Solid-Supported Synthesis of Flexible Dimeric Pyridinium Salts and Their Catalytic Activities

Article abstract of DOI:10.1055/s-0035-1560425

The synthesis of flexible dimeric pyridinium ionic liquids by both conventional and solid-supported approaches are described. We have optimized the Biginelli reaction with various concentrations of our synthesized ionic liquids with various counter ions.

Full text of DOI:10.1055/s-0035-1560425

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2016, 27, A–D
letter
A
C. Manikandan, K. Ganesan
Letter
Synlett
Solid-Supported Synthesis of Flexible Dimeric Pyridinium Salts
and Their Catalytic Activities
Br–
Chitrarasu Manikandan
Br–
N
N
MeCN, r.t.,
5–8 h, 92–96%
Kilivelu Ganesan*
Br
O
K2CO3
MeCN
O
N
O
+
PG & Research Department of Chemistry,
Presidency College (Autonomous),
Chennai – 600 005, India
solvent-free reaction,
30–45 min, 90–92%
N
OH
r.t., 5.5 h,
94%
R
R
Br
R
Br
O
kiliveluganesan@yahoo.co.in
MX, H2O
r.t., 2 h
91–94%
N
X–
R = H, NO2
N
O
X–
N
O
R
–
X– = BF–4, PF–6, CF3SO3
R
8 examples
Received: 27.12.2015
Accepted after revision: 05.02.2016
Published online: 24.03.2016
chemistry of IL has been very recently reviewed.12 Ionic liq-
uids have shown promising applications in multicompo-
nent reactions (MCR), a procedure recently described as ‘a
perfect synergy for eco-compatible heterocyclic synthe-
sis’.13 We have recently reported the preparation of some
imidazolium as well as pyridinium type of IL and studied
their catalytic activities.14 Multicomponent condensation
can be used to construct complicated heterocyclic scaf-
folds.15,16 Herein, we report the preparation of a flexible di-
meric pyridinium cation with different anions.
DOI: 10.1055/s-0035-1560425; Art ID: st-2015-d1002-l
Abstract The synthesis of flexible dimeric pyridinium ionic liquids by
both conventional and solid-supported approaches are described. We
have optimized the Biginelli reaction with various concentrations of our
synthesized ionic liquids with various counter ions. Among these, bro-
mide-containing ionic liquids showed best catalytic activity.
Key words ionic liquid, o-alkylation, solid supported, Biginelli reaction
1,4-Dibromobutane was treated with 2-hydroxypyri-
dine and anhydrous K2CO3 in the presence of dry MeCN for
5.5 hours at ambient temperature to afford the alkylated
product 1 in 94% of yield. Compound 1 was treated with
benzylbromide and 4-nitrobenzylbromide in the presence
of dry MeCN for 5–8 hours to give quarternized pyridinium
bromides 2a,b in quantitative yield, their structures being
confirmed by both spectroscopic and analytical data.17 Af-
ter completion of the quarternization reaction, anion-ex-
change reaction was carried out in the presence of various
counter ion-containing inorganic salts such as K4PF6, NaBF4,
and LiCF3SO3 in water and at room temperature with stir-
ring for two hours to give anion-exchanged products of
compound 3a–f in quantitative yield (Scheme 1). Separat-
ing the pyridinium salt from metallic bromide was not easy,
because organic solvent extraction was not feasible due to
the water-soluble nature of both metallic bromide and pyr-
idinium salt. Under these circumstances, we carried out
Soxhlet extraction with THF for two hours to yield the met-
al bromide free pyridinium salts with excellent yield. Verifi-
cation with aqueous AgNO3 solution did not result in any
yellow precipitate, confirming that these exchanged pyri-
Synthetic strategies for the nucleus involve one-pot and
multistep approaches. The classical Biginelli reaction is a
one-pot condensation using β-dicarbonyl compounds, aro-
matic or aliphatic aldehydes, and urea or thiourea in etha-
