Employment of
Green and Sustainable Protocols for C(sp3)-H bond Functionalization
of 2-Methyl azaarenes and subsequent C-C bond formation
Ratnakar Dutt Shuklaa*,
Byanju Raia
a,a*Department
of Chemistry, Pt. DDU Govt. Model College, Bahua, Fatehpur, India
*Corresponding Author:
E-mail Address: rdbhuchem09@gmail.com
Article available online
at: https://esciencesspectrum.com/AbstractView.aspx?PID=2021-1-1-4
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ARTICLE INFO
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ABSTRACT
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Original
Research Article
Received:
9 November 2021
Accepted:
11 November 2021
KEYWORDS
PDE,
C(sp3)-H
Functionalization,
2-Methyl
azaarenes,
C-C
bond construction,
Green
and sustainable protocols
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Twenty-first
century witnessed the importance of C-H bond functionalization which is
regarded as a potent, promising and direct tool for the construction of the
carbon-carbon bond. The concept of C-H bond functionalization has been highly
explored in the field of synthetic organic chemistry. The current scenario of
research is shifted towards the development of novel sustainable protocols
which should have great environmental impact. It does not need
pre‐functionalization of the substrates and thus offers an atom‐economic
strategy hence regarded as green and sustainable approach. The applications
of C-H functionalization approach, as a potential synthetic tool, have been
well exemplified in the formation of C-C bond and carbon-heteroatom bonds
(C-O, C-N, C-S and C-X) which have notable applications in the preparation of
complex natural products and medicinally potent compounds. The present review
covers the employment of numerous novel and innovative sustainable approaches
in the field of C(sp3)-H Functionalization reactions.
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Introduction
The
C-H functionalization of inactivated C-H bonds has been extensively explored
strategies of the twenty-first century in synthetic organic chemistry[1], [2].Because of the ever-presence of C-H
bonds, the C-H functionalization has now revolutionized as a potential
synthetic strategies for the installation of various functional groups in
organic substances (Figure 1). This concept does not need pre‐functionalization
of the substrates and thus offers an atom‐economic strategy. The applications
of C-H functionalization approach, as a potential synthetic tool, have been
well exemplified in the construction of C-C bond [3]
and carbon-heteroatom bonds (C-O, C-N, C-S and C-X) which
have notable applications in the synthesis of valuable organic molecules such
as complex natural products, and medicinally potent compounds [4]–[6].
Medicinal
importance of Azaarenes (Pyridine and Quinoline): Quinolines
and related scaffolds have always been significant candidates for drug
development program. Among N-heterocycles,
pyridine and quinoline are privileged scaffolds that appear as an important
constituent in several FDA approved drugs (Figure 2). Pyridine moiety is an
important constituent in several natural products like niacin, vitamin B6,
nicotinamide adenine dinucleotide (NAD), and alkaloids such as trigonelline. Pyridine
is one of the most extensively used azaarene in pharmaceutical research with
numerous biological applications[7].
Figure 1: Common Approach to C-H
Functionalization
The
quinoline ring system presents in several natural products like Quinine,
Chimanine A, B and D, Cusparine, etc. with interesting biological activities[8]–[10]. Quinoline nucleus is endowed with
several biological activities; therefore, quinoline and related moieties
constitute a significant group of heterocycles for the development of novel
drugs. Notably, many biological activities like antibacterial, antimalarial,
anticancer, antiviral, anthelmintic, antifungal, anti-inflammatory, central
nervous system, analgesic, hypoglycemic and cardiovascular have been observed
from quinoline derivatives[11], [12].
C(sp3)-H Functionalization
of 2-methylazaarene
Owing
to the medicinal importance of quinoline and pyridine, the C(sp3)-H
functionalization of 2-methylazaarenes has secured a remarkable position in the
area of synthetic organic chemistry. A growing repertoire of C-H
functionalization of 2-methyl azaarenes are continuously widening via an array of protocols by using
transition metals with ligands,[13] transition metals without ligands[14], [15],
Lewis acids[16], Brønsted Acids[17],
etc. Some representative protocols for C(sp3)-H
functionalization of 2-methylazaarenes are demonstrated in figure 3.
