Synthesis of indoles by conjugate addition and ligand-free copper-catalyzed intramolecular arylation of activated acetylenes with o-haloanilines

Article abstract of DOI:10.1002/chem.201002628

Air and water welcome-ligands need not apply! A simple and efficient new synthesis of variously functionalized and substituted indoles was achieved by the addition and copper-catalyzed coupling of N-formyl-o-haloanilines with acetylenic sulfones, esters a

Full text of DOI:10.1002/chem.201002628

COMMUNICATION
DOI: 10.1002/chem.201002628
Synthesis of Indoles by Conjugate Addition and Ligand-Free
Copper-Catalyzed Intramolecular Arylation of Activated Acetylenes
with o-Haloanilines
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
Detian Gao, Masood Parvez, and Thomas G. Back*[a]
The indole moiety is ubiquitous in both nature and phar-
ported by Hurtley[8] and arylations of other substrates con-
3
À
macology, and comprises the core structure of numerous al-
kaloids and other biologically important compounds.[1] Con-
siderable effort has been expended in the development of
versatile, efficient and economical synthetic routes to such
compounds. Many modern approaches are based on Pd-cat-
alyzed coupling reactions, which have been extensively in-
vestigated and can provide highly selective routes to vari-
ously substituted indole derivatives.[2]
taining sp -hybridized activated C H bonds are also well-
known.[6b,d] Numerous procedures for the coupling of aryl
groups with sp2-hybridized carbon centers have been repor-
ted,[6c] while acetylenic substrates lead to aryl-substituted al-
kynes.[6a–c,9] A palladium-catalyzed aza-Heck hydroamina-
tion reaction of o-haloanilines and alkynes has been shown
to afford indole products.[10]
In earlier work,[3c] we demonstrated that the conjugate ad-
ditions of o-iodoaniline derivatives to acetylenic sulfones
containing g-hydrogens generally proceed via prior isomeri-
zation of the latter to the corresponding allenic sulfones and
not by direct addition to the acetylenes, to afford the ob-
served allylic sulfone products 3 as mixtures of geometrical
isomers. We now report that these unseparated mixtures
smoothly undergo intramolecular copper-catalyzed coupling
to afford variously substituted 3-(p-toluenesulfonyl)indoles
4. The cyclizations were conducted in the presence of
Our earlier studies of palladium-catalyzed syntheses of re-
lated carbazoles[3a,b] and quinolones[3c] from readily available
o-iodoanilines and dienyl or acetylenic sulfones[4] prompted
us to investigate conjugate additions of o-iodoanilines to ac-
tivated acetylenes, followed by intramolecular Pd-catalyzed
arylations to afford indole products. However, the capricious
nature of the process in our initial experiments and the high
cost of palladium compounds prompted us to search for
cheaper and more efficient catalysts for the cyclization step.
We now report a more successful protocol based on a
ligand-free copper-catalyzed intramolecular arylation reac-
tion.
Cs2CO3 and catalytic CuACTHUNTRGNE(UNG OAc)2 in DMF at 1258C, without
protection from the atmosphere. The results are shown in
Scheme 1 and Table 1. N-Deformylation occurred simultane-
ously under the basic conditions of the reaction. This ap-
Since the discovery of the Ullman–Goldberg reaction[5]
more than a century ago, a variety of other copper-catalyzed
cross-coupling reactions of aryl halides leading to hetero-
ACHTUNGTRENNUNG
atom–aryl and C-aryl products have been investigated.[6]
Table 1. Preparation of indoles 4 and 7 from adducts 3 and 6.[a,b]
Most such procedures rely upon CuI catalysts coordinated to
various ligands, which can profoundly affect the reactivity of
the catalyst. The mechanisms and ligand requirements of O-
aryl[7a] and N-aryl[7b,c] coupling reactions have been particu-
larly well-investigated. Copper-mediated C-arylations of
active methylene compounds with aryl halides were first re-
Entry
Product
R
R’
Yield [%]
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4 f
4g
4h
4i
H
H
H
H
CO2Me
CO2Me
CO2Me
CO2Me
CN
nPr
ACHTUNGTRENNUNG
66
73
78
75
81
78
80
82
77
89
68
71
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
9
ACHTUNGTRENNUNG
[a] D. Gao, Dr. M. Parvez, Prof. Dr. T. G. Back
Department of Chemistry, University of Calgary
Calgary, AB, T2N 1N4 (Canada)
Fax : (+1)403-289-9488
10
11
12
4j
7a
7b
Me
H
H
ACHTUNGTRENNUNG
H
Ph
E-mail: tgback@ucalgary.ca
[a] The conjugate additions were performed as reported in ref. [3c].
[b] Enamine 3, Cu(OAc)2 (0.3 equiv), and Cs2CO3 (2 equiv) were heated
in DMF for 3 h at 1258C.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201002628.
ACHTUNGTRENNUNG
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14281

