Three-component synthesis of amidomethylarenes and -heteroarenes over HΒ zeolite under solvent-free conditions

Article abstract of DOI:10.1016/j.catcom.2017.11.002

A highly efficient and eco-friendly protocol has been described for the synthesis of amidomethylarenes and -heteroarenes via one-pot three-component coupling reaction of amides, aldehydes and (hetero)arenes over a heterogeneous catalyst (Hβ zeolite) in solvent-free conditions. The scope and limitations of this catalytic process are demonstrated with various amides and arenes and the corresponding amidoalkylated arene products were obtained in moderate to excellent yields. The preliminary mechanistic insight (control experiments) suggest that bisamide and/or N-(hydroxymethyl)benzamide are probable intermediates in this reaction. Moreover, the catalyst can be reused without any significant loss of the catalytic activity and only water is produced as by-product.

Full text of DOI:10.1016/j.catcom.2017.11.002

Accepted Manuscript
Three-component synthesis of amidomethylarenes and -
heteroarenes over Hβ zeolite under solvent-free conditions
Durgaiah Chevella, Naresh Mameda, Srujana Kodumuri,
Rammurthy Banothu, Krishna Sai Gajula, Boris Ivanovich
Kutepov, Narender Namaa
PII:
DOI:
Reference:
S1566-7367(17)30450-8
doi:10.1016/j.catcom.2017.11.002
CATCOM 5242
To appear in:
Catalysis Communications
Received date:
Revised date:
Accepted date:
7 July 2017
31 October 2017
6 November 2017
Please cite this article as: Durgaiah Chevella, Naresh Mameda, Srujana Kodumuri,
Rammurthy Banothu, Krishna Sai Gajula, Boris Ivanovich Kutepov, Narender Namaa
, Three-component synthesis of amidomethylarenes and -heteroarenes over Hβ zeolite
under solvent-free conditions. The address for the corresponding author was captured
as affiliation for all authors. Please check if appropriate. Catcom(2017), doi:10.1016/
j.catcom.2017.11.002
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ACCEPTED MANUSCRIPT
Three-componentsynthesis of amidomethylarenes and -heteroarenes overHβ
zeolite under solvent-free conditions
Durgaiah Chevellaa, Naresh Mamedaa,b, Srujana Kodumuria, Rammurthy Banothua,b, Krishna Sai
Gajulaa,b, Boris Ivanovich Kutepovc, Narender Namaa,b,*
a I&PC Division, CSIR-IICT, Hyderabad 500 007, India
b Academy of Scientific and Innovative Research, CSIR-IICT, Hyderabad 500 007, India
c
IPC RAS, 141 prosp, Oktyabrya, 450075 Ufa, Russian Federation
* Corresponding author. Tel.: +91–40-27191703; Fax: +91-40-27160387/27160757.
E-mail address: narendern33@yahoo.co.in; nama.iict@gov.in

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ABSTRACT
A highly efficient and eco-friendly protocol has been described for the synthesis of
amidomethylarenes and -heteroarenes via one-pot three-component coupling reaction of amides,
aldehydes and (hetero)arenes over a heterogeneous catalyst (Hβ zeolite) in solvent-free
conditions. The scope and limitations of this catalytic process are demonstrated with various
amides and arenes and the corresponding amidoalkylated arene products were obtained in
moderate to excellent yields. The preliminary mechanistic insight (control experiments) suggest
that bisamide and/or N-(hydroxymethyl)benzamide are probable intermediates in this reaction.
Moreover, the catalyst can be reused without any significant loss of the catalytic activity and
only water is produced as by-product.
Keywords: Amides, Arenes, Multicomponent reactions, Heterogeneous catalysis, Zeolites.

