Synthesis of N-substituted indole derivatives via PIFA-mediated intramolecular cyclization

Article abstract of DOI:10.1021/ol062288o

(Chemical Equation Presented) A variety of N-arylated and N-alkylated indole derivatives were synthesized by way of a phenyliodine bis(trifluoroacetate) (PIFA)-mediated intramolecular cyclization. This novel method allows for the construction of an indole skeleton by joining the N-atom on the side chain to the benzene ring at the last synthetic step. Other novel pyrrole-fused aromatic compounds can also be achieved by this method.

Full text of DOI:10.1021/ol062288o

ORGANIC
LETTERS
2006
Vol. 8, No. 26
5919-5922
Synthesis of N-Substituted Indole
Derivatives via PIFA-Mediated
Intramolecular Cyclization
Yunfei Du, Renhe Liu, Gregory Linn, and Kang Zhao*
College of Pharmaceuticals and Biotechnology, Tianjin UniVersity, 300072, PRC
combinology@yahoo.com
Received September 17, 2006
ABSTRACT
A variety of N-arylated and N-alkylated indole derivatives were synthesized by way of a phenyliodine bis(trifluoroacetate) (PIFA)-mediated
intramolecular cyclization. This novel method allows for the construction of an indole skeleton by joining the N-atom on the side chain to the
benzene ring at the last synthetic step. Other novel pyrrole-fused aromatic compounds can also be achieved by this method.
The construction of a substituted indole skeleton has been a
topic of great interest for many years because the indole unit
has found ever-expanding uses in both natural products and
designed medicinal agents.1 Accordingly, there exists a large
and varied selection of methods for their synthesis.2 A survey
of the literature shows that these methods can be basically
generalized into the following categories: (1) The N-atom
of the indole nucleus is introduced by applying the N-
functionalized arene (e.g., an aryl amine or a nitroarene, etc.)
as the starting material in the early synthetic stage (a in
Figure 1).2,3 In the overall strategy, the functionalization of
the indole’s benzenoid portion greatly depends on the
diversity of the N-containing benzene derivatives. (2) The
N-moiety is connected to the benzene ring through transition-
metal-catalyzed aryl amination reactions (b in Figure 1).2,4
However, for the substrates of this class, the presence of a
halogen substituent in the ortho position of the benzene ring
is indispensable. (3) The N-moiety on the side chain is joined
to the benzene ring without a halogen substituent in the ortho
Figure 1. General strategies for the construction of the indole
skeleton.
(1) For recent references of indole-containing natural products and
designed medicinal agents, see: (a) Lounasmaa, M.; Tolvanen, N. Nat. Prod.
Rep. 2000, 17, 175-191. (b) Hibino, S.; Choshi, T. Nat. Prod. Rep. 2002,
19, 148-180. (c) Wacker, D. A.; Kasireddy, P. Tetrahedron Lett. 2002,
43, 5189-5191. (d) Smart, B. P.; Oslund, R. C.; Walsh, L. A.; Gelb, M.
H. J. Med. Chem. 2006, 49, 2858-2860.
(2) For recent reviews of indole synthesis, see: (a) Gribble, G. W. J.
Chem. Soc., Perkin Trans. 1 2000, 1045-1075. (b) Cacchi, S.; Fabrizi, G.
Chem. ReV. 2005, 105, 2873-2920.
position at the last synthetic step. To the best of our
knowledge, this least exploited strategy only includes the
synthesis of N-unsubstituted indoles via a thermolytic
rearrangement of R-arylazirines5 and the synthesis of N-
hydroxyindoles from 1-aryl-2-nitroalkene derivatives6 (c in
Figure 1).
10.1021/ol062288o CCC: $33.50
© 2006 American Chemical Society
Published on Web 11/22/2006

