Divergent and Orthogonal Approach to Carbazoles and Pyridoindoles from Oxindoles via Indole Intermediates

Article abstract of DOI:10.1021/acs.orglett.8b01827

The previously unexplored Grignard addition to oxindoles provides a regiospecific approach to 2- and 2,3-disubstituted indole derivatives in high yields via a one-pot aromatization driven dehydration pathway. This method allows a convenient preparation of diallyl indoles that are used as ring-closing metathesis (RCM) precursors for the orthogonal synthesis of pyrido[1,2-a]indoles and carbazoles. The synthetic utility of this method is illustrated by the synthesis of a microtubulin inhibitor and naturally occurring carbazole alkaloids.

Full text of DOI:10.1021/acs.orglett.8b01827

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Divergent and Orthogonal Approach to Carbazoles and
Pyridoindoles from Oxindoles via Indole Intermediates
Tirtha Mandal, Gargi Chakraborti, Shilpi Karmakar, and Jyotirmayee Dash*
Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700032, India
S
* Supporting Information
ABSTRACT: The previously unexplored Grignard addition to oxindoles provides a regiospecific approach to 2- and 2,3-
disubstituted indole derivatives in high yields via a one-pot aromatization driven dehydration pathway. This method allows a
convenient preparation of diallyl indoles that are used as ring-closing metathesis (RCM) precursors for the orthogonal synthesis
of pyrido[1,2-a]indoles and carbazoles. The synthetic utility of this method is illustrated by the synthesis of a microtubulin
inhibitor and naturally occurring carbazole alkaloids.
Scheme 1. Regiospecific Synthesis of Indole Derivatives and
Modular Construction of Carbazoles and Pyridoindoles
ndole is a fundamental structural unit in organic chemistry
that is present in a myriad of natural products, pharmaceutical
I
agents, and advanced materials.1 In addition to the classical
Fischer indole synthesis,2 a large number of methods are known
for the synthesis of substituted indoles.3,4 Despite these
advances, the development of a modular and regiospecific
approach to substituted indoles is of considerable interest.
Herein, we disclose a regiospecific synthesis of indole
derivatives, which are used as intermediates for the construction
of indole-fused saturated and unsaturated pyrido[1,2-a]-
indoles5,6 and carbazoles (Scheme 1).4a,7−9 Owing to their
prevalence in natural products and biologically active mole-
cules,5,7 the development of practical and scalable synthetic
approaches for indole-fused heterocyclic scaffolds is desirable.
We commenced our studies with the regiospecific synthesis of
indole derivatives from oxindoles (Scheme 1). Previously, Lu et
al. and Furman et al. reported regiospecific synthesis of 2,3-
disubstituted indoles utilizing the differential electrophilicity of
the two carbonyl groups of isatins.10 These methods are useful
only for the synthesis of disubstituted indoles. However, the
synthesis of 2,3-diallyl indoles and C3-allyl-containing disub-
stituted indoles remains a formidable challenge (Scheme 1).11
We envisioned that Grignard addition of oxindole might provide
a novel route to 2-substituted as well as 2,3-disubstituted indoles
via a one-pot dehydrative aromatization protocol, enabling the
synthesis of 2,3-diallyl indoles as well as disubstituted indoles
containing a C3 allyl group that could be used as precursors for
olefin metathesis (Scheme 1).
(Scheme 1).16 Considering the structural features of pyrio-
doindoles 7 and carbazoles 8, we anticipated that the C2, C3,
and N1 positions of oxindole could be utilized for the diversity
oriented synthesis (DOS)17 of these two classes of tricyclic ring
While much attention has been paid to the functionalization
of the C3 carbon of oxindoles,12 the reactivity of the C2 carbonyl
group has been far less explored.10,11a,13 Recently, we have used
an allyl metal addition to isatins to obtain diallyl oxindoles that
are used for the synthesis of carbazoles via ring-closing
metathesis14,15 (RCM) and ring rearrangement aromatization
Received: June 12, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01827
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Letter
systems in an orthogonal manner by RCM of diallyl indole
precursors 3 and 4 followed by aromatization (Scheme 1).
