A one-pot "back-to-front" approach for the synthesis of benzene ring substituted indoles using allylboronic acids

Article abstract of DOI:10.1039/d1cc01512e

Synthesis of only benzene ring functionalized indoles and poly-substituted carbazoles is reported via a one-pot triple cascade benzannulation protocol. Usage of differently substituted and readily accessible allylboronic acids as a 3-carbon annulating partner enables diverse aliphatic and aromatic substitution patterns, which is still a daunting task. This scalable synthetic protocol tolerates broad scope, thus enabling further downstream modifications. As an application, carbazole based natural products glycozoline and glycozolinol were synthesized. This journal is

Full text of DOI:10.1039/d1cc01512e

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A one-pot ‘‘back-to-front’’ approach for
the synthesis of benzene ring substituted indoles
Cite this: DOI: 10.1039/d1cc01512e
using allylboronic acids†
Received 19th March 2021,
Accepted 20th April 2021
Ganesh Karan, Samrat Sahu
and Modhu Sudan Maji
*
DOI: 10.1039/d1cc01512e
rsc.li/chemcomm
Synthesis of only benzene ring functionalized indoles and poly- removal steps, regiochemical issues, low functional group
substituted carbazoles is reported via a one-pot triple cascade tolerance, strong acidic conditions, and diminished yields.4
benzannulation protocol. Usage of differently substituted and readily In contrast, functionalization at the C6-position is scarcely
accessible allylboronic acids as a 3-carbon annulating partner enables reported as it is remotely located from the nearby directing
diverse aliphatic and aromatic substitution patterns, which is still a groups, and has low intrinsic reactivity towards electrophiles.5
daunting task. This scalable synthetic protocol tolerates broad scope, Apart from this, in general, installation of multiple linear as
thus enabling further downstream modifications. As an application, well as branched aliphatic substitutions of choice on the
carbazole based natural products glycozoline and glycozolinol were benzene ring of indole without regiochemical ambiguity while
synthesized.
still keeping C2 and C3-positions free is still arduous since
most of the methods are known to react with ‘‘activated
The chemistry of p-excessive heterocycle indoles is extensive electrophiles’’. In 2015, Baran et al. developed a ligand controlled
due to their wide-spread presence in natural products, alka- C6 borylation of a tryptophan derivative under Ir-catalysis along
loids, amino acids, neurotransmitters, plant hormones such as with its C5-regioisomer (Scheme 1a).5e Recently, Shi et al. reported a
serotonin and melatonin, bacterial metabolites, agro-chemicals copper catalyzed C6 functionalization under Cu(II)-catalysis, applic-
and various FDA approved medicines (Fig. 1).1 Recent studies able to arylation only (Scheme 1b).5f A much less explored benzan-
have shown that the functionalization at the benzene ring of nulation on the pyrrole to forge a benzene ring represents a
active pharmaceutical ingredients (APIs) leads to better phar- complementary method due to no substrate pre-functionalization
macological properties and is closely responsible for their and no regiochemical ambiguity. It can be sub-categorized such
druglikeness, shape, and structural complexity.2 However, the as transition metal catalyzed cyclization,6 [4+2] cycloaddition,7
general trends show predominance of a certain substitution 6p-electrocyclization,8 and Brønsted and Lewis acid catalyzed
pattern in these with a particular set of reactions being used transformations.9 Although development in this area has gained
exhaustively. This inaccessibility to other sites is mostly due to substantial traction in recent years, development of more general
the lack of a well-defined method or often needs extra synthetic
maneuvers. Functionalization at the C2/C3-position of an
indole nucleus is quite straightforward due to the embedded
nucleophilic character, however defining a suitable substitu-
tion pattern at the benzene ring is found to be quite challen-
ging and cumbersome while leaving the C2 and C3-positions
un-substituted (Fig. 1).3 Substitutions at the C4, C5, and C7
positions are generally installed by transition metal catalyzed
C–H bond functionalization, Fischer indole synthesis, Bartoli
indole synthesis, etc. (Fig. 1). They are often plagued by
prefunctionalized starting materials, extra installation and
Department of Chemistry, Indian Institute of Technology Kharagpur,
Kharagpur 721302, WB, India. E-mail: msm@chem.iitkgp.ac.in
Fig. 1 FDA approved drugs containing an indole nucleus and current
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
indole ring substitution overview.
d1cc01512e
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Table 1 Optimization of the reaction conditionsa
Entry
Solvent
Temp [1C] (step I/II)
Yield of 3ab (%)
1
2
3
4
5
6
7
8
CHCl3
THF
DCE
r.t./r.t.
r.t./r.t.
r.t./r.t.
r.t./r.t.
r.t./r.t.
r.t./r.t.
r.t./r.t.
r.t./r.t.
r.t./r.t.
r.t./r.t.
