A diversity-oriented approach to indolocarbazoles: Via Fischer indolization and olefin metathesis: Total synthesis of tjipanazole D and i

Article abstract of DOI:10.1039/c6ob01679k

New synthetic strategies to indolocarbazoles have been reported via two-fold Fischer indolization under green conditions using l-(+)-tartaric acid and N,N-dimethyl urea. Starting with cyclohexanone, a bench-top starting material, this methodology has been extended to the total synthesis of natural products such as tjipanazoles D and I as well as the core structure of asteropusazole and racemosin B. Here, atom economical reactions like ring-closing metathesis, enyne-metathesis, and the Diels-Alder reaction have been used as key steps. Diverse strategies demonstrated here are useful in medicinal chemistry and materials science to design a library of decorated indoles.

Full text of DOI:10.1039/c6ob01679k

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Diversity-Oriented Approach to Indolocarbazoles via Fischer Indolization and
Olefin Metathesis: Total Synthesis of Tjipanazole D and I
Sambasivarao Kotha*, Mohammad Saifuddin and Vikas R. Aswar
Department of Chemistry, Indian Institute of Technology Bombay Powai, Mumbai, 400 076,
India. E-mail: srk@chem.iitb.ac.in
ABSTRACT: New synthetic strategies to indolocarbazoles have been reported via a two-fold
Fischer indolization under green conditions using L-(+)-tartaric acid and N,N-dimethyl urea.
Starting with cyclohexanone, a bench-top starting material, this methodology has been extended
to the total synthesis of natural products such as tjipanazoles D and I as well as core structure of
asteropusazole and racemosin B. Here, an atom economic reactions like ring-closing metathesis,
enyne-metathesis, and Diels–Alder reaction have been used as key steps. Diverse strategies
demonstrated here are useful in medicinal chemistry and material science to design a library of
decorated indoles.
INTRODUCTION
Indoles are considered as privileged structures because of their unique role in various
biochemical processes. They are extensively used as critical building blocks in developing new
drugs which are suitable for the treatment of cancer, circulatory disease, Alzheimer’s, and other
neurological disorders (Figure 1).1 Recently, there has been growing interest in using indole
motifs as the starting materials for library design2 and such activity leads to the identification of
high-affinity ligands.3 Here, various indolocarbazole scaffolds have been assembled by judicious
selection of well-known reactions in an orchestrated sequence.
Among indole-based heterocycles, carbazoles and indolocarbazoles are found in a number of
natural products and as an important drugs (1-11).4 The chemistry of indolo[2,3-a]carbazoles has
been widely studied because of their promising antifungal, antimicrobial, anticancer and
antihypertensive activities.5 Now, several indolocarbazole alkaloids are in the clinical trials due
1

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to their potential use in cancer therapy.6 Additionally, they were also used for optical and solar
cell applications, viz organic field-effect transistors (OFET), organic thin film transistors (OTFT)
and organic light-emitting diodes (OLEDs).7
In view of our interest to design diverse polycycles using Fischer indolization (FI),8 ring-closing
metathesis (RCM),9 enyne metathesis (EM),10 Diels–Alder (DA)11 reaction and Suzuki–Miyaura
(SM) cross-coupling12 as key steps, here we conceived various strategies to indolocarbazoles
based on these key reactions and our efforts in this direction are described here.
FIGURE 1.Various naturally and biologically active compounds
RESULTS AND DISCUSSION
The required phenylhydrazine hydrochloride derivatives 13a-f were prepared by using the
literature procedure starting with commercially available aniline derivatives (Scheme 1).13
Scheme 1: Synthesis of various phenyl hydrazine hydrochloride derivatives 13
Our journey towards indolocarbazoles commenced with the synthesis of the substrates 17a-c
(Scheme 2), as key intermediates, was accomplished via FI between cyclohexanone 15 and
phenylhydrazine hydrochlorides 13a-f, 14 followed by regioselective oxidation sequence using
periodic acid (Scheme 2).14 Besides, the other two keto derivatives 18a and 18b were prepared
by FI/DDQ oxidation protocol.15
2

