Atom-economical transformation of diaryliodonium salts: Tandem C-H and N-H arylation of indoles

Article abstract of DOI:10.1021/ja5124754

Arylation using diaryliodonium salts generates one equivalent of an iodoarene as a side-product, a significant waste of atom economy. Here, we show that diaryliodoniums can undergo Cu-catalyzed tandem C-H/N-H arylation, producing novel indoles that incorporate both aryl groups from the reagent.

Full text of DOI:10.1021/ja5124754

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Communication
pubs.acs.org/JACS
Atom-Economical Transformation of Diaryliodonium Salts: Tandem
C−H and N−H Arylation of Indoles
Sachin G. Modha and Michael F. Greaney*
School of Chemistry, University of Manchester, Oxford Rd, Manchester M13 9PL, United Kingdom
*
S Supporting Information
Scheme 1. Transition-Metal-Catalyzed Activation of
Diaryliodonium Salts
ABSTRACT: Arylation using diaryliodonium salts gen-
erates one equivalent of an iodoarene as a side-product, a
significant waste of atom economy. Here, we show that
diaryliodoniums can undergo Cu-catalyzed tandem C−H/
N−H arylation, producing novel indoles that incorporate
both aryl groups from the reagent.
iaryliodonium salts are receiving increasing attention as
1
D
versatile arylating reagents. They offer the appealing
combination of excellent usability, being stable crystalline solids
that are readily prepared using simple procedures, and high
reactivity that can access novel reaction pathways. Recent
applications have centered on metal-catalyzed arylation under
2
mild conditions, aryl radical chemistry using photoredox
3
catalysis, as well as metal-free arylation with simple
4
nucleophiles under Friedel−Crafts or S -type mechanisms.
N
Despite these advances, diaryliodonium arylation is charac-
terized by poor atom economy. The aryl iodide nucleofuge,
weighing a minimum of 204 Da, is jettisoned on transfer of the
reacting aryl group to the substrate or catalyst (Scheme 1).
Nearly all iodonium arylation reactions to date, across all
reaction classes, generate one equivalent of an iodoarene as
5
waste that must be separated from the desired product.
followed by N-arylation using the in situ-generated aryl iodide
and the same metal catalyst. Gaunt’s iodonium Cu-catalyzed
indole arylation system appeared particularly well-suited for the
6
Our interest in arylation chemistry led us to question
whether this hitherto extraneous aryl iodide moiety could be
captured in a second arylation reaction, such that both
iodonium aryl groups underwent incorporation in a single
operation. In particular, if the aryl iodide underwent a second
arylation distinct from the first, we could achieve dual arylation
at separate sites in a substrate in one step, with no wastage of
arene residues. Literature precedent for atom economical use of
iodoniums is very limited; Bumagin, Belatskaya et al. showed
that 2 equiv of Ar IX underwent Suzuki−Miyaura cross-
coupling with Ph BNa to yield 4 equiv of Ar-Ph in 97% yield,
i.e., near-perfect utilization of aryl residues. More recent work
from the Nachtscheim and Wen groups has used cyclic
iodonium salts to form tricyclic compounds (via intramolecular
reaction of the incipient aryl iodide), a novel approach but one
9b
first C−H activation, as it proceeds efficiently under mild
conditions for a range of iodonium salts. For indole N-arylation,
Buchwald has reported effective Cu-catalysis using chelating
10
diamines and aryl iodides.
Early trial reactions established, not unexpectedly, that the C-
and N-arylation conditions were orthogonal to one another,
e.g., indole arylation with Ph
Cu(OTf) catalysis in DCM using di-tert-butylpyridine (dtbpy)
IOTf using Gaunt’s conditions of
2
2
2
as base gave the C-arylated product 3a in 82% yield (Table 1,
entry 1), with no N-arylation detected. Whereas indole
arylation using ArI under Buchwald’s conditions in dioxane
gave N-phenyl indole in high yield, with no sign of C-arylation
4
7
11
(
entry 2). To overcome this dichotomy and merge the two
8
processes, we first needed a common solvent. The N-arylation
was ineffective in DCM or DCE used in C−H arylation, but the
C−H arylation could proceed using dioxane (65% yield of 3a,
entry 4). Next, we established that CuI could be used as the
catalyst for both steps (entry 5), requiring a higher temperature
limited to the synthesis of tricyclic aromatics. Harnessing
discrete aryl groups in a diaryliodonium for two different bond-
forming events has, to the best of our knowledge, not been
reported.