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1. Introduction
In recent years, multicomponent reactions (MCRs) are becoming a powerful synthetic
approach [1-3] to generate compounds with structural complexity and diversity in a single
step, with improved atom and time economy, simplicity and a lower number of reactions
and purification steps [4,5]. In particularly, coupling of aldehydes, alkynes and amides
(A3-coupling) is one of the best examples of such a process and this alteration has
received much attention [6,7]. Amidoalkylated arenes and heteroarenes obtained from A3-
coupling reactions are synthetically versatile and key intermediates for the preparation of
many biologically active nitrogen compounds and biological active molecules [8], such as
luotonin A [9], an alkaloid, or the antiretroviral Raltegravir [10]. Hence, the synthesis of
α-substituted amide derivatives has attracted great interest to synthetic chemists. Among a
variety of methods for the synthesis of functionalized α-substituted amides, three-
component aza-Friedal-type amidoalkylations with in situ generated acylimines or
acyliminium ions is one of the most straightforward and atom-economic approach to
access a variety of corresponding α-substituted amides [11-15]. Especially, the in situ
generation of reactive imine derivatives from an aldehyde and an amide embodies an
atom-economical [16] synthesis of amidoalkylated (hetero)arenes due to the fact that
water is only side product and these reactions could meet the requirements of modern
sustainable organic synthesis [17]. However, most of these methods experience one or
more disadvantages, such as the use of stoichiometric amounts of Lewis or Brønsted acids
[18-20] and the substrate scope is strictly limited to the indole and naphthol [21-23].
Recently, Bi(OTf)3-catalyzed three-component reaction between amides, formaldehyde

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and arenes was reported by George Manolikakes et al. and Jaratjaroonphong et al. [24-26].
However, the recovery and reuse of catalyst and the need of organic solvent as the
reaction medium are the main drawbacks associated with this system. Therefore, the
development of a solvent-free and eco-friendly heterogeneous catalytic method for the
synthesis of amidomethylarenes and -heteroarenes from amides, formaldehyde and arenes
is highly desirable.
Solvent-free synthesis is an important part of green chemistry because of need to eliminate
the use of toxic organic solvents, which are the cause for the majority of waste and pollution
generated by chemical processes. Furthermore, there are distinct advantages of these solvent-free
protocols, such as reduction costs, less energy requirements, faster reaction rates and thus
reduction in reactor size and capital investment [27-29]. Over the past decades, catalysis by
zeolites and related materials has become an attractive research area in the fields of
heterogeneous catalysis and green chemistry. As an important type of solid acid catalysts,
zeolites have been extensively used for replacement of highly toxic and corrosive mineral acids
or inorganic Lewis acids in the synthesis of fine chemicals [30, 31]. This is mainly due to the fact
that zeolites have well defined porous structures with large amount of acid sites (both Bronsted
and Lewis type) present on the inner surface of these zeolitic materials. One of the most
important properties of zeolites is the great variety of topologies and pore architectures, together
with the possibility to adjust their acidity (type, concentration and strength of acid sites) [32, 33].
Hence, the catalytic activity of zeolites could be tailored for special chemical transformations.
Additionally, their eco-friendly nature, high surface area and adsorption capacity, chemical and
thermal stability, make them ideal materials for heterogeneous catalysis. In a continuation of our
efforts toward the development of novel and eco-friendly synthetic procedures using zeolites

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[34], we herein report a new, efficient and environmentally friendly catalytic method for the
synthesis of amidomethylarenes and -heteroarenes from amides, formaldehyde and
(hetero)arenes over Hβ zeolite under solvent-free conditions.
2. Results and discussion
2.1. Catalyst screening
In the initial investigation, the reaction between benzamide (1a), aqueous formaldehyde (2a)
and m-xylene (3a) was chosen as a model system to optimize the different parameters of the
reaction. The reaction was performed with various zeolites, HMCM-41, montmorillonate K10,
SiO2, SiO2-Al2O3, HCl, H2SO4 and L-proline at 100 °C in a sealed tube for 10 h to find out the
best catalyst (Table 1, entries 1-12). Among the catalysts screened, Hβ zeolite displayed a higher
catalytic activity and gave 4a product yield of 91% (Table 1, entry 5).
2.2. Optimization of reaction conditions
The influence of temperature was investigated, after found the best catalyst (Hβ zeolite) for
this transformation. The reaction was remarkably accelerated by varying the reaction temperature
o
from room temperature to 100 C, and the yield was increased from 0 to 91% (Table 1, entries 5
and 14-16). The molar ratio of formaldehyde and arene had a significant influence on the product
yield (Table 1, entries 5 and 17-20). The present reaction was also conducted with different
amounts of catalyst. It was found that 100 mg of catalyst gave the best result (Table 1, entries 5
and 21-23). The product 4a was not obtained in the absence of catalyst, thus confirming the

