New acridizinium salts derived from [2-(bromomethyl)phenyl]carbonyl compounds

Article abstract of DOI:10.1007/s10593-013-1246-9

A new method is proposed for the preparation of 1-hydroxypyrido[1,2-b] isoquinolinium bromides by intramolecular aromatic electrophilic substitution in 3-hydroxy-1-(2-formylbenzyl)pyridinium, 3-hydroxy- and 3-amino-1-[2-(4- chlorobenzoyl)benzyl]pyridinium bromides. The alkylation of pyridine and some of its derivatives by 2-(bromomethyl)benzaldehyde, 2-(bromomethyl)benzophenone derivatives, and methyl 2-(bromomethyl)benzoate was studied.

Full text of DOI:10.1007/s10593-013-1246-9

Chemistry of Heterocyclic Compounds, Vol. 49, No. 2, May, 2013 (Russian Original Vol. 49, No. 2, February, 2013)
NEW ACRIDIZINIUM SALTS DERIVED FROM
[2-(BROMOMETHYL)PHENYL]CARBONYL COMPOUNDS
L. M. Potikha1*, V. V. Sypchenko1, and V. A. Kovtunenko1
A new method is proposed for the preparation of 1-hydroxypyrido[1,2-b]isoquinolinium bromides by
intramolecular aromatic electrophilic substitution in 3-hydroxy-1-(2-formylbenzyl)pyridinium,
3-hydroxy- and 3-amino-1-[2-(4-chlorobenzoyl)benzyl]pyridinium bromides. The alkylation of pyridine
and some of its derivatives by 2-(bromomethyl)benzaldehyde, 2-(bromomethyl)benzophenone
derivatives, and methyl 2-(bromomethyl)benzoate was studied.
Keywords: 2-(bromomethyl)benzaldehyde, 2-(bromomethyl)benzophenone, methyl 2-(bromomethyl)-
benzoate, pyrido[1,2-b]isoquinoline, aromatic electrophilic substitution, cyclization.
Pyrido[1,2-b]isoquinolinium (acridizinium) salts are capable of Diels–Alder cycloadditions and are used
in the synthesis of a range of biologically active compounds. These salts have been used in the preparation of
drugs for the treatment of neurodegenerative conditions, neurotoxic injuries, and AIDS [1-3]. The high
photochemical activity of these salts accounts for their use as efficient fluorescence probes in biological [4] and
chemical studies [5]. Many workers have been actively developing methods for the synthesis of acridizinium
salts following their discovery by Bradsher [6]. With a single exception, all these methods are based on the
addition of the isoquinoline fragment to 2-carbonyl-, 2-cyano-, and 2-benzylpyridine derivatives, as proposed
by Bradsher [7, 8]. The fusion of a pyridine ring to an isoquinoline fragment has been used to prepare only a
single compound, namely, 3-hydroxypyrido[1,2-b]isoquinolinium salt [1, 2]. Each of these routes has its
limitations due to the cyclization reaction mechanism or difficulties in obtaining 2-substituted pyridines. In the
present work, still another method is proposed for the preparation of pyrido[1,2-b]isoquinolinium salts using
pyridine and its readily available derivatives.
γ-Halocarbonyl compounds as 1,4-dielectrophilic reagents are convenient building blocks for the
preparation of various heterocyclic systems, including isoquinoline systems. In previous work [9, 10], we
showed that condensed isoquinolines are readily formed by the cyclization of quaternary 1,3-diazolium salts
using 2-(bromomethyl)benzaldehyde (1a), 2-(bromomethyl)benzophenone derivatives 1b,c, and methyl
2-(bromo-methyl)benzoate (1d). In the present work, we studied the reaction of bromomethyl derivatives 1a-d
with pyridine (2d) and some of pyridine derivatives 2a-c,e-h, yielding new pyridinium salts 3a-m, which are
potential precursors for the proposed synthesis of new pyrido[1,2-b]isoquinoline derivatives.
_______
*To whom correspondence should be addressed, e-mail: potikha_l@mail.ru.
1Kyiv Taras Shevchenko National University, 64 Volodymirska St., Kyiv 01033, Ukraine.
________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 318-326, February, 2013. Original
article submitted September 12, 2012.
294
0009-3122/13/4902-0294©2013 Springer Science+Business Media New York

