PIDA-mediated oxidative C-C bond formation: Novel synthesis of indoles from n-aryl enamines

Article abstract of DOI:10.1021/ol900576a

A variety of functionalized indoles were synthesized from N-aryl enamines via PIDA-mediated oxidative carbon-carbon bond formation. The features of the present reaction include facilitative preparation of substrates 2, good functional group tolerance, and mild reaction conditions without transition metals.

Full text of DOI:10.1021/ol900576a

ORGANIC
LETTERS
2009
Vol. 11, No. 11
2417-2420
PIDA-Mediated Oxidative C-C Bond
Formation: Novel Synthesis of Indoles
from N-Aryl Enamines
Wenquan Yu, Yunfei Du, and Kang Zhao*
Tianjin Key Laboratory for Modern Drug DeliVery & High-Efficiency, School of
Pharmaceutical Science and Technology, Tianjin UniVersity, Tianjin 300072, China
combinology@yahoo.com
Received March 18, 2009
ABSTRACT
A variety of functionalized indoles were synthesized from N-aryl enamines via PIDA-mediated oxidative carbon-carbon bond formation. The
features of the present reaction include facilitative preparation of substrates 2, good functional group tolerance, and mild reaction conditions
without transition metals.
Carbon-carbon bond construction1 is the essence of organic
synthesis and the foundation for the formation of complicated
structures. In recent decades, there has been great progress
on C-C bond formation because of the development of
transition metal-catalyzed processes, such as the Suzuki,2a-c
Stille,2d,e Heck,2f and olefin metathesis reactions,2g-i which
have been widely used in the synthesis of natural products
and pharmacologically active compounds. However, there
are still some problems with these metal-catalyzed reactions,
such as carefully controlled reaction conditions (e.g., exclu-
sion of air, moisture, and impurities), cost of transition-metal
catalysts or ligands, and heavy metal residue in drug
development. Additionally, in view of the increased attention
to environmental problems, transition-metal-free methods are
preferable for the construction of C-C bonds. In this paper,
we report a new transition-metal-free synthetic technology
for direct oxidative C-C bond formation mediated by
polyvalent iodine reagents.
Owing to the facilitation of preparation and low toxicity
compared with classic transition-metal oxidants, polyva-
lent iodine reagents have been extensively used in modern
organic synthesis,3 of which iodine(III) derivatives (e.g.,
PIFA, phenyliodine(III) bis(trifluoroacetate) and PIDA,
phenyliodine(III) diacetate) have become extremely pow-
erful tools for oxidizing the nitrogen atom4,5 for new C-N
or N-N bond formation. Nevertheless, the utilization of
hypervalent iodine reagents to construct C-C bonds is
seldom reported, especially without transition metals. Based
on our successful application of PIFA in constructing the
indole framework via C-N bond formation,5 herein we
(2) (a) Kotha, S.; Lahiri, K.; Kashinath, D. Tetrahedron 2002, 58, 9633–
9695. (b) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457–2483. (c)
Suzuki, A. Pure Appl. Chem. 1991, 63, 419–422. (d) Espinet, P.; Echavarren,
A. M. Angew. Chem., Int. Ed. 2004, 43, 4704–4734. (e) Stille, J. K. Angew.
Chem., Int. Ed. 1986, 25, 508–524. (f) Beletskaya, I. P.; Cheprakov, A. V.
Chem. ReV. 2000, 100, 3009–3066. (g) Grubbs, R. H. Tetrahedron 2004,
60, 7117–7140. (h) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34,
18–29. (i) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413–4450.
(3) For recent reviews on polyvalent iodine reagents: (a) Zhdankin, V. V.;
Stang, P. J. Chem. ReV. 2008, 108, 5299–5358. (b) Stang, P. J. J. Org.
Chem. 2003, 68, 2997–3008.
(1) For recent reviews on C-C bond formation, see: (a) Beccalli, E. M.;
Broggini, G.; Martinelli, M.; Sottocornola, S. Chem. ReV. 2007, 107, 5318–
5365. (b) Fagnoni, M.; Dondi, D.; Ravelli, D.; Albini, A. Chem. ReV. 2007,
107, 2725–2756. (c) Li, C. Chem. ReV. 2005, 105, 3095–3165. (d) Dilman,
A. D.; Ioffe, S. L. Chem. ReV. 2003, 103, 733–772. (e) Fagnou, K.; Lautens,
M. Chem. ReV. 2003, 103, 169–196. (f) Ritleng, V.; Sirlin, C.; Pfeffer, M.
Chem. ReV. 2002, 102, 1731–1769. (g) Trost, B. M.; Toste, F. D.; Pinkerton,
A. B. Chem. ReV. 2001, 101, 2067–2096. (h) Sammelson, R. E.; Kurth,
M. J. Chem. ReV. 2001, 101, 137–202.
10.1021/ol900576a CCC: $40.75
Published on Web 05/06/2009
 2009 American Chemical Society

