Environmentally benign nucleophilic substitution reaction of arylalkyl halides in water using CTAB as the inverse phase transfer catalyst

Article abstract of DOI:10.1039/c9nj03941d

An environmentally benign, practically scalable and highly selective C-arylalkylation of active methylene compounds is developed using CTAB as the inverse phase transfer catalyst in water. The methodology developed is elaborated into the one-pot synthesis of quinoline derivatives and also applicable to the regioselective N-aralkyl of 2-pyridones.

Full text of DOI:10.1039/c9nj03941d

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Environmentally benign nucleophilic substitution
reaction of arylalkyl halides in water using CTAB
as the inverse phase transfer catalyst†
Cite this: New J. Chem., 2019,
43, 16041
Atul K. Godha, Jayaraman Thiruvengadam, Viswanadhan Abhilash, Prajwal Balgi,
A. V. Narayanareddy, Kumaresan Vignesh, Amol V. Gadakh,*
A. M. Sathiyanarayanan * and Sambasivam Ganesh*
Received 30th July 2019,
Accepted 11th September 2019
An environmentally benign, practically scalable and highly selective C-arylalkylation of active methylene
compounds is developed using CTAB as the inverse phase transfer catalyst in water. The methodology
developed is elaborated into the one-pot synthesis of quinoline derivatives and also applicable to the
regioselective N-aralkyl of 2-pyridones.
DOI: 10.1039/c9nj03941d
rsc.li/njc
The alkylation of 1,3-dicarbonyl compounds and other active reaction media such as ionic liquids8a and supercritical CO2.8b
methylene compounds is a fundamental and useful transformation On the other hand, water, the universal solvent in which most
involving C–C bond formation.1 This reaction is generally biochemical transformations occur in living systems, has been
accomplished by treating various metal enolates with alkylating conveniently ignored when planning a synthetic strategy; or
reagents such as alkyl halides or alkyl sulfonates. These reactions more often than not its use is limited to that of a co-solvent or as
warrant the use of polar aprotic solvents such as DMF/DMSO as an additive. This selective exclusion of water is attributed to the
the reaction medium and the use of appropriate strong bases, viz. poor solubility of organic substrates/reactants and catalysts in water.
sodium hydride and t-BuOK, in most cases.2 Direct nucleophilic
To address the solubility issues, chemists have resorted to
substitution of the hydroxy group in alcohols with enolate the use of surfactants.9 Due to the hydrophobic effects involved,
nucleophiles was achieved by various methods involving either they form a cage around the organic substrates wherein the
a high reaction temperature or use of Lewis3a and heteropoly reaction takes place.10 In a more similar manner, use of inverse
acids3b,c as the catalytic promoter or by employing transition phase transfer catalysts transports two immiscible reactants
metal reagents.4 The majority of these approaches are largely into the aqueous phase and the reaction proceeds.11 This
limited to laboratory scale synthesis and are highly substrate concept was successfully invoked by Shimizu and co-workers
dependent.5 Hence, development of an environmentally benign in their study of base mediated alkylation of active methylene
process for this fundamental C–C bond formation might be compounds with various alkyl halides using the water-soluble
beneficial when applied on the industrial scale. Owing to the calix[n]arenes (n = 4, 6 and 8) as an inverse phase-transfer
increased awareness of the need for sustainable technology that catalysts (i-PTC) that contains trimethylammoniomethyl groups
complies with Green chemistry principles, chemists worldwide on the upper rim.12 Inspired by this work, we envisaged that
have resorted to safer, environmentally benign practices that regioselective, mono-C-aralkyl/alkylation can be effected with
avoid the formation of waste at the locus.6 Studies indicate that equal efficiency using various surfactants that are commercially
over 80% of organic waste generated from both academic and available and economically viable on an industrial scale. In this
industrial set-ups is attributed to the use of solvents as the regard, herein, we report an environmentally benign, relatively
reaction medium.7 The use of solvents in organic synthesis has milder and practical approach for regioselective C-aralkylation
become indispensable as most substrates and catalysts are of 1,3-dicarbonyl derivatives that employs CTAB as the i-PTC
soluble only in organic solvents. Stringent environmental concerns and enables us to utilize water as the reaction medium. The
have resulted in the shift in the paradigm, driving scientists across application of the methodology can be extended to the multi-
the globe to resort to greener solvents as well as various alternate gram scale synthesis of various industrially useful key API
starting materials and intermediates.
Anthem Biosciences Pvt. Ltd., #49, Canara Bank Road, Bommasandra Industrial
Our initial efforts were directed towards identifying an
appropriate catalyst for C-benzylation of b-ketoester 1a. Accordingly,
commercially available non-ionic surfactants such as Tween 40t,
Area, Bommasandra, Bengaluru-560099, Karnataka, India.