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Table 1: Screening of reaction conditions for the synthesis of N-(2,4-dimethylbenzyl)benzamide.
Entry
Catalyst
Temperature
(°C)
100
100
100
100
100
100
100
100
100
100
100
100
100
RT
Yield (%)a
4a
20
-
5a
35
62
-
1
2
3
HY
NaY
HZSM-5(40)
H-mordenite
49
4
-
91
5
-
6
29
<3
<5
36
-
5b
Hβ
HMCM-41
Montmorillonate K10
6
7
8
9
SiO2
SiO2-Al2O3
HCl
H2SO4
9
-
10b,c
11c
12c
13
54
44
-
20
21
-
L-proline
Without catalyst
-
-
14
15
Hβ
Hβ
Hβ
Hβ
Hβ
Hβ
Hβ
Hβ
Hβ
Hβ
-
-
60
80
38
68
34
80
51
92
32
54
70
-
-
5
10
18
<3
-
-
-
16b
17d
18b,e
19b,f
20b,g
21h
22b,i
23b,j
100
100
100
100
100
100
100
Reaction conditions: 1a (1 mmol), aqueous formaldehyde (2a) (37%,
1.5 mmol), 3a (2 mmol), catalyst (100 mg), 100 °C, 10 h, sealed
tube. a Isolated yields. b Obtained as a 12:1 mixture of regioisomers.
c 30 wt.% of catalyst. d 2a (37%, 1 mmol). e 2a (37%, 2 mmol).
f 3a (1 mmol). g 3a (3 mmol). h Catalyst (25 mg). i Catalyst (50 mg).
j Catalyst (75 mg).

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catalyst role in the reaction (Table 1, entry 13). In all cases, the amidoalkylated product was
obtained as a mixture of regioisomers (12:1 ortho/para -vs ortho/ortho-substitution). After
extensive screening, we have observed that 1:1.5:2 molar ratio of benzamide, formaldehyde and
m-xylene (1 mmol of benzamide, 1.5 mmol of aqueous formaldehyde and 2 mmol of m-xylene)
o
at 100 C over Hβ zeolite (100 mg) under solvent-free conditions are the optimum conditions to
get the maximum yield of the desired product.
2.3. Variation of carboxamides
With the optimized conditions established, the generality of the Hβ zeolite-catalyzed
approach was investigated with a variety of amides (Table 2). Surprisingly, all the
carboxamides used in the reaction were reacted smoothly with formaldehyde and m-
xylene to afford moderate to excellent yields of the corresponding amidomethylated arene
products (Table 2). The reaction with various electron-donating groups present on

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Table 2: Variation of carboxamides.a
a
Reaction conditions: 1a-1p (1 mmol), 2a (37%, 1.5 mmol), 3a (2
b
mmol), Hβ zeolite (100 mg), 100 °C, 10 h, sealed tube. Isolated
yields.
c
d
Temperature (80 °C).
Obtained as a mixture of
regioisomers, ratio of regioisomers given in parentheses.

