A metal free, eco-friendly protocol for the synthesis of 2,3-dihydro-1H-perimidines using commercially available Amberlyst 15 as a catalyst

Article abstract of DOI:10.1016/j.catcom.2014.08.024

An efficient protocol has been developed to synthesize various dihydro-1H-perimidine derivatives using commercially available Amberlyst-15 as a catalyst. Dihydro-1H-perimidine derivatives are potential candidates for pharmaceutical and high tech applicati

Full text of DOI:10.1016/j.catcom.2014.08.024

Catalysis Communications 57 (2014) 138–142
Contents lists available at ScienceDirect
Catalysis Communications
journal homepage: www.elsevier.com/locate/catcom
Short Communication
A metal free, eco-friendly protocol for the synthesis of
2,3-dihydro-1H-perimidines using commercially available
Amberlyst 15 as a catalyst
⁎
Vilas Venunath Patil, Ganapati Subray Shankarling
Department of Dyestuff Technology, Institute of Chemical Technology, N. P. Marg, Matunga, Mumbai 400019, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 17 July 2014
Received in revised form 14 August 2014
Accepted 16 August 2014
Available online 23 August 2014
An efficient protocol has been developed to synthesize various dihydro-1H-perimidine derivatives using
commercially available Amberlyst-15 as a catalyst. Dihydro-1H-perimidine derivatives are potential candidates
for pharmaceutical and high tech applications. The conspicuous features of this protocol are short reaction
time, compared to higher product yield, easy recovery, reusability and regeneration of catalyst. The reaction
was successfully scaled up to gram level, which reflects the practicability of the present protocol.
© 2014 Elsevier B.V. All rights reserved.
Keywords:
Amberlyst-15
β-Keto amide
2,3-Dihydro-1H-perimidine
Ketone
Naphthalene-1,8-diamine
1. Introduction
derivatives using ketone. In earlier reports, protonic acids are used as
catalyst to carry out above transformations with ketones [17,18].
Nitrogen containing fused heterocyclic naphthalenes are good
candidates for biological, agricultural and medicinal applications
[1–4]. Perimidine derivatives serve as ligand scaffolds [5], stoppers
for supramolecules [6], and couplers in hair colorants [7]. Their
spiroperimidine derivatives exhibit reversible photochromic and
thermochromic properties and thus used in molecular switches, and
photochemical memory devices [8–10]. The squaraine dyes with 2,3-
dihydro-1H-perimidine skeleton possess very good photoconductive
and semi conductive properties which are found to be useful in various
high-tech applications such as organic solar cells, plasma display panels,
and optical recording media [11].
Synthesis of 2,3-dihydro-1H-perimidine comprises reaction of
naphthalene-1,8-diamine with various carbonyl functionalities under
acidic condition [12–16]. The most frequent approach used for the prep-
aration of dihydroperimidine derivatives is the reaction of naphthalene-
1,8-diamine with an aldehyde. To the best of our knowledge, there are
very few reports available on the synthesis of dihydroperimidine
Higher acidity of these catalysts results into the formation of various
by-products, which in turn lower the yield of desired product. The
metal catalysts such as InCl3 [19], BiCl3 [20], Zn(CH3COO)2·2H2O
[21], RuCl3 [22], Yb(OTf)3 [23], and HBOB [24] emerged as good al-
ternatives for these conventional protic acids. Though most of
these reactions were carried out at ambient temperature, issues
such as high cost and commercial availability of catalyst, and longer
reaction time (0.5 to 32 h) limit their applicability on commercial
scale. Furthermore, most of these metal catalysts are moisture sensi-
tive and get decomposed or deactivated by moisture to form unde-
sirable hazardous products; for example, BiCl3 get decomposed by
moisture to form bismuth oxychlorides. Therefore, a cost effective,
non-toxic, and commercially available catalyst for the synthesis of
2,3-dihydro-1H-perimidines is still in demand.
In the last few decades Amberlyst-15 has gained much attention
due to its easy availability, mild and environment friendly nature with
high selectivity. It is a macro reticular polymeric resin with cross linked
styrene divinyl benzene co-polymer which has high acidity. It has high
H + ion exchange capacity (4.2 meq/g) and surface area (42 m2/g) [25].
