Br?nsted Acid Mediated Nucleophilic Functionalization of Amides through Stable Amide C?N Bond Cleavage; One-Step Synthesis of 2-Substituted Benzothiazoles

Article abstract of DOI:10.1002/ejoc.202100645

We have developed a Br?nsted acid mediated synthetic method to directly cleave stable amide C?N bonds by a variety of alcohol and amine nucleophiles. Reverse reactivity was observed and alcoholysis of amides by activated primary and secondary benzylic, and propargylic alcohols have been achieved instead of the expected nucleophilic substitution of alcohols. As an application, 2-substituted benzothiazole derivatives have been synthesized in one pot employing 2-aminothiophenol as nucleophile.

Full text of DOI:10.1002/ejoc.202100645

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Brønsted Acid Mediated Nucleophilic Functionalization of Amides
through Stable Amide C-N Bond Cleavage; One Step Synthesis
of 2-Substituted Benzothiazoles
Authors: Srabani Maity, Arnab Roy, Surajit Duari, Subrata Biswas,
Asma M Elsharif, and Srijit Biswas
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202100645
Link to VoR: https://doi.org/10.1002/ejoc.202100645
01/2020

10.1002/ejoc.202100645
European Journal of Organic Chemistry
COMMUNICATION
Brønsted Acid Mediated Nucleophilic Functionalization of Amides
through Stable Amide C-N Bond Cleavage; One Step Synthesis of
2-Substituted Benzothiazoles
Srabani Maity,†[a] Arnab Roy,†[a] Surajit Duari,[a] Subrata Biswas,[a] Asma M. Elsharif,[b] and Srijit
Biswas*[a]
Dedication ((optional))
[a]
Ms. S. Maity, Mr. A. Roy, Mr. S. Duari, Mr. S. Biswas, Dr. S. Biswas
Department of Chemistry
University of Calcutta
92, A. P. C. Road, Kolkata 700009, W. B. INDIA
E-mail: sbchem@caluniv.ac.in; srijit_biswas@yahoo
Dr. A. M. Elsharif
[b]
Department of Chemistry, College of Science
Imam Abdulrahman Bin Faisal University
P.O. Box 1982, Dammam 31441, SAUDI ARABIA
These authors contributed equally
†
Supporting information for this article is given via a link at the end of the document.
Abstract: We have developed a Brønsted acid mediated synthetic
method to directly cleave stable amide C–N bonds by a variety of
alcohol and amine nucleophiles. Reverse reactivity was observed
and alcoholysis of amides by activated primary and secondary
benzylic, and propargylic alcohols have been achieved instead of the
expected nucleophilic substitution of alcohols. As an application, 2-
substituted benzothiazole derivatives have been synthesized in one
pot employing 2-aminothiophenol as nucleophile.
Amides are important class of organic compounds and key
building block of proteins as well as several biologically active
molecules.[1] These moieties are reported as thermodynamically
stable enough due to conjugation of nitrogen lone pair to the
carbonyl group.[2] Owing to its nucleophilic character, primary
amides are widely employed as N-centered nucleophile to
construct new C–N bonds during the last two decades[3,4]
through catalytic direct nucleophilic substitution of the hydroxy
group of activated alcohols.[4] However, the opposite reactivity,
i.e., functionalization of amides through nucleophilic substitution
of the amide C–N bonds are rare although Nature can easily
cleave amides through the action of enzymes, such as
proteases.[5] Among the chemical transformations of amide,[6]
alcoholysis has drawn much interest to the chemists, as the
resulting esters become much more reactive than the amide
which can farther undergo a range of useful transformations.[7] In
a ground breaking work, Hie and co-workers[8] reported a
method of conversion of amides to esters by nickel-catalyzed
activation of amide C–N bonds (Scheme 1A).[8a] Their method
was found to be successful employing tertiary amide as the
electrophile. A handful the alcoholysis of tertiary amide has also
been reported by other groups subsequently, but they too are
limited to tertiary amides.[9] Sun and co-workers reported an iron-
catalyzed esterification of amides via C–N bond activation using
excess HCl as additive.[10a] Corma and co-workers have recently
explored the catalytic
Scheme 1. Previous reports of alcoholysis of amides, nucleophilic substitution
of alcohols and this work.
activity of Zr-MOF-808 for amide esterification.[10b] Importantly,
activated alcohols which are susceptible to nucleophilic
substitution by the amides (Scheme 1B) has rarely been
reported.[11] To address these issues such as limited substrate
scope, excess amounts of use of toxic additives, and use of
transition metal catalysts, we herein report a simple and general
protocol of Brønsted acid mediated alcoholysis and trans-
amidation of amides through amide C–N bond functionalization.
A wide range of primary as well as secondary, and tertiary
1