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aromatic ring of benzamide furnished respective products in 72-92% yields (Table 2, 4a-
4d). Electron-withdrawing groups bearing benzamides also afforded the corresponding
products in 65-85% yields (Table 2, 4g-4i). Halogen substituted aromatic amides
participated well in this reaction to afford the desired products in 74 and 72% yields,
respectively (Table 2, 4e and 4f). In the case of heteroaryl amides, different results were
observed. Thiophene-2-carboxamide proceeded smoothly and afforded the corresponding
product in 94% yield (Table 2, 4j), whereas nicotinamide and picolinamide did not react
under the present reaction conditions even after a prolonged reaction time (Table 2, 4k
and 4l). Notably, cinnamamide afforded the respective product in 51% yield (Table 2,
4m). Further, the efficiency of this reaction was also investigated with aliphatic amides
i.e., acrylamide, acetamide and propanamide provided the corresponding products in 48-
56% yields (Table 2, 4n, 4o and 4p).
2.4. Variation of arenes and heteroarenes
Under similar reaction conditions, a variety of arenes were employed to further extend the
scope of the Hβ zeolite, which is the promotion of the three-component coupling reaction (Table
3). The results show that both aromatic and heteroaromatic arenes (except electron-poor
heteroarenes) underwent the multicomponent reaction smoothly to provide the corresponding
amidomethylated arene products, in moderate to excellent yields, with high regioselectivity
(Table 3, 4aa-4aj and 4am-4ar). Di- and tri-alkyl substituted arenes (p-xylene, mesitylene,
1,2,4-trimethylbenzene and 4-tert-butyltoluene) yielded the respective products in 62-82% yields
(Table 3, 4aa-4ad). Whereas mono alkyl substituted benzenes (toluene 3k and cumene 3l) were
unsuccessful under similar reaction conditions due to the fact that the methyl and isopropyl
(mono alkyl benzene) are less ring activating groups compared to other activating groups (Table

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3). Anisole and substituted anisoles furnished the desired amidoalkylated products in 64-92%
yields (Table 3, 4ae-4ai). 4-Methoxyphenol also afforded the corresponding amidoalkylated
product in 85% yield (Table 3, 4aj). The electron-rich naphthalenes such as 2-
methoxynaphthalene and 1-methoxynaphthalene were reacted smoothly and yielded the
Table 3: Variation of arenes and heteroarenes.a
a
Reaction conditions: 1a (1 mmol), 2a (37%, 1.5 mmol), 3a-3r (2
b
c
mmol), Hβ (100 mg), 100 °C, 10 h, sealed tube. Isolated yields.
Temperature (80 °C). Obtained as a mixture of regioisomers,
d
ratio of regioisomers given in parentheses.

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respective products in 94 and 70% yields (Table 3, 4am and 4an). In the case of heterocycle
arenes, electron-rich heterocycles, such as different substituted thiophenes and 2-methyl furan,
gave the corresponding amidomethylated arene products in 54-83% yields (Table 3, 4ao-4ar).
On the contrary, electron-deficient heteroaromatic arenes (2-methylpyridine, 3-methylpyridine
and 3,6-dimethylpyridine) were unsuccessful under similar reaction conditions.
In heterogeneous catalysis, the recovery and reusability of the catalyst is an important
feature for their industrial applications and environmental considerations. The catalyst (zeolite)
was easily separated from the reaction mixture by simple filtration and the collected catalyst was
calcined at 450 °C to use in the next cycle. The reusability of the catalyst was checked by the
reaction of benzamide with formaldehyde and m-xylene under standard reaction conditions. The
reused catalyst showed persistent activity even after the fifth reuse (see the ESI, Fig. S1). The
powder XRD analysis of reused catalyst matched well with fresh catalyst, thus suggesting that
the crystallinity of the reused catalyst is comparable to the original material (see the ESI, Fig.
S2). There was no leaching of aluminium or silicon from zeolite (Hβ) which was confirmed by
elemental analysis.
2.5. Temperature-programmed desorption of ammonia (NH3-TPD)
Temperature-programmed desorption of ammonia (NH3-TPD) was carried out to determine
the amount and strength of acid sites present in the Hβ zeolite. The NH3-TPD profile recorded is
shown in Fig 1. Two desorption peaks are observed centered at 205 and 380 °C on the Hβ
zeolite, corresponding to its weak (53.8%) and strong (46.2%) acidic sites, respectively. The total
amount of acidity measured by NH3-TPD for the Hβ zeolite was 1.16 mmol/g. These results
reveal that the combination of weak and strong acidic sites are largely responsible for the high
yields of the corresponding amidomethylarene and -heteroarene products (4) in this reaction.

