An Efficient Route to Highly Substituted Indoles via Tetrahydroindol-4(5H)-one Intermediates Produced by Ring-Opening Cyclization of Spirocyclopropanes with Amines

Article abstract of DOI:10.1002/chem.201702622

An efficient route to highly substituted indoles was developed. It included regioselective functionalization of tetrahydroindol-4(5H)-ones, prepared by ring-opening cyclization of cyclohexane-1,3-dione-2-spirocyclopropanes with primary amines, and subsequent oxidation. The 6-substituted indoles were synthesized from a readily available 5-substituted cyclohexane-1,3-dione-2-spirocyclopropane. The synthesis of 5- and 7-substituted indoles was achieved by regioselective electrophilic alkylation of tetrahydroindol-4(5H)-one, followed by oxidation. The 4-substituted indoles were synthesized by nucleophilic alkylation of the corresponding pyrrole derivative, which was prepared by partial oxidation of tetrahydroindol-4(5H)-one, and sequential oxidation. The synthesis of 4-substituted indoles was also accomplished by palladium-catalyzed coupling of 4-hydroxyindole-derived triflates. Furthermore, the synthesis of 4,5,6,7-tetrasubstituted indoles was achieved by using these regioselective alkylations.

Full text of DOI:10.1002/chem.201702622

A Journal of
Accepted Article
Title: An Efficient Route to Highly Substituted Indoles via
Tetrahydroindol-4(5H)-one Intermediates Produced by Ring-
Opening Cyclization of Spirocyclopropanes with Amines
Authors: Hisanori Nambu, Wataru Hirota, Masahiro Fukumoto,
Takafumi Tamura, and Takayuki Yakura
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Chemistry - A European Journal
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An Efficient Route to Highly Substituted Indoles via
Tetrahydroindol-4(5H)-one Intermediates Produced by Ring-
Opening Cyclization of Spirocyclopropanes with Amines
Hisanori Nambu,* Wataru Hirota, Masahiro Fukumoto, Takafumi Tamura, and Takayuki Yakura*[a]
Abstract: An efficient route to highly substituted indoles was
developed. It includes regioselective functionalization of
tetrahydroindol-4(5H)-ones, prepared by ring-opening cyclization of
cyclohexane-1,3-dione-2-spirocyclopropanes with primary amines,
and subsequent oxidation. 6-Substituted indoles were synthesized
and alkoxy-substituted in the benzene portion employing acid-
catalyzed cyclization of pyrroles possessing side chains, [8] and
demonstrated the utility of this approach through the syntheses
of various natural products (Scheme 1, eq. 3).[9] Yanagisawa
and Yoshida developed the synthetic method for highly
substituted indoles employing the ring-closing olefin metathesis
(RCM)/dehydration sequence of highly functionalized pyrrole
precursors (Scheme 1, eq. 4).[10] Recently, approach C, i.e., the
direct introduction of substituents onto the indole benzene ring
by transition-metal-catalyzed C–H functionalization was reported
from
a readily available 5-substituted cyclohexane-1,3-dione-2-
spirocyclopropane. Synthesis of 5- and 7-substituted indoles was
achieved by regioselective electrophilic alkylation of tetrahydroindol-
4(5H)-one, followed by oxidation. 4-Substituted indoles were
synthesized by nucleophilic alkylation of the corresponding pyrrole
derivative, prepared by partial oxidation of tetrahydroindol-4(5H)-one, (Scheme 1, eq. 5).[11–15] Regioselective functionalization at the
and a sequential oxidation. Synthesis of 4-substituted indoles was
also accomplished by Pd-catalyzed coupling of 4-hydroxyindole-
derived triflates. Furthermore, synthesis of 4,5,6,7-tetrasubstituted
indoles was achieved by using these regioselective alkylations.
C4 (R4)[12,13] and C7 (R ) positions was achieved by employing
3 [14]
2
1
directing groups at C3 (R ) and N1 (R ), respectively. Although
these synthetic approaches to highly substituted indoles are
useful for the synthesis of specific indoles, they still involve
some drawbacks, such as difficulties in the preparation of the
cyclization precursors and the limitation of introducible positions.