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10.1002/ejoc.202100645
European Journal of Organic Chemistry
COMMUNICATION
amides were successfully employed as electrophiles and
primary, secondary, aromatic and activated alcohols and amines
as nucleophiles. To the best of our knowledge, this is the first
report of a general and single protocol under which alcoholysis
of 1°, 2° and 3° amides by activated and unactivated primary,
secondary, benzylic, propargylic, aliphatic and aromatic alcohols
has been achieved; instead of the expected nucleophilic
substitution products for activated alcohols (Scheme 1C). As an
application, important heterocycles such as 2-substituted
benzothiazole derivatives[12] were synthesized in one pot using
2-aminothiophenol as nucleophile. This benzothiazole forms a
part of firefly luciferin and aroma constituents of tea leaves.[10]
Also, the structural motif has drawn keen interest due to their
wide range of biological application viz. anti-cancer,[13] anti-
microbial,[14] anti-convulsant,[15] anti-viral,[16] analgesic,[17] anti-
diabetic,[18] anti-inflammatory,[19] fungicidal activities.[20] It is
noteworthy that, a subtle strategy was taken to make the
molecules water soluble by tagging amino acid with
benzothiazole molecules. It is found that amino acid levelled
water soluble prodrugs known as Phortress shows anti-tumour
activity against human mammary carcinoma cell lines which is
comparable to doxorubicin.[21]
trifluoroacetic acid (TFA) was found to be the best to mediate
the reaction between 1a and 2a to generate 3a. Unfortunately,
using TFA in catalytic amount generated the product, but in low
yield.
Table 2. Substrate scope of alcoholysis of amides and trans-amidation.[a]
Table 1. Optimization of reaction parameters.
Entry
1
Deviation from Reaction Condition A
None
Yield (%)[a]
82
50
12
10
0
2
110 °C
3
p-TSA·H2O instead of TFA
TfOH instead of TFA
Trizma hydrochloride instead of TFA
PhB(OH)2 instead of TFA
20 mol% TFA
4
5
6
0
[a] Reaction conditions: 1 (0.5 mmol), 2 (1.25 mmol), TFA (0.5 mmol), in
toluene solvent (1.5 mL) at 130 °C for 18 h. [b] The reaction was run for 48 h.
[c] Benzanilide (1f) was used in place of benzamide (1e). [d] Weinreb amide
(1g) was used in place of benzamide (1e).
7
16
76
80
71
68
8
1.0 mmol 2a
9
1.5 mmol 2a
The optimized reaction conditions were applied to a variety
of amides and alcohols the results of which are summarized in
Table 2. The protocol was found to be general with respect to
primary and secondary benzylic, propargylic, aliphatic, aromatic,
and natural alcohols. Secondary benzylic alcohol such as 1-
phenyl ethanol (2a) which is susceptible to nucleophilic
substitution of the hydroxyl group[4] showed reverse reactivity
when subjected to react with 4-nitro benzamide (1a) generating
the corresponding ester 3a in 82% yields. 1a also reacted with
propargylic alcohols 2b and 2c to furnish the esters 3b and 3c in
65% and 60% yields respectively. Benzyl alcohol 2d
successfully reacted with 1a to generate the product 3d in 45%
yield. Other types of primary and secondary alcohols, such as,
2-phenylethan-1-ol (2e), 3-phenylpropan-1-ol (2f), 2-propanol
10
11
1.0 mL PhMe
2.0 mL PhMe
[a] Yield refers to pure and isolated products.
To optimize the reaction parameters,
a
challenging
combination of substrates 4-nitrobenzamide (1a) and 1-phenyl
ethanol (2a) were chosen considering their susceptibility of
direct nucleophilic substitution of 2a (Scheme 1B). The
temperature and the time were fixed at 130 °C and 18 h after an
initial screening. As a continuation of our effort to develop
transition metal-free Brønsted acid catalyzed protocol,[22]
variety of Brønsted acids were tested (Table 1). 1 equivalent of
a
2
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10.1002/ejoc.202100645
European Journal of Organic Chemistry
COMMUNICATION
(2g), 3-methylbutan-1-ol (2h) and heptan-2-ol (2i) reacted
smoothly with 1a to furnish the desired products 3e–3i in good to
excellent yields. Aromatic alcohols such as phenol (2j) and p-
cresol (2k) also serve as O-centered nucleophile under the
optimized reaction conditions to generate 3j and 3k in 60% and
55% yields respectively.[23] Importantly, naturally occurring
alcohols such as menthol (2l) and cholesterol (2m) generated
the desired ester 3l and 3m in 60% and 52% yield respectively
when subjected to react with 1a. The protocol was found to be
general with respect to the amides. Presence of methoxy (1b)
and chloro (1c) groups in the aromatic ring of the amide did not
affect the outcome of the reaction. It is noteworthy to mention
that secondary and tertiary amides such as benzanilide (1f) and
Weinreb amide (1g) were found to be susceptible under the
present reaction conditions. Along with benzamide (1e), 1f and
