Tandem synthesis of aromatic amides from styrenes in water

Article abstract of DOI:10.1016/j.tetlet.2018.06.021

An expedient one-pot synthesis of aromatic amides has been reported from styrenes in the presence of N-bromosuccinimide and iodine by using aqueous ammonia in water. The reaction proceeds through the formation of α-bromoketone as an intermediate in the pr

Full text of DOI:10.1016/j.tetlet.2018.06.021

Accepted Manuscript
Tandem Synthesis of Aromatic Amides from Styrenes in Water
Pratima A. Sathe, Aniket S. Karpe, Aniket A. Parab, Babasao S. Parade,
Kamlesh S. Vadagaonkar, Atul C. Chaskar
PII:
S0040-4039(18)30763-9
https://doi.org/10.1016/j.tetlet.2018.06.021
TETL 50059
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
15 April 2018
5 June 2018
6 June 2018
Please cite this article as: Sathe, P.A., Karpe, A.S., Parab, A.A., Parade, B.S., Vadagaonkar, K.S., Chaskar, A.C.,
Tandem Synthesis of Aromatic Amides from Styrenes in Water, Tetrahedron Letters (2018), doi: https://doi.org/
10.1016/j.tetlet.2018.06.021
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Pratima A. Sathea, Aniket S. Karpea, Aniket A. Paraba, Babasao S. Paradea, Kamlesh S. Vadagaonkar*b, Atul C.
Chaskar*a

Tetrahedron Letters
Tandem Synthesis of Aromatic Amides from Styrenes in Water
Pratima A. Sathea, Aniket S. Karpea, Aniket A. Paraba, Babasao S. Paradea, Kamlesh S. Vadagaonkar*b
Atul C. Chaskar*a
aNational Centre for Nanosciences and Nanotechnology, University of Mumbai, Mumbai 400098, India
bDepartment of Dyestuff Technology, Institute of Chemical Technology, Mumbai 400019, India
Tel.: +91-7507375261; E-mail: achaskar25@gmail.com, vadgaonkarks@gmail.com
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An expedient one-pot synthesis of aromatic amides has been reported from styrenes in the
presence of N-bromosuccinimide and iodine by using aqueous ammonia in water. The reaction
proceeds through the formation of α-bromoketone as an intermediate in the presence of NBS and
water. α-Bromoketone on reaction with iodine forms bromodiiodoketone which on nucleophilic
substitution with aqueous ammonia gives aromatic amide. Substituted aromatic amides were
obtained in good yields with wide functional group compatibility.
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved.
Aromatic amides
N-Bromosuccinimide (NBS)
Iodine
Styrenes
Water
Introduction
reported several environment-friendly protocols, which include i]
I2 mediated direct transformation of acetophenones, carbinols to
benzamides by using aq. ammonia in water,17 ii] combination of
I2 with NaN3 in presence of a base to form benzamides from
acetophenones,18 iii] conversion of styrenes to benzamides in the
Amides fall under a category of well-known and widely
utilized molecules since they exist as integral structural units of a
variety of natural products.1-3 Moreover, amides have been
extensively employed in the manufacturing of pharmaceutical
compounds due to their wide range of biological activities e.g.
antifungal, antiprotozoal, anti-inflammatory, etc.4 Various amide
derivatives such as primary amides, aromatic and heteroaromatic
amides have been used as precursors for the synthesis of
numerous biomolecules, agrochemicals, plastics, detergents,
lubricants, and are crucial parts of many established drugs.4,5
o
presence of TBHP and aq. ammonia or amines at 105 C for 16
h,19 iv] use of Cu2O as a catalyst and TBHP as an oxidant to
obtain benzamides from aldehydes and ammonium chloride,20 v]
Cu2O catalyzed reaction of phenylacetic acids and α-
hydroxyphenyl acetic acids with aq. ammonia in water to obtain
benzamides.21 Recently, benzamides have also been prepared
from ethylarenes.22
Particularly, primary amides are important intermediates in
organic synthesis as a result of their facile conversion into
nitriles, primary amines and heterocycles.6 In this context, several
methods have been developed by researchers to synthesize
amides. Classical synthesis of primary amides involves the
reaction of various starting materials such as acyl halides, esters,
aldehydes, and mixed anhydrides with ammonia or its
equivalent.7
Although scientists have developed these methods with aims
to improve yields of amides and reduce environmental hazards,
majority of these synthetic protocols suffer from drawbacks such
as use of transition metal catalyst, hazardous as well as expensive
reactants/ reagents, organic solvents, longer reaction times,
higher reaction temperatures and low yield of products. Hence,
development of economically viable and environmentally benign
protocol is ever demanding and never ending process. In view of
our continuing interest in development of C-H functionalization
inspired protocols for the synthesis of key building blocks,23
herein we report the synthesis of aromatic amides from styrenes
in presence of NBS and iodine by using aq. ammonia in water as
a solvent (Scheme 1).
Other approaches used for the synthesis of primary amides
involve reduction of acyl azides and acyl hydrazides,8 as well as
hydration of nitriles in presence of acids, bases and transition
metal catalysts.9 Aldoximes undergo rearrangement in presence
of transition metal catalysts to produce amides.10 In addition,
metalloporphyrins-catalyzed oxidation of terminal alkynes,11
ruthenium-catalyzed dehydrogenative coupling of primary
alcohols with amines,12 direct oxidation of benzyl amines/ benzyl
alcohols,13,14 aerobic oxidative amidation of methylarenes,15
palladium-catalyzed aminocarbonylation of aryl halides,16 are
some other methods used for the preparation of amides.
Considering the necessity to develop a ecofriendly method in
order to reduce impact on environment, many researchers have
Scheme 1. Tandem synthesis of aromatic amides from styrenes.
 Corresponding author. Tel.: +91-7507375261; e-mail: achaskar25@gmail.com, vadgaonkarks@gmail.com

