Efficient synthesis of 2,3-dihydro-1H-perimidine derivatives using HBOB as a novel solid acid catalyst

Article abstract of DOI:10.1071/CH11381

An efficient method for the synthesis of substituted 2,3-dihydro-1H- perimidine derivatives is described using bis(oxalato)boric acid (HBOB) as catalyst. The methodology provides an easily handled and recyclable catalyst for this type of reaction as an al

Full text of DOI:10.1071/CH11381

CSIRO PUBLISHING
Aust. J. Chem. 2012, 65, 86–90
Full Paper
http://dx.doi.org/10.1071/CH11381
Efficient Synthesis of 2,3-Dihydro-1H-Perimidine
Derivatives Using HBOB as a Novel Solid Acid Catalyst
A
B
A C
,
Sunanda B. Phadtare, R. Vijayraghavan, Ganapati S. Shankarling,
B C
,
and Douglas R. MacFarlane
A
Department of Dyestuff Technology, Institute of Chemical Technology, Matunga,
Mumbai 400019, India.
B
School of Chemistry, Monash University, Clayton Campus, Vic. 3800, Australia.
C
Corresponding authors. Email: ganu23@gmail.com; douglas.macfarlane@monash.edu
An efficient method for the synthesis of substituted 2,3-dihydro-1H-perimidine derivatives is described using bis(oxalato)
boric acid (HBOB) as catalyst. The methodology provides an easily handled and recyclable catalyst for this type of
reaction as an alternative platform to the conventional acid-catalyzed thermal processes. The time required to complete the
reaction using HBOB was found to be shorter than conventional methods. Recycling of the catalyst has been efficiently
achieved using a simple procedure.
Manuscript received: 28 September 2011.
Manuscript accepted: 17 October 2011.
Published online: 21 November 2011.
Introduction
oxychlorides in the presence of water. Recently a variety of
substituted 2-aryl-2,3-dihydro-1H-perimidines were synthe-
sized[10] at room temperature using Zn(OAc)2ꢀ2H2O as catalyst.
There were also reports on the use of transition metal chlorides
(RuCl3) and triflates (Ytterbium (III) triflate, a mild Lewis acid)
as catalysts for the synthesis of perimidine derivatives.[11–12]
In these cases the use of heavy metals presents problems in
handling and also environmental issues on disposal. Hence
there is interest in developing new, more efficient, and ‘green’
catalysts for this organic transformation.
In this study a relatively mild, reusable, solid-acid catalyst,
namely bis(oxalato)boric acid (HBOB), is described for the
synthesis of perimidine derivatives. The bisoxaloto borate anion
was first identified as a very weakly coordinating anion[13] as its
lithium salt, having properties of interest in lithium battery
electrolytes. This prompted the preparation and study of the
acid form, which was shown to be a very useful proton source for
cationic polymerization of styrene[14–15] replacing metal ion
based Lewis acid initiators. HBOB has been employed as a
catalyst in Friedel–Crafts reactions and vinyl ether condensa-
tions.[16] It has also been previously shown to be very active as
an acid catalyst[15] despite not being a very strong acid (pKa ,1
in aqueous solution). It is sufficiently acidic in ethanol (similar
behaviour to HCl) to protonate the ꢁNH2 moieties in the first
step of the formation of perimidine reaction. The subsequent
precipitation of the crystalline product from the reaction solu-
tion drives the deprotonation of the product to regenerate the
HBOB catalyst.
2,3-dihydro-1H-perimidine derivatives are of wide interest
because of their diverse biological activities and chemical
applications.[1] The interest in pyrido-fused 2,3-dihydro-1H-
perimidine derivatives stems from the appearance of these
heterocyclic systems in many biologically active compounds.
Consequently, there has been ongoing interest in the synthesis of
perimidine ring structures.[1–6] The chemistry of 2,3-dihydro-
1H-perimidines and their benzo derivatives, including quina-
zolines, perimidines, and benzoperimidines has recently been
reviewed.[7] The review covers new synthetic routes to many
heterocycles, as well as modern synthetic techniques, including
microwave assisted procedures. Several examples of biologi-
cally important 2,3-dihydro-1H-perimidines and quinazoline
derivatives are identified, and in this context the signal trans-
duction inhibitor, imatinib (Gleevec), is highlighted as one of
the most significant new 2,3-dihydro-1H-perimidine derivatives
to have been identified in recent years. However, the preparation
of 2,3-dihydro-1H-perimidine derivatives using naphthalene-
1,8-diamine with ketones is still in the developing stage and
only protic acids have been used as catalysts for this trans-
formation.[8] However, their typically strong acidity leads
to the occurrence of side reactions. Reddy and Rao reported
the synthesis of 2-methyl-2-aryl-2,3-dihydro-1H-perimidines
using naphthalene-1,8-diamine with aromatic ketones in
acetic acid with moderate product yields (60 %).[8c] These acid-