Being insoluble in almost all solvents, it is easy to separate the catalyst
from the product. Commercial availability has made utilization of
this heterogeneous catalyst possible at commercial scale in various
important transformations such as quinolone synthesis [26], esterification
⁎
Corresponding author. Tel.: +91 22 33612708; fax: +91 22 33611020.
E-mail addresses: gsshankarling@gmail.com, gs.shankarling@ictmumbai.edu.in
(G.S. Shankarling).
http://dx.doi.org/10.1016/j.catcom.2014.08.024
1566-7367/© 2014 Elsevier B.V. All rights reserved.

V.V. Patil, G.S. Shankarling / Catalysis Communications 57 (2014) 138–142
139
[27], in Prins reaction [28], alkylation [29], halogenation [30],
acetalization [31] deprotection [32] in the manufacture of fused
homocyclic compounds [33] and in Biginelli reaction [34].
In the present context, we are exploring the heterogeneous catalytic
reaction by utilizing commercially available Amberlyst-15 catalyst
to synthesize various dihydro perimidine derivatives by reacting
naphthalene-1,8-diamine with various ketones. This protocol offers a
simple, environmentally benign route for the synthesis of 2,3-dihydro-
1H-perimidines.
7.29–7.19 (m, 5H, Ar–H), 7.12–7.09 (d, 2H, Ar–H, J = 8.4), 6.51–6.49
(d, 2H, Ar–H, J = 7.6), 4.69 (broad singlet, 2H, N–H), 1.79 (s, 3H,
–CH3); MS (EI) 261.1 (M + H), 244.1.
3. Result and discussion
3.1. Reaction condition optimization
The reaction parameters were optimized using naphthalene-1,8-
diamine 1a and acetophenone 2a as model substrates with 20% (w/w)
Amberlyst-15 catalyst. Under solvent free condition, 36% yield of 3a was
obtained after 10 h (Table 1, entry 1). Higher yield was obtained when
ethanol was employed as a solvent (Table 1, entry 7). The yield of 3a
was increased exponentially with rise in temperature. At room temper-
ature no product formation was observed (Table 1, entry 8) while the
highest yield was obtained at 80 °C (Table 1, entry 7). The catalyst load-
ing was optimized to 20% (w/w) as further rise in catalyst quantity did
not show any influence on yield and reaction time (Table 1, entries 7,
14–16). Under catalyst free conditions only starting material was ob-
served on TLC (Table 1, entry 17). When we replaced Amberlyst-15
with other acidic catalyst such as Amberlite IR-120, sulfated zirconia, re-
action did not occur (Table 1, entries 18–19) while with Indion-130,
poor yield of 3a was obtained in 10 h (Table 1, entry 20).
2. Experimental
2.1. Materials and equipments
All the reagents and reactants were purchased from commercial
suppliers and were used without further purification. Melting points
were uncorrected and recorded on standard melting point apparatus
from Sunder Industrial Products, Mumbai. 1H NMR spectra were record-
ed on 400 MHz Bruker spectrometer using CDCl3 as a solvent and chem-
ical shifts have been expressed in δ ppm using TMS as an internal
standard. Infrared spectra were recorded on Jasco-FT/IR 4100 LE
ATR PRO450-S spectrometer. Mass spectral data was obtained with
micromass-Q-Tof (YA105) spectrometer.
2.2. General procedure for the synthesis of 2,3-dihydro-1H-perimidine
3.2. Reaction of naphthalene-1,8-diamine with various ketones
A mixture of naphthalene-1,8-diamine (1a) (0.5 g, 3.16 mmol),
ketone/ β-keto derivative (2) (3.16 mmol) and Amberlyst-15
(20%, w/w) was stirred in ethanol (5 ml) at 80 °C. The progress of reac-
tion was monitored using thin layer chromatography. The catalyst was
filtered off and washed with ethanol (3 × 5 ml). Filtrate and all washings
were collected and evaporated under vacuum using rotary evaporator to
get crude solid mass. The crude product was purified by column chroma-
tography using toluene as an eluting system. The compounds were
characterized using spectroscopic techniques (FT-IR, MS, 1H-NMR).