Therefore, the development of efficient and flexible methods for
the synthesis of highly substituted indoles remains challenging
and highly desirable.
Introduction
Indoles are important structural components of a wide range of
biologically-active alkaloids and pharmaceutical agents.[1]
Consequently, the development of efficient synthetic methods
for indoles continues to attract considerable attention.[2] Although
a number of effective approaches to indoles substituted on the
nitrogen-containing pyrrole ring have been reported, there are
only a few examples of regiocontrolled access to indoles bearing
multiple substituents on the benzene ring[3] because of the lower
reactivity of the benzene moiety. In general, there are three
approaches to indoles possessing substituents on the benzene
ring; (A) pyrrole ring formation from substituted aniline
derivatives, (B) benzene ring formation from pyrroles possessing
side chains, and (C) regioselective functionalization of non-
substituted indoles (Scheme 1). Representative examples of
approach A include the Larock and Kerr indole syntheses.
Larock group reported Pd-catalyzed coupling between highly
substituted o-iodoanilines and alkynes to afford highly
[
4]
substituted indole derivatives (Scheme 1, eq. 1). Kerr and co-
workers developed
a
Diels–Alder/Plieninger indolization
sequence[ and demonstrated its application to total syntheses
of natural products (Scheme 1, eq. 2).[7] As representative
examples of approach B, two synthetic methods are illustrated.
Natsume et al. reported the synthesis of indoles that were alkyl-
5,6]
[
a]
Dr. H. Nambu, W. Hirota, M. Fukumoto, T. Tamura, Prof. Dr. T.
Yakura
Graduate School of Medicine and Pharmaceutical Sciences
University of Toyama
Sugitani, Toyama 930-0194 (Japan)
Fax: (+81)76-434-5053
E-mail: nambu@pha.u-toyama.ac.jp; yakura@pha.u-toyama.ac.jp
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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Scheme 2. Synthesis of 4-hydroxyindole 4a via the ring-opening cyclization of
cyclohexane-1,3-dione-2-spirocyclopropane 1a with benzylamine.
Results and Discussion
Synthetic strategy for highly substituted indoles
Our synthetic strategy for indoles bearing multiple substituents
on the benzene ring is outlined in Scheme 3. Because 2a is
easily oxidized to 4-hydroxyindole 4a, we planned to use
functionalized tetrahydroindol-4(5H)-ones as potential key
synthetic intermediates for substituted indoles. 6-Substituted
1
tetrahydroindol-4(5H)-one 2 (R H) can be prepared from 5-
substituted cyclohexane-1,3-dione-2-spirocyclopropane 1 (R1

H) according to our ring-opening cyclization procedure.[17]
Tetrahydroindol-4(5H)-one 2 substituted at the other positions
could be regioselectively converted from non-substituted 2 using
its several reactive sites based on its -enaminone structure: 2
can react with an electrophile as the corresponding enolate at
the '- and -positions of the enaminone (i.e., the 5- and 7-
positions of the indole), and can also react with a nucleophile at
the carbonyl carbon (4-position). After regioselective
functionalization of 2, the resulting products 5, 7, and 9 would be
readily oxidized to the 5-, 7-, and 4-substituted indoles 6, 8, and
10,
respectively.
Alternatively,
transition-metal-catalyzed
Scheme 1. Synthetic approaches to highly substituted indoles.
coupling of indole-4-O-triflate 11 would produce the 4-
substituted indole 10 and also the non-substituted 12.
As a part of our efforts toward the synthesis of functionalized
indoles based on cyclopropane chemistry,[16] we recently
reported a novel synthesis of 4-hydroxyindole 4a through
2,3,6,7-tetrahydro-1H-indol-4(5H)-one 2a. The ring-opening
cyclization of cyclohexane-1,3-dione-2-spirocyclopropane 1a
with benzylamine and the subsequent stepwise oxidation of the
resulting product 2a gave 4-hydroxyindole 4a via 4-
hydroxyindoline 3a in high overall yield (Scheme 2).[17] Herein,
we report an efficient route to highly substituted indoles
employing regioselective alkylations of 2 as a key synthetic
intermediate.