Figure
2: Examples of Azaarene (pyridine and quinoline) containing FDA approved drugs
Figure
3: Representative examples of various
developed protocols for C(sp3)-H functionalization of
2-methylazaarene
The
present review covers some selected publications on the C(sp3)-H
Functionalization of 2-methylazaarene.
1. Preparation of Alkyl Azarene
Pyridinium (AAP) Zwitterions via C(sp3)-H Bond functionalization
using Iodine
In
2011, Atul Kumar et al described a potent as well as conceptually greener strategy
for the C-H bond functionalization using iodine for the preparation of alkyl
azaarene pyridinium zwitterions. This transition-metal-free approach
demonstrates the remarkable importance of being the first preparation of a
novel group of alkyl azaarene pyridinium zwitterion (Scheme 1). The designed
the scheme for the aforementioned synthesis using the reactions of 2-methyl
quinoline, aromatic aldehydes, meldrum acid, pyridine in the presence of iodine
as Lewis acid catalyst and triethylamine as base. The salient feature of this
report includes that the complete multicomponent reaction is performed in one
pot without using transition metal catalyst. This article may be considered as
a breakthrough in the field of synthetic chemistry for conducting the C-H
functionalization reaction in absence of hazardous transition metal catalysts
as well as ligands.
Scheme 1: Iodine
catalyzed C(sp3)-H Bond functionalization of 2-methyl azaarenes
The
plausible mechanism for the above reaction is well demonstrated in Figure 4.
Functionalization of methyl azaarenes by coordination to iodine as Lewis acid
enhances the acidity of the benzylic C-H bonds. In presence of Lewis acid
breaking of the C-H bond generates a 1-iodo-2-methylene-1, 2- dihydroquinoline
species (2). In next step, pyridine
attacks 2 as a nucleophile to
generate 1-(quinolin-2-ylmethyl) pyridinium iodide (3). Finally, the attack of iodide salt is done on arylidene dione
(an adduct of aromatic aldehyde meldrum acid generated through Knoevenagel
condensation) to form AAP zwitterions.
The
developed protocol is efficiently explored for the synthesis of number of AAP
zwitterionic salts in good to excellent yields.
2. Benzylic C-H Bond Functionalization
of Azaarenes in presence of Lewis Acid
Motomu
Kanai and group (2011) have described a Lewis acid catalyzed C(sp3)-H
bond functionalization of 2-methyl azaarenes(Scheme 2)[11].
Scheme 2: Lewis acid catalyzed C(sp3)-H
Bond functionalization of 2-methyl pyridine
Here
Sc(OTf)3 and Y(OTf)3 have been used as Lewis acid which
promotes the direct addition of 2-methyl pyridine to enones and an α,
β-unsaturated N-acylpyrrole. This
Lewis acid promoted protocol provides the products were in 60-96% yield.
On
the basis of literature reports regarding Lewis acid catalyzed intramolecular C(sp3)-H functionalization,[18] Lewis acid promoted C(sp2)-H
functionalization of quinolines and/or pyridines[19], as well as acid/base catalyzed
proton transfer reactions[20], herein it is suggested that Lewis
acid has been employed for the functionalization of 2-methyl azaarenes in the
presence proton-transfer conditions[21]. A plausible mechanistic approach
for the present reaction is clearly depicted in figure 5
Figure
4: Probable mechanistic strategy for Methyl
azaarene Pyridinium (AAP) Zwitterions
Figure
5: Plausible mechanism for Lewis acid catalyzed C-H functionalization of
alkyl-substituted azaarenes with enones
3.
TBAF (Tetrabutylammonium fluoride)-catalyzed C(sp3)-H
functionalization of 2-methyl azaarenes for the synthesis of azarene
substituted 3-hydroxy-2-oxindoles
A
mild, smooth, efficient and metal-free sustainable protocol for direct addition
of 2-alkylazaarenes to isatins via C(sp3)-H functionalization in the
presence of controlled microwave radiation using water as reaction medium[22].