The optimized reaction conditions were then tested with various
ketonic compounds (Scheme 1) and the results obtained were sum-
marized in Table 2. It was found that, the alkyl–aryl ketones with an
electron withdrawing group on the aryl ring kinetically favored the
reaction as the reaction was completed within a shorter period com-
pared to the corresponding electron donating group. For instance, reac-
tion with 4-nitro acetophenone (2b) was observed to be terminated in
45 min to give 90% yield of 3b (Table 2, entry 2), while reaction with 4-
methoxy acetophenone (2d) required 2.15 h to give 95% of 3d (Table 2,
entry 4). Compared to aryl–alkyl ketones, dialkyl ketones (Table 2, en-
tries 9–13) showed high reactivity with even shorter reaction time of
less than 30 min. The reason for high reactivity of dialkyl ketones over
aryl–alkyl ketones could be due to the steric hindrance exerted by phenyl
ring. It is also noticeable that, under present reaction conditions, 87% yield
of compound 3m was obtained which was significantly higher than the
earlier reported yield (25%) by Yavari et al. [35] in 60 h.
2.2.1. Spectral data of a representative compound
2.2.1.1. 2-Methyl-2-phenyl-2,3-dihydro-1H-perimidine (entry 3a, Table 2).
Off white solid. 0.485 g, 97%, m.p. 138 °C (from toluene); IR(KBr):
υ
max/cm−1 3369, 3283, 1592, 1404, 812, 754, 700 cm−1 1H NMR
;
(400 MHz; CDCl3; Me4Si) δppm 7.56–7.54 (d, 2H, Ar–H, J = 7.6),
Table 1
Optimization of reaction parameters.a
Entry
Solvent
Catalyst
Cat. concn (%, w/w)
Temp (°C)
Time (h)
Isolated yield (%)
1
2
3
4
5
6
7
8
Neat
Water
Amberlyst-15
Amberlyst-15
Amberlyst-15
Amberlyst-15
Amberlyst-15
Amberlyst-15
Amberlyst-15
Amberlyst-15
Amberlyst-15
Amberlyst-15
Amberlyst-15
Amberlyst-15
Amberlyst-15
Amberlyst-15
Amberlyst-15
Amberlyst-15
No catalyst
20
20
20
20
20
20
20
20
20
20
20
15
17
23
25
30
–
80
80
80
80
80
80
80
rt
50
60
70
80
80
80
80
80
80
80
80
80
10
10
10
10
10
10
2.15
15
10
10
3
10
10
2.15
2.15
2.00
10
10
10
36
No reaction
No reaction
No reaction
Traces
52
97
No reaction
62
68
78
75
84
96
97
Acetonitrile
DESb
DMF
1,3-Dioxane
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
9
10
11
12
13
14
15
16
17
18
19
20
97
No reaction
No reaction
No reaction
18
Amberlite 120
Sulfated zirconia
Indion-130
20
20
20
10
rt: room temperature (30–32 °C).
a
Reaction conditions: naphthalene-1,8-diamine (0.2 g, 1.26 mmol), acetophenone (1.26 mmol), Amberlyst-15 (20%, w/w), ethanol (3 ml).
DES–choline chloride–urea.
b

140
V.V. Patil, G.S. Shankarling / Catalysis Communications 57 (2014) 138–142
Further, the reaction of naphthalene-1,8-diamine with β-keto amide
was found to be selective for acyl group over benzoyl. It was found that
the perimidine formation occurs easily when acyl substituent was
present. The reaction of N-(2-chlorophenyl)-3-oxobutanamide 4a
with naphthalene-1,8-diamine gave compound 5a in 1.45 h (Table 2,
entry 14). Whereas, we carried out reactions with sterically hindered
ketonic groups such as benzophenone (diaryl ketone) (Table 2, entry
15) and N-(2-chlorophenyl)-3-oxo-3-phenylpropanamide (Table 2,
entry 16) no product formation was observed even after 10 h. This is
Scheme 1. Synthesis of dihydroperimidine derivatives using Amberlyst-15.
