I2-catalyzed indole formation via oxidative cyclization of N-aryl enamines

Article abstract of DOI:10.1002/asia.201100045

Cat.'s Is: An I₂-catalyzed synthesis of indoles, taking advantage of intramolecular dehydrogenative coupling reactions of enamines, afforded a variety of multifunctionalized indole derivatives in good to excellent yields under transition-metal-

Full text of DOI:10.1002/asia.201100045

COMMUNICATION
DOI: 10.1002/asia.201100045
I2-Catalyzed Indole Formation via Oxidative Cyclization of N-Aryl Enamines
Zhiheng He, Weiping Liu, and Zhiping Li*[a]
The indole moiety exists in a wide variety of natural prod-
ucts and pharmaceuticals. Its importance has stimulated con-
siderable interest in developing reactions for their synthe-
sis.[1] Until now, the Fischer indole synthesis is still one of
the most-powerful synthetic methods to construct the indole
skeleton.[2] However, its drawbacks are also apparent in
view of todayꢀs drive towards sustainable chemistry. Conse-
quently, chemists are endeavoring to develop new reactions
for synthesizing indoles by applying environmentally benign
oxidative-coupling strategies, which has been documented in
the literatures.[3] For examples, Glorius and co-workers have
reported an efficient oxidative synthesis of indoles from N-
above-mentioned transition-metal-catalyzed synthesis of in-
doles can be modified to its metal-free variant. Recently,
Zhao and co-workers have reported an oxidative synthesis
of indoles from enamines, in which hyperiodides instead of
transition metals were used.[9] Even though this process is
metal-free, stoichiometric quantities of expensive iodoben-
zene diacetate was consumed. We hypothesized that
iodine,[10] which is cheap and less toxic, could also function
as the catalyst for this oxidative indole synthesis and we un-
dertook an investigation of this possibility in order to devel-
op a better way to indole synthesis. Herein, we report a
novel and efficient iodine-catalyzed indole synthesis.
aryl enamines using Pd
N
(Z)-Ethyl 3-phenyl-3-(phenylamino)acrylate (1a) was
used as a model substrate for optimization of the reaction
conditions (Table 1). The desired product, ethyl 2-phenyl-
indole-3-carboxylate (2a), was obtained in 6% yield in the
workers disclosed a practical indole synthesis using the pal-
ladium-catalyzed reactions of simple anilines and alkynes
using dioxygen as the oxidant.[5] Preliminary mechanistic
studies showed that the reaction was comprised of two se-
quential steps: the addition of aniline to alkyne and the in-
tramolecular oxidative coupling of the thus-formed N-aryl
enamine. Very recently, Cacchi and co-workers have devel-
oped an efficient copper-catalyzed multisubstituted indole
synthesis from N-aryl enaminoes.[6] Moreover, the intramo-
lecular oxidative-coupling method was also applied to con-
struct the oxindole skeleton using stoichoimetric amounts of
copper salts.[7]
Even though the power of transition metal catalysis has
been well-demonstrated in synthesis, we believe that, if a re-
action catalyzed by transition metals can be replaced by a
metal-free analogue with the same efficiency, the non-metal-
catalyzed reaction will have greater advantage in synthesis.
With this in mind, we wanted to investigate whether some
transition-metal-catalyzed reactions can be adapted to their
metal-free versions. As such, we decided to whether the
Table 1. Optimization of the reaction conditions.[a]
Entry
Catalyst (mol%)
Oxidant
–
Yield [%][b]
1
2
3
4
5
6
I2 (5)
I2 (5)
I2 (5)
I2 (5)
I2 (5)
6
5
[c]
O2
H2O2
[d]
trace
n.d.[e]
n.d.[e]
87
NaNO2
CAN
NIS
I2 (5)
7
8
9
10
11
12
13
14
15[g]
I2 (5)
NBS
NBS
NBS
NBS
NBS
NBS
NBS
96
92
94
88
85
trace
7
IBr (10)
NaI (10)
KI (10)
CuI (10)
FeI2 (5)
–
[f]
–
PhI
G
6
[a] Z. He, W. Liu, Prof. Dr. Z. Li
Department of Chemistry
Renmin University of China
Beijing, 100872 (China)
I2 (5)
n.d.[e]
[a] Conditions: 1a (0.5 mmol), oxidant (0.55 mmol), K2CO3 (0.6 mmol),
and DMF (1.0 mL) under nitrogen; unless otherwise noted. [b] Detected
by 1H HMR using mesitylene as an internal standard. [c] Oxygen balloon.
Fax : (+86)10-6251-6444
E-mail: zhipingli@ruc.edu.cn
[d] 30% aqueous. [e] n.d.=Not detected by TLC. [f] PhIACHTUNGTRENNUNG(OAc)2
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201100045.
(0.65 mmol). [g] TEMPO (0.55 mmol) was added. DMF=N,N-dimethyl-
formamide.
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Chem. Asian J. 2011, 6, 1340 – 1343