catalyzed reactions are therefore not very efficient. Aksenova
et al.reported perimidine formation during the synthesis of
6-phenyl-1,3,7-triazapyrenes using fairly rigorous reaction
conditions (benzonitrile in polyphosphoric acid, at 70–808C).[9a]
Improvements were made to synthesize perimidine derivatives
using a less expensive catalyst such as BiCl[39b] under ambient
conditions, but the catalyst is fairly toxic and can form
The objective of the present study therefore was to investi-
gate HBOB in the synthesis of biologically active 2,3-dihydro-
1H-perimidines derivatives. We show that this catalyst is indeed
very effective in this reaction and is capable of producing
.90 % yields.
Journal compilation Ó CSIRO 2012
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Efficient Synthesis of Perimidine Derivatives
87
Experimental
Recovery and Reuse of HBOB Catalyst and Solvent
Materials and Equipment
The filtrate from the above reaction contains ethanol and HBOB.
The recycled HBOB and ethanol was used for the next reaction
without purification. The same procedure was followed for
consecutive cycles.
All melting points were uncorrected and recorded in degrees
Celsius. FT-IR spectra were recorded on a Bomem Hartmann
1
and Braun MB-Series FT-IR spectrometer. H NMR spectra
were recorded on a Varian 300 MHz spectrometer or 400 MHz
Mercury Plus spectrometer, and chemical shifts are expressed in
d ppm using TMS as an internal standard. Mass spectral data
were obtained with a Micromass Q-Tof (YA105) spectrometer
using electron ionization mode. Reagent grade chemicals were
procured from S. D. Fine-Chem. Ltd, (Mumbai) and were used
without any further purification.
Results and Discussion
To evaluate the scope and generality of this methodology, sev-
eral aromatic and aliphatic ketones were subjected to the reac-
tion. In general, with aliphatic ketones, the reactions showed
better product yields and shorter reaction times than with aro-
matic ketones (Table 1). In the case of aromatic ketones such as
acetophenone, the phenyl ring plays a key role in affecting the
rate of reaction, with electron-withdrawing substituents in the
aromatic ketone moiety decreasing the reaction time; the effect is
reversed with electron donating substituents. 1-(4-Nitrophenyl)
ethanone showed the highest product yields (entry 2) (95 %).
Benzophenone, because of the conjugation effect of the two
phenyl rings and steric hindrance, gave the lowest yield (70 %).
We also evaluated the amount of HBOB required for this
transformation. Experimental studies showed the optimum
amount of HBOB required for this transformation from
1-(4-nitrophenyl)ethanone was 10 mol-%. A comparison reac-
tion with 10 mol-% of concentrated HCl produced only 85 %
yield after 4 h. As little as 5 mol-% HBOB can catalyze the
reaction to the same extent as concentrated HCl in ethanol, but
longer reaction times (12 h) were required. Further studies
showed that increasing the amount of catalyst (greater than
10 mol-% HBOB) did not improve the yield of the product (see
Table, ESI-1).
Preparation of HBOB Catalyst
HBOB was prepared by the reported method,[16] which involves
a very simple reaction having 100 % atom economy, other than
four moles of water produced per mole of product. Typically the
synthesis of HBOB involves dehydrating aqueous solutions of
2 moles of oxalic acid (9.6 g) with 1 mol of boric acid (3.3 g)
under vacuum to produce a dry white solid (9.8 g) in 98 % yield
(Scheme 1). Electron spray ionization mass spectroscopy was
carried out to identify the presence of anion (HBOB, m/z ¼
186.8 for the BOB anion).
Typical Experimental Procedure for the Synthesis of
Perimidine Derivatives Using HBOB Catalyst
Naphthalene-1,8-diamine A (1 mmol), corresponding ketone B
(1 mmol), ethanol (5 mL), and HBOB (10 mol-%) were stirred at
reflux and the general reaction is given in Scheme 2. The
reaction was monitored by TLC (toluene:ethyl acetate 80:20).
At completion, the mixture was cooled to room temperature and
filtered. The solid product was washed with ethanol and dried in
an oven at 508C under vacuum until constant weight is obtained.
Characterization data for the compounds prepared are provided
as Supplementary Material (ESI-1).
The HBOB catalyst is soluble in many organic solvents such
as methanol, ethanol, ethyl acetate, and chloroform; therefore,
its recovery can be achieved easily. Typically after the reaction,
the mixture was cooled to room temperature and the precipitated
product was filtered. The filtrate, which contains ethanol and
O
O
C
C
O
O
O
O
C
C
ϩ
Ϫ
2H2C2O4 ϩ H3BO3 ϩ H2O
Ϫ4H2O
B
H
O
O
HBOB
Scheme 1.
NH2
NH2
R1
R2
NH
O
HN
10 mol-% HBOB
Ethanol, reflux
ϩ
R1
R2
Ketone
(R1, R2 ϭ alkyl or aryl)"
Naphthalene-1,8-diamine
2,3-dihydro-1H-perimidine
A
B
C
Scheme 2. R1, R2 ¼ alkyl or aryl.