E-mail: ganesh.s@anthembio.com, amol.g@anthembio.com,
sathiya037@gmail.com, sathiyanarayanan.a@anthembio.com
TPGS-750-Mt, Triton X-100t and Brij 58t were screened initially
† Electronic supplementary information (ESI) available: Detailed experimental
procedures and analytical data. See DOI: 10.1039/c9nj03941d
with limited or no desired reaction using K2CO3 as the base.
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in entries 8–10. With optimized conditions in hand, the scope of
various differentially substituted benzyl halides and other alkyl
halides was studied next.
Table 2 outlines the scope of the various electrophiles employed.
It was observed that substitution on the benzyl halides does not
have any detrimental effect on the outcome of the reaction, as both
electron releasing (Table 2, entries 1–4 and entries 6 and 7) and
electron withdrawing substituents (Table 2, entry 5) were found to
deliver the desired mono-alkylated products 3aa–3ag in high yields.
Also, alkyl halides, viz. methyl iodide (2h) and n-propyl iodide (2i),
were employed in these conditions quite effectively rendering the
mono-C-alkylated product 3ah and 3ai, respectively, in good yields
(Table 2, entries 8 and 9). In all these trials, very little side reactions
(o10%) were observed as deduced by the LCMS analysis of the
crude reaction mixture. The scope of the nucleophiles was studied
by choosing diethyl malonate (1b) as the benchmark substrate.
Thus, 1b was subjected to selective C-aralkylation with various
differentially substituted benzyl bromide derivatives 2a–2g to
furnish the desired mono-C-benzylated malonate derivatives
3ba–3bg in an uneventful manner as shown in Table 3, entries
1–7. After successfully studying the substrate scope of the
methodology, it was envisaged that the same methodology can
be employed for the synthesis of quinoline derivatives in ‘one-
pot’ using water as the reaction medium.
Quinoline motifs are part of the structure of various natural
products and were found to exhibit various biological activity
functioning as antiviral, antimalarial and antituberculosis agents.13
Conventional strategies often require harsh reaction conditions
and are often marred by unwanted side reactions.14 Condensation
of o-aminobenzaldehdyes with ketones (the Friedlander approach)
is another useful strategy, however, the stability and economic
viability of the key SM demerits the approach.15 Transition metal
catalyzed reactions of o-haloanilines with allyl alcohol equivalents16
are widely used among various other useful alternates.17,18 Recently,
Xing et al. reported the reductive cyclization of o-nitrochalcones
to furnish quinolines.19 Based on which, we reasoned that the
C-benzylation of 1,3-dicarbonyl compounds with o-nitro benzyl-
bromide (2j) and subsequent reductive cyclization in ‘‘one-pot’’
would lead to the formation of 2,3-disubstituted quinoline
derivatives. To test the hypothesis, as depicted in Scheme 1,
ethylbenzoyl acetate (1a) was reacted with o-nitrobenzyl bromide
(2j) using the optimized protocol to procure the benzylated
ketoester 3aj. Upon completion of the reaction, Zn/NH4Cl, as
performed by Lipshutz et al.,20 was introduced into the reaction
medium leading to the reductive cyclization of in situ generated
aniline 6aj, to furnish 7aj. 7aj underwent oxidative aromatization,
rendering 2,3-disubstituted quinoline derivative 9aj, in a tandem
fashion with good overall yield.
Fig. 1 Influence of various surfactants/i-PTC catalysts on C-benzylation
of ethyl-3-oxo-3-phenylpropanoate using K2CO3 as the base at 60 1C.
However, switching from non-ionic surfactants to ionic surfactants
such as AOTt and CTAB had a dramatic effect on the reaction
profile, rendering mono C-benzylated product 3aa in respectable
yield (Fig. 1). Details of the same are incorporated in the ESI.†
Screening of various bases was taken up next. Accordingly,
various bases were screened using CTAB in H2O at 60 1C. The
progress of the reaction was monitored using LCMS and the
results are summarized in Table 1. Use of milder bases such as
NaHCO3 and K3PO4 resulted in incomplete consumption of
starting b-ketoester 1a after 16 h, with moderate conversion to
the desired product 3aa along with a small amount of undesired
reaction (Table 1, entries 1 and 2). Switching from inorganic to
organic bases was not effective as well, as the use of DIPEA
resulted in formation of a mixture of C- and O-benzylated
products (Table 1, entry 3), whereas use of Et3N resulted in
partial conversion (Table 1, entry 4). DABCO was inefficient in
effecting the conversion and DBU resulted in the formation of a
complex reaction profile (Table 1, entries 5 and 6). The best
result was obtained when K2CO3 was used as the base (Table 1,
entry 7). On the contrary, increased basicity resulted in for-
mation of a mixture of mono- and poly alkylated products as
observed with the use of Cs2CO3, NaOH and CsOH as the base
Table
1
Screening of bases for C-benzylation of ethyl-3-oxo-3-
phenylpropanoate using CTAB in water
% conversion by LCMSa
Entry
Base
1a
3aa
4aa
5aa
1
2
3
4
NaHCO3
K3PO4
DIPEA
Et3N
DABCO
DBU
K2CO3
Cs2CO3
NaOH
CsOH
36
18
6
22
53
0
8
12
0
55
53
68
42
6
32
80
63
46
43
3
6
10
1.2
0.2
2
5
10
3
0.9
6
4
0.5
0.5
10
2
6
27
32
With successful demonstration of the methodology for the
quinoline synthesis, we then turned our attention towards the
regioselective N-alkylation of 2-pyridones. The ambident character
of 2-pyridones makes selective N- versus O-alkylation a formidable
problem21 and to date it remains an actively pursued research
area.22,23 In this context, we attempted the N-benzylation of
2-1H-pyridone (10) using various bases with 2% w/w of CTAB in
water. The study revealed K2CO3 to be the base of choice and
5
6b
7
8
9
10
0
2
a
In all the cases the ratio was monitored using LCMS analysis of the
b
crude reaction mixture. Formation of an unidentified product was
observed at ca. 35%.