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Synthesis of 5- and 7-substituted indole derivatives
Next, the synthesis of 5- and 7-substituted indole derivatives
was investigated. Mariano and co-workers reported
[
19]
regioselective enolization and alkylation of -enaminones. The
’-alkylated product was obtained through kinetic enolate

formation when using lithium diisopropylamide (LDA) as a base,
whereas the -alkylated product was formed through
thermodynamic enolate formation when using lithium
hexamethyldisilazide (LiHMDS). Therefore, we applied this
protocol to regioselective alkylation of 2 with alkyl halides (Table
1). 2a was reacted with LDA in THF at –78 °C, and then the
reaction was quenched with methyl iodide at –78 °C to rt to
afford 5-methylated product 5a in 89% yield (entry 1). Similar
reactions of 2a with benzyl and allyl bromides as the alkyl halide
gave 5-benzylated and 5-allylated products 5b and 5c in 76%
and 59% yields, respectively (entries 2 and 3). Conversely, the
reaction of 2a with methyl iodide using LiHMDS as a base
produced 7-methylated product 7a in 84% yield (entry 4).
Regioselective benzylation and allylation at C7 were also
achieved by using LiHMDS and 7-benzylated and allylated
products 7b and 7c were obtained in 89% and 71% yields,
respectively (entries 5 and 6).
Scheme 3. Strategy for syntheses of highly substituted indoles.
Synthesis of 6-substituted indole derivatives
Table 1. Regioselective alkylation of 2a using LDA or LiHMDS.[a]
We initially synthesized 6-substituted indoles according to our
published method, as shown in Scheme 2. When 5-
methylcyclohexane-1,3-dione-2-spirocyclopropane 1b[18] was
reacted with benzylamine in tetrahydrofuran (THF) at room
temperature, the ring-opening cyclization reaction proceeded
smoothly to provide 6-methyltetrahydroindol-4(5H)-one 2b in
9
8% yield (Scheme 4). Oxidation of 2b to indoline 3b was
achieved by bromination with CuBr followed by aromatization
using a combination of LiBr and Li CO . After protection of the
2
Entry Base
R−X
Product
Yield [%][b]
2
3
1
2
3
4
5
6
LDA
LDA
LDA
LiHMDS
LiHMDS
LiHMDS
methyl iodide
benzyl bromide
allyl bromide
methyl iodide
benzyl bromide
allyl bromide
5a
5b
5c
7a
7b
7c
89
76
59
84
89
71
phenolic hydroxy group in 3b as a tert-butyldimethylsilyl (TBS)
ether, oxidation of 13 with chloranil furnished 6-methylindole 4b
in 75% yield from 3b. Furthermore, we explored a sequential
conversion of these processes. Ring-opening cyclization of 1b
followed by oxidation to indole proceeded without purification of
any intermediate by column chromatography on silica gel,
providing 4b in 51% overall yield.
[a] All reaction were performed on a 0.2 mmol scale with 1.5 equiv of alkyl
halides and 1.5 equiv (for LDA) or 1.3 equiv (for LiHMDS) of bases. [b] All
products were isolated as a diastereomeric mixture.
Next, we performed the conversion of the 5- and 7-alkylated
products into indoles (Scheme 5). According to Schemes 2 and
4, the bromination of 5- and 7-methyl compounds 5a and 7a with
CuBr followed by aromatization using LiBr and Li CO provided
2
2
3
the corresponding indoline products 14 and 15 in 86% and 50%
yields, respectively. After protection of the phenolic hydroxy
groups in 14 and 15 with TBSCl to give the corresponding silyl
ethers 16 and 17 in 98% and 86% yields, treatment of 16 and 17
with chroranil afforded 5-methylindole 6a and 7-methylindole 8a
in 58% and 83% yields, respectively. Oxidation of 16 with MnO
2
furnished 6a in 83% yield. Thus, regioselective synthesis of 5-
and 7-methylindoles was achieved.