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Scheme 2: Synthesis of keto derivatives 17, 18 and 19
Having the desired substrates 17a-c and 19a-b in hand, we next investigated the feasibility of FI
sequence with suitable phenylhydrazines. Initially, carbazole derivative 17a was subjected to FI
by treating with phenylhydrazine hydrochloride 13a using conventional methods (e.g.
SOCl2/EtOH, AcOH/TFA, MeCN/H2SO4, EtOH/H2SO4 and HCl system) to deliver a mixture of
non-aromatized 20a and aromatized 21a compounds with different ratios (Scheme 3).
Interestingly, reaction of 17a with phenylhydrazine hydrochloride 13a in the presence of N,N-
dimethyl urea (DMU)/L-(+)-tartaric acid (TA) conditions,8f delivered a fully aromatized
indolocarbazole 21a in 73% yield along with the trace amounts of 20a. To expand the diversity
of carbazole derivatives, the indolocarbazoles 17b-c and 19a-b were subjected to FI with other
hydrazine derivatives 13b-f and 14 to generate the corresponding indolocarbazole derivatives
21b-o in 46-78% yield (Scheme 4). Surprisingly, when the indole derivative 17a was treated
with 4-bromo phenylhydrazine 13e aromatized indolocarbazole 21e was obtained along with de-
brominated carbazole 21a.
Scheme 3: Optimization of indolocarbazole 21 via conventional methods
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R4
NNH3Cl
DMU/L(+)-TA
(70:30)
R3
R1
R1
+
R3 80 °C, 24-48 h
46-77%
N
R2
N
R4
N
R2
O
21a-o
17a-c / 19a-b
13a-f / 14
Cl
N
H
N
N
N
Me
, 69%
N
N
H
H
H
Me
, 77%
21a
21b
, 73%
21c
OMe
Me
Cl
Cl
Br
Br
Br
N
H
21d
N
H
, 78%
N
H
N
N
N
H
H
H
21e
21f
, 63%
, 46%
OMe
Br
N
N
N
H
N
H
N
H
N
H
H
21g
21h
21i
, 53%
, 61%
, 77%
Br
Br
N
N
N
N
N
N
H
Me
, 70%
Me
21j
21k
, 60%
21l
, 67%
Cl
Cl
Cl
Cl
N
N
H
N
H
N
H
N
N
H
H
H
Br
21m
21n,
21o
, tjipanazole D, 72%
, 0%
tjipanazole I, 75%
Scheme 4: Synthesis of indolocarbazoles 21a-o via Fischer indolization
The target molecules tjipanazoles B and E can be synthesized by known N-substitution reaction
condition from tjipanazole D (Scheme 5).16
Scheme 5: Formal synthesis of tjipanzoles B and E
The core structure of asteropusazole was also synthesized by using this methodology. In this
regard, the indole derivatives 18a and 18b containing keto group were subjected to FI with
phenylhydrazine hydrochloride 13a. Unfortunately, the desired indolocarbazoles 22 and 23 were
not obtained. However, N-protected indole derivative 18b was reacted with N-
methylphenylhydrazine 14 to deliver the fully aromatized product 24 in 51% yield, whose carbon
framework is similar to that of indole natural products asteropusazole16-17 and racemosin B18
(Figure 1, Scheme 6).
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Scheme 6: Synthesis of core structure of asteropusazoles and racemosin B via Fischer
indolization
To expand the carbazole chemical space, SM cross-coupling reaction of 21h was studied with 4-
substituted phenylboronic acids 25. In this regard, functionalized indolocarbazoles 26a-c were
obtained in 67-75% yield (Scheme 7).
Scheme 7: Synthesis of carbazole derivatives 26 via SM cross-coupling reaction
Since many natural products (Figure 1) are N-protected indolocarbazoles, our strategies were
directed to assemble N-annulated or N-allylated indolocarbazoles. To this end, we synthesized
various N-annulated indolocarbazoles using RCM, EM and DA reaction as key steps. The di-
allyl compound 27 was prepared starting with N-allylation of the keto derivative 17a followed by
FI/N-allylation sequence. Alternatively, 27 was also synthesized from 21a using N-allylation,
whereas 21a was synthesized by FI of the keto derivative 17a (Scheme 8).
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Scheme 8: Synthesis of indolocyclophane 29 via RCM and hydrogenation sequence
Subsequently, the di-allyl indolocarbazole 27 was subjected to the RCM sequence with the aid of
Grubbs first generation (G-I) catalyst in refluxing toluene produced the desired macrocyclic
compound 28 in 76% yield. Finally, hydrogenation of double bond present in 28 delivered the
cyclophane 29 in 70% yield (Scheme 8).19
To expand the substrate scope, the mono-allyl compound 21i was successfully converted into an
enyne building block 30 by treatment with propargyl bromide using NaH in dry THF. The diene
building block 31 was generated via metathesis protocol and different reaction conditions were
screened in the presence of G-I and Grubb’s second generation (G-II) catalysts. However, these
attempts were unsuccessful and ultimately, we found that the presence of the titanium
isopropoxide and ethylene20 atmosphere facilitate the metathesis protocol.21 Under these
conditions, enyne building block 30 was reacted with G-II catalyst in dry CH2Cl2 to furnish the
diene 31.
Scheme 9: Synthesis of indolocarbazole 32 via enyne metathesis and DA reaction
Later, without isolating the intermediate 31, it was subjected to DA sequence with
tetracyanoethylene as a dienophile in refluxing toluene to deliver a novel heptacyclic compound
32 in 72% yield (Scheme 9).
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Scheme 10: Synthesis of octacyclic indolocarbazole 34 via N-alkylation
Creation of molecular complexity and variety from simple precursors is the major objective of
the diversity-oriented synthesis (DOS).22 To this end, we wish to synthesize the crownophane
derivative,23 34 which is a hybrid of crown ether and indolocyclophane. For this purpose, the
required dibromo derivative 33 was prepared using the literature procedure.24 In this regard, the
indolocarbazole moiety 21a was subjected to bis-N-alkylation in dry DMF using NaH conditions
to deliver the desired indolocrownophane derivative 34 in 90% yield (Scheme 10).
CONCLUSIONS
In summary, we have developed a diversity oriented approach to indolocarbazoles via deep
eutectic solvents.8f, 25 Also, twenty five indolocarbazoles with additional functionalities have
been generated using a variety of reactions such as RCM, EM, DA reaction and SM cross-
coupling as key steps. These strategies have been extended for the synthesis of natural products
tjipanazole D and I as well as core structure of asteropusazole and racemosin B. Various
methodologies demonstrated to deliver multitude of compounds for biological as well as material
science applications. The hybrid molecule containing indolocyclophane derivative 34 with crown
ether moiety is useful in host-guest chemistry for metal ion binding studies. The tactics used here
to deliver distinct indole building blocks demonstrate the power of synthetic convergence of
well-known reactions.
SUPPORTING INFORMATION
1
13
The copies of H and C NMR for all the new compounds associated with this article can be
found at http://dx.doi.org/
ACKNOWLEDGMENT
We are grateful to Department of Science and Technology (DST), New Delhi for the financial
support. M. S. thanks IIT Bombay for Institute postdoctoral fellowship and financial support.
VRA thanks CSIR-New Delhi for financial support. S. K. thanks the DST for the award of a J. C.
Bose fellowship and Praj industries for Chair Professorship (Green Chemistry).
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