HΒ Catalyzed Condensation Reaction Between Aromatic Ketones and Anilines: To Access Ketimines (Imines)

Article abstract of DOI:10.1007/s10562-017-2196-0

Abstract: A simple approach for the formation of imines by condensation of ketones and anilines over heterogeneous catalyst (Hβ zeolite) has been successfully developed. The present catalytic system scope was explored for various aromatic ketones and anil

Full text of DOI:10.1007/s10562-017-2196-0

Catal Lett
DOI 10.1007/s10562-017-2196-0
Hβ Catalyzed Condensation Reaction Between Aromatic Ketones
and Anilines: To Access Ketimines (Imines)
Vasu Amrutham1 · Naresh Mameda1,2 · Srujana Kodumuri1 · Durgaiah Chevella1 ·
Rammurthy Banothu1,2 · Krishna Sai Gajula1,2 · Nellya Gennadievna Grigor’eva3 ·
Narender Nama1,2
Received: 22 June 2017 / Accepted: 15 September 2017
© Springer Science+Business Media, LLC 2017
Abstract A simple approach for the formation of imines
by condensation of ketones and anilines over heterogene-
ous catalyst (Hβ zeolite) has been successfully developed.
The present catalytic system scope was explored for various
aromatic ketones and anilines. Furthermore, Hβ zeolite can
be easily separable and recycled several times (five times)
without considerable loss of its catalytic activity.
plays a vital role in biological and chemical systems [1–3].
In particularly, due to their diverse reactivity, imines and
their derivatives have become crucial intermediates in the
synthesis of biologically active nitrogen compounds and
have been broadly used in the preparation of pharmaceuti-
cals, dyes, fragrances, fungicides and agricultural chemicals
[4, 5]. Imines also serve as versatile components in nucleo-
philic addition with organometallic reagents [6], cycloaddi-
tion reactions [7, 8] and have potential for therapeutic appli-
cations [9–12]. Several methods have been described in the
literature for their synthesis, such as condensation of amines
with the carbonyl compounds [13–16], self-condensation of
primary amines upon oxidation [17–19], oxidative coupling
of alcohols and amines [20, 21], hydroamination of alkynes
with amines [22–25], oxidation of secondary amines and
the partial hydrogenation of nitriles followed by coupling
with the amines [26, 27]. Among the all approaches for the
synthesis of imines, the condensation of amines with the car-
bonyl compounds is a well-established, direct and attractive
synthetic route to prepare imines, although problems still
remain to achieve this chemical transformation economi-
cally. Therefore, given the importance of imines as interme-
diates in organic synthesis, the development of convenient
procedures for their preparation is of interest.
Graphical Abstract
NH2
O
N
Ar
Hβ zeolite
Toluene 120 ° 24 h
R
R
Ar
C
,
,
Keyword Condensation · Heterogeneous catalyst ·
Imines · Aromatic ketones · Zeolites
1 Introduction
The C–N bond-formation reaction is one of the most impor-
tant transformations in modern synthetic chemistry and
Electronic supplementary material The online version of this
article (doi:10.1007/s10562-017-2196-0) contains supplementary
material, which is available to authorized users.
Recently, growth of new processes that reduce pollution
in the chemical industry has received substantial considera-
tion due to growing environmental concerns. In this route,
heterogeneous catalysis has appeared as a convenient tool
to diminish waste production with regard to the simplicity
of the process and separation and recycling of the catalysts
[28–31]. Catalysis by zeolites and related materials has
become an attractive research area over the past decades in
the heterogeneous catalysis and green chemistry [32, 33]. As
an important type of solid acids, zeolites have been broadly
used as replacement for highly toxic and corrosive mineral
* Narender Nama
narendern33@yahoo.co.in; nama.iict@gov.in
1
I&PC Division, CSIR-Indian Institute of Chemical
Technology, Hyderabad, Telangana 500 007, India
2
Academy of Scientific and Innovative Research,
CSIR-Indian Institute of Chemical Technology, Hyderabad,
Telangana 500 007, India
3
IPC RAS, 141 prosp, Oktyabrya, 450075 Ufa,
Russian Federation
Vol.:(0123456789)
1 3

V. Amrutham et al.
acids or inorganic Lewis acids in synthesis of fine chemicals
[34, 35]. 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 the pores. One of the paramount properties of zeolites is
the great variety of topologies and pore architectures. The
acidic properties of zeolites are mainly dependent on the Si/
Al molar ratio as well as the temperature of activation [36,
37]. All the characteristics of zeolite-acidity such as, distri-
bution of Lewis and Bronsted sites, strength, density of the
acid sites can be modified by a large number of treatments.