2
Initially, the reaction of styrene (1a) with 2.0 equiv N-
68-72% yields. Styrenes bearing electron-withdrawing
chlorosuccinimide (NCS) as a halogen source as well as an
oxidant in H2O was carried out at 80 C for 2 h. Iodine (2.2
substituents such as 4-NO2, 3-CF3 and 4-OCF3 produced
corresponding benzamides 2i-2k in good yields (74-76%).
Similarly, 2-vinylnaphthalene formed corresponding product 2l
in 82% yield. Heteroarylethylenes such as 2-vinylfuran and 2-
vinylthiophene formed respective products 2m and 2n in 60%
and 65% yields, respectively. The scope of this reaction was
extended by replacing aq. ammonia with n-butylamine. The
reaction offered corresponding amide 2o in 78% yield. We also
attempted one reaction with trans-β-methylstyrene as the starting
substrate. We observed the formation of 2-amino-1-
phenylpropan-1-one and 2-amino-2-bromo-1-phenylpropan-1-
one under the optimized reaction conditions confirmed by GC-
MS. However, we did not observe the formation of benzamide as
no haloform reaction took place due to presence of terminal
methyl group.
o
equiv) and 30% aq. ammonia solution (10 equiv) were added and
heating was continued for 1 h to afford benzamide (2a) in 65%
yield (Table 1, entry 1). The same reaction in the presence of N-
bromosuccinimide (NBS) and N-iodosuccinimide (NIS)
produced benzamide 2a in 80% and 68% yields, respectively
(Table 1, entries 2 and 3). To improve the yield of reaction, we
o
next studied the effect of temperature. The reaction at 70 C and
90 oC offered benzamide 2a in 70% and 75% yields, respectively
(Table 1, entries 4 and 5). Further, different solvents namely
DMSO, DMF and MeOH were screened for this reaction instead
of H2O. But, the reactions in these solvents could form
benzamide 2a only in trace amounts (Table 1, entries 6-8). This
clearly highlighted the key role of H2O as an oxygen source as
well as a solvent in this reaction. We also used different ammonia
sources such as (NH4)2CO3, (NH4)2SO4, NH4Cl and HCOONH4
for this reaction instead of aq. ammonia to check the possibility
of enhancement in the yield (Table 1, entries 9-12). However, all
of these reactions were failed to produce benzamide 2a. Thus,
use of 2.0 equiv NBS and 2.2 equiv I2 at 80 °C with a combined
time of 3 h in water as a solvent was found to be the best reaction
condition for the conversion of styrene 1a to benzamide 2a
resulting in 80% yield of the product.
Table 2 Tandem metal-free synthesis of aromatic amides from
styrenes.a,b
Table 1 Optimization of reaction conditions.a
Entry Halogen source
Ammonia source Solvent Yield (%)b
1
2
NCS
NBS
NIS
NH3.H2O
NH3.H2O
NH3.H2O
NH3.H2O
NH3.H2O
NH3.H2O
NH3.H2O
NH3.H2O
(NH4)2CO3
(NH4)2SO4
NH4Cl
H2O
H2O
H2O
65
80
3
68
4c
5d
6e
7e
8e
9f
10f
11f
12f
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
H2O
70
H2O
75
DMSO
DMF
MeOH
H2O
trace
trace
trace
ND
ND
ND
ND
a Reaction conditions: substituted styrene 1 (1.0 mmol), NBS (2.0 mmol) and
water (2.0 mL) were heated at 80 oC for 2 h, then iodine (2.2 mmol), 30% aq.
ammonia or n-butylamine (10 mmol) were added and heating continued at 80
oC for 1 h.
b Isolated yields.
H2O
To gain insights into the reaction mechanism, few control
H2O
experiments were performed (Scheme 2). When styrene (1a) was
o
HCOONH4
H2O
reacted with NBS in water at 80 C for 2 h, formation of α-
bromoacetophenone (D) was observed (Scheme 2, a). This
indicated that the reaction involves formation of α-
a Reaction conditions: styrene 1a (1.0 mmol), halogen source (2.0 mmol) and
solvent (2.0 mL) were heated at 80 oC for 2 h, then iodine (2.2 mmol),
o
ammonia source (10 mmol) were added and heating continued at 80 C for 1
bromoacetophenone
(D)
as
an
intermediate.
α-
h.
Bromoacetophenone (D) on reaction with iodine and aq.
ammonia in water produced benzamide 2a in good yields
(Scheme 2, b).
b Isolated yields.
c Reaction performed at 70 oC.
d Reaction performed at 90 oC.
e Reaction performed with different solvents.
f Reaction performed with different ammonia sources. ND= Not Detected.
With optimized reaction conditions in hand, we investigated
the scope and limitations of this one-pot reaction by using
different substituted styrenes. Various functional groups were
found to be compatible under the optimized reaction conditions
forming the desired products 2a-2o (Table 2) in good yields.
Styrene 1a furnished benzamide 2a in 80% yield under the
optimized reaction conditions. Styrenes bearing halogen
substituents such as 3-Br, 3-Cl, 4-Br and 2,4-Cl2 offered
corresponding benzamides 2b-2e in yields ranging from 81-84%.
Styrenes with electron-donating substituents such as 4-Me, 2-
OMe and 2,5-di-OMe afforded respective benzamides 2f-2h in
Scheme 2. Control experiments.

