Tandem copper-catalysed aryl and alkenyl amination reactions: The synthesis of N-functionalised indoles

Article abstract of DOI:10.1039/b817254d

A Cu-diamine complex effectively catalyses tandem C-N bond formation on 2-(2-haloalkenyl)-aryl halide substrates, to deliver a series of N-functionalised indoles. Anilines, amides and carbamates are all effective coupling partners under the developed cond

Full text of DOI:10.1039/b817254d

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COMMUNICATION
www.rsc.org/obc | Organic & Biomolecular Chemistry
Tandem copper-catalysed aryl and alkenyl amination reactions: the synthesis
of N-functionalised indoles†
Roy C. Hodgkinson,a Jurgen Schulzb and Michael C. Willis*a
Received 1st October 2008, Accepted 1st December 2008
First published as an Advance Article on the web 9th December 2008
DOI: 10.1039/b817254d
A Cu-diamine complex effectively catalyses tandem C–N
bond formation on 2-(2-haloalkenyl)-aryl halide substrates,
to deliver a series of N-functionalised indoles. Anilines,
amides and carbamates are all effective coupling partners
under the developed conditions.
The abundance of indole ring systems in natural products
and particularly in designed medicinal agents has resulted in the
development of a wide range of synthetic methods,6 with transition
metal catalysed approaches being particularly well represented.7,8
We have previously shown that 2-(2-haloalkenyl)-aryl halides can
undergo tandem palladium catalysed coupling reactions, one
intermolecular, one intramolecular, to deliver a variety of 1-
functionalised indole products (Reaction A, Scheme 1).9 Although
the process could incorporate a variety of N-nucleophiles, includ-
ing amines, anilines and carbamates, we were not able to effectively
prepare N-acyl indoles using this process.9b This limitation,
resulting from the poor reactivity of amide coupling partners in the
developed reaction, together with potential economic advantages,
prompted us to explore a copper-catalysed variant of the same
indole-forming transformation (Reaction B, Scheme 1).10,11
The development of palladium catalysed aryl C–N coupling
reactions employing aryl halides as substrates has had an enor-
mous impact on synthetic chemistry. The wide range of N-
based coupling partners, the ability to employ iodo-, bromo-,
chloro- and sulfonate-substituted arenes as substrates, together
with the availability of commercial catalysts are all responsible
for the popularity and utility of this class of transformation.1
More recently, copper-based methods to achieve the same bond
constructions have emerged as alternatives to the palladium
catalysed reactions.2 Although the substrate scope, with respect to
both the N-nucleophile and the aryl halide components, is more
limited than with the corresponding palladium-based methods,
there are situations when the use of the copper catalysed process
may be attractive.3 For example, the cost of palladium salts are
significantly higher than the corresponding copper sources used in
these processes. In addition, the palladium based methods usually
partner the metal with a phosphine ligand; the most common
ligands for the copper based reactions are diamines, diketones, and
phenanthrolines. In general, the phosphine ligands again attract a
higher cost. These factors must be balanced against the amount
of catalyst needed in the respective reactions, with significantly
lower catalyst loadings usuallybeingachievable withthe palladium
based reactions. An additional cost consideration is the type of
aryl halide substrate that can be employed in the reaction under
consideration; there are now many examples of aryl chlorides
being used in combination with palladium catalysts,4 however
the equivalent copper-catalysed examples are less common.5
These simple economic arguments must be balanced against the
differences in reactivity and selectivity possible with the two
metals, considerations that are at least as important from a
synthetic perspective. In this Communication we demonstrate that
a tandem copper-catalysed amination process allows the efficient
preparation of a range of N-functionalised indoles, and also
document important reactivity differences when compared to an
analogous palladium catalysed process.
Scheme 1 Pd- and Cu-catalysed tandem amination routes to indoles.