For example, the treatment at high temperature of protonic
zeolites causes the transformation of Bronsted acid sites into
Lewis acid sites. Yet the protonic sites of the dehydroxy-
lated zeolites are stronger than those of the starting zeolites.
On the other hand, dealumination decreases the acid site
density but can increase the acid strength and modify the
porosity. Therefore, the catalytic activity of zeolites could be
tailored for special chemical transformations. Additionally,
their environmentally benign nature, high surface area and
adsorption capacity, as well as outstanding chemical and
thermal stability, make them ideal candidates for heterogene-
ous catalysis. In continuation of our efforts toward the devel-
opment of novel and eco-friendly synthetic protocols using
zeolites [38–42], we herein report the Hβ zeolite catalyzed
synthesis of imines from aromatic ketones and anilines.
2.2 General Procedure
Hβ zeolite (100 mg) was added to the well stirred solution
of aromatic ketone (2 mmol), aniline (2 mmol) and toluene
(1 mL) in a 15 mL sealed tube and the reaction mixture
was allowed to stir at 120 °C. After 24 h, the reaction mix-
ture was cooled to room temperature and diluted with ethyl
acetate (10 mL). The catalyst was separated by simple filtra-
tion and the exclusion of solvent in vacuo yielded the crude
which was further purified by column chromatography using
silica gel (100–200 mesh) to afford pure products. All the
products were identified on the basis of H and 13C NMR
1
spectral data.
3 Results and Discussion
In the preliminary investigation, a typical reac-
tion of acetophenone with p-anisidine to give
Table 1 Optimization of reaction conditions-the condensation of
acetophenone with p-anisidine
O
NH2
N
Catalyst
O
O
3a
1a
2a
2 Experimental Section
2.1 General Information
Entry Catalyst
Tem-
Conver- Selectiv- Yield (%)b
perature sion 1a
ity 3a
(°C)
(%)a
(%)a
All chemicals were acquired from Sigma-Aldrich and used
as received without further purification. The catalyst Hβ
Zeolite (Si/Al = 19) was procured from Alfa Aesar, Eng-
land. 1HNMR spectra were recorded at 300, 400 or 500 MHz
and 13CNMR spectra at 75, 100 or 125 MHz in CDCl3. The
chemical shifts (δ) are reported in ppm units relative to TMS
as an internal standard for 1HNMR and CDCl3 for 13CNMR
spectra. Coupling constants (J) are reported in hertz (Hz)
and multiplicities are indicated as follows: s (singlet), br s
(broad singlet), d (doublet), dd (doublet of doublet), t (tri-
plet), m (multiplet). The GC analysis were carried out using
GC Shimadzu (GC-2014) gas chromatograph equipped with
FID detector and capillary column (EB-5, length 30 m, inner
diameter 0.25 mm, film 0.25 mm). TLC inspections were
performed on Silica gel 60 F254 plates. Column chromatog-
raphy was performed on silica gel (100–200 mesh) using
n-hexane-EtOAC as eluent. The XRD patterns of the sam-
ples were obtained on a Regaku miniflex X-ray Diffractom-
eter using Ni filtered CuKα radiation at 2θ=2°–80° with a
scanning rate of 2° min−1 and the beam voltage and currents
of 30 kV and 15 mA, respectively.
