On water phosphine-free palladium-catalyzed room temperature C-H arylation of indoles

Article abstract of DOI:10.1002/chem.201302838

Get on top of your chemistry! An "on water", palladium-catalyzed, phosphine-free direct C-H arylation of indoles, with iodoarenes at 25-30°C, is disclosed (see scheme; TBDMS=N-tert-butyldimethylsilyl ether; SEM=N-2-(trimethylsilyl)ethoxymethyl; Bn=benzyl, Piv=pivabyl). The mildness of the reaction conditions permits the tolerance of a variety of N1-protected indoles.

Full text of DOI:10.1002/chem.201302838

COMMUNICATION
DOI: 10.1002/chem.201302838
À
“On Water”, Phosphine-Free Palladium-Catalyzed Room Temperature C H
Arylation of Indoles
Saidul Islam and Igor Larrosa*[a]
À
Direct arylation of inert C H bonds has received consid-
erable attention in the last few years as an alternative to the
classical transition-metal-catalyzed cross-coupling reac-
tions.[1] Direct arylations generally suffer from harsh reac-
tion conditions, such as elevated reaction temperatures, and/
or the need for strong oxidants, acids or bases,[2] which can
result in functional-group incompatibilities. Further, solvents
with undesirable toxicities, such as DMF and dimethylacet-
À
Scheme 1. Effect of Ag-carboxylate on the room temperature direct C H
arylation of indoles in DMF.
amide (DMA), or acidic solvents, such as AcOH and tri-
fluoroacetic acid (TFA), are generally required. Although
direct arylation benefits from high atom and step-economy,
further progress is needed towards more environmentally
friendly reaction conditions. In particular, and following the
principles of green chemistry, these reactions should be
energy efficient (carried out at near room temperature), and
the use of (toxic) flammable organic solvents should be
minimized.[3] The use of water as a solvent would have nu-
merous benefits in terms of safety, cost and environmental
impact. However, only a handful of methodologies for the
water resulted in a biphasic reaction system that led to a dis-
appointing 22% yield in the arylation of 1 with iodobenzene
2a (Table 1, entry 1) and decomposition of the remainder of
the indole starting material. With the aim of developing
a more environmentally friendly direct arylation method we
envisaged that varying the nature of the Ag-carboxylate salt
would allow us to modulate the reactivity of the system to
achieve room temperature arylation in water.
À
direct C H arylation of arenes and heteroarenes in which
water is used as the only solvent have been reported.[4] De-
Table 1. Optimization of the C2-arylation of indole 1 at room tempera-
ture and using water as the solvent.[a,b]
À
spite the high levels of interest in developing mild C H ar
ation reactions, only one room temperature C H activation
yl-
À
U
and aryl cross-coupling reaction in neat water has been re-
ported, albeit requiring the use of surfactants and super-stoi-
chiometric amounts of the strong acid HBF4.[4f] We now
report that the direct arylation of indoles with iodoarenes
can be achieved at room temperature and “on water” by
using a carefully chosen Ag-carboxylate salt as the base in
the reaction.
Entry
Pd [mol%]
AgX[c]
2 [equiv]
t [h]
3a [%][d]
1
2
3
4
5
6
7
8
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
2-NO2BzOAg
4-tBuBzOAg
CH3CO2Ag
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
1
16
0.5
16
0.5
0.5
0.5
0.5
0.5
4
0.5
0.5
0.5
0.5
0.5
1
22
42
20
<1
2
71
45
15
10
5
78
35
42
42
92
65
88
86
72
94
CH3CO2Ag
n-C4H9CO2Ag
n-C5H11CO2Ag
n-C6H13CO2Ag
n-C7H15CO2Ag
n-C17H35CO2Ag
c-C5H9CO2Ag
c-C6H11CO2Ag
c-C7H13CO2Ag
t-C4H9CO2Ag
1-Ad-CO2Ag
c-C6H11CO2Ag
c-C6H11CO2Ag
c-C6H11CO2Ag[e]
c-C6H11CO2Ag[f]
c-C6H11CO2Ag
c-C6H11CO2Ag
In 2008, we reported that Ag-carboxylates are key to
achievACHTUNGTRENNUNGing the Pd-catalyzed direct C2 arylation of N-methyl
indoles with iodoarenes in DMF at room temperature
(Scheme 1).[5] Our research highlighted that subtle changes
in the nature of the Ag-salt could lead to tremendous varia-
tions in the catalytic activity of the system, with electron-de-
ficient benzoate salts being vastly superior to any others.
Preliminary investigations replacing the DMF solvent with
9
10
11
12
13
14
15
16
17
18
19
20
1
16
1
1
4
5
5
2.5
2.5
1.2
2
2
[a] Dr. S. Islam, Dr. I. Larrosa
School of Biological and Chemical Sciences
Queen Mary University of London, Joseph Priestley Building
Mile End Road, London, E1 4NS (UK)
E-mail: i.larrosa@qmul.ac.uk
1.5
[a] Reactions carried out on a 0.5 mmol scale with respect to 1 and
1.5 equiv of AgX. [b] Comprehensive table can be found in the Support-
ing Information. [c] 1.5 equiv. [d] Determined by 1H NMR spectroscopy
against an internal standard. [e] 1.2 equiv. [f] 1.0 equiv.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201302838.
Chem. Eur. J. 2013, 19, 15093 – 15096
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15093