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200
300
400
500
600
700
Temperature (oC)
Fig. 1: NH3-TPD profile recorded on Hβ zeolite.
2.6. Activity studies and FT-IR spectra of fresh, pyridine and 2,6-dimethylpyridine adsorbed Hβ
zeolite
In order to know the nature of active sites for this reaction, we have performed two separate
experiments. For this purpose, two bases were chosen as acid site blockers, such as pyridine and
2,6-dimethylpyridine. These bases were adsorbed on the Hβ zeolite separately. The surface
poisoned samples were analyzed by FT-IR and used for the three-component coupling reaction
of benzamide, formaldehyde and m-xylene (see ESI for further details). The results show that
Bronsted acid sites are responsible for this reaction.
2.7. Control experiments
After evaluating the scope and limitations of this present catalytic system, we were
interested in gaining insight into the reaction mechanism. In this context, a couple of experiments
were carried out and these are presented in Scheme 1. During our initial screenings with Hβ

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zeolite, we could observe the formation of bisamide (6a) along with N-
(hydroxymethyl)benzamide (5a), and these are the expecting intermediates which we prepared
for both products using our previous report [Scheme 1, Eq. (1) and (2)] [35]. To find the
intermediate for this transformation, we performed the reaction between bisamide and 4-
bromoanisole in the presence of Hβ catalyst, where the expected amidoalkylated product in 64%
yield was obtained [Scheme1, Eq. (3)]. The reaction of N-(hydroxymethyl)benzamide with 4-
bromoanisole also gave the same product [Scheme 1, Eq. (4)].
Scheme 1: Control experiments.
Based on the above investigated results and literature reports [24, 25], a plausible reaction
mechanism for the three-component amidoalkylation reaction over Hβ zeolite has been proposed
as shown in Scheme 2. It is speculated that the reaction is initiated by the adsorption of
formaldehyde on the acid sites of Hβ zeolite (Bronsted acid sites activates the carbonyl group of
the formaldehyde and weak conjugate base (framework oxygen) activates the amine group of the
amide), which subsequently reacts with amide (I) to provide the carbinolamide intermediate (II).
After formation of the carbinolamide intermediate, two different paths were evaluated based on
the above experimental reactions, either an elimination of water leads to the formation of a

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reactive acylimine or acyliminium species, or it further reacts with another amide in the presence
of acidic sites of zeolite to give the bisamide (III), which can decompose to form the acylimine.
In the presence of a suitable nucleophilic arene, the electrophilic acylimine can react in an aza-
Friedel-Crafts reaction to afford the amidoalkylated product (IV).
Scheme 2: Proposed mechanism.
3. Conclusions
In summary, we have developed a simple and green protocol for the three-component
synthesis of amidomethylarenes and -heteroarenes from readily available amides, formaldehyde
and (hetero)arenes over Hβ zeolite under neat conditions. The noteworthy features of the present
method are the use of non-hazardous and reusable catalyst, broad substrate scope, absence of
solvent, higher yields of the desired products, high atom economy (only water as by-product),
simple work-up procedure and mild reaction conditions, which make it an inexpensive and
environmentally benign protocol. Moreover, the scope and limitations of this protocol are
demonstrated with various amides and arenes.
Acknowledgements
We thank the DST, New Delhi for financial support under Indo-Russia (DST-RSF) (No.
INT/RUS/RSF/P-7) programme. Ch. D., G. K. and M. N. acknowledge the CSIR, India and K. S.
and B. R. acknowledge the UGC, India for financial support (fellowship).

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Graphical abstract

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Highlights
 Hβ exhibits excellent activity towards the synthesis of amidomethylated arenes.
 This protocol was developed under solvent-free conditions
 The reaction was explored with variety of amides and (hetero)arenes
 The catalyst can be reused without significant loss in their catalytic activity.