Pyridinophanes as two-centre phase-transfer catalyst for N-alkylation reaction

Article abstract of DOI:10.1055/s-2006-926304

The synthetic utility of water-soluble pyridinophanes 1 and 2 as an efficient two-centre phase-transfer catalyst for N-alkylation of indoles, imidazole, benzimidazole and benzotriazole has been explored. Application of such pyridinophanes for the synthesis of various precyclophanes involving bis-N alkylation is also described. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-926304

654
PAPER
Pyridinophanes as Two-Centre Phase-Transfer Catalyst for N-Alkylation
Reaction
Pyridinophane
e
s
as Cataly
r
st for
N
-A
u
lkylation
R
m
eaction al Rajakumar,* Manickam Dhanasekaran
Department of Organic Chemistry, University of Madras, Guindy Campus, Chennai 600 025, India
Fax +91(44)22352494; E-mail: perumalrajakumar@hotmail.com
Received 19 August 2005; revised 8 September 2005
the synthesis and complete account of ‘inclusion-electro-
static’ catalytic hydrolysis of aromatic ester by water-sol-
uble positively charged heterocyclophane.
Abstract: The synthetic utility of water-soluble pyridinophanes 1
and 2 as an efficient two-centre phase-transfer catalyst for N-alkyl-
ation of indoles, imidazole, benzimidazole and benzotriazole has
been explored. Application of such pyridinophanes for the synthesis
of various precyclophanes involving bis-N alkylation is also de-
scribed.
The synthesis of cationic benzimidazolophanes,15
benzotriazolophanes16 and pyridinophanes17 with m-ter-
phenyl and pyridyl building block has been reported from
our laboratory. The synthesis of cyclophanes 1, 2, and 3
(Figure 1) have been reported earlier,14,15 and their appli-
cation as phase-transfer catalyst has not been explored.
Further, single-crystal X-ray18 analysis of pyridinophane
1 was carried out recently which reveals the existence of
both syn and anti conformers as shown in Figure 2.
Key words: phase-transfer catalyst, N-alkylation, pyridinophanes
Synthetic approaches involving phase-transfer catalyst
(PTC) are the most important and useful methods in syn-
thetic organic chemistry because of its simple reaction
procedure, mild conditions, inexpensive and environmen-
tally as well as eco-friendly reagents, and the ease in scal-
ing up the reaction.1 Phase-transfer catalysis excels in a
very wide range of base-catalysed C/N/S alkylation,2
etherification,3 esterification,4 nucleophilic substitution,5
dehydrohalogenation,6 aldol reaction,7 and oxidation re-
actions.8 The catalysts most commonly employed are the
quaternary ammonium compounds and macrocyclic poly-
ethers.
We describe herein the application of dicationic pyridi-
nophanes 1, 2 and 3 as two-centre PTC for the N-alkyla-
tion reactions.
In order to test the utility of cationic cyclophanes as PTC
for N-alkylation, indoles were chosen as model com-
pounds. Reaction of substituted indoles with benzene-
sulfonyl chloride in a heterogeneous mixture of benzene
and aqueous NaOH (50%) in the presence of catalytic
amount of either pyridinophane 1 or 2 gave the corre-
sponding N-alkylated indoles 4a–c in good yields
(Table 1). On account of the very poor solubility of cyclo-
phane 3 in water19 as well as in usual organic solvents, the
cyclophane 3 did not function as PTC. Though cyclo-
phane 3 has structural similarity with pyridinophanes 1
and 2, the enhanced chelation effect and solubility of py-
ridinophanes 1 and 2 makes them potentially effective
phase-transfer catalysts.
Cationic cyclophanes are important members in the cyclo-
phane family, as they can have wide range of applications
in anion recognition,9 metal ion,10 charge-transfer
complexation11 and to construct supramolecular assem-
bly.12 The positively charged water-soluble tetra-
aza[8.1.8.1]paracyclophane accelerated the nucleophilic
substitution reactions as well as the Diels–Alder reaction
of cyclopentadiene with diethyl fumarate in dioxane–wa-
ter mixtures.13 Tabushi and co-workers14 have reported
N
N
N
N
N
N
N
N
+
+
+
+
+
+
N
N
N
N
N
N
N
N
2Br–
2Br–
2Br–
2
1
3
Figure 1 Structure of cationic cyclophanes
SYNTHESIS 2006, No. 4, pp 0654–0658
x
x
.
x
x
.2
0
0
6
Advanced online publication: 19.01.2006
DOI: 10.1055/s-2006-926304; Art ID: Z15905SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Pyridinophanes as Catalyst for N-Alkylation Reaction
655
Figure 2 X-ray structure (syn and anti conformations) of cationic pyridinophane 1
Table 1 Phase-Transfer Catalyzed N-Alkylation of Substituted
are shown in Table 2. The structure of all the precyclo-
phanes were confirmed by spectral and analytical data and
the structure of the few precyclophanes were also con-
firmed by single crystal X-ray analysis. The ORTEP18 di-
agrams of the precyclophanes 5d and 6f are shown in
Figure 3 and Figure 4.
Indoles
R2
R2
R1
pyridinophane 1 or 2
+
Ph-SO2Cl
50% NaOH (aq),
benzene
N
R1
N
SO2Ph
4a–c
H
Similarly N-alkylation of imidazole has been carried out
under PTC condition using pyridinophanes 1 and 2 as cat-
alyst to give the corresponding bis(N-alkylated) products
7a–e (Table 3).
Entry Product R1
R2
Time (h) Yield (%)a
Catalyst 1 Catalyst 2
1
2
3
4a
4b
4c
H
CH3
SPh
2
80
88
72
75
80
75
In order to compare the activity of the catalyst 1 with con-
ventional PTC, bis(N-alkylation) reactions of benzimida-
zole/benzotriazole were carried out utilizing tetra-
butylammonium bromide (TBAB), and triethylbenzyl-
ammonium bromide (TEBAB) as PTC. The results ob-
CH3
CH3
1
CHO
1.5
a Isolated yield.
To further explore the synthetic utility of pyridinophanes
1 and 2 as PTC, N-alkylations of benzimidazole/benzotri-
azole were carried out with alkyl bromides under PTC
condition using aqueous NaOH (25%) solution and aceto-
nitrile in the presence of pyridinophanes 1 or 2 to give the
corresponding bis(N-alkylated) benzimidazoles 5a–h/
benzotriazoles 6a–g in good yields. The results obtained
Figure 4 ORTEP diagram of compound 6e
Figure 3 ORTEP diagram of compound 5d
Synthesis 2006, No. 4, 654–658 © Thieme Stuttgart · New York