nol with a catalytic amount of acid to give dihydropyrimi-
dines (DHPM). However, the method requires extended re-
action times, harsh conditions, and can result in poor
yields.1 Nevertheless, this approach offers a straightforward
approach to multifunctional DHPM and related heterocyclic
compounds.2,3 Recent modifications of the synthesis of
DHPM have been developed in aqueous media.4
Some marine alkaloids containing the dihydropyrimi-
dine core possess interesting biological properties. Batzella-
dine alkaloids have been found as potent HIV gp-120-CD4
inhibitors.5 DHPM derivatives display a broad range of bio-
logical properties such as antitumor,6 antihypertensive,7
anti-HIV,8 antioxidant,9 antimalarial,10 antimicrobial, anti-
inflammatory, antibacterial, antifungal, and anthelmintic
activities.11
Ionic liquids (IL) consist of an organic cation with an in-
organic anion or an organic cation with an organic anion
and can act as homogeneous catalysts. The impressive
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

B
C. Manikandan, K. Ganesan
Letter
Synlett
CA
Br
2 Br–
N
1,4-dibromobutane
R
N
K2CO3
MeCN
r.t., 5.5 h
94%
O
N
OH
N
O
SSA
O
N
O
R = H, NO2
1
R
2a,b
R
MX, H2O, r.t., 2 h, 91–94%
2 X–
N
O
N
O
MX = K4PF6, NaBF4, LiCF3SO3
R
R
3a–f
Scheme 1 Synthesis of 2-hydroxy pyridinium salt under conventional and silica-supported approaches. Reagents and conditions: Conventional ap-
proach (CA): MeCN, r.t., 5–8 h, 92–96%. Silica-supported approach (SSA): silica gel (60–120 mesh), Muffle furnace, 50–100 °C, 30–45 min, 90–92%.
dinium salts were metal bromide free. The compositions of
compounds 3a–f are confirmed from spectroscopic and an-
alytical data.18
N,N-dimethylaminobenzaldehyde in the presence of our
synthesized dimeric pyridinium salts along with dry MeCN
at ambient reaction conditions (Scheme 2).
The multicomponent reaction between 4-nitrobenzal-
dehyde, urea, and ethylacetoacetate in the presence of 10
mL of dry MeCN along with our synthesized dimeric pyri-
dinium salts was studied for times between 2–75 minutes
at ambient reaction conditions, afforded the dihydropyrim-
idines, and was found good to excellent catalytic activities.
Zhi-Liang et al. reported this conversion under conventional
reflux conditions in ethanol for 12 hours to afford the de-
sired product in lower yield.19 With our system, the same
reaction required 2.56·10–5 mmol of our dimeric pyridini-
um salts, requiring only 14–24 minutes to complete, which
is around 15 times faster than previously reported.20 Chan-
dra Nandi et al. have reported that the reaction assisted by
SiO2·H2SO4 took 2.5–3.5 hours to afford the condensation
products in moderate to good yield,21 and the application of
the Xantphos catalyst likewise required extended reaction
times.22
Carrying out the reaction with the above substrates in
dry MeCN with 2.56·10–5 mmol concentration of pyridini-
um salts 2a,b and 3a–f, we observed that nitro-substituted
dimeric pyridinium salts 2a,b showed good to excellent cat-
alytic activities compared to the unsubstituted dimeric pyr-
idinium salts. Then we extended the Biginelli reaction to
various aryl aldehydes with the same catalytic concentra-
tion and found that p-nitrobenzaldehyde reacted much
faster than the meta isomer that, in turn, reacted faster than
other aromatic aldehydes (Table 1). Furthermore, when
5.12·10–5 mmol of the dimeric pyridinium salts was used
we observed that the reaction time was nearly halved (Ta-
ble 2). With 7.67·10–5 mmol of dimeric pyridinium salts
2a,b and 3a–f the reaction was still faster (Table 3), but by
increasing to 1.02·10–4 mmol, no appreciable increase in re-
action time or yield was observed.