developed a novel C-C bond formation strategy for indole
synthesis via the PIDA-mediated oxidization of the N-aryl
enamine 2.
PIDA was optimal for the total conversion of 2b to 1b
and more oxidant led to a lower yield.
A variety of 3-aryl-3-arylaminoacrylonitriles 2 were
subjected to the above optimal reaction conditions (Table
1, entry 5) to probe the reaction scope and generality
(Table 2, entries 1-13). Substrates with both electron-
donating (Table 2, entries 2, 4-7, and 9-13) and electron-
withdrawing (Table 2, entries 3 and 8) substituents were
directly converted to desired indoles in 33-91% yields.
The presence of methoxy group in substrates (Table 2,
entries 4, 6, and 12) decreased the yields of corresponding
indoles, with unidentified byproduct. In the case of 3,4-
disubstituted and meta-substituted substrates (Table 2,
entries 5 and 8), two regioisomeric indole products were
formed. At the same time, a good regioselectivity was
observed during the formation of 1f (Table 2, entry 6),
which could be due to the steric hindrance caused by the
methoxy group. The steric block effect of the ortho-
substituted methyl group on the other benzene ring could
be responsible for the lower yield of 1m (Table 2, entry
13).
3-Phenyl-3-phenylaminoacrylonitrile derivatives 2 were
readily prepared as a mixture of cis and trans isomers,
via the acetic acid-catalyzed condensation6 of 3-oxo-3-
arylpropionitriles7 and corresponding anilines. Screening
of a series of solvents, including CH2Cl2, CHCl3,
ClCH2CH2Cl, MeCN, THF, EtOAc, 1,4-dioxane, EtOH,
DMF, and DMSO, showed that alkyl chlorides are desired
for the conversion of 2 to 1. Further optimization results
are summarized in Table 1. Oxidation of substrates 2a-c
Table 1. Reaction Conditions Optimization for Indole Synthesis
from 3-Phenyl-3-phenylaminoacrylonitrile Derivatives 2a
Good functional group tolerance of this methodology
also allows for the replacement of the cyano group in
substrates by other electron-withdrawing groups, such as
nitro and carboxylic ester groups (Table 2, entries 14 and
15). Substrates 2n and 2o, generated only as the Z-
isomers8 via the condensation of anilines with 2-nitro-1-
phenylethanone9 and 3-oxo-3-phenylpropionic acid methyl
ester,10 respectively, also furnished the indoles in decent
yields.
entry oxidant (equiv) T (°C) time (h) product 1 yieldb (%)
1c
2c
3c
4d
5d
6d
7d
PIFA (1.3)
PIFA (1.3)
PIFA (1.3)
PIDA (1.1)
PIDA (1.3)
PIDA (1.5)
PIDA (1.3)
-78 to rt
-78 to rt
-78 to rt
60
1a
1b
1c
1b
1b
1b
1b
40
54
55
72
84
61
76
5
2
2
2
60
60
80
In light of the encouraging results, we initiated further
studies by replacing the aromatic R group in the substrates
with an alkyl group (Table 3, entries 1-4). The required
substrates were obtained through the condensation of
3-oxo-3-alkylpropionitriles4,11 and 4-methylaniline. The
desired indoles were successfully achieved under the optimal
reaction conditions. The substrate 2t, containing benzoyl and
carboxylic ester groups (Table 3, entry 5), was also oxidized
to corresponding indole 1t, using 1.8 equiv of PIDA at
refluxing temperature. The structure of 1t was further
confirmed by X-ray crystallography (Figure 1).
a Optimal reaction conditions: 2 (1 equiv), PIDA (1.3 equiv),
ClCH2CH2Cl, 60 °C. b Isolated yields after silica gel chromatography.
c The reactions were run in CH2Cl2. d The reactions were run in
ClCH2CH2Cl.
by PIFA in CH2Cl2 afforded the desired indoles in
moderate yields at -78 °C (Table 1, entries 1-3), but
decreased yields at elevated temperature (not shown). Use
of PIDA in 1,2-dichloroethane improved the yield of 1b
greatly (84%) at 60 °C (Table 1, entry 5). The conversion
was very slow at 40 °C (not shown) and resulted in a
slightly decreased yield (76%) at 80 °C (Table 1, entry
7). Parallel experiments (Table 1, entries 4-6), using 1.1,
1.3, and 1.5 equiv of PIDA indicated that 1.3 equiv of
An intramolecular SN2′-type cyclization mechanism for
PIDA-mediated oxidation of substrate 2a to indole 1a is
shown as follows (Scheme 1): The intermediate 3a is
formed from the reaction of substrate 2a with PIDA by
losing one molecule of acetic acid. Due to the presence
of EWG at the ꢀ position, the enamine formation, which
can be confirmed by NMR, might promote the facile
production of 3a. Then the N-I bond in 3a cleaves, with
comcomitant electrocyclic ring closure and the subsequent
(4) For selected examples, for C-N bond formation: (a) Tellitu, I.; Serna,
S.; Herrero, M. T.; Moreno, I.; Domnguez, E.; SanMartin, R. J. Org. Chem.
2007, 72, 1526–1529. (b) Huang, J.; Liang, Y.; Pan, W.; Yang, Y.; Dong,
D. Org. Lett. 2007, 9, 5345–5348. (c) Fan, R.; Wen, F.; Qin, L.; Pu, D.;
Wang, B. Tetrahedron Lett. 2007, 48, 7444–7447. (d) Correa, A.; Tellitu,
I.; Domnguez, E.; SanMartin, R. J. Org. Chem. 2006, 71, 8316–8319. (e)
Aggarwal, R.; Sumran, G.; Saini, A.; Singh, S. P. Tetrahedron Lett. 2006,
47, 4969–4971. For N-N bond formation: (f) Correa, A.; Tellitu, I.;
Dom´ınguez, E.; SanMartin, R. J. Org. Chem. 2006, 71, 3501–3505. (g)
Correa, A.; Tellitu, I.; Dom´ınguez, E.; SanMartin, R. Tetrahedron 2006,
62, 11100–11105.
(8) The assignment of the Z-isomer could be due to the existence of a
hydrogen bond between NH group and the carbonyl group of the ester (or
nitro group). For the references, see ref 5. Casarrubios, L.; Pe´rez, J. A.;
Brookhart, M.; Templeton, J. L. J. Org. Chem. 1996, 61, 8358–8359.
(9) Augustine, R. L.; Gustavsen, A. J.; Wanat, S. F.; Pattison, I. C.;
Houghton, K. S.; Koletar, G. J. Org. Chem. 1973, 38, 3004–3011.
(10) EidJr., C. N.; Konopelski, J. P. Tetrahedron 1991, 47, 975–992.
(11) Chen, C.; Wilcoxen, K. M.; Huang, C. Q.; McCarthy, J. R.; Chen,
(5) Du, Y.; Liu, R.; Linn, G.; Zhao, K. Org. Lett. 2006, 8, 5919–5922.
(6) Rao, V. V. R.; Wentrup, C. J. Chem. Soc., Perkin Trans. 1 2002,
1232–1235.
(7) AI-Omran, F.; Khalik, M. M. A.; AI-Awadhi, H.; Elnagdi, M. H.
Tetrahedron 1996, 52, 11915–11928.
T.; Grigoriadis, D. E. Bioorg. Med. Chem. Lett. 2004, 14, 3669–3673
.
2418
Org. Lett., Vol. 11, No. 11, 2009