We evaluated the effectiveness of a range of Cu-based conditions
t
in the coupling of dibromo styrene 1 and Bu-carbamate, to
generate indole 2, as a test reaction (Table 1). We initially explored
the use of the four ligands 3–6, known to be effective systems
for simple Cu-catalysed arylation reactions,12 in combination with
CuI; the simple diamine 3 was most effective, delivering 48% of
the required indole (entries 1–4). Variation of the copper:ligand
proportions established that a 1:2 ratio employing 10 mol% copper
for a 24 h reaction was optimal (entries 5–8). Alternative Cu-
sources could also be employed, with both CuOAc and CuTC
(copper(I) thiophene-2-carboxylate)13 both effective, although
with reduced efficiency compared to CuI (entries 9 and 10). Finally,
we also found that the base could be varied from K2CO3 to K3PO4
and an effective system still maintained, particularly when used in
combination with CuOAc (entries 11 and 12).
Having established that we could achieve the required tandem
amination sequence employing Cu-catalysis, we turned our at-
tention to exploring the scope of the N-coupling partner. We
again employed the simple dibromo styrene 1 as our test substrate
(Table 2).‡
aDepartment of Chemistry, University of Oxford, Chemistry Research
Laboratory, Mansfield Road, Oxford, UK OX1 3TA. E-mail: michael.
willis@chem.ox.ac.uk; Fax: +44 1865 285002; Tel: +44 1865 285126
bSchering Plough Corporation, Newhouse, UK ML1 5SH
† Electronic supplementary information (ESI) available: Experimen-
tal procedures and analytical data for new compounds. See DOI:
10.1039/b817254d
t
Extending from the Bu-carbamate employed in our optimi-
sation studies we found that both Et- and Bn-carbamates were
432 | Org. Biomol. Chem., 2009, 7, 432–434
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Table 3 Variation of 2-(2-haloalkenyl)-aryl halides substratesa
Table 1 Evaluation of Cu-catalysts in the conversion 1 → 2a
Cu source
entry (mol%)
ligand metal:ligand base
time yield (%)b
K2CO3 24 h 48
entry
1c
substrate
base
yield (%)b
79
1
2
3
4
5
6
7
8
9
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (5)
3
4
5
6
3
3
3
3
3
3
3
3
1:1
1:1
1:1
1:1
1:2
1:4
1:2
1:2
1:2
1:2
1:2
1:2
K3PO4
K2CO3 24 h
K2CO3 24 h
K2CO3 24 h
0
0
0
K2CO3 24 h 85
K2CO3 24 h 54
K2CO3 24 h 60
K2CO3 48 h 27
K2CO3 24 h 76
K2CO3 24 h 68
K3PO4 24 h 61
K3PO4 24 h 88
2
Cs2CO3
82
CuI (5)
3d
4
Cs2CO3
K3PO4
62
80
CuOAc (10)
CuTC (10)
CuI (10)
CuOAc (10)
10c
11
12
a Reaction conditions: dihalide (1.0 equiv.), carbamate (2.0 equiv.), K2CO3
(3.0 equiv.), toluene, 110 ◦C, 24 h. b Isolated yields. c CuTC = copper(I)
thiophene-2-carboxylate.
5e
6c
Cs2CO3
K3PO4
53
70
Table 2 Variation of N-coupling partnera
7
8
K3PO4
K3PO4
56
0
entry
1
Cu source
CuI
N-substrate
yield (%)b
81
a Reaction conditions: dihalide (1.0 equiv.), carbamate (2.0 equiv.), base
(3.0 equiv.), Cu source (10 mol%), ligand 3 (20 mol%), toluene, 110 ◦C,
24 h. b Isolated yields. c 40 mol% ligand employed. d 5.0 Equivalents of
carbamate used. e 1.75 Equivalents of carbamate used.