In conclusion, we have synthesized dimeric pyridinium
cations with different counterions and have studied the
Biginelli reaction in the presence of these dimeric pyridini-
um salts. We examined the effect of catalyst concentration
and found that 7.67·10–5 mmol concentration gave highest
yields with shortest reaction times.
Hence low concentrations of our dimeric pyridinium
salts acted as efficient catalysts for Biginelli reaction be-
tween equimolar concentrations of urea, ethylacetoacetate,
and various aryl aldehyde such as p-hydroxybenzaldehyde,
o-/m-/p-nitrobenzaldehyde, p-chlorobenzaldehyde, and p-
R
H
O
C
O
O
K2CO3/MeCN
O
O
+
7.67⋅10–5 mmol of pyridinium salt
EtO
Me
NH
H2N
NH2
+
R
EtO
Me
r.t., 2–75 min
N
O
H
R = 4-N(Me)2, 4-OH, 3-NO2, 4-NO2, 3-NO2, 4-Cl
4a–f
Scheme 2 Biginelli reactions with optimized concentration of our dimeric pyridinium salts
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

C
C. Manikandan, K. Ganesan
Letter
Synlett
Table 1 2.56·10–5 mmol Concentration of Dimeric Pyridinium Salts for Biginelli Reactiona,b
4-NO2
3-NO2
2-NO2
4-OH
4-Cl
4-NMe2
Catalyst
Time (min) Yield (%)c Time (min) Yield (%)c Time (min) Yield (%)c
Time (min) Yield (%)c Time (min) Yield (%)c Time (min) Yield (%)c
2a
3a
3b
3c
2b
3d
3e
3f
14
17
22
22
12
16
21
24
88
82
80
80
92
86
80
80
14.5
18.5
22
82
81
78
78
80
81
75
69
18.5
20
78
76
76
74
88
78
73
73
19
31
39
45
16
28
35
41
70
60
66
65
70
73
58
69
14
21
21
26
16
16
18
23
77
69
60
70
78
72
70
58
30
45
33
32
45
55
73
75
87
76
78
75
78
74
70
70
24.5
26
24
13
16
16
18
23
24.5
27
25
a Reaction conditions: p-nitrobenzaldehyde (6.61·10–3 mmol; 1.0 equiv), urea (6.74·10–3 mmol; 1.02 equiv), and ethyl acetoacetate (6.74·10–3 mmol; 1.02
equiv), MeCN (10 mL), pyridinium salts of 2a,b and 3a–f (2.56·10–5 mmol) concentration.
b Absence of pyridinium salt: no appreciable change even after 3 h.
c Yield of isolated product.
Table 2 5.12·10–5 mmol Concentration of Dimeric Pyridinium Salts for Biginelli Reactiona,b
4-NO2
3-NO2
2-NO2
4-OH
4-Cl
4-NMe2
Catalyst
Time (min) Yield (%)c Time (min) Yield (%)c Time (min) Yield (%)c
Time (min) Yield (%)c Time (min) Yield (%)c Time (min) Yield (%)c
2a
3a
3b
3c
2b
3d
3e
3f
09
84
80
80
87
90
84
82
80
08.5
10
15
15
07
09
15
14
84
85
76
84
88
87
80
87
09
12
16
16.5
09
11
17
16
80
84
80
78
86
89
80
84
08
21
28
34.5
07
18
26
32
88
79
74
68
88
78
82
70
09
16
18
19
06
12
12
14
88
82
80
76
90
88
88
80
18
29
17
17
23
37
55
60
88
74
78
78
80
69
72
70
09
13
14.5
06.5
09
14
14
a Reaction conditions: p-nitrobenzaldehyde (6.6·10–3 mmol; 1.0 equiv), urea (6.74·10–3 mmol; 1.02 equiv), and ethyl acetoacetate (6.74·10–3 mmol; 1.02 equiv),
MeCN (10 mL), pyridinium salts of 2a,b and 3a–f (5.12·10–5 mmol) concentration.
b Absence of pyridinium salt: no appreciable change even after 3 h.
c Yield of isolated product.