80/r.t.
r.t./80
80/80
45
54
41
35
55
46
76
75c
62d
55e
70
72
65
Toluene
EtOAc
MeCN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
9
10
11
12
13
14
15
f
r.t./r.t.
r.t./r.t.
—
52g
a
Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), solvent (2.0 mL),
Scheme 1 Literature reports and our work.
r.t., Ar; Et3N (0.5 mmol), MsCl (0.3 mmol), r.t., Ar; decalin (2.0 mL).
b
c
Isolated yield. Step III was carried out in the presence of DDQ
d
e
instead of O2. DIPEA was used as a base. DABCO was used as a base.
f
g
Cinnamyl zinc (0.3 mmol) was used as an allylating agent. Cinnamyl-
BPin (0.24 mmol) was used as an allylating agent.
and sustainable methods from cheaper feedstock chemicals using
step-economic pathways is still elusive. In this direction, metal
catalyst free organic synthesis has evolved as contemporary path-
way due to its various advantages.10 Recently, allylboronic acids
have emerged as a powerful allylating reagent due to their easy
access from the corresponding allyl alcohol, geometrical stability,
and high reactvity.11 In line with our ongoing research towards
functionalization of indole and pyrrole,12 we herein report a one-
pot triple cascade protocol for the synthesis of functionalized
indoles and carbazoles by employing allyl alcohol based allylboro-
nic acids as a 3-carbon annulating partner.
pyrrole-2-carboxaldehydes and a wide range of allylboronic
acids (Scheme 2). Incorporating an electron donating methoxy
group at the C2- and C3-positions of the benzene ring shows
mild variation in the yields and the products 3b–3c were
At the outset of the optimization, we chose N-tosyl-pyrrole-2-
carboxaldehyde 1a and cinnamyl boronic acid 2a as a coupling
partner (Table 1). In CHCl3, the reaction provided 45% isolated
yield of product 3a using decalin as a solvent for the final
electrocyclization and O2 as a terminal oxidant (entry 1). Changing
the solvent to other protic and aprotic ones shows that CH2Cl2 is
the best one providing 3a in 76% yield (entries 2–7). Changing the
terminal oxidant to DDQ provided comparable yields (entry 8), so
we have chosen O2 for its shear abundance and environment
friendly nature. Changing the organic base to DIPEA or DABCO
for the elimination step diminished the yields (55–62%, entries
9 and 10). Screening of the temperature showed that increasing
the temperature to 80 1C by different combinations for the first
two steps is detrimental on the outcome (65–72% yields, entries
11–13). To check the compatibility of the other allylating-agents,
though, a zinc mediated allylation using cinnamyl bromide was
not fruitful as the reaction did not proceed further after the first
step (entry 14), cinnamyl-BPin provided 52% of 3a by employing
10 mol% of diphenyl phosphate as a catalyst (entry 15).
Having the optimized conditions in hand, we set out to
investigate the generality of the reaction first by synthe-
Scheme 2 Scope of indoles. Reaction conditions: step I: 1a (0.2 mmol), 2
(0.3 mmol), CH2Cl2 (2 mL), r.t.; step II: Et3N (0.5 mmol), MsCl (0.3 mmol),
sizing several benzene ring substituted indoles employing r.t.; step III: decalin (2.0 mL), 180 1C; isolated yield.
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isolated in 62–68% yields. Gratifyingly, bromine substitution at
the C2-position of the benzene ring, which can act as a template
for further synthetic manipulations, was well tolerated under the
optimized conditions providing the corresponding C6-substituted
indole 3d in 67% yield. Similarly, naphthyl substituted indole 3e
was also synthesized in 66% yield. The thiophene moiety is a key
building block and precursor to various functional groups. To
check whether such heteroaromatics can be incorporated or not,
(E)-(3-(thiophen-2-yl)allyl)boronic acid 2f was used as an allylating
partner and to our joy, indole 3f was isolated in 54% yield.