We chose to explore this idea through the double arylation of
indole (1a), as arylated indoles are fundamental building blocks
9
of biologically active compounds and functional materials. We
Received: December 8, 2014
planned an initial C−H-arylation under copper catalysis,
©
XXXX American Chemical Society
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DOI: 10.1021/ja5124754
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Table 1. Reaction Optimization
a
yield (%)
entry
catalyst/ligand
Cu(OTf) (10 mol %)
base
temp (°C)
time (h)
(3a:3a′:5a)
b
1
dtbpy (1.1 equiv)
K PO (2 equiv)
rt
110
110
rt
24
12
12
24
24
24
24
16
12
82:0:0
0:96:0
0:0:86
65:0:0
78:0:0
0:0:0
2
c
2
CuI (5 mol %), DMEDA (10 mol %)
CuI (5 mol %), DMEDA (10 mol %)
3
4
d
3
K PO (2 equiv)
3 4
4
5
6
Cu(OTf) (10 mol %)
dtbpy (1.1 equiv)
dtbpy (1.1 equiv)
dipea (1.1 equiv)
2
CuI (5 mol %)
60
CuI (5 mol %)
60
e
7
CuI (5 mol %)
K PO (1.5 equiv)
rt
30:25:0
0:30:0
0:94:0
40:0:20
3
4
e
8
CuI (5 mol %), DMEDA (10 mol %)
CuI (5 mol %), DMEDA (10 mol %)
K PO (1.5 equiv)
110
110
3
4
c
9
K PO (2 equiv), dtbpy (1.1 equiv)
3 4
e
1
0
CuI (5 mol %); then CuI (5 mol %), DMEDA (10 mol %) dtbpy (1.1 equiv); then K PO4
60, then 110 24, then 16
60, then 110 24, then 16
60, then 110 24, then 16
3
(
2 equiv)
1
1
CuI (5 mol %); then CuI (50 mol %), DMEDA
100 mol %)
dtbpy (1.1 equiv); then K PO4
0:0:65
0:0:63
3
(
(2 equiv)
f
1
2
CuI (20 mol %); then DMEDA (30 mol %)
dtbpy (1.1 equiv); then K PO4
3
(
2 equiv)
Unless otherwise noted, all reactions were run with 1a (0.2 mmol) and 2a (1.1 equiv) in a crimped cap glass vial under an inert atmosphere.
a
b
c
d
e
Isolated yields. CH Cl as solvent. Iodobenzene used instead of 2a. 3-Phenyl indole 3a and iodobenzene used instead of 1a and 2a. Reaction
2
2
f
did not reach completion. 1.05 equiv of 2a was used.
of 60 °C for C−H arylation relative to Cu(OTf) . The base/
Table 2. Scope of Cu(I)-Catalyzed Diarylation of Indole by
Symmetrical Diaryliodonium Salts
2
ligand requirements for each step, however, remained distinct
(entries 6−8). While the DMEDA required for N-arylation was
observed to completely suppress C-arylation (entry 8), we were
pleased to find that the dtbpy required for C-arylation was well
tolerated under the N-arylation conditions (entry 9).
Accordingly, simple addition of an inorganic base and
DMEDA to the reaction vessel on completion of the first
arylation would in principle enable tandem arylation.
Initial efforts in this direction using two additions of CuI (5
mol %), however, gave low yields of 5a (entry 10). It appeared
that excess diphenyliodonium 2a (∼10 mol %) remaining in
solution from the C-arylation was problematic, inhibiting the
second N-arylation. Increasing the CuI loading to 50 mol %
successfully circumvented this problem, producing 1,3-diphenyl
indole in 65% yield (entry 11). Optimally, we could lower the
catalyst loading to 20 mol %, using 1.05 equiv of iodonium 2a,
to give 5a in 63% overall yield.