ductive, oxidative and cross-coupling methods,[12] and certain
other 3-sulfonylindoles display anti-HIV activity.[13]
We also report that similar conjugate additions to alky-
noate esters and alkynones afforded 11, which underwent
copper-mediated cyclizations to indoles 12 (Scheme 3 and
Table 2) in shorter reaction times and with less catalyst than
Scheme 3. Synthesis of indoles from o-iodoanilines and ynoates or
ynones.
required in the case of the acetylenic sulfones. While this
work was in progress, Cacchi et al.[14] reported cyclizations
of N-(2-iodoaryl)enaminones, catalyzed by CuI in the pres-
ence of the ligand 1,10-phenanthroline. The products were
3-aroyl-2-arylindoles, along with one example of a 2-alkyl
derivative. Our results indicate that a 2-alkyl group can be
readily incorporated into variously substituted indole prod-
ucts (Table 2, entries 1–5 and 7–16) as well as in the acyl
moiety at C-3 (entries 15–16). Both electron-withdrawing
and -donating substituents are tolerated at the 4-position of
the aniline, including 4-halo substituents (entries 3, 4, 10, 11
and 16), and remain intact in the final products 12. More-
over, the corresponding 2-bromoaniline (entry 9; X=Br in-
stead of I) was also successfully cyclized, while preliminary
Scheme 1. Synthesis of indoles from o-iodoanilines and acetylenic sul-
fones 2 and 5.
proach proved more effective than the use of CuI as the cat-
alyst, as the latter required longer reaction times of ca. 16 h
at 1508C, even in the presence of 1.0–1.2 equiv of the cata-
lyst, when applied to 3a–c and 3e–h.
Furthermore, the terminal acetylenic sulfone 5a and its
phenyl derivative 5b, where isomerization to the corre-
sponding allenic sulfones is not possible, also afforded the
indoles 7a and 7b via the vinyl sulfones 6a and 6b, respec-
tively (Scheme 1 and Table 1), while the conjugate addition
products of chloroalkyl-substituted acetylenic sulfones 9a–c
underwent deformylation and cyclization, followed by intra-
molecular N-alkylation to afford the tricyclic products 10a–c
in a one-pot reaction (Scheme 2).[11] The sulfone moiety has
the potential for further transformation via a variety of re-
Table 2. Preparation of indoles 12 from adducts 11.[a,b]
Entry
Product
R
R’
X
EWG
Yield [%]
1
2
3
4
5
6
7
8
12a
12b
12c
12d
12e
12 f
12g
12h
12h
12i
12j
12k
12l
12l
12m
12n
H
H
Cl
I
Me
CN
H
CN
CN
Cl
Me
I
I
I
I
I
I
I
I
Br
I
I
I
I
Cl
I
I
CO2Et
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
PhCO
PhCO
PhCO
PhCO
PhCO
PhCO
PhCO
PhCO
nPrCO
nPrCO
81
80
83
83
81
81
87
85
69
92
85
86
81
–
nC5H11
nC5H11
nC5H11
nC5H11
Ph
nBu
nBu
nBu
nBu
nBu
nBu
nBu
nBu
nBu
nBu
9
10
11
12
13
14
15
16
I
Me
CO2Me
CO2Me
CN
I
76
91
[a] Products 11 were chiefly the Z isomers, but in entries 2–5 small
amounts of the regioisomeric b,g-unsaturated esters were detected.
[b] Enamine 11, Cu
ACHTUGNRTNE(NUNG OAc)2 (0.15 equiv), and Cs2CO3 (1–2 equiv) were
Scheme 2. Tandem cyclizations with acetylenic sulfones 8.
heated in DMF for 0.5–3 h at 1258C.
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Chem. Eur. J. 2010, 16, 14281 – 14284