Incorporation of linear as well as branched alkyl chains onto
the benzene nucleus of indole is extremely challenging. To check
whether this newly developed method can solve this long-
standing issue, we screened several g-alkyl substituted allylboro-
nic acids. Simple linear aliphatic chains such as methyl, propyl,
and benzyl groups were readily introduced using this sequential
protocol, providing 3g–3i in 56–62% yield. Similarly, the reaction
allowed us to incorporate sterically encumbered branched alipha-
tic groups such as isopropyl and cyclohexyl moieties also at the C6
position, providing 3j–3k in 55–61% yields. The synthetically
challenging citronellal moiety was also introduced with no alkene
isomerization despite the high reaction temperature, thus providing
the corresponding indole 3l in 44% yield. Next several aromatic
as well as aliphatic groups containing b,g-disubstituted boronic
acids 2m–2o were screened for their compatibility and pleasingly
di-substituted indoles 3m–3o were isolated in 45–67% yields. This is
in particular remarkable since simultaneously C5 and C6 functio-
nalized indoles can be synthesized in a one-pot operation.
Scheme 3 Scope of carbazoles. Reaction conditions: step I: 4a
(0.2 mmol), 2 (0.3 mmol), CH2Cl2 (2 mL), r.t.; step II: Et3N (0.5 mmol),
MsCl (0.3 mmol), r.t.; step III: decalin (2.0 mL), 180 1C; isolated yield.
and the product 3a was isolated in 1.02 g (71% yield, Scheme 4).
To check further applicability of the synthesized indoles and
carbazoles, 3a was first deprotected under methanolic KOH
conditions to give 6 in 76% yield. In this line, 5c was also
deprotected using TBAF at 75 1C to furnish 7 in 97% yield. As a
synthetic application, two carbazole based natural products
glycozoline and glycozolinol were targeted. Treatment of
N-protected indole 8 with crotyl boronic acid 2g under standard
conditions, and finally deprotection resulted in glycozoline 9 in
45% overall yield over two steps. Treatment of glycozoline with
BBr3 resulted in glycozolinol 10 in 92% yield.
To scrutinize whether the complimentary regiodivergence
can be achieved using the same allyl boronic acids by only
changing the allyl acceptor, we next choose N-Ts-pyrrole-3-
carboxaldehyde, and screened several aromatic, aliphatic, and
di-substituted boronic acids. Pleasingly this one-pot sequential
protocol also provided indoles 3p–3s in 45–64% yields.
After investigating the scope of indoles, we next switched
our attention toward extrapolating this approach to the synth-
esis of substituted carbazoles (Scheme 3). Screening of aro-
matic and heteroaromatic substituted boronic acids shows that
they can be easily incorporated at the C3-position of carbazole,
thus providing carbazoles 5a–5b in 65–74% yields. To our joy,
branched as well as linear alkyl chains were also installed under
the reaction conditions furnishing 5c–5d in 49–59% yields. To
install a –SPh group directly at the C3-position of carbazole,
–SPh substituted boronic acid 2q was reacted under the opti-
mized conditions and the corresponding carbazole 5e was
isolated in 62% yield. Next, screening of di-substituted boronic
acids enables 2,3-di-alkyl and aryl substituted carbazoles 5f–5h
in 51–65% yields. Lastly, a-carboline 5i was synthesized from
the corresponding 7-azaindole derivative in 57% yield. Upon
implementing regio-isomeric indole 2-carboxaldehyde, C2-aryl
and -alkyl substituted carbazoles 5j–5k were isolated in 51–67%
yields which are extremely difficult to prepare via traditional
cross-coupling approaches as the corresponding carbazole pre-
cursors are difficult synthetic tasks.
To check the scalability of the developed protocol, a gram
scale reaction was performed on 1a (4.0 mmol, 1.2 g) using 2a
Scheme 4 Scalability and synthetic applications.
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Based on the obtained results, we have postulated a plau-
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six-membered chair-like transition state 11 to provide homo-
allylic alcohol 12. Next, mesylation of the benzylic alcohol
followed by Et3N mediated E2 elimination furnished conju-
gated alkene 14. Next, 6p-electrocyclization under thermal
conditions and subsequent aromatization accomplished
indoles and carbazoles 3–5 in one-pot.
In conclusion, a one-pot sequential triple cascade protocol
was developed for the synthesis of functionalized indoles and
carbazoles based on the benzannulation approach. Allyl alcohol
based allylboronic acids were utilized as a 3-carbon annulating
partner. The easy access and high reactivity of the allylboronic
acid facilitates a wide range of substitution patterns, especially
the aliphatic functionality. The reaction was amenable to gram
scale and two carbazole based natural products were synthe-
sized. We believe that this approach provides a solution to
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