Table 1. Synthesis of N-Substituted Indole-3-carbonitrile Derivatives via Intramolecular Cyclization Mediated by PIFA*
* Conditions: all reactions were carried out by adding dropwise 1.3 equiv of PIFA in CH2Cl2 to a solution of 1 equiv of 1 in CH2Cl2 over 30 min, stirred
at room temperature. a Isolated yield after silica gel chromatography.
Herein, we report an entirely new and general synthetic
technology for the construction of the N-substituted indole
framework (Schemes in Tables 1 and 2), which is character-
ized by the following features: (1) The indole ring formation
allows for the N-moiety to be annulated to the benzene ring
at the last synthetic step, which enables the easy function-
alization of the benzenoid portion with a variety of substit-
uents. (2) The presence of a halogen substituent in the ortho
position is not required.
To our knowledge, phenyliodine bis(trifluoroacetate)
(PIFA), a readily available hypervalent iodine reagent with
low toxicity, has been used widely as a selective oxidizing
agent to generate a nitrenium ion intermediate, which can
undergo inter- or intramolecular reaction.7 This prompts us
(3) (a) Ragaini, F.; Rapetti, A.; Visentin, E.; Monzani, M.; Caselli, A.;
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S. I.; Dhondge, A. P.; Gaikwad, D. D.; Borhade, A. S.; Chavhan, S. W.
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R. C. J. Org. Chem. 2006, 71, 62-69.
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1030. (b) Wagaw, S.; Yang, B. H.; Buchwald, S. L. J. Am. Chem. Soc.
1999, 121, 10251-10263. (c) Willis, M. C.; Brace, G. N.; Holmes, I. P.
Angew. Chem., Int. Ed. 2005, 44, 403-406. (d) Ackermann, L. Org. Lett.
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Int. Ed. 2003, 42, 4257-4260.
(5) (a) Tercel, M.; Gieseg, M. A.; Denny, W. A.; Wilson, W. R. J. Org.
Chem. 1999, 64, 5946-5953. (b) Taber, D. F.; Tian, W. J. Am. Chem. Soc.
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(6) (a) Foucaud, A.; Razorilalana-Rabearivony, C.; Loukakou, E.; Person,
H. J. Org. Chem. 1983, 48, 3639-3644. (b) Zhang, R.; Liao, X.; Gao, Z.
Synthesis 1990, 9, 801-802.
(7) (a) Romero, A. G.; Darlington, W. H.; Jacobsen, E. J.; Mickelson, J.
W. Tetrahedron Lett. 1996, 37, 2361-2364. (b) Correa, A.; Herrero, M.
T.; Tellitu, I.; Dom´ınguez, E.; Moreno, I.; SanMartin, R. Tetrahedron 2003,
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3505.
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Org. Lett., Vol. 8, No. 26, 2006

to test whether a substrate such as 2-aryl-3-arylamino-2-alkene-
nitriles 1 (Scheme 1) could also give stable nitrenium ion 2
by reaction of ketonitriles with alkylamines in the presence
of acetic acid in ethyl alcohol. To our pleasant surprise, the
substrates of this class also smoothly afford the desired
cyclized products (Table 1, 3i-n′) within 30 min and in good
yields (70-87%). Similarly, for the substrate with a chloro
group in the meta position (Table 1, 1n), the cyclization also
furnished the 5-substituted and 7-substituted regioisomers,
in a yield of 41% and 45%, respectively (Table 1, entry 14).
Encouraged by the above results, we initiated studies
toward using other aromatic rings and found that the
compounds 3o-q shown in Table 2 were successfully
Scheme 1. Proposed Scheme for the Construction of
N-Arylated Indole Derivatives Mediated by PIFA
mediated by PIFA, followed by intramolecular cyclization
to furnish N-arylated indole-3-carbonitrile derivatives 3.
Generation of the required substrates 1 is readily achieved
in 68-81% yields by reaction of the ketonitriles with
substituted anilines in acetic acid.8 The ketonitriles are
obtained by reaction of various substituted benzyl cyanides
with carboxylic ester in a basic medium provided by NaH
in THF9 (see Supporting Information).
Table 2. Synthesis of Novel Pyrrole-Fused Heterocyclic
Compounds via Intramolecular Cyclization Meidated by PIFA*
We first utilized 2-phenyl-3-phenylamino-but-2-enenitrile
1a (Table 1, entry 1), a mixture of trans and cis isomers, to
examine the possibility of the proposed transformation.
Treating 1a with PIFA in CH2Cl2 nearly instantly furnished
the desired cyclized product 3a in 86% yield. Other solvents
such as CH3CN, THF, EtOH, and EtOAc were also studied.
The results indicated that CH3CN and EtOAc were the
desirable solvents for this reaction, whereas THF and EtOH
gave poor results. Parallel experiments using 1, 1.1, 1.3, and
1.5 equiv of PIFA showed that 1.3 equiv of PIFA was enough
for the total conversion of 1a (see Supporting Information).
Having established the optimal conditions, we then sought
to probe the scope of the reaction and found that both
electron-rich and electron-poor substrates could be success-
fully employed (Table 1, entries 2-8). All of the reactions
were very fast and completed in just 30 min, over which the
dropwise adding of PIFA in CH2Cl2 was finished. Compara-
tive experiments by adding PIFA in one pot to a solution of
the substrates in CH2Cl2 indicated that in all cases the
reaction was finished within 5 min. Good to high yields (71-
92%) were obtained for these reactions. The lower yield of
3d, shown in Table 1, is likely due to the formation of some
unidentified byproducts. It is worth noting that for the
substrate with a CF3 group in the meta position of the
benzene ring (Table 1, entry 8) the intramolecular cyclization
furnished a mixture of 5-substituted and 7-substituted re-
gioisomers, in a yield of 41% and 43%, respectively.
Contrary to our expections, the strong electron-withdrawing
group CF3 did not affect the reaction time and yield.
The scope and utility of this method is further studied by
changing arylamines into alkylamines. The required sub-
strates (Table 1, 1i-n) are readily obtained in 67-90% yields
* Conditions: see Table 1. a Isolated yield after silica gel chromatography.
achieved in 64-78% yields within 30 min by this method.
The requisite substrates 1o-q10 were prepared by a method
similar to that described above (see Supporting Information).
In light of the above results, we replaced the cyano group
with a carboxylic ester and came to investigate the reactions
of the substrates 1r,s, which were prepared by a similar
method and should possess Z-geometries due to the existence
of a hydrogen bond between the NH group and the carbonyl
group of the ester.11 To our delight, substrates 1r,s also
furnished the desired cyclized product under the same
reaction conditions, in a yield of 75% and 68%, respectively
(see Scheme 2).
All the structures of the products are determined by
detailed study of the spectroscopic data. Furthermore, product
3d is unambiguously confirmed through X-ray crystal-
lographic analysis (see Supporting Information).
We initially postulated that 1 would give stable aryl
nitrenium ion intermediate 2 in the presence of PIFA, which
would act as an electrophile to attack the benzene ring and
(8) (a) Walther, R. V. J. Prakt. Chem. 1911, 83, 171-182. (b) Heller,
K. J. Prakt. Chem. 1929, 121, 193-203. (c) Hauser, C. R.; Murray, J. G.
J. Am. Chem. Soc. 1955, 77, 2851-2852. (d) Ryabukhin, Y. J. Heterocycl.
Chem. 1999, 36, 97-104.
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T.; Grigoriadis, D. E. Bioorg. Med. Chem. Lett. 2004, 14, 3669-3673.
(10) For the preparation of the required (1-methyl-1H-indol-3-yl)-
acetonitrile, see: Snyder, H. R.; Eliel, E. L. J. Am. Chem. Soc. 1948, 70,
1703-1705.
(11) For the assignment of this Z-geometry, see: Casarrubios, L.; Pe´rez,
J. A.; Brookhart, M.; Templeton, J. L. J. Org. Chem. 1996, 61, 8358-8359.
Org. Lett., Vol. 8, No. 26, 2006
5921