R1
O
R3
R1
Br
R3
R2
_
+
N
N
O
Br
R2
+
R4
R4
R5
2a–h
R5
1a–d
3a–m
Starting
Product
R1
R2
R3
R4
R5
compounds
H
H
H
H
H
H
H
H
H
H
H
H
OH
OH
OH
OH
NH2
H
1a, 2a
1a, 2b
1b, 2a
1b, 2b
1b, 2c
1a, 2d
1b, 2d
1b, 2e
1b, 2f
1a, 2g
1b, 2h
1c, 2c
1d, 2a
3a
3b
3c
3d
3e
3f
H
H
Me
H
4-ClC6H4
4-ClC6H4
4-ClC6H4
H
H
H
Me
H
H
H
H
4-ClC6H4
4-ClC6H4
4-ClC6H4
H
H
H
H
3g
3h
3i
H
H
Me
Br
H
H
H
H
NH2
NMe2
H
H
3j
4-ClC6H4
Ph
H
H
H
3k
3l
NO2
H
H
NH2
OH
OMe
H
H
3m
We discovered that maintaining γ-halocarbonyl compounds 1a-d in benzene or acetone with pyridines
2a-h led to the formation of quaternary pyridinium salts 3a-m in 58-91% yields. Products 3a-f,h-l were
obtained at room temperature, while the preparation of salts 3g,m required heating (see Experimental). Salts 3
dissolved readily in water, but were only moderately soluble in methanol and ethanol. The physicochemical and
spectral characteristics of these new salts 3a-m are given in Tables 1 and 2.
It is known [11] that upon the action of base, quaternary pyridinium salts are capable of forming
pyridinium ylides, which are commonly used in chemical synthesis. These ylides are usually represented as a set
of resonance structures A, B, and C.
_
_
+
N
+
N
+
N
_
A
B
C
In our case, the addition of NaOH or Et3N to solutions of salts 3 resulted in a darker color, but attempts
to isolate and characterize the transformation products of these salts were unsuccessful, and heating these salts
for 3-10 h led to complex mixtures of unidentified compounds. At the same time, heating solutions of salts 3a-e
in 48% hydrobromic acid at reflux gave their cyclization products, namely, 1-hydroxypyrido[1,2-b]iso-
quinolinium bromides 4a-d.
The structure of bromides 4a-d was established on the basis of their spectral and analytical data (Tables
1
1 and 2). A characteristic feature of the H NMR spectra of these salts was the presence of a low-field one-
proton singlet for H-6 (> 10 ppm). The presence of the 4-chlorophenyl substituent at position 11 in salts 4c,d led
to an upfield shift of the hydroxyl proton and H-10 proton signals by 0.6-1.0 ppm relative to the analogous
proton signals of unsubstituted salts 4a,b. The observed shift was evidently a consequence of shielding by the
benzene ring, which was perpendicular to the plane of the tricyclic pyrido[1,2-b]isoquinoline system.
295

_
R3
Br
+
N
HBr
3a–e
, 2–30 h
R1
4a–d
OH
_
OH
O
Br
+
HBr
N
3m
, 10 h
OH
3n
4 a R1 = R3 = H; b R1 = H, R3 = Me; c R1 = 4-ClC6H4, R3 = H; d R1 = 4-ClC6H4, R3 = Me
The yield of cyclization products 4a-d depended on the structure of the starting pyridinium salt 3. Thus,
the yields of bromides 4a,b from formyl derivatives 3a,b were higher than for bromides 4c,d from the
corresponding benzoyl derivatives 3c,d. The yields of products 4a,c from salts 3a,c, which were unsubstituted at
position 2 in the pyridine ring, were higher than for products 4b,d from the corresponding 2-methyl derivatives
3b,d. The amino-substituted salt 3e cyclized much more readily than its hydroxy-substituted analog 3c. The
cyclization of salt 3e was accompanied by hydrolysis, thus the same product 4c was obtained in 68% and 10%
yields, respectively, from both salts 3e,c. These results might have been expected in light of the data of Matsuda
et al. [12] on the transformations of structurally similar 8-aminoquinolizinium salts. The observed dependence
of the yield of cyclic products on the structure of the starting pyridinium salts was due to the cyclization
reaction mechanism involving electrophilic aromatic substitution in the pyridine ring with participation of the
salt 3 carbonyl group activated in acidic medium.
A similar type of transformation has been used for the preparation of 8-aminoquinolizinium salts [12]
involving cyclization of 3-aminopyridinium N-allylylides derived from alkyl but-2-enoate derivatives in an
acidic medium. The back-donated 1,6-cyclization mechanism, in the opinion of these authors, entails
participation of the pyridinium ylide resonance form B. Factors stabilizing this resonance form should clearly
favor such a mechanism. In a study of a similar cyclization reaction of N-allyl-1,3-diazolium ylides obtained
from dypnone derivatives (generated from the corresponding N-allyl-1,3-diazolium salts) [13], we found an
increase in reaction rate and yield of cyclization products (azolo[a]pyridines) with stronger electron-
withdrawing properties of the 1,3-diazole substituents.
In order to check the probability of the ylide mechanism for the cyclization of salts 3a-e, we studied the
behavior of salts 3f-k with different substituents at different positions of the pyridine ring under various
conditions. Mixtures of unidentified products were obtained in basic medium under standard conditions for the
formation of ylides [11]. The desired acridizinium salts also did not form in acidic medium, regardless of the
acidity of the medium and reaction temperature. Similarly, an attempt to cyclize the salt 3l also failed, while
only the hydrolysis product, acid 3n, was obtained in the case of 3-hydroxy-1-[2-(methoxycarbonyl)-
benzyl]pyridinium bromide (3m).
Thus, the presence of strong electron-donating substituents at the meta position of the pyridine ring in
the starting pyridinium salt 3, as well as an acidic medium were necessary for the formation of acridizinium
salts 4. Cyclization was also facilitated by the presence of other electron-donor substituents in the pyridine ring
and enhanced carbonyl activity of the substituent in the N-benzyl fragment. These findings, in our view,
unequivocally indicate an electrophilic aromatic substitution mechanism for the cyclization of salts 3a-e.
296

