Formation of N-alkoxyindole framework: Intramolecular heterocyclization of 3-alkoxyimino-2-arylalkylnitriles mediated by ferric chloride

Article abstract of DOI:10.1021/jo7024477

(Chemical Equation Presented) A variety of functionalized N-alkoxyindole-3-carbonitrile derivatives are achieved under remarkably mild conditions by applying a FeCl₃-mediated intramolecular heterocyclization of 3-alkoxyimino-2-arylalkylnitriles. This novel synthesis allows the N-moiety on the side chain to be annulated to the benzene ring as the final synthetic step, which enables the functionalization of the benzenoid portion of the indole at an early stage of the synthesis.

Full text of DOI:10.1021/jo7024477

replacing the indole N-H with an N-methoxy moiety.2 While
the potential importance of the N-alkoxyindole skeleton is
evident, a survey of the literature indicated that the methods
developed for the synthesis of the N-alkoxyindole nucleus can
be generalized into the following types: (1) methylation of
N-hydroxyindoles with dimethyl sulfate or diazomethane (path
a in Figure 1);1c,3 (2) dehydration of 2-hydroxyindoline deriva-
tives catalyzed by aqueous HCl (path b in Figure 1);4 (3)
cyclization of the requisite o-nitro functionalized substrate
mediated by NaCl/DMSO at high temperature (path c in Figure
1);5 (4) alkylative cycloaddition of nitrosoarenes with alkynes
in the presence of K2CO3/Me2SO4 (path d in Figure 1);6 and
(5) intramolecular cyclization of an a-aryl ketone oxime
derivative via a nitrenium ion intermediate (path e in Figure
1).7
Formation of N-Alkoxyindole Framework:
Intramolecular Heterocyclization of
3-Alkoxyimino-2-arylalkylnitriles Mediated by
Ferric Chloride
Yunfei Du,† Junbiao Chang,*,†,‡ John Reiner,† and
Kang Zhao*,†
The School of Pharmaceutical Science and Technology,
Tianjin UniVersity, Tianjin 300072, China, and Department of
Chemistry, Zhengzhou UniVersity, Zhengzhou 450001, China
combinology@yahoo.com
An intramolecular cyclization strategy in which a pendant
nitrogen moiety is annulated to a benzene ring provides a unique
access to multiply substituted indoles since such a method would
avoid using the use of “privileged” N-functionalized arenes as
starting materials and the introduction of the nitrogen atom could
be postponed to a later synthetic step.8 Herein, we report such
an intramolecular cyclization method for the construction of
N-alkoxyindoles by direct C-H amination of an aromatic ring
with a side chain N-moiety thus enabling access to an assortment
of benzo-functionalized indoles.
ReceiVed NoVember 15, 2007
In a previous study,8g we reported a PIFA-mediate oxidative
cyclization for the conversion of compound 2′ to compound 3′.
Since this cyclization protocol easily produced indoles with
either an N-alkyl or N-aryl group, we were interested in
extending the reaction to access natural products with the
N-alkoxyindole skeleton. The oxime ether substrate 2, prepared
from â-ketonitriles 1, under identical cyclization conditions
could also produce the desired N-alkoxyindole 3;9 however, the
yield (9-35%) was fairly unsatisfactory (entries 1-6, Table
A variety of functionalized N-alkoxyindole-3-carbonitrile
derivatives are achieved under remarkably mild conditions
by applying a FeCl3-mediated intramolecular heterocycliza-
tion of 3-alkoxyimino-2-arylalkylnitriles. This novel synthesis
allows the N-moiety on the side chain to be annulated to the
benzene ring as the final synthetic step, which enables the
functionalization of the benzenoid portion of the indole at
an early stage of the synthesis.
(2) (a) Neave, A. S.; Sarup, S. M.; Seidelin, M.; Duss, F.; Vang, O.
Toxicol. Sci. 2005, 83, 126. (b) Stephensen, P. U.; Bonnesen, C.; Schaldach,
C.; Andersen, O.; Bjeldanes, L. F.; Vang, O. Nutr. Cancer 2000, 36, 112.
(c) Tsotinis, A.; Eleutheriades, A.; Hough, K.; Sugden, D. Chem. Commun.
2003, 382.
(3) (a) Dean, F. M.; Patampongse, C.; Podimuang, V. J. Chem. Soc.,
Perkin Trans. 1 1974, 583. (b) Masanori, S.; Kensuke, K.; Keiko, T.;
Toshihiko, M.; Yumiko, K.; Yoshikazu, F. Heterocycles 1995, 40, 119.