Table 2. Scope of PIDA-Mediated Indole Synthesisa
Table 3. Further Variation of Substrates 2a
a Optimal reaction conditions: 2 (1 equiv), PIDA (1.3 equiv),
ClCH2CH2Cl, 60 °C. b Isolated yields after silica gel chromatography. c The
reaction was carried out using 1.8 equiv of PIDA in ClCH2CH2Cl at
refluxing temperature.
proton elimination to afford 4a. Finally, the tautomeriza-
tion of 4a forms the indole structure 1a.
In summary, we have established an efficient, direct
oxidative and transition metal-free C-C bond formation
method to construct the indole framework. In this meth-
odology, prefunctionalization of the reaction center is not
required, which makes the preparation of substrates from
a Optimal reaction conditions: 2 (1 equiv), PIDA (1.3 equiv),
ClCH2CH2Cl, 60 °C. b Isolated yields after silica gel chromatography. c The
ratio of the regioisomers was determined by H NMR. d The reaction was
1
carried out using 1.8 equiv of PIDA in ClCH2CH2Cl at refluxing
temperature.
Figure 1. X-ray crystal structure of 1t.
Org. Lett., Vol. 11, No. 11, 2009
2419

tuted indoles to form from corresponding substrates under
mild reaction conditions. Use of PIDA without transition
metals makes the reactions friendlier to the environment.
Now our group is studying further application of this C-C
bond formation method in other heterocyclic compounds
synthesis.
Scheme 1. Intramolecular SN2′-type Cyclization Mechanism for
the PIDA-Mediated Construction of Indole 1a
Acknowledgment. We acknowledge the National Natu-
ral Science Foudation of China (No. 20802048) for
financial support. We also thank Dr. Xiaodong Xu of
Institute for Hepatitis and Virus Research for critical
reading of the manuscript and Miss Xiling Zhao, Univer-
sity of California, San Diego, for revising our English text.
Supporting Information Available: Experimental pro-
cedures and spectral data for all new compounds and X-ray
structural data (CIF). This material is available free of charge
via the Internet at http://pubs.acs.org.
available starting materials more facilitative. Good func-
tional group tolerance allows structurally diverse substi-
OL900576A
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Org. Lett., Vol. 11, No. 11, 2009