1g also reacted with alcohol 2e and 2i to generate the product in
85%, 92%, 90%; and 60%, 92%, 90% yields, respectively.
Cinnamamide (1h) also showed excellent reactivity and
generated the ester 3t in quantitative yield when subjected to
react with 2e. The scope of the present protocol was further
generalized when it was observed that benzylamine (2n) was
also acted as N-centered nucleophile and reacted with all types
of amides to generate the products 3u–3z in good to excellent
yields.
substitution of alcohols. Natural alcohols such as menthol and
cholesterol took
Scheme 2. Plausible mechanism of alcoholysis of amides.
part in the reaction under the present reaction conditions to
generate the desired esters. Structurally important 2-substituted
benzothiazole derivatives have been synthesized in one pot
employing 2-aminothiophenol as nucleophile.
Table 3. One step synthesis of 2-substituted benzothiazole derivatives.[a]
Experimental Section
General procedure for TFA mediated amide C–N bond activation to
synthesize the products (3a–3z) (Table 2): Amide 1a–1h (0.5 mmol),
nucleophile (alcohol or amine) 2a–2n (1.25 mmol) and freshly distilled
toluene solvent (1.5 mL) were taken in a 5 mL VWR reaction vial
containing a small magnet without using inert atmosphere, then TFA (40
µL, 0.5 mmol) was added. The cap of the vial was closed and the
reaction mixture was stirred at r. t. for 5 min then reaction mixture was
stirred at 130 °C for 18 h in an aluminum dry heating block. After
completion of the reaction (by TLC, 1H NMR), the crude was directly
purified by silica-gel (100–200 mess) column chromatography (flash)
using ethyl acetate /hexane solution to afford the desired products 3a–3z.
[a] Reaction conditions: 1 (0.5 mmol), 2 (1.25 mmol), TFA (0.5 mmol), in
toluene solvent (1.5 mL) at 130 °C for 18 h.
As an important application, the present method was found
to be useful for direct synthesis of 2-substituted benzothiazole
derivatives (Table 3). 2-Aminothiophenol (2o) reacted with
amides 1c, 1e and 1d under the developed reaction conditions
to generate 4a, 4b, 4c respectively in 82%, 60% and 64% yields
respectively. The reaction proceeded via sequential nucleophilic
substitution of aryl C–N bonds through S-center of 2o to
Acknowledgements
generate
intermediate
5
which
upon
intramolecular
SB acknowledge the University Grants Commission (UGC), Govt.
of India for start-up grant through FRP program (F.4-5(80-
FRP)(IV-Cycle)/2017(BSR)). SM thanks DST-INSPIRE program
for her fellowship. AR, SD and SB thank CSIR, Govt. of India for
their fellowships.
condensation produce the desired products. Amide 1h was also
successfully employed to generate 2-vinyl substituted
benzoxazole derivative 4d in 90% yields.
Based on the results and previous report,[7c] a mechanism of
alcoholysis of amide has been proposed where the amide (1)
was first protonated by the acid to generate 1’ which facilitated
the nucleophilic addition of the alcohol (2) to generate
intermediate 2’. Finally, elimination of amine from 2’ generated
the desired ester 3 (Scheme 2).[24]
Keywords: Brønsted Acid
• Amide • Functionalization •
Benzothiazole • Amide C–N Bond Cleavage
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In conclusion, we have developed a Brønsted acid mediated
general synthetic protocol to directly cleave amide C–N bonds
by a variety of alcohol and amine nucleophiles. Reverse
reactivity was observed when activated primary and secondary
benzylic, and propargylic alcohols were used yielding the
corresponding esters instead of the expected nucleophilic
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10.1002/ejoc.202100645
European Journal of Organic Chemistry
COMMUNICATION
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[24] The possibility of hydrolysis of the amide to the corresponding acid
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apparatus under inert atmosphere.
.
4
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10.1002/ejoc.202100645
European Journal of Organic Chemistry
COMMUNICATION
Entry for the Table of Contents
Insert graphic for Table of Contents here. ((Please ensure your graphic is in one of following formats))
A TFA mediated general and simple synthetic protocol to directly cleave stable amide C–N bonds by a variety of alcohol and amine
nucleophiles has been developed. Natural alcohols such as menthol and cholesterol took part in the reaction under the present
reaction conditions to generate the desired esters. Structurally important 2-substituted benzothiazole derivatives have been
synthesized in one pot employing 2-aminothiophenol as nucleophile.
Institute and/or researcher Twitter usernames: SrijitDr
5
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