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Table 2 C-Arylalkylation of ethyl-3-xxo-3-phenylpropanoate using K2CO3 and CTAB in water: scope of electrophiles
Halides
Product distribution by IPC-LCMS
Entry
R/R0
1a
3
4
5
Product
Yielda (%)
1
2
3
4
5
6
7c
8
9
2a
2b
2c
2d
2e
2f
2g
2h
2i
H
4-Cl
4-I
4-Me
4-NO2
4-Br
4-OMe
Me
8
2.8
7
80
70
77
82
73
80
60
NA
NA
5
7
0.9
n.d.
n.d.
3
4
NA
NA
2
5
6
4.5
n.d.
8
3
NA
NA
3aa
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
65 (60)b
57
63
5
69 (30)b
15
Trace
4
NA
NA
61b
71
65
60
70
n-Pr
a
b
c
Isolated yield after column purification. Isolated yield obtained using AOT. 25% of the corresponding acid of 3ag was found in LCMS analysis.
Note: all reactions were carried out on a 1 g scale of 1a and were analysed by IPC-LCMS after 16 h, entry 5 in 4 h. Entries 8 and 9 were monitored by
TLC. Legend: NA – Data not available; n.d. – not detected. Extractions were necessary in these cases owing the physical nature of the product and
are relative to the scale of the reaction. Solvent extractions can be conveniently avoided when performed on a larger scale.
Table 3 C-Arylalkylation of diethylmalonate (1b) using K2CO3 and CTAB
manner with only traces of 2-benzyloxy pyridine (12a) being
in water: scope of electrophiles
formed (Table 4, entry 1). When benzyl chloride was employed,
the reaction was equally efficient albeit with prolonged reaction
time (B24 h). With the optimized conditions in hand, attention
was turned towards studying the substrate scope of the reaction.
Accordingly, various para-substituted benzyl bromides were
efficiently coupled with pyridone 10 to furnish their respective
Entry
Halides
Product
Yielda (%)
1
2
3
4
5
6
7
2a
2b
2c
2d
2e
2f
3ba
3bb
3bc
3bd
3be
3bf
65
59
55b
60b
30c
58
Table 4 Scope of N-arylalkylation of 2-pyridones using K2CO3 and CTAB
in water
2g
3bg
62
a
b
Isolated yield after column purification. 15% v/v THF was added as
c
the co-solvent. Isolated yield obtained using AOT as a surfactant, as
no desired reaction was observed using CTAB. Note: all reactions were
carried out on a 1 g scale of 1b for 16 h and the progress of the reaction
was monitored by TLC.
N vs. Oa
RCH2Br
Yield of 11 (%)
Entry
11 : 12
1
2
3
4
5
6
7
8
PhCH2Br
PhCH2Cl
2a
2a0
2b
2c
2d
2e
2f
2j
2k
2l
2p
2q
2r
2s
2t
99 : 1
87 : 13
96 : 4
93 : 7
97 : 3
93 : 2
92 : 8
98 : 2
11a
11a
11b
11c
11d
11e
11f
11j
11k
11l
11p
11q
11r
11s
82
—
76
86
86
75
85
75
4-Cl-C6H4-CH2Br
4-I-C6H4-CH2Br
4-Me-C6H4-CH2Br
4-NO2-C6H4-CH2Br
4-Br-C6H4-CH2Br
2-NO2-C6H4-CH2Br
3-Cl-C6H4-CH2Br
3-NO2-C6H4-CH2Br
2,4,6-(Me)3-C6H2CH2Br
PhCOCH2Br
9
90 : 10
98 : 2
70
70
63
10
11
12
13
14
15
13 : 1c
Z19 : 1c
Z19 : 1c
Z19 : 1c
72
CH2QCH-CH2Br
CH3(CH2)3CH2I
i-Pr-I
62 (87)d
69
Scheme 1 Indirect Friedlander’s approach: ‘‘one-pot’’ synthesis of quinolines
using water as the reaction medium and the mechanistic pathway.