1
2
3
4
5
6
Hβ
NaY
120
120
92
70
65
74
66
64
98
99
99
98
99
99
90
69
64
72
65
63
HZSM-5 (150) 120
H-Mordenite
HY
120
120
Montmorillonite 120
K10
7
8
HMCM-41
120
120
67
20
99
99
66
20
Absence of
catalyst
9
Hβ
Hβ
Hβ
Hβ
100
80
120
120
72
52
61
91
99
99
99
99
71
10
11
12
52
60c
90d
Reaction conditions: 1a (2 mmol), 2a (2 mmol), toluene (1 mL), cata-
lyst (100 mg), 120 °C, 24 h, sealed tube
aConversion and selectivity based on GC
bIsolated yields
c50 mg
d150 mg
1 3

Hβ Catalyzed Condensation Reaction Between Aromatic Ketones and Anilines: To Access Ketimines…
Table 2 Scope of the condensation reaction of acetophenone with various substituted anilines over Hβ zeolite
NH2
O
N
Ar
Hβ zeolite, 120 °
C
R
Ar
R
(1
),
Toluene mL 24 h
2r-2aa
3a-3aa
1a-1q
Entry
R
Ar
Conversion 1a–1q (%)a
Selectivity 3a–3aa (%)a
Yield (%)b
1
2
3
4
5
6
7
8
4-MeO
H
4-Me
2-Me
2-Et
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
92
57
79
85
54
46
53
59
75
64
61
68
73
00
00
00
52
79
90
89
94
97
94
92
79
89
92
98
97
98
97
98
97
98
97
98
99
97
98
96
–
3a; 90
3b; 55
3c; 77
3d; 82
3e; 50
3f; 45
3g; 50
3h; 69
3i; 73
3j; 63
3k; 60
3l; 66
3m; 70
3n; –
4-i-Pr
4-t-Bu
2,6-Me,Me
2,4-Me,Me
4-F
4-Cl
4-Br
3,4-Cl,Cl
4-NO2
4-COOH
4-CONH2
2-CH2C6H5
4-MeO
4-MeO
4-MeO
4-MeO
4-MeO
4-MeO
4-MeO
4-MeO
4-MeO
4-MeO
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
–
–
3o; –
3p; –
C6H5
97
98
97
98
97
97
98
97
98
97
98
3q; 50
3r; 77
3s; 88
3t; 87
3u; 92
3v; 95
3w; 92
3x; 90
3y; 75
3z; 86
3aa; 90
4-MeOC6H5
3-MeOC6H5
3-MeC6H5
4-NO2C6H5
4-FC6H5
3-ClC6H5
4-ClC6H5
3-BrC6H5
4-BrC6H5
2-Napthyl
Reaction Conditions: 1a–1q (2 mmol), 2r–2aa (2 mmol), toluene (1 mL), Hβ (100 mg), 120 °C, 24 h, sealed tube
aConversion and selectivity based on GC
bIsolated yields
(E)-4-methoxy-N-(1-phenylethylidene)aniline (3a) was
chosen as a model system to elevate the best reaction condi-
tions for this transformation. To get the best catalyst, the
reaction was carried out over various zeolites, MCM-41 and
montmorillonite K10 using toluene as solvent at 120 °C in
sealed tube for 24 h (Table 1, entries 1–7). Among the cata-
lysts surveyed, Hβ zeolite exhibited a higher catalytic activ-
ity and gave the corresponding imine 3a in 90% yield due
to its strong acidic sites (higher acid strength) and special
three-dimensional large size porous structure12 (Table 1,
entry 1). In the absence of a catalyst, the yield of 3a was
only 20% (Table 1, entry 8) and this observation obviously
indicates the role of catalyst in the reaction (the influence of
the catalyst on the reaction).
The influence of temperature was studied, after Hβ cata-
lyst was found as the best catalyst for this reaction. A grad-
ual improvement was observed in the reaction yield of 3a
(52–90%) by varying the reaction temperature from 80 to
1 3

V. Amrutham et al.
120 °C and further increase of temperature did not have any
accountable effect on the yield (Table 1, entries 1, 9 and
10). The present reaction was also conducted using differ-
ent amounts of catalyst and found that 100 mg of catalyst
gave the best results (Table 1, entries 1, 11 and 12). Next,
various solvents were studied under similar reaction condi-
tion over Hβ and the results were suggested that toluene was
the best medium for this transformation (see the ESI Tables
S1). From the above obtained results, the optimized reac-
tion conditions to acquire the highest yield for this reaction
are 1:1 mol ratio of acetophenone to p-anisidine in toulene
(1 mL) at 120 °C over Hβ zeolite (100 mg) (Table 1, entry
1).
acetophenone with p-anisidine under standard reaction con-
ditions. The catalyst 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. No obvious loss
of the catalytic activity was discovered even after five cycles
(Fig. 1). The 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
(Fig. 2).