Table 2
Reaction with various ketones.a
Entry
1
Substrate
Product
Reaction time
1.30 h
Isolated yield [%]
97
M.P. (°C)
Reported
Observed
137–138 [24]
136–138
2a
2b
2c
3a
3b
2
3
45 min
2.00 h
90
91
192–193 [24]
129–130 [20]
193–194
129–130
3c
4
5
2.15 h
2.00 h
95
94
178–180 [24]
117–119 [24]
179–180
118–119
2d
2e
3d
3e
3f
6
7
30 min
1.15 h
92
85
–
81–82
2f
193 [24]
191–192
2g
3g
8
1.00 h
97
244–246 [24]
242–244
2h
2i
3h
3i
9
30 min
30 min
90
90
105 [24]
105–107
142–143
10
140–142 [24]
2j
3j
11
30 min
86
95–97 [20]
96–97

V.V. Patil, G.S. Shankarling / Catalysis Communications 57 (2014) 138–142
141
Table 2 (continued)
Entry
Substrate
Product
Reaction time
Isolated yield [%]
M.P. (°C)
Reported
Observed
2k
3k
3l
12
13
30 min
30 min
88
87
85–86 [24]
84–85
2l
227–228 [35]
226–227
2m
3m
14
1.45 h
88
150-151
2n
3n
15
16
No reaction
10 h
10 h
–
–
–
–
–
–
2o
2p
No reaction
a
Reaction conditions: naphthalene-1,8-diamine (0.5 g, 3.16 mmol), ketone/ β-keto amide (3.16 mmol), Amberlyst-15 (20%, w/w), ethanol (5 ml).
an added advantage in the present protocol, as dihydroperimidine will
form selectively with dialkyl or aryl alkyl ketones than diaryl ketones.
used for further runs. The catalyst remained effective till the last cycle
studied here (Fig. 1). The reaction was scaled up to 5 g which gives
96% yield of 3a in 2.30 h. In all, the catalyst can be used over several
runs without affecting its activity and also feasible on large scale.
3.3. Recyclability and scale up studies
The recyclability study was carried out on 2 g scale. After completion
of reaction, the catalyst was filtered off and washed with ethanol. It was
then treated with 0.1 N HCl solution and dried at 65 °C for 30 min before
4. Conclusion
In conclusion, we have developed a clean, cost effective and environ-
mentally benign metal free route for the synthesis of various substituted
2,3-dihydro-1H-perimidine derivatives. The catalyst, Amberlyst-15 can
be easily separated and regenerated thus can be recycled for several re-
actions. The present protocol was found to be selective for dialkyl and
aryl alkyl ketones while sterically hindered ketone remains unaffected
under the present reaction conditions. Further study with β-keto
amide shows that, dihydroperimidine was selectively obtained when
acyl group was present at β-position with respect to amide than the
benzoyl group.
Yield of reacꢀon catalysed
by Amberlyst-15
97
97
96
95
93
89
Acknowledgments
The author is thankful to the Institute of Chemical Technology and
UGC-CAS for providing financial assistance and, SAIF IIT-Bombay for re-
cording mass spectra, IIRBS, M. G. University — Kottayam for recording
1H NMR spectra.
Appendix A. Supplementary data
Supplementary data to this article can be found online at http://dx.
doi.org/10.1016/j.catcom.2014.08.024. These data include MOL files
and InChiKeys of the most important compounds described in this
article.
Fig. 1. Studies in recycling of Amberlyst-15 in the synthesis of dihydroperimidine
derivative 3a.

142
V.V. Patil, G.S. Shankarling / Catalysis Communications 57 (2014) 138–142
[17] S.H. Kim, J.H. Kim, J.Z. Cui, Y.S. Gal, S.H. Jin, K. Koh, Dyes Pigments 55 (2002) 1–7.
References
[18] I.V. Aksenova, A.V. Aksenov, A.S. Lyakhovnenko, I.V. Borovlev, Chem. Heterocycl.
Compd. 44 (2008) 891–892.
[19] Z. Yasaei, P. Mirzaei, A. Bazgir, C.R. Chim. 13 (2010) 1308–1312.
[20] U.T. Mueller Westerhoff, B. Vance, D. Ihl Yoon, Tetrahedron 47 (1991) 909–932.
[21] M.M. Belmonte, E.C. Escudero Adán, J. Benet-Buchholz, R.M. Haak, A.W. Kleij, Eur. J.
Org. Chem. 2010 (2010) 4823–4831.
[22] J. Zhang, S.L. Zhang, J.M. Zhang, Chin. Chem. Lett. 18 (2007) 1057–1060.
[23] S.L. Zhang, J.M. Zhang, Chin. J. Chem. 26 (2008) 185–189.