In order to examine the feasibility of our proposed approach, a
variety of N-allyl 2-oxindoles 1 were prepared from different N-
allyl isatin derivatives (see Supporting Information, Schemes
S1−S2). We were delighted to observe that the reaction of N-
allyl oxindole 1a with allylmagnesium bromide in THF at room
temperature led to the formation of 2-allyl indole derivative 3a in
86% yield (Scheme 2). We then explored the scope and
Scheme 3. Regiospecific Synthesis of 2,3-Disubstituted
Indoles
a b
,
a b
,
Scheme 2. Synthesis of 2-Substituted Indoles
a
The addition of allylmagnesium bromide (3 equiv, 1 M in Et2O) to 1
(2.0 mmol, 1 equiv) was carried out in THF (10 mL) at rt for 3 h.
b
The addition of alkyl or arylmagnesium bromide (5 equiv, 1 M in
Et2O) to 1 (2.0 mmol, 1 equiv) was carried out in THF (10 mL) at
70 °C for 6 h.
a
The addition of allylmagnesium bromide (3 equiv, 1 M in Et2O) to 2
(2.0 mmol, 1 equiv) was carried out in THF (10 mL) at rt for 3 h.
The addition of alkyl or arylmagnesium bromide (5 equiv, 1 M in
Et2O) to 2 (2.0 mmol, 1 equiv) was carried out in THF (10 mL) at
70 °C for 6 h.
generality of this approach with respect to oxindoles and
Grignard reagents. Various oxindoles having both electron-rich
and -withdrawing groups bearing different N-substituents
afforded the corresponding 2-allyl indole derivatives 3a−o in
excellent yields. Although the reactions with alkyl or aryl
Grignard reagents were slow at room temperature, impressive
results were obtained at 70 °C, affording 2-substituted alkyl or
aryl indole derivatives 3p−s in good yields (Scheme 2). It is
important to mention that there is a lack of general and efficient
method(s) for the preparation of 2-allyl indoles, and only
recently the synthesis of 2-allyl indoles has been achieved by
using protecting group directed transition metal catalyzed18
reactions. In this context, our strategy provides a practical access
to 2-substituted indoles, particularly 2-allyl indoles in a one-pot
operation.
b
oxindole derivative (I) containing a C3 allyl group nor the C3
allyl iminium ion (II) as C3 allyl migration takes place readily in
both cases under the reaction conditions (Scheme 4). We
Scheme 4. Proposed Aromatization-Driven Dehydration
Pathway with Insight to the Formation of 2,3-Diallyl and C3
Allyl-Containing Disubstituted Indoles
Next we carried out the Grignard reaction with C3-
substituted 2-oxindoles 2 (Schemes S3−S7). The allyl Grignard
reaction proceeded smoothly at room temperature affording the
corresponding 2,3-disubstituted indoles 4a−o in excellent yields
with broad functional group tolerance (Scheme 3). The
disubstituted indole derivatives 4f, 4g, and 4a′ containing a
C3 indolyl group, a pyrrolidine ring with a bulky substituent, and
a phenylethynyl group, respectively, were synthesized in good
yields. As expected, the addition of alkyl or aryl Grignard
reagents proceeded at high temperature (70 °C) giving the
products 4p−4b′ in good to high yields. The disubstituted
indole derivative 4b′ containing a bulky mesityl group at C2
position was obtained in 60% yield.
The synthesis of 2,3-disubstituted indoles generally involves
annulation of an azacycle to an existing aromatic ring, leading to
the formation of regioisomeric mixtures. Recently, Nakamura
and co-workers have reported a regioselective method for the
synthesis of disubstituted indoles via cyclative formation of 2,3-
dizincioindoles.11b By using the literature methods,10 it is
possible to prepare neither the 2,3-disubstituted dihydroxy
reported that the addition of allyl Grignard reagents to isatins
provides the rearranged 2,2-diallyl 3-oxindole derivatives (III)
instead of the diallyl dihydroxy oxindole derivatives (I; when R3
= allyl) (Schemes 1 and 4).16 Based on the above results and
previous reports, we presume that Grignard reaction of 2-
oxindoles proceeds with the formation of intermediate A, which
upon workup generates the indolinium ion intermediate B.
Subsequently, aromatization of the intermediate B by
deprotonation provides indole derivatives 3 and 4. The
intermediate A upon workup may also directly lead to indoles
via dehydrative aromatization (Scheme 4).