88
S. B. Phadtare et al.
Table 1. Reaction using 10 mol-% HBOB catalyst in ethanol
Product (C)
Entry
Ketones used (B)
Acetophenone
Reaction time [h]
YieldA [%]
Lit. mp [8C]
Observed [8C]
HN
NH
1
2
85
136–138[9b]
137
NO2
NO2
Br
HN
NH
2
p-nitroacetophenone
1
95
192–193[9b]
193
HN
NH
2aB
p-nitroacetophenone
4
85
–
–
HN
NH
3
4
5
p-bromoacetophenone
p-methoxyacetophenone
p-methylacetophenone
2
3
3
93
87
83
126–128[9b]
178–180[9b]
117–119[9b]
125
178
115
OCH3
HN
NH
HN
NH
HN
NH
6
Benzophenone
3
70
209–210[9b]
210
(continued)

Efficient Synthesis of Perimidine Derivatives
89
Table 1. (Continued)
YieldA [%]
Lit. mp [8C]
Observed [8C]
Product (C)
Entry
Ketones used (B)
Reaction time [h]
HO
HN
NH
7
o-hydroxyacetophenone
2.5
91
–
193
HN
O
244–246[9c]
242
HN
NH
8
Isatin
5
93
HN
NH
9
4-methylpentan-2-one
0.25
88
–
105
HN
NH
10
2,6-dimethylheptan-4-one
0.25
90
–
140–142
HN
NH
11
Isophorone
0.5
81
–
Decompose .225
HN
NH
12
Cyclopentanone
0.5
88
85–86[9b]
84
AIsolated yield.
BReaction with 10 mol-% conc. HCl as catalyst in ethanol.