Scheme 4. Synthesis of 6-methylindole 4b.
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Table 2. Oxidation of 2a to pyrrole 18.
Entry Oxidant
Solvent
t [h]
Yield (%)
1
2
3
4
DDQ
Pd/C
chloranil
1,4-dioxane
EtOAc
1,4-dioxane
3
24
1
trace
trace
60
MnO
2
CH
2
Cl
2
1
90
We then examined nucleophilic addition to pyrrole 18
Scheme 7). The reaction of 18 with methyllithium in THF
Scheme 5. Synthesis of 5-methyl and 7-methylindole derivatives 6a and 8a.
(
proceeded smoothly to produce a mixture of exo- and endo-
olefin 20 through methylation of the ketone and subsequent
dehydration of the resulting tertiary alcohol. The conjugated
olefin 20 was easily oxidized with chloranil, and 4-methylindole
derivative 10a was obtained in 64% yield from 18. The reaction
of 18 with phenyllithium also occurred very well to afford
conjugated olefin 21 and a sequential oxidation with chloranil
gave 4-phenylindole derivative 10b in 84% yield from 18. To
demonstrate the utility of this synthetic method, we investigated
Synthesis of 4-substituted indole derivatives
4-Substituted indole 10 was obtained by nucleophilic addition to
the carbonyl group at C4 of the tetrahydroindol-4(5H)-one. We
initially investigated the reaction of 2a with nucleophiles
(
Scheme 6). However, the reaction of 2a with methyllithium gave
a complex mixture of products and tertiary alcohol 9a was not
detected. We assumed that the electrophilicity of the carbonyl
group in 2a was reduced by the donating effect of the nitrogen
atom. Therefore, we planned to oxidize 2a to pyrrole 18 prior to
addition of the nucleophile to the carbonyl carbon. The tertiary
alcohol 19 obtained by the addition of a nucleophile to ketone
could be converted into 4-substituted indole derivative 10 by
dehydration and subsequent oxidation.
the removal of the benzyl protecting group. According to the
procedure of Deaton-Rewolinski,[20] treatment of N-benzylindole
1
0a with potassium tert-butoxide/dimethyl sulfoxide (DMSO) and
oxygen at room temperature afforded N-debenzylated product
0c in 76% yield.
1
Scheme 6. Attempts to introduce the methyl group at C4 and a synthetic
strategy for 4-substituted indole 10.
Scheme 7. Synthesis of 4-methyl and 4-phenylindoles 10a–c.
Introduction of C4 substitutions by Pd-catalyzed coupling of
triflates
Conversion of tetrahydroindol-4(5H)-one 2a to pyrrole 18
was somewhat troublesome (Table 2). The usual oxidation with
DDQ and dehydrogenation with Pd/C gave only trace amounts
of 18 (entries 1 and 2), and the reaction with chloranil in 1,4-
dioxane afforded 18 in moderate yield (entry 3). Gratifyingly, we
Here, we demonstrate the transition-metal-coupling method for
the synthesis of 4-phenylindole 10b from 4-hydroxyindole as an
alternative (Scheme 8), because it has been disclosed that the
4-hydroxy group of the indole could be converted into other
substituents, such as alkynyl, aryl, or hydro groups, by
transition-metal-catalyzed coupling of the corresponding O-
found that MnO
2
was the most effective oxidant for 2a and gave
18 in 90% yield (entry 4).
triflate.[3g, 21] Bromination of pyrrole 18 with CuBr
followed by
2
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2 3
aromatization using LiBr and Li CO provided the corresponding
4
-hydroxyindole 22[22] in 64% yield. Reaction of 22 with triflic
anhydride and pyridine afforded indole triflate 11a in 86% yield.