3
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On the basis of control experiments, a plausible mechanism for
this transformation is depicted in Scheme 3. Initially, styrene (1a)
in the presence of NBS forms cyclic bromonium ion A which
undergoes a ring opening through nucleophilic attack of H2O to
give bromohydrin B as an intermediate. Bromohydrin B in the
presence of NBS undergoes oxidation to form α-
D on subsequent
iodination with iodine forms bromodiiodoketone E which on
haloform reaction with aq. ammonia offers benzamide (2a).
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In conclusion, we have developed an efficient and practical
one-pot synthesis of substituted benzamides from easily available
styrenes in the presence of N-bromosuccinimide and iodine by
using aq. ammonia in water. Use of inexpensive reagents, water
as an oxygen source as well as a solvent, metal-free conditions,
broad substrate scope, good yields of benzamides are notable
features of this protocol. We strongly believe that this protocol
will be widely used for the synthesis of benzamides.
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Acknowledgment
P.A.S. thanks University Grants Commission, New Delhi, for
providing fellowship. A.S.K., B.S.P. and A.A.P. thank Defence
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(ERIP/ER/1503212/M/01/1666), New Delhi, India for funding
support. K.S.V. and A.C.C. thank DST-SERB, India (sanction
no. SB/FT/CS-147/2013) for financial support.
Supporting Information
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amides: A sealed tube equipped with a magnetic stirring bar was
charged with styrene 1 (1.0 mmol), NBS (2.0 mmol) and water
(2.0 mL) at room temperature. The resulting mixture was heated to
o
80 C for 2 h. After disappearance of the reactant (monitored by
TLC), reaction mixture was cooled to room temperature. To this
reaction mixture molecular iodine (2.2 mmol) and 30% aq.

5
Highlights of the work
 A metal-free tandem protocol
 An efficient access to aromatic amides from
readily available styrenes
 Use of inexpensive reagents such as N-
bromosuccinimide (NBS) and iodine with
easy operational procedure
 Use of water as an oxygen source as well as
a solvent
 Wide functional group compatibility and
good yields of the products