Table 3 7.67·10–5 mmol Concentration of Dimeric Pyridinium Salts for Biginelli Reactiona,b
4-NO2
3-NO2
2-NO2
4-OH
4-Cl
4-NMe2
Catalyst
Time (min) Yield (%)c Time min Yield (%)c Time (min)
Yield (%)c Time (min)
Yield (%)c Time (min) Yield (%)c Time (min) Yield (%)c
2a
3a
3b
3c
2b
3d
3e
3f
02
82
80
80
80
96
90
90
84
2.5
06
93
88
83
87
96
88
90
93
04
92
89
80
83
96
90
90
89
04.5
07.5
08
94
88
88
89
95
90
89
84
03
06
12
13
02
07
08
08
88
88
82
83
92
90
84
80
06
10
08
09
12
17
26
33
93
86
90
84
88
89
86
82
04.5
09
07.5
12
10
10
12
11
10.5
03.5
05
01.5
04.5
07
1.5
05.5
09
02.5
08
10.5
12
06
09.5
10.5
09
a Reaction conditions: p-nitrobenzaldehyde (6.61·10–3 mmol; 1.0 equiv), urea (6.74·10–3 mmol; 1.02 equiv), and ethyl acetoacetate (6.74·10–3 mmol; 1.02 equiv),
MeCN (10 mL), pyridinium salts of 2a,b and 3a–f (7.67·10–5 mmol) concentration.
b Absence of pyridinium salt: no appreciable change even after 3 h.
c Yield of isolated product.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

D
C. Manikandan, K. Ganesan
Letter
Synlett
(10) Brown, D. J.; Evans, R. F.; Cowden, W. B.; Fenn, M. D. Chemistry
of Heterocyclic compounds: The Pyrimidines: Supplement II; John
Wiley & Sons: New York, 1985, Vol. 16.
Acknowledgment
The authors thank Dr. R. Sundaram, Assistant Professor, Department
of Chemistry, Presidency College, Chennai – 5 for cooperation.
(11) Ramesh, B.; Bhalgat, C. M. Eur. J. Med. Chem. 2011, 46, 1882.
(12) Neto, A. D.; Spencer, J. J. Braz. Chem. Soc. 2012, 23, 987.
(13) Isambert, N.; Duque, M. D. S.; Plaquevent, J. C.; Genisson, Y.;
Rodriguez, J.; Constantieux, T. Chem. Soc. Rev. 2011, 40, 1347.
(14) (a) Manikandan, C.; Ganesan, K. Synth. Commun. 2014, 44, 3362.
(b) Ganapathi, P.; Ganesan, K. Synth. Commun. 2015, 45, 2135.
(c) Naveenkumar, R.; Ganapathi, P.; Ganesan, K. J. Heterocycl.
Chem. 2016, in press; DOI: 10.1002/jhet.2538.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1560425.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
(15) Yu, J.; Shi, F.; Gong, L.-Z. Acc. Chem. Res. 2011, 44, 1156.
(16) Dondoni, A.; Massi, A. Acc. Chem. Res. 2006, 39, 451.
(17) 2,2′-(Butane-1,4-diyl)bis(oxy)dipyridinium Benzylbromide
(2a)
References and Notes
(1) Peng, J.; Deng, Y. Tetrahedron Lett. 2001, 42, 5917.
(2) (a) Dondoni, A.; Massi, A. Acc. Chem. Res. 2006, 39, 451. (b) Aron,
Z. D.; Overman, L. E. Chem. Commun. 2004, 253. (c) Kappe, C. O.
Acc. Chem. Res. 2000, 33, 879.