Pd-catalyzed coupling of 11a with phenylboronic acid and
Cs
6% yield. Furthermore, reductive coupling of 11a and formic
acid in the presence of Pd(OAc) afforded 4-hydroindole 12a in
3% yield. These results indicate that a variety of 4-substituted
2 3
CO proceeded smoothly to provide 4-phenylindole 10b in
8
2
7
indole derivatives can be synthesized via the Pd-catalyzed
coupling of indole triflates.
Scheme 9. Synthesis of 4,5,6,7-tetramethyl-substituted indoles 27a and 27b.
Finally, the synthesis of indole bearing various substitutions on
the benzene ring was examined (Scheme 10). C7-Selective
benzylation of 6-methyltetrahydroindol-4(5H)-one 2c with benzyl
bromide using LiHMDS and sequential C5-selective allylation
with allyl bromide using LDA provided 5-allyl-7-benzyl-6-methyl-
substituted product 28 in 56% yield. After oxidation to pyrrole 29
with chloranil (55% yield), C4-selective phenylation of 29 with
phenyllithium followed by oxidation with chloranil furnished 5-
allyl-1,7-dibenzyl-6-methyl-4-phenylindole (30) in 31% yield. The
regioselectivity of 30 was confirmed by an observed 1H NOE
correlation between N1- and C7-benzylic protons.
Scheme 8. Synthesis of 4-phenylindoles 10b and 4-hydroindole 12a via indole
triflate 11a.
Synthesis of 4,5,6,7-tetrasubstituted indole derivatives
Having achieved the regioselective alkylation of tetrahydroindol-
4(5H)-one 2, we then investigated the synthesis of indoles
possessing fully substituted benzene rings, such as 4,5,6,7-
tetramethylindoles 27a and 27b (Scheme 9). C7-Selective
methylation of 6-methyltetrahydroindol-4(5H)-ones 2b (R = Ph)
and 2c (R = H)[23] using LiHMDS and methyl iodide followed by
C5-selective methylation with LDA and methyl iodide afforded
5,6,7-trimethyl derivatives 24a and 24b in 88% and 74% yields,
respectively. After oxidation of 24a and 24b with chloranil, C4-
selective methylation of pyrroles 25a and 25b with methyllithium
followed by oxidation of conjugated olefins 26a and 26b with
chloranil furnished 4,5,6,7-tetramethylindoles 27a and 27b in
59% and 79% yields, respectively.
Scheme 10. Synthesis of 4,5,6,7-tetrasubstituted indole 30.
Conclusions
We demonstrated the syntheses of highly substituted indoles via
the common synthetic intermediates tetrahydroindol-4(5H)-ones.
6-Methyl-substituted indoles were synthesized from a readily
available 5-methylcyclohexane-1,3-dione-2-spirocyclopropane.
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Synthesis of 5- and 7-methyl-substituted indoles was achieved
by regioselective methylation of tetrahydroindol-4(5H)-one
followed by oxidation to indoles. 4-Methyl-substituted indoles
were synthesized by oxidation to the pyrrole derivative,
methylation with methyllithium, and oxidation to the indole. In
addition, synthesis of 4,5,6,7-tetrasubstituted indoles was
achieved from 6-methyl-substituted tetrahydrondol-4(5H)-ones
using these regioselective alkylations. Further application of the
present synthetic method to the synthesis of biologically active
indole alkaloids is currently in progress.
saturated aqueous NaHCO
and dried over anhydrous MgSO . Filtration and evaporation in vacuo
4
furnished the crude product, which was purified by column
chromatography (silica gel, 5% EtOAc in hexane) to provide 10a (19 mg,
3
(3 x 5 mL), water (5 mL) and brine (5 mL),
64%).
Acknowledgements
This research was supported, in part, by a Grant-in-Aid for
Scientific Research (C) (Grant No. JP15K07853) from the Japan
Society for the Promotion of Science (JSPS).