B
DOI: 10.1021/acs.orglett.8b01827
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Letter
To demonstrate the synthetic potential of this transformation,
we synthesized a 2,3-disubstituted indole derivative 11, an
inhibitor of microtubulin polymerization.19 The addition of 4-
methoxyphenylmagnesium bromide to the oxindole 2u
(Scheme S12, SI) afforded the required disubstituted indole
derivative 9. The deprotection of the N-benzyl group followed
by DDQ-mediated C3 methyl oxidation furnished the target
compound 11 in 54% overall yield (Scheme 5).
Scheme 7. (a) Synthetic Applications of Dihydro-pyrido-
indole Derivatives 5 and (b) Natural Products Containing a
Tetrahydro-pyrido-indole Ring
Scheme 5. Synthesis of Microtubulin Inhibitor
In order to validate our design strategy (Scheme 1), we used
diallyl indoles 3 and 4 for the orthogonal synthesis of fused
nitrogen-containing heterocycles using RCM. Various orthog-
onal approaches have been reported for the efficient
construction of heterocyclic ring systems.20 In this approach,
the RCM of 1,2-diallyl indolyl derivatives 3a−n and 4a−f with
10 mol % of Grubbs’ first-generation catalyst (G-I)21 in CH2Cl2
at room temperature provided the desired dihydro-pyrido-
indole derivatives 5 in excellent yields (Scheme 6). The halo
could be successfully achieved to obtain the corresponding
products 12a−b, 13, and 14 in excellent yields (Scheme 7). The
tetrahydro-pyrido-indole derivatives 12 are important scaffolds
in synthetic organic chemistry, and many natural products such
as goniomitine,23a tronocarpine,23b vincamine,23c and mitose-
nes23d contain this motif in their molecular structures.
Only a limited number of methods are known for accessing
this heterocyclic ring system, and most of the methods involve
multisteps and extensive prefunctionalization as well as demand
selective hydrogenation of the fully aromatic pyridoindole
core.6,24 Our method, which starts from simple precursors, is
amenable to variations and should prove valuable for the
synthesis of an array of highly functionalized pyridoindole
derivatives.
Scheme 6. Ring-Closing Metathesis of 1,2-Diallyl Indole
a
Derivatives
On the other hand, the cyclization of 2,3-diallyl indolyl
derivatives 4h−o with catalyst G-I (10 mol %) provided
dihydrocarbazole derivatives 6a−h in excellent yields (Scheme
8). The dihydrocarbazole derivatives were efficiently aromatized
to the corresponding carbazole derivatives 8a−h by oxidation
with 100 mol % DDQ at room temperature (Scheme 8). Under
similar conditions, 6g afforded 8g via aromatization as well as C5
Scheme 8. Synthesis of Carbazole Derivatives by RCM and
a b
,
Aromatization
a
The reactions were performed using of 3 or 4 (0.3 mmol, 1 equiv)
b
and G-I catalyst (10 mol %) in CH2Cl2 (4 mL) at rt for 8 h. The
reaction was performed using 4f (0.3 mmol, 1 equiv) with G-II
catalyst (5 mol %) in CH2Cl2 (4 mL) at rt for 12 h.
dihydro-pyrido-indoles 5f−i can be applied for cross-coupling
reactions. Compound 5o containing a C3-indolyl substituent
was prepared by using 5 mol % of Grubbs’ second-generation
catalyst (G-II)22 in 74% yield. The presence of the isolated
double bond makes these dihydro-pyrido-indole derivatives
attractive intermediates for further transformations (Scheme 7).
The DDQ-mediated aromatization of compounds 5 provided
heteroaromatic pyrido[1,2-a]indole derivatives 7a−h in good
yields. Under similar conditions, 5j afforded 7g via aromatiza-
tion as well as benzylic oxidation. The chemoselective reduction,
isomerization, and selective hydroxylation of the double bond
a
The reactions were performed using 4 (0.3 mmol, 1 equiv) and G-I
b
catalyst (10 mol %) in CH2Cl2 (4 mL) at rt for 8 h. The reactions
were performed using 6 (0.2 mmol, 1 equiv) with DDQ (100 mol %)
in EtOAc (3 mL) at rt for 8 h.