This
green strategy offers a simple and practical synthetic route for bioactive
azaarene-substituted 3-hydroxy-2-oxindoles in good to excellent yields. The
present innovative approach will provide a new organocatalytic option for the
functionalization of C-H bonds.
Scheme 3: TBAF catalyzed C(sp3)-H
functionalization of 2-methyl azaarenes
In
view point of green chemistry, synthetic community is trying to replace
conventional hazardous catalysts and solvents in order to develop a sustainable
protocol. Taking into account the necessity of environmental and economic
awareness, the employment of a more general and practical method under mild
conditions, preferably using solvent of natural origin for C-H
functionalization is need of the day. Water is considered as one of the most
important gift from nature. The exploitation of water as a solvent in synthetic
chemistry is completely following the green chemistry mandate. The emergence of
organocatalysis has attracted the great interest due to its unique advantages.
The exploration of organocatalysts in combination to aqueous medium will give
the promising practical outcomes in field of green chemistry.
4. β-Cyclodextrin catalysed C(sp3)-H
functionalization of 2-methyl azaarenes with diones using water as reaction
medium
Atul
Kumar and Ratnakar Dutt Shukla have reported first time exploration of
β-cyclodextrin as catalyst for the functionalization of C(sp3)-H
bonds of 2-alkyl-azaarenes with heterocyclic as well as homocyclic diones water[23].
Scheme 4: β-Cyclodextrin catalysed
C(sp3)-H functionalization of 2-methyl azaarenes
This
biomimetic catalyst dependent approach gives a green and sustainable
methodology for C-H functionalization reactions. This study exploited the
easily available, biodegradable, non-toxic and reusable β-cyclodextrin as
catalyst and hence breaks the dominancy of hazardous transition metal catalyzed
C-H bond functionalization reactions. This β-cyclodextrin catalyzed methodology
expands the repertoire of a sustainable and green protocol for C-H bond
functionalization reactions, the one of the most important approach in
synthetic organic chemistry.
Cyclodextrins as a reusable catalyst
Cyclodextrins
(CD) are readily available cyclic oligosaccharides consisting of D (+)-glucose
units associated by α-1,4-glycosidic bonds (Figure 6). Cyclodextrins contains a
hydrophobic central cavity as well as a hydrophilic outer surface which have
attracted great interest as aqueous-based hosts for inclusion complex phenomena
with a variety of guest. Cyclodextrins have substrates selective
binding potential and catalyze numerous chemical reactions under the concept of
supramolecular catalysis[24]. The inclusion complex is
formed via non-covalent bond interaction between hydrophobic guest molecule and
the hydrophobic cavity of CD.
Figure 6: Schematic
representation of α-, β-, and ϒ-CD with their equivalent truncated cone
structure
With
view point of green chemistry, the employment of readily available, cost
effective and eco-friendly catalysts and solvents remains highly recommended.
From green chemistry prospective, water, the readily available and
environmentally benign, is a most suitable replacement for the hazardous
organic solvents. Water, the nature’s solvent, has been employed many times as
a solvent in numerous organic reactions. β-CD is a well-known green, reusable,
biodegradable and environmentally compatible catalyst for organic synthesis.
Scheme
5: Synthesis of azaarene-substituted 3-hydroxy-2-oxindoles
A
number of 2-methylazaarenes viz.,
2-methyl pyridine, 2-methyl quinoline, 6-fluoro-2-methyl quinoline,
6-chloro-2-methyl quinoline, 8-chloro-2-methyl quinoline, 6-bromo-2-methyl
quinoline were smoothly functionalized and prepared to react with various
possible substituted isatins, for example, 5-methylisatin, 5-nitroisatin,
7-fluoroisatin, 5-chloroisatin, 5-bromoisatin, 5-iodoisatin, N-methylisatin, N-benzylisatin to generate a variety of
3-substituted-3-hydroxy-2-oxindoles (3a-3p).