We were pleased to find that the tandem C−H/N−H
process was productive for a variety of diaryliodonium salts.
Using 1.05 equiv of 2 in each case, the one pot, two-step
protocol proved broadly applicable, with chlorine, fluorine,
methyl, and methoxy-substituted aryl iodoniums all being
tolerated (Table 2) for a variety of indoles. The di(meta-
tolyl)iodonium was somewhat anomalous in producing 16% of
indole C2 arylation (no N-arylation) as a byproduct (entry 11);
all other iodoniums gave clean C3 selectivity. The reaction was
not effective for 2-substituted indoles, with 2-methylindole
giving a low yield of 5k after prolonged heating.
R1
R2
a
entry
Ar
yield (%)
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
H
H
H
Me
H
4-(Cl)C H4
60 (5b)
58 (5c)
67 (5d)
41 (5e)
66 (5f)
53 (5g)
55 (5h)
65 (5i)
57 (5j)
20 (5k)
46 (5l)
6
4-(F)C H4
6
1
2
H
4-(Me)C H
6 4
H
4-(OMe)C H4
6
5-OMe
5-OMe
5-OMe
5-Me
5-F
C H
6
5
4-(Me)C H4
6
4-(Cl)C H4
6
4-(Me)C H4
6
9
4-(F)C H4
6
b
1
0
H
C H
6
5
c
1
1
H
b
3-(Me)C H4
6
a
Isolated yields. Step 1 at 75 °C and Step 2 at 150 °C. Reaction did
not reach completion even after 48h at 150 °C. 2-Aryl indole isolated
c
in 16% yield.
productive under the reaction conditions. Selectivity using
electronic control, by contrast, is well-precedented for metal-
free reactions, but poorly exemplified for metal-mediated
processes. Trial reactions with simple electron-rich/-poor
diaryliodoniums bore this out, producing regio-isomeric
mixtures of 1,3-diarylated indoles. More promising results
were obtained, however, using the phenyl dimethyluracil
iodonium salts recently introduced by Gaunt et al. for the
14
15
Having established the reaction for symmetrical diary-
liodoniums, we were keen to extend it to unsymmetrical
analogs. Controlling this reaction presented an immediate
challenge, as selective aryl transfer in metal-catalyzed iodonium
arylation is usually achieved via steric differentiation of the two
2
b−i,13
16
arene units.
The N-arylation step in our sequence is,
organocatalytic arylation of aldehydes. Following some
however, very sensitive to steric hindrance in the aryl ortho-
optimization studies (see Supporting Information), we were
position, indicating that hindered aryl iodides will not be
pleased to observe successful sequential C−H and N−H
B
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J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
arylation with the phenyl-uracil iodonium triflate 6a, producing
the novel indoyl uracil 8a in 48% yield (Scheme 2). The 5-
Notes
The authors declare no competing financial interest.
Scheme 2. Scope of Cu(I)-Catalyzed Diarylation of Indole
by Unsymmetrical Diaryliodonium Salts
ACKNOWLEDGMENTS
a
■
We thank the EPSRC for funding (postdoctoral support for
S.G.M. and Leadership fellowship to M.F.G.).
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ASSOCIATED CONTENT
■
̈
*
S
Supporting Information
1
Optimization tables and characterization data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(
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4
AUTHOR INFORMATION
Corresponding Author
Michael.Greaney@manchester.ac.uk
■
Ph BiX reagents: Barton, D. H. R.; Blazejewski, J.-C.; Charpiot, B.;
Finet, J. P.; Motherwell, W. B.; Papoula, M. T. B.; Stanforth, S. J.
Chem. Soc. Perkin Trans. 1 1985, 2667.
*
C
DOI: 10.1021/ja5124754
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Journal of the American Chemical Society
Communication
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DOI: 10.1021/ja5124754
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