Synthesis of Indoles
COMMUNICATION
experiments with the 2-chloro derivative were unsuccessful
(entry 14; X=Cl instead of I). The conjugate addition and
cyclization steps in entries 8 and 10 were also performed in
one pot, whereby the conjugate additions were conducted in
the usual manner (DMF/K2CO3/room temperature), fol-
functions as both ligand and substrate in this process, an
added ligand is not required. We propose that subsequent
reduction of 14 to the required CuI species 15, likely accom-
panied by dissociation of one enaminone ligand, is followed
À
by oxidative addition of the aryl iodine bond of 15 to the
lowed by the addition of Cu
N
metal center to form the CuIII intermediate 16, and finally
reductive elimination to afford the indole product
(Scheme 4). The latter two steps are based on those indicat-
for 45–60 min, affording the products in 63 and 60%, yield,
respectively.
Further investigations of the reaction in entry 8 revealed
that the CuII species 14, containing two enaminone ligands,
was formed in the initial stages of the reaction. It was isolat-
ed in high yield when the reaction was performed at room
temperature and its structure was determined unequivocally
by X-ray crystallography (Figure 1). Since the enaminone
Scheme 4. CuACTHUNRGTNEUNG(OAc)2-mediated enaminone cyclization.
ed by Evindar and Batey[7a] in their CuI-catalyzed intramo-
lecular O-arylation of o-haloanilides, and by Cacchi et al.[14]
in their enaminone cyclizations. The initial reduction of CuII
to CuI is very likely effected by the solvent DMF.[15] This is
supported by the observation that CuACTHNUTRGENUN(G OAc)2 failed to cata-
lyze the cyclization in other polar solvents such as water or
HMPA, while CuI afforded the same indole products in
neat HMPA or DMF, in comparable and poorer yields, re-
spectively. The intermediates 3, 6, 9 and 11, derived from
acetylenic sulfones and ynoates, undergo deformylation in
situ prior to cyclization under the higher temperatures
(1258C) of the latter step. The mechanisms of the cycliza-
tions of the ynoates are likely similar to those of the ynones
Figure 1. ORTEP diagrams (50% probability) of the two conformations
of 14 (see Supporting Information for details).[16]
Chem. Eur. J. 2010, 16, 14281 – 14284
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T. G. Back et al.
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shown in Scheme 4, while those of the acetylenic sulfones
require further study and may follow different pathways.
In conclusion, we have demonstrated that the conjugate
addition products of o-haloanilines to acetylenic sulfones,
ynoates or ynones can be effectively cyclized to afford vari-
ously substituted indoles by means of a novel ligand-free
CuACHTUNGTRENNUNG(OAc)2-mediated intramolecular arylation step. The un-
expected formation of 14 in the initial stages of the reaction
in the ynone series indicates that the corresponding enami-
none serves as both the ligand and the substrate in the cata-
lytic cycle, and that formation of the complex precedes the
reduction of CuII to a catalytically active CuI species.
Acknowledgements
We thank the Natural Sciences and Engineering Research Council of
Canada for financial support. D.G. thanks the University of Calgary for a
Queen Elizabeth II scholarship.
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Keywords: acetylenes · copper · cyclization · indoles
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A Biosynthetic Ap-
Received: September 12, 2010
Published online: December 8, 2010
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Chem. Eur. J. 2010, 16, 14281 – 14284