Experimental Section
Keywords: indole • regioselective alkylation • enaminone •
dehydrogenation • spirocyclopropane
Typical
procedure
for
the regioselective alkylation of
tetrahydroindol-4(5H)-ones 2 and 23 with LDA (Table 1, Schemes 9
and 10)
[
1]
a) E. Fattorusso, O. Taglialatela-Scafati, Modern Alkaloids: Structure,
Isolation, Synthesis and Biology; Wiley-VCH: Weinheim, 2008; b) P. M.
Dewick, Medicinal Natural Products: A Biosynthetic Approach; John
Wiley & Sons Inc.: Chichester, 2009; c) A. J. Kochanowska-Karamyan,
M. T. Hamann, Chem. Rev. 2010, 110, 4489−4497; d) S.-M. Li, Nat.
Prod. Rep. 2010, 27, 57−78; e) M. Ishikura, T. Abe, T. Choshi, S.
Hibino, Nat. Prod. Rep. 2013, 30, 694−752; f) I. S. Marcos, R. F. Moro,
I. Costales, P. Basabe, D. Díez, Nat. Prod. Rep. 2013, 30, 1509−1526;
g) N. Netz, T. Opatz, Mar. Drugs 2015, 13, 4814−4914; h) T. V.
Sravanthi, S. L. Manju, Eur. J. Pharm. Sci. 2016, 91, 1−10.
A solution of LDA (1.0 M in THF, 0.30 mL, 0.30 mmol) was added to a
solution of tetrahydroindol-4(5H)-one 2a (61 mg, 0.20 mmol) in THF (2
mL) at −78 C. After stirring at −78 C for 1 h, methyl iodide (0.019 mL,
0
.30 mmol) was added to the mixture and the whole was allowed to
warm to room temperature over 1 h. The reaction mixture was quenched
with saturated aqueous NH Cl (5 mL), and the whole mixture was
4
extracted with EtOAc (2 x 5 mL). The combined organic layers were
washed with water (5 mL) and brine (5 mL), and dried over anhydrous
MgSO
4
. Filtration and evaporation in vacuo furnished the crude product,
[2]
For recent reviews, see: a) J. J. Song, J. T. Reeves, D. R. Fandrick, Z.
Tan, N. K. Yee, C. H. Senanayake, ARKIVOC, 2010, i, 390−449; b) S.
Cacchi, G. Fabrizi, A. Goggiamani, Org. Biomol. Chem. 2011, 9,
3
which was purified by column chromatography (silica gel, 4% Et N in
EtOAc) to provide 5-methylated product 5a (57 mg, 89%).
6
41−652; c) S. Cacchi, G. Fabrizi, Chem. Rev. 2011, 111,
PR215−PR283; d) D. F. Taber, P. K. Tirunahari, Tetrahedron 2011, 67,
195−7210; e) R. Vicente, Org. Biomol. Chem. 2011, 9, 6469−6480; f)
Typical
tetrahydroindol-4(5H)-ones 2 with LiHMDS (Table 1, Schemes 9 and
0)
procedure
for
the regioselective alkylation of
7
M. Inman, C. J. Moody, Chem. Sci. 2013, 4, 29−41; g) N. Yoshikai, Y.
Wei, Asian J. Org. Chem. 2013, 2, 466−478; h) T. Guo, F. Huang, L. Yu,
Z. Yu, Tetrahedron Lett. 2015, 56, 296−302.
1
A solution of LiHMDS (0.83 M in THF/hexane, 0.66 mL, 0.55 mmol) was
added to a solution of 2a (61 mg, 0.20 mmol) in THF (5 mL) at −78 C.
After stirring at −78 C for 1 h, methyl iodide (0.047 mL, 0.75 mmol) was
added to the mixture and the whole was allowed to warm to room
temperature over 1 h. The reaction mixture was quenched with saturated
[
[
3]
4]
For recent examples, see: a) N. Thies, C. G. Hrib, E. Haak, Chem. Eur.
J. 2012, 18, 6302−6308; b) Lam, T. Y.; Wang, Y.-P.; Danheiser, R. L. J.
Org. Chem. 2013, 78, 9396−9414; c) T. P. Willumstad, O. Haze, X. Y.