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M.; Yamada, K.; Teranishi, S.; Sato, H.; Kaneko, C. Chem. Pharm. Bull.
2001, 49, 87. (b) Somei, M.; Sato, H.; Kaneko, C. Heterocycles 1983, 20,
1797.
(5) (a) Selvakumar, N.; Reddy, Y.; Azhagan, A. M.; Khera, M. K.; Babu,
J. M.; Iqbal, J. Tetrahedron Lett. 2003, 44, 7065. (b) Selvakumar, N.; Khera,
M. K.; Reddy, Y.; Srinivas, D.; Azhagan, M.; Iqbal, J. Tetrahedron Lett.
2003, 44, 7071. (c) Selvakumar, N.; Rajulu, G. G. J. Org. Chem. 2004, 69,
4429.
(6) Penoni, A.; Palmisano, G.; Broggini, G.; Kadowaki, A.; Nicholas,
K. M. J. Org. Chem. 2006, 71, 823.
The N-alkoxyinodoles have attracted considerable attention
since a number of alkaloids possessing the N-methoxyindole
skeleton have been isolated and reported in the literature.1
Furthermore, the biological activity of some indole-based
pharmaceutical agents can be considerably improved after
† Tianjin University.
‡ Zhengzhou University.
(1) (a) Konda, Y.; Onda, M.; Hirano, A.; Omura, S. Chem. Pharm. Bull.
1980, 28, 2987. (b) Ito, C.; Wu, T.-S.; Furukawa, H. Chem. Pharm. Bull.
1988, 36, 2377. (c) Kawasaki, T.; Kodama, A.; Nishida, T.; Shimizu, K.;
Somei, M. Heterocycles 1991, 32, 221. (d) Somei, M. Heterocycles 1999,
50, 1157. (e) Soledade, M.; Pedras, C.; Sorenson, J. L. Phytochemistry 1998,
49, 1959. (f) Selvakumar, N.; Khera, M. K.; Reddy, B. Y.; Srinivas, D.;
Azhagan, A. M.; Iqbal, J. Tetrahedron Lett. 2003, 44, 7071. (g) Boger, D.
L.; Keim, H.; Oberhauser, B.; Schreiner, E. P.; Foster, C. A. J. Am. Chem.
Soc. 1999, 121, 6197. (h) Somei, M. AdV. Heterocycl. Chem. 2002, 82,
101. (i) Kinoshita, T.; Tatara, S.; Ho, F.-C.; Sankawa, U. Phytochemistry
1989, 28, 147. (j) Ohmoto, T.; Koike, K. Chem. Pharm. Bull. 1983, 31,
3198. (k) Sung, Y.-I.; Koike, K.; Nikaido, T.; Ohmoto, T.; Sankawa, U.
Chem. Pharm. Bull. 1984, 32, 1872. (l) Kinoshita, T.; Tatara, S.; Sankawa,
U. Chem. Pharm. Bull. 1985, 33, 1770. (m) Agerbirk, N.; Petersen, B. L.;
Olsen, C. E.; Halkier, B. A.; Nielsen, J. K. J. Agric. Food Chem. 2001, 49,
1502. (n) Kutschy, P.; Dzurilla, M.; Takasugi, M.; To¨ro¨k, M.; Achbergerova´,
H. R.; Ra´ria, M. Tetrahedron 1998, 54, 3549. (o) Acheson, R. M. In
AdVances in Heterocyclic Chemistry; Katritzky, A. R., Ed.; Academic
Press: San Diego, CA, 1990; Vol. 51, pp 105-175.
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Chem., Int. Ed. 2000, 39, 2501. (c) Foucaud, A.; Razorilalan-Rabearivony,
C.; Loukakou, E.; Person, H. J. Org. Chem. 1983, 48, 3639. (d) Tercel,
M.; Gieseg, M. A.; Denny, W. A.; Wilson, W. R. J. Org. Chem. 1999, 64,
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Brown, J. A. Tetrahedron Lett. 2000, 41, 1623. (g) Du, Y.; Liu, R.; Linn,
G.; Zhao, K. Org. Lett. 2006, 8, 5919.
(9) For our previous work describing this, see: Zhao, K.; Chang, J.; Guo,
H.; Du, Y. Faming Zhuanli Shenqing Gongkai Shuomingshu, CN 1 629
140, 22 Jun 2005; Chem. Abstr. 2006, 144, 128851.
