometer. Liquid NMR spectra
were recorded on a Bruker AC-250 spectrometer. All chem-
ical shifts were measured relative to residual 1H or
13C NMR resonances in the deuterated solvents: CDCl3, d=
actions (i.e., indoles 9 and 14) where the original
Larock procedure failed and for which previous suc-
cesses required the use of expensive ligand systems.
Furthermore, this heterogeneous catalyst was found
to be extremely robust despite the use of aerobic con-
ditions and was successfully re-used over several
cycles. However, for reactions involving diphenylace-
tylene, we established that Pd/C catalysts [i.e.,
Pd/C(ALD) or Pd/C(EVO)] have to be used in order to
obtain the target compounds (i.e., indoles 1 and 4).
1
7.26 ppm for H, 77.0 ppm for 13C; DMSO, d=2.50 ppm for
1H, 39.5 ppm for 13C. Data are reported as follows: chemical
shift, multiplicity (s=singlet, d=doublet, t=triplet, q=
quartet, m=multiplet, br=broad). High resolution mass
spectra (HRMS) were recorded on a Thermo Finnigan
MAT 95 XL spectrometer, with isobutane as reactant gas
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First Heterogeneous Ligand- and Salt-Free Larock Indole Synthesis
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for CI at the “Centre Commun de Spectromꢀtrie de Masse, References
UMR5246 CNRS-Universitꢀ Claude Bernard Lyon 1”.
Melting points were determined in open capillary tubes and
are uncorrected.
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Typical Procedure for Palladium-Catalysed
Heteroannulation
The aryl iodide (1 mmol), the alkyne (3 mmol), the appro-
priate base (3 mmol), Pd catalyst (2 mol%) and DMF
(4 mL) were introduced into a tube and sealed. The reactor
was placed under stirring in a preheated oil bath at 1208C.
The reaction completion was monitored by GC. After cool-
ing to room temperature, the reaction mixture was filtered
through a celite pad, which was washed with EtOAc
(100 mL). The resulting organic layer was washed with
Na2CO3 (2ꢃ40 mL) then brine (40 mL). The organic layer
was dried over Na2SO4 and the solvent was removed under
reduced pressure. If necessary (for the silylated compounds),
the crude product was fully deprotected according to the
method A or B before being purified by flash chromatogra-
phy over silica.
Method A: To a solution of crude product dissolved into
MeOH (20 mL) was added 2N HCl (4 mL, 8 equiv.). After
completion (monitored by GC), the resulting mixture was
evaporated and the residue was partitioned between AcOEt
and saturated Na2CO3 solution. The phases were separated
and the organic phase was washed with saturated brine,
dried over Na2SO4 and the solvent was removed under re-
duced pressure to afford the corresponding crude fully de-
protected compound.
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Supporting Information
Complete descriptions of experimental details and product
characterisation are available as Supporting Information.
Acknowledgements
NB thanks the Rꢀgion Rhꢁne-Alpes for grants. The authors
gratefully acknowledge the Rꢀgion Rhꢁne-Alpes, Programme
CIBLE-2007 (Contract number 07 016376 01/02/03) for
funding and EVONIK for a gift of palladium catalyst.
Adv. Synth. Catal. 2009, 351, 2055 – 2062
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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