TABLE 1. Physicochemical Characteristics of Compounds 3-6
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
Mp*, °С
Yield, %
86
C
H
Br
Cl
—
N
3а
C13H12BrNO2
53.10
53.08
4.15
4.11
27.14
27.16
4.73
4.76
170-171
3b
3c
3d
3e
3f
C14H14BrNO2
54.53
54.56
56.42
56.39
57.40
57.37
56.50
56.53
56.13
56.14
58.70
58.71
59.67
59.65
4.55
4.58
3.75
3.74
4.11
4.09
3.97
3.99
4.37
4.35
3.91
3.89
4.23
4.25
25.96
25.93
19.72
19.74
19.04
19.08
19.81
19.79
28.75
28.73
20.58
20.56
19.83
19.84
—
4.56
4.55
3.45
3.46
3.39
3.35
6.92
6.94
5.05
5.08
3.59
3.60
3.50
3.48
201-202
226-227
199-200
188-189
181-182
203-205
204-205
74
90
69
91
89
87
88
С19H15BrClNO2
С20H17BrClNO2
С19H16BrClN2O
C13H12BrNO
8.80
8.76
8.48
8.47
8.75
8.78
—
3g
3h
С19H15BrClNO
С20H17BrClNO
9.10
9.12
8.82
8.80
3i
С19H14Br2ClNO
С13H13BrN2O
С21H20BrClN2O
C19H16BrN3O3
C14H14BrNO3
C13H12BrNO3
C13H10BrNO
48.80
48.81
53.30
53.26
58.40
58.42
55.11
55.09
51.84
51.87
50.30
50.34
56.56
56.55
57.98
57.95
3.05
3.02
4.50
4.47
4.65
4.67
3.91
3.89
4.36
4.35
3.91
3.90
3.67
3.65
4.19
4.17
34.20
34.18
27.30
27.26
18.55
18.51
19.32
19.29
24.62
24.65
25.79
25.76
28.93
28.94
27.53
27.54
7.60
7.58
—
3.02
3.00
9.55
9.56
6.45
6.49
10.13
10.14
4.35
4.32
4.51
4.52
5.06
5.07
4.85
4.83
190-191
176-177
195-196
168-169
196-198
211-213
71
91
3j
3k
3l
8.20
8.21
87
—
—
—
—
—
58
3m
3n
4a
4b
4c
4d
5
60
55
> 235
(decomp.)
> 250
(decomp.)
69
C14H12BrNO
74
С19H13BrClNO
С20H15BrClNO
С19H12ClNO
59.07
59.02
59.98
59.95
74.66
74.64
3.41
3.39
3.80
3.77
3.97
3.96
20.65
20.66
19.96
19.94
9.18
9.17
8.88
8.85
11.63
11.60
3.64
3.62
3.48
3.50
4.57
4.58
> 300
10 (68)*2
38
> 300
—
> 235
(decomp.)
72
6
С21H15BrClNO2
58.85
58.83
3.57
3.53
18.66
18.64
8.23
8.27
3.26
3.27
> 260
(decomp.)
64
_______
*Recrystallization solvents: MeNO2 (compounds 3a-e,h-n), 1:1 mixture of
2-propanol–n-hexane (compounds 3f,g), methanol (compounds 4a-d), 2-propanol
(compounds 5 and 6).
*2The yield in the cyclization of salt 3e.
The chemical properties of 1-hydroxyacridizinium salts have hardly been examined. Only Earley et al.
[1, 2] noted a cycloaddition reaction of 1-hydroxypyrido[1,2-b]isoquinolinium perchlorate, which was obtained
by hydrolysis of the corresponding 1-methoxy derivative. Jones [8] has reported that structurally similar
1(3)-hydroxyquinolizinium derivatives exhibited acidic properties and yielded deprotonated (betaine) forms
upon reaction with bases. The reaction of 11-aryl-1-hydroxyacridizinium bromide 4c with Et3N at room
temperature also lead to the betaine 5, which was indicated by the lack of an OH signal in 1H NMR spectra and
upfield shift of all the signals for the protons of the tricyclic fragment. We should also note the upfield position
of the signal for the H-2 proton (at 6.33 ppm) due to the effect of the anionic site in this molecule. The IR
spectrum of betaine 5 lacked a hydroxy group band, while a band was found at 1597 cm-1 characteristic for the
olate C–O bond [14].
297