A comprehensive screening of Ag-carboxylates was un-
dertaken. All Ag-benzoates tested led to a degree of decom-
position of the starting material. Aliphatic Ag-carboxylates,
however, led to cleaner reactions (Table 1, entries 3–19). In
fact, a remarkable size-dependent effect on reaction rate
was observed when the size and shape of the aliphatic chain
was studied. Very high yields of C2 arylation product 3a
were obtained in a very narrow range of aliphatic chain
sizes (compare C5, C6, C7 and C8, entries 5–8).[6] We then
identified Ag-cyclohexanoate as the optimum Ag base for
the reaction over linear and branched aliphatic carboxylic
acids (entries 10–14). This Ag base led to a 92% yield of 3a
after only 1 h of reaction at 308C (entry 15). This represents
a remarkable increase in reactivity relative to the optimized
DMF-based system, which required seven hours to complete
the same coupling.[5] Further optimization led us to identify
tuted iodoarenes gave relatively diminished, but still satis-
factory, yields (3g, 3h). On the other hand, iodopyridines
led to lower reactivity (3i, 3j), presumably due to deactiva-
tion of the Pd catalyst by coordination. This could be cir-
cumvented in one case (3j) by heating up to 608C. Remark-
ably, in all cases complete C2 regioselectivity for the aryla-
tion was observed, except for 3b, for which <1% of C3 ar-
AHCTUNGTREUNyGNN lACHTUNEGRTNNUNGaACTUHNGTRENNUGN
indole coupling partner. A long-standing problem with cur-
rent direct indole arylation methods is the need to attune re-
action conditions to the indole N-protecting group.[7,8]
A
general regioselective arylation protocol would provide
a powerful solution to this. Thus we tested a variety of N-
protected indoles under our water-based catalytic system.
Notably, several protecting groups with differing steric and
electronic properties were found to be compatible with the
reaction conditions, without any adjustments being required:
N-2-(trimethylsilyl)ethoxymethyl (SEM) (4), N-Bn (5), N-
tert-butyldimethylsilyl ether (TBDMS) (6), and N-pivaloyl
(7)-protected indoles could be C2-arylated in high yields
(Table 3). The arylation of N-pivaloyl indole at 308C is par-
ticularly noteworthy given its lower nucleophilicity relative
to N-alkyl indoles. These are the first examples of room
temperature direct C2 arylation of N-acyl-[8d–i] and N-SEM-
that just 2.5 mol% of PdACTHNUTRGNE(UGN OAc)2 and 1.5 equivalents of the
iodoarene were sufficient, in the presence of the Ag salt, to
afford full conversion to product in four hours (entry 20).
Although the reaction does proceed as effectively at 258C,[6]
308C is more convenient to maintain experimentally in dif-
ferent laboratory environments and was selected as the stan-
dard reaction temperature.
The scope of the reaction with respect to iodoarenes was
then explored (Table 2). Good to excellent yields were ob-
tained with iodoarenes possessing a broad range of syntheti-
cally useful electron-withdrawing and -donating functionali-
ties. This included fluoro-containing iodoarenes (3b, 3c),
bromo- and chloro-substituted arenes (3d, 3e) that would
allow further metal-catalyzed functionalizations, and elec-
tron-donating MeO and CH3 groups (3 f, 3g). Ortho-substi-
[8a,k]
indoles. The direct arylation of N-silyl indoles has never
been reported. Indoles bearing the highly electron-
AHCTUNGTREGwNNNU ithdrawing tert-butoxycarbonyl (Boc) (8) and Ts (9) pro-
tecting groups were unreactive, whereas unprotected N-H
indole (10) was completely consumed to afford unidentified
products. A variety of electron-withdrawing and -donating
substituents were tolerated around the indole core. In par-
ticular, these mild conditions are compatible even with sen-
sitive functional groups, such as unprotected benzylic alco-
hols (12) and aldehydes (13). Benzyloxy-groups and methyl
esters are also compatible (11 and 19), as are halogenated
indoles (15, 16, 18, 21, 22), amongst others (14, 17, 20). Sub-
stitution at the C3 position by a CH3 group led to lower
yields of C2 arylation (23). A CH3 substituent at C2 did
allow C3 arylation to proceed, albeit in low yields (24).
The reported methodology is operationally simple. The
reactions are not air sensitive and are amenable to scale up
on a gram scale without loss in yield or selectivity. As an ex-
ample, the direct arylation of 1 with 2a on a 10 mmol scale
was carried out in an open flask, leading to 3a in an isolated
yield of 93% (1.92 g) (Scheme 2). The purification involved
a simple aqueous workup, followed by crystallization.[6] This
demonstrates that this methodology is an excellent candi-
date for scaling up to multi-gram quantities without substan-
tial optimization.
[a]
À
Table 2. Direct C H arylation of indole 1 with various iodoarenes.
[a] Isolated yields given after purification by silica gel chromatography.
Crude GCMS analysis revealed exclusive C2 arylation, except for 3b
(C2/C3 >99:1). [b] Reactions carried out at 608C.
Scheme 2. Gram-scale phenylation of indole 1.
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Arylation of Indoles
COMMUNICATION
[a]
À
Table 3. Direct C H phenylation of a variety of N-protected indoles.
In conclusion, a phosphine-free palladium-catalyzed direct
À
C H arylation of indoles with readily available iodoarenes
has been achieved in neat water and at room temperature.
The key for the realization of this mild methodology is the
use of Ag-cyclohexanoate as the base. These conditions are
compatible with a variety of N-protected indoles and
a broad range of functional groups. The protocol is opera-
tionally simple and can be scaled up to a gram-scale. We are
À
currently investigating other C H activation chemistries
under the aqueous, room temperature manifold.
Acknowledgements
We gratefully acknowledge the Engineering and Physical Sciences Re-
search Council for generous funding, the European Research Council for
a Starting Research Grant (to I.L.) and the EPSRC National Mass Spec-
trometry Service (Swansea).
À
Keywords: arylation · C H functionalization · indoles ·
palladium · water
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Received: July 19, 2013
Published online: October 7, 2013
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