C
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Letter
methyl oxidation. The carbazole derivatives having remote
C4Me or Ph substituents (8c and 8d) could be easily prepared
using our protocol.25 These results validate our previous
hypothesis that carbazole derivatives can be synthesized from
isatins by using RCM and aromatization of 2,3-diallyl indolyl
precursors.16
The optimized reaction sequence was then employed for the
synthesis of dimeric pyridoindole and carbazole derivatives
(Scheme 9). The allyl Grignard addition to oxindole precursors
the resulting diallyl indolyl precursor 21 afforded the
dihydrocarbazole derivative 22 in 81% yield. DDQ-mediated
aromatization followed by debenzylation produced glycozoli-
ne27b−d 24 in 56% overall yield. BBr3-mediated demethylation of
24 afforded glycozolinol27a 25 (Scheme 10).
Further, our method was used to obtain 2-hydroxy-3-
methylcarbazole 28, a common intermediate for the synthesis
of a library of carbazole alkaloids.28 The allyl Grignard addition
to oxindole 2y (Scheme S23, SI) and RCM of the resulting
dialkene precursor 26 followed by DDQ-mediated aromatiza-
tion provided the N- and O-benzyl-protected carbazole
derivative 27. The hydrogenolysis of 27 provided 28, which
was subsequently used for the synthesis of girinimbine,
murrayacine, and euchrestifoline.
Scheme 9. Synthesis of Dimeric Pyridoindole and Carbazole
Derivatives
̈
Knolker and co-workers reported the synthesis of euchrestifo-
line by cyclization of the free −OH group of the Buchwald
adduct followed by one-pot C−C bond formation−Wacker
oxidation.29 Subsequently, LiAlH4-mediated dehydration of
euchrestifoline provided girinimbine.29 In this work, girinimbine
30 was directly obtained via the cyclization of 28 with prenal 29
using titanium isopropoxide.28a The DDQ-mediated oxidation
of girinimbine 30 provided murrayacine28a,30 31, and the
Wacker oxidation of girinimbine produced euchrestifoline 32 in
excellent yields (Scheme 10).
In conclusion, we have developed a dehydrative aromatization
protocol for the synthesis of substituted indole derivatives from
readily available oxindole derivatives. Importantly, this method
provides an efficient access to otherwise inaccessible 2-allyl and
2,3-disubstituted symmetrical or unsymmetrical diallyl indole
derivatives. These diallyl indoles have been used as ring-closing
metathesis precursors for the synthesis of an array of indole-
fused heterocycles such as carbazoles, pyrido[1,2-a]indoles, and
the challenging dihydro and tetrahydro pyrido[1,2-a]indole
derivatives. Moreover, we have applied this chemistry to a
concise synthesis of a microtubulin inhibitor and carbazole
alkaloids. This work highlights Grignard addition to substituted
2-oxindoles as a tool for generating otherwise difficult nitrogen-
containing heterocycles using simple organic transformations.
2v and 2w (Schemes S20 and S21, SI) furnished the
corresponding dimeric 1,2- and 2,3-diallyl indoles 15 and 18
in excellent yields. RCM of these dimeric dialkenes produced
dihydro-pyrido-indole 16 and dihydrocarbazole 19, which
underwent smooth aromatization to provide indole-fused
dimeric heterocycles 17 and 20 in high yields.
The utility of our method was further illustrated by the
straightforward synthesis of carbazole natural products such as
glycozoline, glycozolinol, girinimbine, murrayacine, and eu-
chrestifoline (Scheme 10). These carbazole alkaloids exhibit a
wide range of pharmacological activities.26 The allyl Grignard
addition of oxindole 2x (Scheme S22, SI) followed by RCM of
Scheme 10. Synthesis of Naturally Occuring Carbazole
Alkaloids
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b01827.
Experimental procedures and the copies of 1H NMR and
13C NMR spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: ocjd@iacs.res.in.
ORCID
Jyotirmayee Dash: 0000-0003-4130-2841
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
J.D. thanks DST for a SwarnaJayanti fellowship. This work was
supported by DST and CSIR-India for funding. T.M., G.C., and
S.K. thank CSIR, India, for research fellowships.
D
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DOI: 10.1021/acs.orglett.8b01827
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