Trace product
a
In all the cases the ratio was monitored using LCMS analysis of the
b
crude reaction mixture, unless or otherwise stated. Isolated yield after
column purification. Ratio was monitored using 1H NMR analysis of
c
LCMS analysis of the crude reaction mixture, after 3 h, revealed the
d
formation of N-benzylated pyridone 11a in a highly regioselective the crude reaction mixture. Yield based on the unreacted 10.
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transfer catalyst employing water as the reaction medium is
developed and demonstrated in a multi-gram scale synthesis of
various mono-benzylated malonate and benzoylacetate derivatives
with good isolated yield. The utility of the protocol was further
exemplified in the ‘‘one-pot’’ indirect Friedlander’s synthesis of
quinolines and highly N-selective benzylation of pyridones. Further,
the methodology was studied for its large scale application and the
measure of the ‘‘green metrics’’ suggested the methodology to be
environment as well as process friendly. The physical chemistry/
mechanistic aspects of the methodology are being probed so as
to adopt the same in a highly efficient manner on an industrial
scale in the synthesis of APIs and other important feedstock
starting materials.
Scheme 2 Application of the methodology on a larger scale.
Author contributions
N-benzylated pyridones 11b–f as depicted in Table 4, entries 3–7.
The use of o- or m-substituted benzyl bromides, 2j–p, as the
electrophile does not have any detrimental effect on the reaction
outcome, thus rendering the pyridone derivatives 11j–p with good
yields and high regioselectivity (Table 4, entries 8–11). The regio-
selective formation of the N-benzylated pyridone was further
ascertained based on the observation of cross peaks in the NOESY
spectra performed on pyridone 11e.24 Further, the scope was
enhanced by using various alkyl halides. Thus, phenacyl bromide
(2q), allyl bromide (2r) and 1-iodopentane (2s) provided the desired
N-alkylated pyridone 11q, 11r and 11s, respectively (Table 4, entries
12–14), whereas isopropyl iodide (2t) was found to be very sluggish
to react and the desired product was formed in a trace amount
(Table 4, entry 15).
The overall research program was managed by GS. Conceptua-
lization of the project and the management of research activity
were done by SAM, AKG and AVG. C-Benzylation reactions were
performed by AKG, TJ, AV and PB under the supervision of AVG.
Quinoline synthesis and pyridone N-alkylation were performed by
NAV and VK under the supervision of SAM. SAM wrote the overall
story of the manuscript along with AVG. The manuscript was further
edited by AKG and GS. All the authors discussed the manuscript.
Conflicts of interest
The authors declare no competing financial interest.
Finally, the methodology developed was probed for its application
on a large scale and for evaluating its ‘‘greenness’’ (Scheme 2). Thus,
4-nitrobenzyl bromide (2e) was chosen as a representative substrate
and was subjected to the arylalkylation reaction with ethyl-3-oxo-3-
phenylpropanoate (1a) using the optimized conditions on a 10 g
(52 mmol) scale. Upon completion, the reaction mixture was allowed
to stand at rt and the organic layer was separated and stirred with
water at 50 1C and further digested with hexanes to procure the
desired product 3ae with 99% purity by LCMS. The environmental
impact of this reaction condition, measured using the reported
modules,25 revealed an EcoScale value of 85 and an E-factor of
2.93, suggesting that the reaction conditions are process friendly as
well as environmentally friendly in nature.
In a similar manner, bromide 2e was treated with 2-pyridone
10 (10 g, 105 mmol) to furnish the desired N-benzylated pyridone
11e with high regioselectivity and excellent yield. Conventional work-
up was avoided by further diluting the reaction mixture with ice-cold
water, thus leading to the precipitation of the desired product 11e as
an off-white solid with 96% purity by LCMS. Measurement of the
‘‘green metrics’’ for the reaction suggests this to be an excellent
synthesis with an EcoScale value of 87 and an E-factor of 1.67.
Acknowledgements
We thank Mr Ajay Bhardwaj (CEO) and Mr Ravindra K. C.
(COO), Anthem Biosciences Pvt. Ltd for constant support and
encouragement. This work was supported financially by Anthem
Bioscience Pvt. Ltd, under the new technology development
program. Analytical support rendered by the ARD department
of Anthem Biosciences Pvt. Ltd is gratefully acknowledged.
Notes and references
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Conclusions
In summary, a highly regioselective mono-C-arylalkylation of
active methylene compounds using CTAB as the inverse phase
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