[24] S.B. Phadtare, R. Vijayraghavan, G.S. Shankarling, D.R. MacFarlane, Aust. J. Chem. 65
(2012) 86–90.
[25] R. Shelkar, A. Singh, J. Nagarkar, Tetrahedron Lett. 54 (2013) 106–109.
[26] B. Das, K. Damodar, N. Chowdhury, R.A. Kumar, J. Mol. Catal. A Chem. 274 (2007)
148–152.
[27] M. Petrini, R. Ballini, E. Marcantoni, G. Rosini, Synth. Commun. 18 (1988)
847–853.
[28] J.S. Yadav, B.V. Subba Reddy, K. Chandra Sekhar, D. Gunasekar, Synthesis (Stuttg)
2001 (2001) 885–888.
[29] S.T. Kadam, P. Thirupathi, S.S. Kim, Tetrahedron 65 (2009) 10383–10389.
[30] H.M. Meshram, P.N. Reddy, K. Sadashiv, J.S. Yadav, Tetrahedron Lett. 46 (2005)
623–626.
[31] S.A. Patwardhan, S.U.K.H. Dev, Synthesis (Stuttg) 1974 (1974) 348–349.
[32] Y.S. Liu, C. Zhao, D.E. Bergbreiter, D. Romo, J. Org. Chem. 63 (1998) 3471–3473.
[33] D. Schinzer, J. Kabbara, K. Ringe, Tetrahedron Lett. 33 (1992) 8017–8018.
[34] S.R. Jetti, D. Verma, S. Jain, ISRN Org. Chem. 2012 (2012) 480989.
[35] I. Yavari, H. Mostafavi, D. Tahmassebi, R. Hekmat-Shoar, Monatsh. Chem. 128 (1997)
675–679.
[1] J.M. Herbert, P.D. Woodgate, W.A. Denny, J. Med. Chem. 30 (1987) 2081–2086.
[2] X. Bu, L.W. Deady, G.J. Finlay, B.C. Baguley, W.A. Denny, J. Med. Chem. 44 (2001)
2004–2014.
[3] D.R. Luthin, A.K. Rabinovich, D.R. Bhumralkar, K.L. Youngblood, R.A. Bychowski, D.S.
Dhanoa, et al., Bioorg. Med. Chem. Lett. 9 (1999) 765–770.
[4] W. Wasulko, A.C. Noble, F.D. Popp, J. Med. Chem. 9 (1966) 599–601.
[5] I.G. Jung, S.U. Son, K.H. Park, K.C. Chung, J.W. Lee, Y.K. Chung, Organometallics 22
(2003) 4715–4720.
[6] S.Y. Hsueh, K.W. Cheng, C.C. Lai, S.H. Chiu, Angew. Chem. Int. Ed. 47 (2008)
4436–4439.
[7] A. Lagrange, M. Mignon, Oxidation Dye Composition Comprising a Particular
Coupler in a Medium Rich in Fatty Substances, and Processes and Device Suitable
Therefor, 2013. (WO2013087631).
[8] V.I. Minkin, V.N. Komissarov, Mol. Cryst. Liq. Cryst. Sci. Technol., Sect. A 297 (1997)
205–212.
[9] Y. Norikane, R. Davis, N. Tamaoki, New J. Chem. 33 (2009) 1327–1331.
[10] R. Davis, N. Tamaoki, Org. Lett. 7 (2005) 1461–1464.
[11] W.D. Ramsden, L.F. Valente, L.S. Bernard, Method of Making Dihydroperimidine
Squaraine Compounds, 2002. (US6348592 B1).
[12] V. Paragamian, M.B. Baker, B.M. Puma, J. Reale, J. Heterocycl. Chem. 5 (1968)
591–597.
[13] A. Shaabani, A. Maleki, Chem. Pharm. Bull. 56 (2008) 79–81.
[14] J.B. Hendrickson, M.S. Hussoin, J. Org. Chem. 52 (1987) 4137–4139.
[15] J.J. Vanden Eynde, F. Delfosse, P. Lor, Y. Van Haverbeke, Tetrahedron 51 (1995)
5813–5818.
[16] V.A. Ozeryanskii, E.A. Filatova, V.I. Sorokin, A.F. Pozharskii, Russ. Chem. Bull. 50
(2001) 846–853.