Mak, T. Y. Lam, Y.-P. Wang, R. L. Danheiser, J. Org. Chem. 2013, 78,
11450−11469; d) X. Feng, H. Wang, B. Yang, R. Fan, Org. Lett. 2014,
aqueous NH
EtOAc (2 x 10 mL). The combined organic layers were washed with
water (10 mL) and brine (10 mL), and dried over anhydrous MgSO
Filtration and evaporation in vacuo furnished the crude product, which
4
Cl (10 mL), and the whole mixture was extracted with
16, 3600−3603; e) X. Li, H. Xie, X. Fu, J. Liu, H. Wang, B. Xi, P. Liu, X.
Xu, W. Tang, Chem. Eur. J. 2016, 22, 10410−10414.
4
.
a) R. C. Larock, E. K. Yum, J. Am. Chem. Soc. 1991, 113, 6689−6690;
b) S. A. Worlikar, B. Neuenswander, G. H. Lushington, R. C. Larock, J.
Comb. Chem. 2009, 11, 875−879. For reviews, see: c) G. Zeni, R. C.
Larock, Chem. Rev. 2004, 104, 2285−2309; d) G. Zeni, R. C. Larock,
Chem. Rev. 2006, 106, 4644−4680.
3
was purified by column chromatography (silica gel, 4% Et N in EtOAc) to
provide 7-methylated product 7a (133 mg, 84%).
Typical procedure for the conversion of pyrrole derivatives 18, 25,
and 29 to 4-substituted indole derivatives 10, 27, and 30 via
conjugated olefins (Schemes 7, 9, and 10)
[
5]
6]
For a review, see: K. Sapeta, T. P. Lebold, M. A. Kerr, Synlett 2011,
1495−1514.
[
a) S. C. Banfield, D. B. England, M. A. Kerr, Org. Lett. 2001, 3,
3
9
6
325−3327; b) P. V. Zawada, S. C. Banfield, M. A. Kerr, Synlett 2003,
71−974; c) D. B. England, M. A. Kerr, J. Org. Chem. 2005, 70,
519−6522.
A solution of methyllithium (2.0 M in Et
added to a solution of pyrrole 18 (30 mg, 0.10 mmol) in THF (5 mL) at
78 C. The mixture was allowed to warm to room temperature over 1 h.
The reaction mixture was quenched with EtOH (10 mL), and the whole
mixture was evaporated in vacuo. The residue was diluted with CH Cl
20 mL), and the whole mixture was washed with water (5 mL) and brine
5 mL), and dried over anhydrous MgSO . Filtration and evaporation in
vacuo furnished the crude product 20 (27 mg), which was used in the
next step without further purfication.
Chloranil (37 mg, 0.15 mmol) was added to a solution of the crude
product 20 in 1,4-dioxane (1 mL). The mixture was stirred at reflux for 1 h.
After cooling, the mixture was evaporated in vacuo. The residue was
2
O, 0.20 mL, 0.40 mmol) was
−
[
7]
8]
a) S. K. Jackson, S. C. Banfield, M. A. Kerr, Org. Lett. 2005, 7,
1
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1
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The synthesis of highly substituted
indoles via tetrahydroindol-4(5H)-one
intermediates was developed. The
synthesis of 5- and 7-substituted
indoles was achieved by
regioselective alkylation followed by
oxidation to indoles. 4-Substituted
indoles were synthesized by oxidation
to the pyrrole derivative, alkylation
with alkyllithium, and oxidation to the
indole. Furthermore, the synthesis of
H. Nambu,* W. Hirota, M. Fukumoto, T.
Tamura, T. Yakura*
Page No. – Page No.
An Efficient Route to Highly
Substituted Indoles via
Tetrahydroindol-4(5H)-one
Intermediates Produced by Ring-
Opening Cyclization of
Spirocyclopropanes with Amines
4,5,6,7-tetrasubstituted indoles was
achieved by using these
regioselective alkylations.
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