10.1021/jo7024477 CCC: $40.75 © 2008 American Chemical Society
Published on Web 02/13/2008
J. Org. Chem. 2008, 73, 2007-2010
2007

TABLE 1. Conditions Screened for the Intramolecular Cyclization
Reaction of 3-Alkoxyimino-2-arylalkylnitriles 2
temp time yield
entrya
oxidant (equiv)
PIFA (1.3)
PIFA (1.3)
PIFA (1.3)
PIFA (1.3)
PIFA (1.3)
PIFA (1.3)
I2 (5)
2
solvent
(°C)
(h)
(%)b
1
2
3
4
5
6
7
8
9
2a CH2Cl2 rt
24
24
24
24
24
12
6
10c
15c
13c
9c
2c
2f
CH2Cl2 rt
CH2Cl2 rt
2o CH2Cl2 rt
2t CH2Cl2 rt
2a toluene 105
2a CH2Cl2 rt
2a CH2Cl2 rt
2a CH2Cl2 rt
FIGURE 1. Existing strategies for construction of the N-methoxyindole
skeleton.
35c
12c
0
MnO2 (3)
DDQ (3)
6
6
0
0
10
11
12
13
14
15
16
17
18
19
20
CAN (3)
Cu(Oac)2‚H2O (4)
Mn(OAc)3‚2H2O (3) 2a AcOH
2a MeOH
2a AcOH
rt
110
110
6
6
6
6
3
2
<1
12
12
12
12
0
0
0
0
FeCl3‚6H2O (3)
FeCl3 (1.5)
FeCl3 (2.0)
FeCl3 (2.2)
FeCl3 (2.2)
FeCl3 (2.2)
FeCl3 (2.2)
FeCl3 (2.2)
2a CH2Cl2 rt
2a CH2Cl2 rt
2a CH2Cl2 rt
2a CH2Cl2 rt
2a MeOH
2a EtOAc
2a MeCN
2a THF
50d
77
82
0
rt
rt
rt
rt
trace
trace
trace
a All reactions were run in commercial grade solvents without inert
atmosphere protection. b Isolated yields after silica gel chromatography.
c Contains several unidentified byproducts. d 20% of 2a recovered.
FIGURE 2. Synthesis of N-substituted indoles by joining the pendent
N-moiety to the benzene ring.
1), although substrate 2 in each case was totally consumed.10
A subtle change in the electronic configuration of the oxime
ether 2 as compared to the enamine 2′ is apparently the cause
for the observed difference in reactivity. Thus new oxidative
cyclization conditions were investigated (entries 7-14, Table
1) which led to the discovery that the single electron oxidant
FeCl3 could conveniently convert 2a into 3a. A study to optimize
reaction parameters by using 2a as substrate (entries 15-20,
Table 1) indicated that CH2Cl2 was a desirable solvent for the
reaction, and at least 2 equiv of FeCl3 was needed for the
complete consumption of 2a. As the reaction proceeded, the
formation of gaseous HCl was observed. Furthermore, it was
found that the isomeric oximes, cis isomer 2b-1 and trans isomer
2b-2, afforded the same cyclized product 3b in yields of 79%
and 82%, respectively. For all subsequent studies, a mixture of
the two oxime isomers11 was used directly without separation.
The results listed in Table 2 demonstrated that both electron-
withdrawing and electron-donating aromatic substituents could
be tolerated. Entries 9 and 10 (Table 2) showed that when R3
was a bulkier n-butyl or benzyl group, the reaction was not
significantly altered. However, when R2 was a bulkier phenyl
or benzyl group (entries 2 and 12-15, Table 2), the reaction
time was obviously longer and the yields were reduced (56-
64%). When R2 was hydrogen (entry 11, Table 2), the
2-unsubstituted N-alkoxyindole 3j was obtained in acceptable
yield. The reaction was also compatible with multiple substit-
uents on the benzene ring (entries 17 and 21, Table 2).
Meta-Substituted aromatic reactants have the possibility of
producing two regioisomeric products. With the m-chloro- or
m-trifluoromethylbenzenes (entries 18 and 19, Table 2), similar
quantities of the regioisomeric indoles were observed; however,
for the substrates 2s, 2t, and 2v, the single regioisomeric
products 3s, 3t, and 3v were found, respectively.