The plausible reaction mechanism for the formation of
imines (ketimines) from aromatic ketones and anilines over
Hβ zeolite is illustrated in Scheme 1. It is assumed that aro-
matic ketone(I) adsorbs on the Bronsted acid sites of zeolite,
which subsequently reacts with aniline to give the intermedi-
ate II, finally, dehydration of the resulting intermediate II
leads to the respective imines (ketimines) III.
After optimizing the reaction conditions, we then turned
our attention to explore the versatility of this condensa-
tion reaction by reacting the various anilines with aromatic
ketones and the results are summarized in Table 2. Various
electron-donating and electron-withdrawing groups were
well tolerated with the present catalytic system and gave
the desired products 3a–3m and 3q–3aa in low to excellent
yields (Table 2, entries 1–13 and 17–27). The condensation
of acetophenone with aniline afforded the corresponding
imine 3b in 55% yield (Table 2, entry 2). Aniline substi-
tuted with activating groups reacted efficiently and produced
the respective imine products 3c–3i in 45–82% yields under
these reaction conditions (Table 2, entries 3–9). However,
higher alkyl chain substituted anilines (Table 2, entries 5–7)
gave the desired products in lower yields compared to methyl
substituted anilines (Table 2, entries 3, 4, 8 and 9). Halo sub-
stituted anilines, such as 4-fluoroaniline (3j), 4-chloroani-
line (3k), 4-bromoaniline (3l) and 3,4 dichloroaniline (3m)
could be transformed into the corresponding imines 3j-3m
in 60–70% yields (Table 2, entries 10–13). Unfortunately,
aniline with strongly electron-withdrawing groups (i.e. NO2,
COOH and CONH2) were unsuccessful under the present
conditions (Table 2, entries 14–16). 2-Benzylaniline yielded
the respective imine 3q in 50% yield (Table 2, entry 17).
To further extend the scope of this reaction, a variety of
aromatic ketones were employed to react with p-anisidine
under optimal conditions (Table 2, entries 18–27) and were
found to be tolerable in this process. Acetophenones having
electron-donating and withdrawing groups reacted smoothly
under optimized conditions to give the corresponding prod-
ucts 3r–3u in good to excellent yields (Table 2, entries
18–21). Halo substituted acetophenones were also provided
respective imines 3v–3z in 75–95% yields (Table 2, entries
22–26). Reaction of polyaromatic ketone i.e. 2-acetonaph-
thone with p-anisidine yielded the respective imine 3aa in
90% yield (Table 2, entry 27).
Fig. 1 Recyclable study of Hβ zeolite on the condensation of aceto-
phenone with p-anisidine
a
b
10
20
30
40
50
60
70
80
For environmental considerations and commercial appli-
cations, the reusability of the catalyst is one of the most
important feature. The possibility of recycling the cata-
lyst was tested using the condensation reaction between
2theta (deg.)
Fig. 2 XRD patterns of Hβ zeolite: a before reaction, b after reaction
1 3

Hβ Catalyzed Condensation Reaction Between Aromatic Ketones and Anilines: To Access Ketimines…
Scheme 1 Plausible mecha-
H
N
R
R
nism for the formation of imines
(ketimines) from aromatic
ketones and anilines
H
R
H
O
H
N
O
Al
Si
Si
-H
2O
Ar
OH
N
Ar
O
( )
II
Ar
H
( )
I
H
O
( )
III
O
O
O
Al
Si
Si
Al
Si
Si
12. Vicini P, Geronikaki A, Incerti M, Busonera B, Poni G, Cabras
CA, Colla PL (2003) Bioorg Med Chem 11:4785–4789
13. Patil RD, Adimurthy S (2013) Asian J Org Chem 2:726–744
14. Angelici RJ (2013) Catal Sci Technol 3:279–296
15. Qin W, Long S, Panunzio M, Biondi S (2013) Molecules
18:12264–12289
4 Conclusion
In summary, a simple heterogeneous catalytic system for the
synthesis of imines involving the condensation of aromatic
ketones with anilines over Hβ zeolite developed successfully.
The scope and limitations of this protocol were investigated
with various anilines and acetophenones. Prominent advan-
tages obtainable by this catalytic strategy are use of non-
hazardous and reusable catalyst, mild reaction conditions
and simple work-up procedures.