Isatins having electron-releasing group (-CH3), electron-withdrawing
(-NO2) substituents, and halogens, participated successfully in
reaction, and the desired products were afforded in good to excellent yields.
The observations showed that N-protected
isatins provided better yield in comparison to unprotected ones. No side products
i.e., bis(quinolin-2-ylmethyl)indolin-2-ones were noticed under the present
synthetic protocol (Scheme 5).
To
check the broadness of the present greener protocol, next, we conducted the
reaction of 2-methylazaarenes with benzo-[b]thiophene-2,3-dione
(4a), i.e., thioisatin. Similar to
isatin, the thioisatin performed well in reaction. Gratifyingly, the
corresponding products (5a-5d) were formed in good to excellent
yields, as well depicted in scheme 6.
Scheme
6: Synthesis of azaarene-substituted 3-hydroxy-benzo[b]thiophen-2(3H)-ones
As
the heterocyclic diones (isatins and thioisatin) afforded the expected products
in excellent yields using present developed protocol (Scheme 5 and Scheme 6),
various homocyclic diones were also explored to evaluate the scope and
compatibility of this sustainable synthetic approach.
Scheme 7: Synthesis
of azaarene-substituted 2-hydroxy acenaphthylene-1(2H)-ones and azaarene-substituted-2-hydroxy aceanthrylene-1(2H)-ones
In
this context, we assessed bicyclic as well as tricyclic homocyclic diones like
acenaphthylene-1,2-dione (6a) and
aceanthrylene-1,2-dione (6b)
respectively (Scheme 7). So, we carried out a reaction of 2-methylpyridine and
2-methyl quinoline with acenaphthylene-1,2-dione under the optimized protocol,
gratifyingly, the desired products 7a
and 7b were obtained respectively.
Next, we explored the present methodology for reaction of polycyclic
aceanthrylene-1,2-dione with 2-methylazaarenes, the observations showed that
the reaction well grown with aceanthrylene-1,2-dione too and expected products
(7c and 7d respectively) were delivered with excellent yields.
To
evaluate the sustainability of present protocol, the reusability of
β-cyclodextrin was examined for five cycles (including the fresh catalyst) for
the syntheses of compounds 3l, 3c, 3m, 5b, and 7b, no significant losses in catalytic
efficacy were shown during the reusability experiments [Figure 7 (a)].
Figure 7: (a) Reusability data for
β-CD; (b) Cross reusability data for β-CD
In
addition, cross catalytic reusability experiments were also performed for the
synthesis compound 3c and 3m, and negligible loss in catalytic
efficacy was reported. The fresh batch of β-cyclodextrin as a catalyst was
employed for the synthesis of compound 3c,
then the recovered catalyst was employed for the synthesis of compound 3m, and vice versa [Figure 7 (b)].
This
environmentally benign protocol is applicable to C(sp3)-H functionalization of
several 2-methylazaarenes with a broad category of heterocyclic as well as
homocyclic diones. This quest confers a greener option for establishing a new
horizon for C-H functionalized reactions.
Conclusion
Initially,
the C(sp3)-H functionalization of 2-methyl pyridines/quinolines was
performed with the employment of strong bases like nBuLi, NaNH2, KNH2,
LDA, etc. Subsequently efficient and practical functionalization reactions have
been emerged, such as at the starting of this decade, it was regarded as C-H
activation reaction. Then it was thought that C-H activation is not suitable to
use as the 2-methyl quinoline is a preactivated molecule because of the
imine-enamine tautomerism. Latter on many Lewis and Brønsted acid and transition
metal-catalyzed reactions were evolved. With the emergence of concept of green
chemistry, numerous sustainable protocols have been developed for C-H
functionalization reactions and many of them have been well covered in this
review. Recently, many catalyst-free, aqueous medium and very recently catalyst
and solvent-free approaches for C-H functionalization were also developed.
Considering the medicinal importance of pyridine/quinoline, the application of
developed C-H functionalization approaches will generate of a wide range of
pyridine/quinoline derivatives.
Conflict of interest:
Authors declares no conflicts of interest.