presence of 5 mol% I2 using K2CO3 as the base and N,N-di-
methylformamide (DMF) as the solvent (Table 1, entry 1).
The outcome was similar when the reaction was carried out
under an oxygen atmosphere (Table 1, entry 2). H2O2,
NaNO2, and ceric ammonium nitrate (CAN), which were
used to oxidize iodide into iodine,[11] showed no effect on
the reaction (Table 1, entries 3–5). Product 2a was formed
in 87% yield when N-iodosuccinimide (NIS) was applied
(Table 1, entry 6). To our delight, a 96% yield of 2a was ob-
tained when N-bromosuccinimide (NBS) was used as the ox-
idant (Table 1, entry 7). Comparable yields were obtained
when using IBr or NaI as the catalyst (Table 1, entries 8 and
9). KI and CuI afforded slight low yields of 2a (Table 1, en-
tries 10 and 11). Only a trace amount of 2a was observed
when FeI2 was used as the catalyst (Table 1, entry 12). It
should be noted that only 7% of the desired indole 2a was
obtained when NBS was used in the absence of I2 (Table 1,
entry 13). Instead, the adduct product 3 was obtained as one
mayor byproduct [Eq. (1)]. This result indicated that the
combination of I2 and NBS is crucial for the success of this
transformation. 2a was isolated in 6% yield when
Scheme 1. The reaction of N-methyl enaminone 4.
thereby affording bromide products 5 and 6. Neither 2-iodo-
dihydroindole 7 nor N-methyl indole 8, which were expected
to be generated from a three-membered iodonium inter-
mediate A, were observed. Moreover, when 4 was treated
with 1.1 equivalents of I2 in the absence of NBS, a 1:1 ratio
of isomers 9 was formed in 56% yield [Eq. (2)]. These re-
sults suggested that 1) an iodocyclization pathway is unlikely
À
to be involved in these reactions, and 2) N H bonding is es-
sential for indole formation.
phenyliodine(III) diacetate (PIDA) was applied as an oxi-
G
dant (Table 1, entry 14).
Recently, we reported an efficient I2-mediated 3H-indole
synthesis [Eq. (3)].[13] In this case, a sequence of an oxidative
iodination and an intramolecular Friedel–Crafts aromatic al-
kylation reaction was proposed for the formation of 3H-
indole 11. On the contrary, a substantially lower conversion
of enamine 10 was obtained under the present catalytic re-
action conditions [Eq. (4)]. This result indicated that the re-
action pathways might be different between the catalytic re-
action and the stoichiometric reaction. Furthermore, this hy-
pothesis is consistent with the fact that I2 or NaI is in situ
oxidized into I+ or other hypervalent iodide species by
NBS. This species can be detected by adding a few drops of
a starch solution, in which a characteristic blue color was
not observed.[14]
It is worth noticing that the isolated yield of 2a improved
slightly (17%) when 1,2-dichloroethane was used as the sol-
vent in the presence of PIDA at 608C for 4 hours.[9] When
TEMPO, a free radical scavenger, was added, 2a was not
observed under the optimized reaction conditions (Table 1,
entry 15). Therefore, a radical pathway might involve in the
present transformation.
With the optimal parameters established, we turned our
attention to investigate the scope of this oxidative coupling
reaction (Table 2). A variety of N-aryl enamines 1 were
readily synthesized from the reactions between anilines and
ketones.[12] Both electron-donating and electron-withdrawing
groups at the para position of N-phenyl enamines 1 were
transformed into their corresponding products in excellent
yields (2a–2 f). The yields declined when the group at the
ortho position, which might be caused by steric hindrance
(2g and 2h). meta-Substituted enamines afforded two re-
gioisomers with excellent combined yields under the stan-