Yield 5.9 g 90%; liquid. 1H NMR (400 MHz, CDCl3): δ = 3.45 (t, 4
H), 4.01 (q, 4 H), 5.23 (s, 4 H), 8.18–8.22 (m, 8 H), 7.28–7.58 (m,
10 H). 13C NMR (100 MHz, CDCl3): δ = 26.1, 51.8, 106.8, 121.1,
124.0, 128.5, 129.9, 137.7, 140.0, 144.7, 147.6. MS: m/z = 586.36.
Anal. Calcd for C28H30Br2N2O2: C, 57.30; H, 5.11; N, 4.77. Found:
C, 57.18; H, 5.04; N, 4.66.
(3) Biginelli, P. Gazz. Chim. Ital. 1893, 23, 360.
(4) (a) Polshettiwar, V.; Varma, R. S. Tetrahedron Lett. 2007, 48,
7343. (b) Kumar, A.; Maurya, R. A. Synlett 2008, 883.
(5) Patil, A. D.; Kumar, N. V.; Kokko, W. C.; Bean, M. F.; Freyer, A. J.;
Debrosse, C. J. Org. Chem. 1995, 60, 1182.
(6) (a) Abdel Hafez, O. M.; Amin, K. M.; Abdel-Latif, N. A.;
Mohamed, T. K.; Ahmed, E. Y.; Maher, T. Eur. J. Med. Chem. 2009,
44, 2967. (b) Kempen, I.; Papapostolou, D.; Thierry, N.; Pochet,
L.; Counerotte, S.; Masereel, B.; Foidart, J-M.; Reboud-Ravaux,
M.; Noel, A.; Pirotte, B. Br. J. Cancer 2003, 88, 1111.
(7) Rovnyak, G. C.; Atwal, K. S.; Hedberg, A.; Kimball, S. D.;
Moreland, S.; Gougoutas, J. Z.; O’Reilly, B. C.; Schwartz, J.;
Malley, M. F. J. Med. Chem. 1992, 35, 3254.
(8) Okabe, M.; Sun, R. C.; Zenchoff, G. B. J. Org. Chem. 1991, 56,
4393.
(18) 2,2′-(Butane-1,4-diylbis(oxy)dipyridinium Benzylhexafluo-
rophosphate (3a)
Yield 0.78 g, 91%; liquid. 1H NMR (400 MHz, CDCl3): δ = 3.50 (t,
4 H), 4.03 (q, 4 H), 5.27 (s, 4 H), 8.20–8.27 (m, 8 H), 7.30–7.60
(m, 10 H). 13C NMR (100 MHz, CDCl3): δ = 26.5, 51.1, 106.5,
121.3, 124.2, 128.8, 129.1, 137.4, 140.1, 144.9, 147.4. MS: m/z =
716.48. Anal. Calcd for C28H30F12N2O2P2: C, 46.89; H, 4.18; N,
3.90. Found: C, 46.81; H, 4.09; N, 3.82.
(19) Zhang, L.; Zhang, Z.; Liu, Q.; Liu, T.; Zhang, G. J. Org. Chem. 2014,
79, 2281.
(20) Shen, Z.; Xu, X.; Ji, S. J. Org. Chem. 2010, 75, 1162.
(21) Chandra Nandi, G.; Samai, S.; Singh, M. J. Org. Chem. 2010, 75,
7785.
(9) (a) Stanchev, S.; Hadjimitova, V.; Traykov, T.; Boyanov, T.;
Manolova, I. Eur. J. Med. Chem. 2009, 44, 3077. (b) Xiao, C.; Song,
Z.-G.; Liu, Z.-Q. Eur. J. Med. Chem. 2010, 45, 2559.
(22) Fuchs, D.; Nasr-Esfahani, M.; Diab, L.; Mejkal, T.; Breit, B. Synlett
2013, 24, 1657.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D