An important extension of this heterocyclization methodology
is to use alternative types of aromatic rings to generate different
classes of pyrrole-fused heterocycles such as the hitherto
unknown 3u-w from the substrates 2u-w. It is noteworthy
that in the 13C NMR spectra, the N-methoxy group signal in 3r
is split into a quartet, apparently the result of through space
coupling12 with the fluorines of the trifluoromethyl group at
the 7 position, while this coupling is not observed in 3r′.
In our investigation of the scope and generality of this
heterocyclization method, we found that seemingly closely
related substrates (4-8 in Figure 3), when applied to the same
reaction conditions, yielded none of the expected cyclized
product, which indicates that a benzylic cyano group plays a
crucial role in the course of the reaction. Interestingly, the result
that substrates 7 and 8 were unable to cyclize could be predicted
by the fact that only a single desired product 3m was obtained
for substrate 2m (entry 14, Table 1), which implies that
formation of an intermediate with a double bond conjugated
with the benzene ring that will be cyclized by the pendent
(10) In all cases, no successful results were achieved by varying
experimental parameters: (a) use of various solvents, (b) adding TFA or
BF3‚Et2O as catalyst, and (c) carrying out the reactions at temperatures
ranging between -78 and 150 °C.
(11) For the assignment of the cis and trans geometries, see: (a) Miyata,
O.; Nishiguchi, A.; Ninomiya, I.; Aoe, K.; Okamura, K.; Naito, T. J. Org.
Chem. 2000, 65, 6922. (b) Johnson, J. E.; Springfield, J. R.; Hwang, J. S.;
Hayes, L. J.; Cuningham, W. C.; McClaugherty, D. L. J. Org. Chem. 1971,
36, 284. (c) Johnson, J. E.; Ghafouripour, A.; Haug, Y. K.; Cordes, A. W.;
Pennington, W. T. J. Org. Chem. 1985, 50, 993. (d) Johnson, J. E.; Nalley,
E. A.; Kunz, Y. K.; Springfield, J. R. J. Org. Chem. 1976, 41, 252.
(12) For the evidence of C-F space-coupling, see: (a) Jaime-Figueroa,
S.; Kurz, L. J.; Liu, Y.; Cruz, R. Spectrochim. Acta, Part A 2000, 56, 1167.
(b) Gribble, G. W.; Olson, E. R. J. Org. Chem. 1993, 58, 1631.
2008 J. Org. Chem., Vol. 73, No. 5, 2008

c
TABLE 2. Synthesis of N-Alkoxyindoles 3 via Intramolecular Heterocyclization of 3-Alkoxyimino-2-arylalkylnitriles 2 Mediated by FeCl3
a Isolated yields after silica gel chromatography. b The structure of 3f was further confirmed by X-ray crystal analysis. See the Supporting Information
for details. c Conditions: all reactions were carried out with 1 equiv of 2, 2.2 equiv of ferric chloride in CH2Cl2 at rt.
any detectable cyclized product under the same reaction
conditions. A possible explanation for this might be that in the
presence of an ester group, FeCl3 would act as a Lewis acid,
rather than a single electron oxidant. However, this method still
has a significant implication for the synthesis of a large number
of N-alkoxyindole derivatives since the cyano group is a versatile
FIGURE 3. Other models that failed to cyclize via FeCl3.
functionality.
Potential mechanistic sequences are proposed in Scheme 1.
(1) The coordination of FeCl3 with the cyano group, followed
by an abstraction of the benzylic proton from 9 and the
N-moiety is required. Besides, it was very surprising to find
that the most similar substrate 5, differing from substrate 2t by
replacement of the nitrile with an ester, also failed to provide
J. Org. Chem, Vol. 73, No. 5, 2008 2009

SCHEME 1. Proposed Mechanistic Pathways
SCHEME 2. An Oxidative Coupling Reaction of 2a
Mediated by K3Fe(CN)6
found that substrate 2a, after treatment with K3Fe(CN)6,
conveniently furnished the homodimer 19 in high yield without
any formation of 3a (Scheme 2). This result suggests that the
radical species initially generated with FeCl3 must be rapidly
converted to the nitrenium ion 14 while K3Fe(CN)6, being a
less potent oxidant (compared with FeCl3), could not fulfill the
transformation of 13 into 14 and gave the intermediate radical
12 long enough lifetime for dimerization to occur.
In summary, we have discovered a conceptually different
route for the preparation of the N-alkoxyindole skeleton.