dard reaction conditions (2i+2i’ and 2j+2j’). N-phenyl en-
aminone 1k affored the corresponding indole 2k in 90%
yield, which was a higher efficiency than the copper-cata-
lyzed reaction.[6] However, amide- and iso-propyl-substituted
enamines proceeded sluggishly and some uncharacterized
byproducts were observed (2l and 2m).
A tentative mechanism is proposed to rationalize the
present I2-catalyzed transform based on our results
N-Methyl enaminone 4 was synthesized and subjected to
the reaction under the standard conditions (Scheme 1),
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www.chemasianj.org
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Z. Li et al.
COMMUNICATION
Table 2. Substrate scope.[a]
nished the indole compound.[15] Meanwhile, the
generated atomic iodine or molecular iodine is oxi-
dized by NBS to regenerate the hyperiodide for cat-
alysis.
In summary, we demonstrated a novel I2-cata-
lyzed methodology for the synthesis of indole skele-
ton. A variety of indole derivatives were obtained
in good to excellent yields through an intramolecu-
lar oxidative cyclization of enamines.[16] The appli-
cation of I2 instead of transition-metal catalysts
makes the methodology attractive in organic syn-
thesis.
Entry
1
Product
Yield Entry Product
[%][b]
Yield
[%][b]
2a
2b
2c
2d
2e
2 f
2g
2h
93
95
87
87
92
90
78
54
9
2i
2i’
2j
91 (1:1)
2
3
4
5
6
7
8
10
11
12
13
14
15
Experimental Section
Typical Procedure for the Synthesis of 2
92 (1:2.5)
N,N-Dimethylformamide (DMF, 1.0 mL) was added to a mix-
ture of N-aryl enaminecarboxylate
(0.025 mmol, 5 mol%), N-bromosuccinimide
1
(0.5 mmol), iodine
(NBS,
0.55 mmol), and K2CO3 (0.6 mmol) under nitrogen at room
temperature. The reaction temperature was raised to 1008C
for 1 h. The temperature of reaction was cooled to room tem-
perature. The resulting solution was quenched with 20 mL
aqueous ammonia (5%) and extracted with 3ꢂ20 mL ethylace-
tate. The extract was washed with 2ꢂ20 mL brine and dried
over MgSO4. The solvent was evaporated in vacuo and the res-
idue was purified by flash column chromatography on silica gel
with ethyl acetate/petroleum ether as an eluent to give the de-
sired product 2.
2a: 1H NMR: d=8.71 (s, 1H), 8.21 (d, J=6.8 Hz, 1H), 7.61–
7.59 (m, 2H), 7.39–7.37 (m, 3H), 7.31–7.23 (m, 3H), 4.26 (q,
J=7.2 Hz, 2H), 1.28 ppm (t, J=7.2 Hz, 3H); 13C NMR: d=
165.4, 144.5, 135.2, 132.0, 129.6, 129.1, 128.0, 127.6, 123.1,
122.1, 122.0, 111.1, 104.6, 59.7, 14.2 ppm.
2j’
2k
2l
90
42
36
2m
[a] Conditions: 1a (0.5 mmol), I2 (0.025 mmol), NBS (0.55 mmol), K2CO3 (0.6 mmol),
and DMF under nitrogen; 1008C, 1 h. [b] Yield of isolated product.
Acknowledgements
Financial support by the National Science Foundation of China
(20832002 and 21072223), the Fundamental Research Funds
for the Central Universities, and the Research Funds of
Renmin University of China (10XNL017) is acknowledged.
We thank Prof. Zhenfeng Xi and Prof. Zhi-Xiang Yu at Peking
University for their helpful discussions.
(Scheme 2). Oxidation of 1 by the hyperiodide generated in
À
situ gives N-iodo intermediate B. Homolysis of the N I
bond affords radical species C. Then radical addition to the
aryl ring, followed by oxidation and deprotonation, fur-
À
Keywords: C H functionalization · enamines · indoles ·
iodine · oxidative cyclization
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Scheme 2. A tentative mechanism.
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Chem. Asian J. 2011, 6, 1340 – 1343

I2-Catalyzed Indole Formation
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Received: January 21, 2011
Published online: April 19, 2011
Chem. Asian J. 2011, 6, 1340 – 1343
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