2
3
CuI
CuI
84
80
also good coupling partners (entries 1 and 2). Aniline could also
be readily introduced, delivering the N-aryl indole in 80% yield
(entry 3). However, simple amines were not effective coupling
partners. This was demonstrated by the use of n-pentylamine, in
which only 21% of the N-alkyl indole was obtained, with the
balance of material being unreacted substrate (entry 4). When
propionamide was employed as the nucleophile we isolated 80%
of the desired N-acyl indole, along with 13% of the N-H indole
(entry 5). Attempts to further exclude moisture from the reaction
resulted in no improvement, with the N-H indole always being
obtained in similar amounts. However, the use of a catalyst derived
from CuTC delivered the N-acyl indole in 89% yield with none
of the N-H indole byproduct (entry 6). The same conditions
could also be used to couple hexamide with comparable results
(entry 7). These successful reactions employing amide coupling
partners are notable, as we were never able to prepare the same
N-acyl indoles using Pd-catalysis in the corresponding transfor-
mations.9b
4
5
CuI
CuI
21
80c
6
7
CuTC
CuTC
89
87
a Reaction conditions: dihalide (1.0 equiv.), N-substrate (2.0 equiv.),
K2CO3 (3.0 equiv.), Cu source (10 mol%), ligand 3 (20 mol%), toluene,
110 ◦C, 24 h. b Isolated yields. c Isolated along with 13% of the N-H indole.
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The 2-(2-haloalkenyl)-aryl halides used as substrates in the
indole syntheses are readily obtained from the corresponding
o-halo benzaldehydes using simple Wittig chemistry. Accordingly,
we prepared a variety of functionalised substrates to probe the
2 Reviews: (a) F. Monnier and M. Taillefer, Angew. Chem., Int. Ed., 2008,
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t
generality of the Cu-catalysed process (Table 3). Bu-carbamate
was used as the N-coupling partner in all examples. A catalyst
derived from CuOAc was found to deliver the most consistent
yields across a variety of substrates, although some variation in
the choice of base was needed. Within these constraints it was
possible to employ substrates featuring a variety of both electron-
donating and electron-withdrawing substituents (entries 1–6). A
limitation of the present method was that two Br-substituents
were needed to achieve efficient reactions. For example, employing
the substrate partnering an alkenyl-chloride with an aryl bromide
delivered the desired indole in a yield of 56% (entry 7); significantly
lower than the corresponding dibromo example (88% yield, table
1 entry 12). The aryl-chloride containing substrate was unreactive
(entry 8).
In summary, we have demonstrated that tandem Cu-catalysed
amination reactions employing 2-(2-haloalkenyl)-aryl halides al-
low the straightforward preparation of N-functionalised indoles.
The range of N-coupling partners that can be used complements
that achievable using Pd-catalysis, with the major advantage being
the successful preparation of N-acyl indoles when employing
the Cu-system. Conversely, couplings employing simple amines
were less efficient when using the Cu-chemistry. Ultimately, the
choice of Pd or Cu catalysis will be determined on a case-by-case
basis, balancing economic considerations of the catalyst and other
reaction components, against the reactivity and efficiency possible
with the two systems.
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Acknowledgements
This work was supported by the EPSRC and Schering Plough,
Newhouse (formerly Organon).
Notes and references
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‡ General procedure for the Cu-catalyst diamination: Table 1, entry
5. Potassium carbonate (316 mg, 2.29 mmol) and tert-butylcarbamate
(179 mg, 1.52 mmol) were added to an oven dried flask charged with
CuI (14 mg, 0.08 mmol) and N,N ¢-dimethylethyldiamine (13 mg, 16 mL,
0.15 mmol) under nitrogen. The reagents were suspended in anhydrous
toluene (0.38 mL) and (Z)-1-bromo-2-(2-bromovinyl)benzene (200 mg,
0.76 mmol) was added. The reaction mixture was stirred for 24 hours at
110 ◦C and then cooled to room temperature. The reaction was diluted
with ethyl acetate, filtered through celite, and reduced under vacuo. The
product was purified by flash chromatography (10% EtOAc: Hexane) to
yield indole (142 mg, 85%) as a yellow oil.
1 (a) Reviews: J. F. Hartwig, in Handbook of Organopalladium Chemistry
for Organic Synthesis, ed. E. I. Negishi, Wiley-Interscience, New York,
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Cross-Coupling Reactions, ed. A. de Meijere and F. Diederich, Wiley-
VCH, Weinheim, 2004, pp. 699.
434 | Org. Biomol. Chem., 2009, 7, 432–434
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The Royal Society of Chemistry 2009
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