16. Ryland BL, Stahl SS (2014) Angew Chem Int Ed 53:8824–8838
17. Su F, Mathew SC, Mohlmann L, Antonietti M, Wang X, Blechert
S (2011) Angew Chem Int Ed 50:657–660
18. Chen B, Wang L, Dai W, Shang S, Lv Y, Gao S (2015) ACS Catal
5:2788–2794
19. Chen B, Wang L, Gao S (2015) ACS Catal 5:5851–5876
20. Blackburn L, Taylor RJK (2001) Org Lett 3:1637–1639
21. Tamura M, Tomishige K (2015) Angew Chem Int Ed 54:864–867
22. Pohlki F, Doye S (2001) Angew Chem Int Ed 40:2305–2308
23. Johnson JS, Bergman RG (2001) J Am Chem Soc 123:2923–2924
24. Li Y, Shi Y, Odom AL (2004) J Am Chem Soc 126:1794–1803
25. Ryken SA, Schafer LL (2015) Acc Chem Res 48:2576–2586
26. Srimani D, Feller M, Ben-David Y, Milstein D (2012) Chem Com-
mun 48:11853–11855
Acknowledgements We thank the DST, New Delhi for financial
support under Indo-Russia (DST-RSF) (No. INT/RUS/RSF/P-7) pro-
gramme. M. N, Ch. D and G. K. acknowledge the CSIR, India and K.
S. and B. R. acknowledge the UGC, India for financial support in the
form of fellowship.
27. Chakraborty S, Berke H (2014) ACS Catal 4:2191–2194
28. Sheldon RA, Dakka J (1994) Catal Today 19:215–246
29. Clark JH (1995) Chemistry of waste minimisation. Chapman and
Hall, London
References
30. Hoelderich WF, Heitmann G (1997) Catal Today 8:227–233
31. Anastas PT, Bartlett LB, Kirchhoff MM, Williamson TC (2000)
Catal Today 55:11–22
1. Ricci A (2000) Modern amination reactions. Wiley, Weinheim
2. Hartwig JF (2002) In: Negishi E, Meijere A (eds) Handbook of
organopalladium chemistry for organic synthesis, vol 1. Wiley,
New York
32. Cejka J, Centi G, Perez-Pariente J, Roth WJ (2012) Catal Today
179:2–15
3. Lawrence SA (2004) Amines synthesis properties and applica-
tion. Cambridge University Press, Cambridge
4. Rappoport ZJ, Liebman F (2009) The chemistry of hydroxy-
lamines oximes and hydroxamic acids. Wiley, New York, p 609
5. Hadjipavlou-Litina DJ, Geronikaki AA (1998) Drug Des Discov
15:199–206
33. Martinez C, Corma A (2011) Coord Chem Rev 255:1558–1580
34. Gupta P, Paul S (2014) Catal Today 236:153–170
35. Clark JH (2002) Acc Chem Res 35:791–797
36. Lok BM, Marcus BK, Angell CL (1986) Zeolites 6:185–194
37. Scherzer J (1990) Octane-enhancing zeolitic FCC catalysts. Mar-
cel Dekker, New York
6. Kuznetsov VV, Palma AR, Aliev AE, Varlamov AV, Prostakov
NS, Zh (1991) Org Khim l27:1579–1581
38. Mohan KVVK, Reddy KSK, Narender N, Kulkarni SJ (2009) J
Mol Catal A 298:99–102
7. Tsuge O, Kanemasa R (1989) Adv Heterocycl Chem 45:231–349
8. Aly MF, Younes MI, Matwally SAO (1994) Tetrahedron
50:3159–3168
39. Mohan KVVK, Narender N, Kulkarni SJ (2007) Micropor
Mesopor Mater 106:229–235
40. Mohan KVVK, Narender N, Kulkarni SJ (2006) Green Chem
8:368–372
9. Hadjipavlou-litina DJ, Geronikaki AA (1996) Drug Des Discov
15:199–206
41. Naresh M, Swamy P, Reddy MM, Srujana K, Durgaiah C, Naren-
der N (2015) Appl Catal A 505:213–216
10. Cushman M, Nagarathnam D, Gopal D, Chakraborti AK, Lin
CM, Hamel EJ (1991) Med Chem 34:2579–2588
11. Cushman M, He HM, Lin CM, Hamel E (1993) J Med Chem
36:2817–2821
42. Narender N, Srinivasu P, Kulkarni SJ, Raghavan KV (2000) Green
Chem 2:104–105
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