656
P. Rajakumar, M. Dhanasekaran
PAPER
Table 2 Phase-Transfer Catalyzed N-Alkylation of Benzimidazole/Benzotriazole
H
R
N
pyridinophane 1 or 2
N
N
N
N
+
X
Br R Br
25% NaOH, CH3CN
X
X
N
5a–h X = CH
6a–g X = N
Entry
Product
R
X
Time
Isolated yield (%)
Cat. 1
Cat. 2
70
1
2
3
5a
5b
5c
o-xylyl
CH
CH
CH
16
12
12
72
65
70
m-xylyl
p-xylyl
68
65
4
5
5d
5e
CH
CH
12
15
73
66
69
70
H2C
H2C
N
CH2
OMe
H2C
H2C
6
7
8
5f
CH
CH
CH
12
18
20
79
62
58
74
65
55
OBn
H2C
H2C
5g
5h
H
CH2
CH2
Br
H2C
9
10
11
6a
6b
6c
o-xylyl
N
N
N
14
14
14
60
65
75
56
62
70
m-xylyl
p-xylyl
12
13
6d
6e
N
N
12
14
42
45
45
43
H2C
H2C
N
CH2
OBn
H2C
H2C
H2C
14
15
6f
N
N
20
24
72
70
70
64
H
CH2
CH2
6g
Br
Synthesis 2006, No. 4, 654–658 © Thieme Stuttgart · New York