90
S. B. Phadtare et al.
Table2. Catalystrecyclingstudy inreactionof1,8-diaminonaphthalene
[3] (a) J.-J. Vanden Eynde, D. Fromont, Bull. Soc. Chim. Belg. 1997,
106, 393.
with p-nitroacetophenone
(b) J.-J. Vanden Eynde, F. Delfosse, T. V. Haverbeke, Tetrahedron
1995, 51, 5813. doi:10.1016/0040-4020(95)00252-4
(c) J.-J. Vanden Eynde, F. Delfosse, A. Mayence, Y. V. Haverbeke,
Tetrahedron 1995, 51, 5111.
Recycle no.
Yield [%]A
Fresh, non-recycled
95
97
94
92
86
82
First
(d) J.-J. Vanden Eynde, A. Mayence, A. Maquestiau, E. Anders,
Heterocycles 1994, 37, 815. doi:10.3987/COM-93-S66
(e) J.-J. Vanden Eynde, A. Mayence, A. Maquestiau, E. Anders,
Synth. Commun. 1992, 22, 3141. doi:10.1080/00397919209409265
(f) A. Maquestiau, L. Berte, A. Mayence, J.-J. Vanden Eynde, Synth.
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[4] R. Brehme, B. Stroede, J. Prakt. Chem. 1987, 329, 246. doi:10.1002/
PRAC.19873290214
Second
Third
Fourth
Fifth
AIsolated yield of perimidine product.
[5] K. Honda, H. Nakanishi, A. Yabe, Bull. Chem. Soc. Jpn. 1983, 56,
HBOB, was recovered and reused (without isolation and purifi-
cation of catalyst) up to five times without loss of activity
(Table 2).
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[6] I. Yavari, M. Adib, F. Jahani-Moghaddam, H. B. Bijanzadeh, Tetra-
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[7] G. W. Rewcastle, in Comprehensive Heterocyclic Chemistry III:
Perimidines and their Benzo Derivatives, 2008, 8, pp. 117–272
(Pergamon: Oxford, UK).
Conclusions
In conclusion, we describe a simple, efficient, and green method
for the synthesis of perimidine derivatives from various ketones
and naphthalene-1,8-diamine using HBOB as a catalyst. The
mild conditions, short reaction times, excellent product yields,
easy workup, and recycling procedure make this methodology
an ideal alternative platform to the conventional acid-catalyzed
thermal processes. Catalyst as well as solvent was easy to
recover and reuse several times without loss of activity. Work is
continuing on other organic transformation reactions with this
convenient solid-acid catalyst and these will be the subject of a
forthcoming publication.
[8] (a) G. Sachs, Justus Liebigs Ann. Chem. 1909, 365, 162.
(b) U. T. Mueller-Westerhoff, B. Vance, D. I. Yoon, Tetrahedron
1991, 47, 909. doi:10.1016/S0040-4020(01)80932-7
(c) R. R. Reddy, C. V. C. Rao, Indian J. Heterocycl. Chem. 1993, 2,
199; S.-H. Kim, J. H. Kim, J. Z. Cui, Y. S. Gal, S. H. Jin, K. Koh, Dyes
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[9] (a) I. V. Aksenova, A. V. Aksenov, A. S. Lyakhovnenko, I. V.
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(b) J. Zhang, S. Zhang, Synth. Commun. 2007, 37, 2615. doi:10.1080/
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Supplementary Material
[10] M. M. Belmonte, E. C. Escudero-Adan, J. B. Buchholz, R. M. Haak,
A. W. Kleij, Eur. J. Org. Chem. 2010, 4823. doi:10.1002/
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Details of analysis of perimidine derivatives are available on the
Journal’s website.
[11] J. Zhang, S. L. Zhang, J. M. Zhang, Chin. Chem. Lett. 2007, 18, 1057.
doi:10.1016/J.CCLET.2007.07.004
Acknowledgements
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Authors are thankful to SAIF-IIT, Mumbai and the Institute of Science,
Mumbai for analytical support. DRM is grateful to the Australian Research
Council for his Federation Fellowship.
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