Then, the N-I bond in 5 would homolytically cleave to give
radicals 6 and 7 (N-radical 6 may tautomerize to give
benzylic radical 8). Next, the intramolecular addition of an
N-radical to the benzene ring would give 9, which generates
carbocation 10 in the presence of radical 7, via a possible
SET pathway. Last, abstraction of a proton from 10 would
regenerate the aromatic system to afford 11. This proposed
mechanism is likely supported by the previous literature
which described radical cyclization reactions12 and the SET
pathway for oxidation reaction of the hypervalent iodine
reagent, respectively.13
Scheme 2. Synthesis of the N-Substituted Indole-3-carboxylic
Acid Ester via Intramolecular Cyclization Mediated by PIFA
In summary, we have demonstrated a novel synthesis of
N-arylated and N-alkylated indole derivatives which allows
for the efficient connection of the N-moiety to the function-
alized benzene ring at the last synthetic step. Furthermore,
this methodology can be extended to the construction of other
novel pyrrole-fused aromatic compounds. The features of
the present method include the availability of the starting
materials, the mild reaction conditions, and the simplicity
of the workup. The widespread use of the indole skeleton in
natural products combined with its pharmaceutical impor-
tance should render this method broadly useful. Ongoing
studies are in progress to elucidate the scope and limitation
of the method by replacing the cyano or ester group with
other substituents.
give the desired product. However, it seemed this mechanism
could not explain well the following experimental facts: (1)
The reaction related to the electron-withdrawing group on
the benzene ring did not affect the rate or yield of the final
products. (2) 2-Aryl-3-alkylamino-2-alkenenitrile derivatives
(Table 1, 1i-n), which were not likely to generate stable
nitrenium ion intermediates, could also furnish the desired
products (Table 1, 3i-n′) in good yields within a short period
of time. On the basis of these, we propose a plausible radical
cyclization pathway, shown in Scheme 3. It is assumed that
Scheme 3. Another Possible Mechanism
Acknowledgment. We acknowledge the Tianjin Munici-
pal Science and Technology Commission (043186011) and
the Basic Research Project (#2003AA223151) of the MOST
for financial support.
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.
OL062288O
(12) (a) Artis, D. R.; Cho, I. S.; Jaime-Figueroa, S.; Muchowski, J. M.
J. Org. Chem. 1994, 59, 2456-2466. (b) Martinez, E.; Newcomb, M. J.
Org. Chem. 2006, 71, 557-561.
(13) Thottumkara, A. P.; Vinod, T. K. Tetrahedron Lett. 2002, 43, 569-
572.
intermediate 5 would be formed from the reaction of the
substrates 4 and PIFA by losing one molecule of CF3COOH.
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Org. Lett., Vol. 8, No. 26, 2006