PAPER
Pyridinophanes as Catalyst for N-Alkylation Reaction
657
tained are shown in Table 4. From these results, it is clear clophanes. Synthesis of other related di- and tetracationic
that the dicationic pyridinophane promoted the reaction pyridinophanes and their application as phase-transfer
approximately twice as fast as the monoammonium bro- catalyst are under way.
mides (TBAB and TEBAB). Thus, our experimental re-
sult indicated that the two-cationic sites present in the
catalyst simultaneously accelerated the reaction. When
the above reactions were carried out in the absence of
PTC, relatively lesser yield of the bis(N-alkylated) prod-
ucts were observed and the reactions required longer du-
ration of nearly 48–55 hours.13–15
N-Alkylation of Benzimidazole/Benzotriazole/Imidazole under
PTC Conditions; General Procedure
To a solution of the appropriate benzimidazole/benzotriazole/imi-
dazole/substituted indole (20 mmol) and 25% aq NaOH (7.5 mL) in
benzene or MeCN (100 mL; benzene was used for reactions of in-
dole; MeCN was used for reactions of imidazole/benzimidazole/
benzotriazole), were added the dibromide (10 mmol) and cationic
pyridinophane 1/2 (0.1 mmol) and the mixture was vigorously
stirred at r.t. The progress of the reaction was monitored by TLC
and after completion of the reaction, the mixture was evaporated in
vacuo and extracted with CHCl3 (3 × 100 mL). The combined or-
ganic extracts were washed with brine (2 × 50 mL), dried (Na2SO4)
and the solvent was evaporated in vacuo. The crude product was pu-
rified by column chromatography using CHCl3–MeOH or hexane–
EtOAc solvent mixture (Tables 1– 4). Two specific examples of the
N-alkylated products prepared by the above procedure are given be-
low.
Table 3 Catalytic Phase-Transfer N-Alkylation of Imidazole
H
N
R
1 or 2
N
N
N
N
+
Br
R Br
25% NaOH, CH3CN
N
7a–e
Entry Product R
Time Isolated yield (%)
Cat. 1
42
Cat. 2
40
Precyclophane 6e
1
2
3
7a
7b
7c
o-xylyl
m-xylyl
16
16
12
Benzotriazole (1.19 g, 10 mmol), 1,3-bis(bromomethyl)-5-benzyl-
oxybenzene (1.85 g, 0.5 mmol), pyridinophane 1 (0.03 g, 0.05
mmol), NaOH (7.5 mL, 25%) in MeCN (100 mL) were subjected to
the procedure described above at r.t. for 14 h. Purification by col-
umn chromatography (SiO2) using hexane–EtOAc (7:3) as eluent
gave precyclophane 6e as a white solid; yield: 1.00 g (45%); mp
119–121 °C.
1H NMR (400 MHz, CDCl3): d = 5.04 (s, 2 H), 5.88 (s, 4 H, NCH2),
6.95 (s, 3 H), 7.35–7.49 (m, 11 H), 8.20 (2 H).
13C NMR (100 MHz, CDCl3): d = 51.82, 70.16, 109.54, 114.13,
119.06, 120.11, 124.07, 127.49, 127.61, 128.17, 128.62, 132.72,
136.01, 137.22, 146.27, 159.72.
35
35
33
30
H2C
H2C
N
CH2
4
5
7d
7e
14
14
31
38
35
40
OBn
H2C
H2C
OMe
MS (70 eV): m/z = 446 (M+).
H2C
Anal. Calcd for C27H22N6O: C, 72.63; H, 4.97; N, 18.82. Found: C,
72.38; H, 5.08; N, 18.62.
Precyclophane 7d
Imidazole (0.68 g, 10 mmol), 1,3-bis(bromomethyl)-5-benzyloxy-
benzene (1.85 g, 0.5 mmol), pyridinophane 1 (0.03 g, 0.05 mmol),
NaOH (7.5 mL, 25%) in MeCN (100 mL) were subjected to the pro-
cedure described above at r.t. for 14 h. Purification by column
chromatography (SiO2) using CHCl3–MeOH (49:1) afforded pre-
cyclophane 7d as a white solid; yield: 0.60 g (35%); mp 59–61 °C.
1H NMR (400 MHz, CDCl3): d = 4.94 (s, 2 H), 5.02 (s, 4 H, NCH2),
6.50 (s, 1 H), 6.63 (s, 2 H), 6.84 (s, 2 H), 7.07 (s, 2 H), 7.29 (m, 5
H), 7.50 (s, 2 H).
Table 4 Comparison of Catalytic Activity of Pyridinophane 1 with
Conventional PTC
Entry Product TBAB
TEBAB
Catalyst 1
Time
(h)
Yield Time Yield Time Yield
(%)a
(h)
25
32
42
(%)a
(h)
12
15
20
(%)a
1
2
3
5d
5e
6f
26
29
42
68
68
73
65
66
66
13C NMR (125 MHz, CDCl3): d = 50.32, 70.05, 113.28, 118.06,
119.20, 127.44, 128.15, 128.61, 129.92, 130.853, 135.99, 137.36,
138.65, 159.67.
56
52
72
a Isolated yield.
MS (70 eV): m/z = 344 (M+).
Anal. Calcd for C21H20N4O: C, 73.23; H, 5.85; N, 16.27. Found: C,
73.01; H, 5.62; N, 16.48.
In conclusion, we have proved for the first time that dica-
tionic water-soluble pyridinophanes can act as excellent
and efficient phase-transfer catalysts. The catalytic activ-
ity is enhanced due to the presence of two cationic centres
and excellent chelation effect caused by the pyridine moi-
Acknowledgment
The authors thank DST, New Delhi for financial assistance and
ety. Further, the synthesised precyclophanes are very UGC for Special Assistance Program to the Department of Organic
Chemistry. M.D. thanks CSIR for providing a Senior Research Fel-
good building blocks for the construction of cationic cy-
lowship.
Synthesis 2006, No. 4, 654–658 © Thieme Stuttgart · New York

658
P. Rajakumar, M. Dhanasekaran
PAPER
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Synthesis 2006, No. 4, 654–658 © Thieme Stuttgart · New York