Compared with existing methods, the key features of this new
method include a tolerance to various functional groups, ready
availability of the starting materials, and remarkably mild
reaction conditions. Complementary to the recently described
cyclodehydration of a-aryl ketone oximes to indoles,8f this
method generates the indole from its alkyl oxime ether 2 but
without cleavage of the N-O bond. The widespread occurrence
of N-alkoxyindole derivatives in natural products and pharma-
ceuticals might render this method broadly useful.
subsequent removal of FeCl2 from 10 would give the stable
nitrogen-based radical 11, with resonance structures carbon
based radical 12 and the N-radical 13. (2) Mediated by ferric
chloride, a second SET (single electron transfer) process would
occur to convert N-radical 13 to the nitrenium ion 14. (3) The
electrophilic attack on the nitrenium ion by the benzene ring13
with the subsequent loss of a proton would afford 3 (path a,
Scheme 1). Alternatively, from the resonance structure 16, the
nitrogen lone pair could nucleophilicly attack the ring carboca-
tion to give 18. Finally, rearomatizaiton of 18 by loss of a proton
would give the titled compounds 3 (path b, Scheme 1). The
above proposed mechanism accounts well for the experimental
facts such as the formation of gaseous HCl and the need for 2
equiv of FeCl3 for a complete reaction.
Experimental Section
General Procedure for the Synthesis of N-Alkoxyindole-3-
carbonitriles 3. To a solution of 3-alkoxyimino-2-aryalkylnitrles
2 (4 mmol) in CH2Cl2 (30 mL) was added in one portion the FeCl3
(10 mmol) powder with stirring at room temperature. TLC was
used to monitor the reaction process until the total consumption of
2. To the solution was then added H2O (20 mL), and stirring was
continued for an additional 5 min. The reaction mixture was
extracted with CH2Cl2 (3 × 20 mL) and the organic layer was dried
with anhydrous Na2SO4. The solvent was removed under vacuum
and the residue was purified by silica gel chromatography, using a
mixture of petroleum ether and EtOAc as eluent, to give the pure
products 3; the reaction time and yields are reported in Table 2.
(See the Supporting Information for details.)
Although no intermolecular coupled products of carbon-based
radical 12 were detected in any of the reactions with FeCl3, we
(13) For selective nitrenium ion’s such intramolecular cyclization reac-
tions, see: (a) Kikugawa, Y.; Kawase, M. J. Am. Chem. Soc. 1984, 106,
5728. (b) Glover, S. A.; Goosen, A.; McCleland, C. W.; Schoonraad, J. L.
J. Chem. Soc., Perkin Trans. 1 1984, 2255. (c) Kawase, M.; Kitamura, T.;
Kikugawa, Y. J. Org. Chem. 1989, 54, 3394. (d) Kikugawa, Y.; Nagashima,
A.; Sakamoto, T.; Miyazawa, E.; Shiiya, M. J. Org. Chem. 2003, 68, 6739.
(e) Glover, S. A.; Goosen, A.; McCleland, C. W.; Schoonraad, J. L.
Tetrahedron 1987, 43, 2577. (f) Wardrop, D. J.; Basak, A. Org. Lett. 2001,
3, 1053. (g) Correa, A.; Herrero, M. T.; Tellitu, I.; Dom´ınguez, E.; Moreno,
I.; SanMart´ın, R. Tetrahedron 2003, 59, 7103. (h) Correa, A.; Tellitu, I.;
Dom´ınguez, E.; Moreno, I.; SanMart´ın, R. J. Org. Chem. 2005, 70, 2256.
(i) Correa, A.; Tellitu, I.; Dom´ınguez, E.; Moreno, I.; SanMart´ın, R. J. Org.
Chem. 2006, 71, 3501. (j) Correa, A.; Tellitu, I.; Dom´ınguez, E.; Moreno,
I.; SanMart´ın R. Org. Lett. 2006, 8, 4811 and references cited therein.
Acknowledgment. We thank the Tianjin Municipal Science
and Technology Commission (043186011) and the Basic
Research Project (No. 2003AA223151) of the MOST for
financial support. J.C. thanks the National Natural Science
Foundation of China (No. 20672030).
Supporting Information Available: Detailed experimental
procedures and spectral data for all new compounds and X-ray
structural data for 3f (CIF). This material is available free of charge
via the Internet at http://pubs.acs.org.
JO7024477
2010 J. Org. Chem., Vol. 73, No. 5, 2008