298

299

_
_
Br
Br
+
+
N
+
N
Et3N
Ac2O
N

MeOH
_
R1
R1
4c
R1 = 4-ClC6H4
R1
O
OH
O
Ac
5
6
1-Hydroxyacridizinium salts 4 displayed properties typical for phenols and gave a red-violet color in
neutral aqueous FeCl3 solutions. These compounds also may be acylated at the oxygen atom. Thus, 1-acet-
oxypyrido[1,2-b]isoquinolinium bromide 6 was obtained upon heating the salt 4c in acetic anhydride, as
1
indicated by the H NMR signal for the H-4 proton at 9.45 ppm and acetyl group at 1.60 ppm, as well as the
ν
C=O stretching band at 1770 cm-1 in the IR spectrum.
Thus, we have discovered a new means for adding an isoquinoline ring to a pyridine ring using an
electrophilic aromatic substitution reaction, which yields 1-hydroxyacridizinium salts.
EXPERIMENTAL
The IR spectra were recorded on a Perkin-Elmer Spectrum BX spectrometer for KBr pellets. The 1H and
13C NMR spectra were recorded on a Varian Mercury 400 spectrometer (400 and 100 MHz, respectively) in
DMSO-d6 with TMS as internal standard. The melting points were determined in a Thiele apparatus. The purity
of the products was checked by HPLC on an Agilent 1100 Series c instrument with an Agilent LC/MSDSL
selective detector using atmospheric pressure chemical ionization (400 V). Gradient elution was carried out with
phase A) H2O + 0.1% HCO2H, phase B) MeCN + 0.1% HCO2H. The elemental analysis was carried out using a
Vario MICRO cube CHNS analyzer. The Schoeniger method was used to determine halogens.
2-(Bromomethyl)benzaldehyde (1a) was prepared according to Zhang and Lippard [15], while
[2-(bromomethyl)phenyl](4-chlorophenyl)methanone (1b) was obtained according to Kim et al. [16] and
[2-(bromomethyl)-5-nitrophenyl](phenyl)methanone (1c) was obtained as a mixture containing 70% methanone
1c according to Gobbi et al. [17]. A sample of methyl 2-(bromomethyl)benzoate (1d) was prepared according to
Osdene and Timmis [18]. Pyridines 2a-h were obtained from Sigma-Aldrich.
1-Benzylpyridinium bromides 3a-e,h-l (General Method). Pyridine 2a-e,h-l (5.5 mmol) was added to
a solution of benzyl bromide 1a-e,h-l (5.0 mmol) in anhydrous acetone (10 ml), and the mixture obtained was
maintained for 72 h at room temperature. The precipitate formed was filtered off and washed with acetone. All
products 3 here and hereinafter were washed with acetone.
1-(2-Formylbenzyl)pyridinium Bromide (3f). Pyridine 2d (0.44 g, 5.5 mmol) was added to a solution
of aldehyde 1a (1.00 g, 5.0 mmol) in anhydrous benzene (10 ml). The mixture was maintained for 24 h at room
temperature. The precipitate of bromide 3f was filtered off.
1-[2-(4-Chlorobenzoyl)benzyl]pyridinium Bromide (3g). A mixture of ketone 1b (0.5 g, 1.6 mmol)
and pyridine (2d) (0.15 ml, 1.8 mmol) in anhydrous acetone (10 ml) was maintained for 2 h at 40-50°C and
then heated at reflux for 1 h. After cooling, the precipitate of bromide 3g was filtered off.
3-Hydroxy-1-[2-(methoxycarbonyl)benzyl]pyridinium Bromide (3m). Product 3m was obtained
according to the method for the preparation of compound 3f from ester 1d and pyridine 2a, maintaining the
reaction mixture at 60-70°C.
3-Hydroxy-1-(2-benzyloxycarbonyl)pyridinium Bromide (3n). Product 3n was obtained according to
the procedure for the preparation of products 4a-d from salt 3m, maintaining the reaction mixture for 10 h.
300

1-Hydroxypyrido[1,2-b]isoquinolinium Bromides 4a-d (General Method). A solution of salt 3a-e
(2.5 mmol) in 48% aqueous hydrobromic acid (20 ml) was heated at reflux for 2-3 h (salts 3b,e), 6 h (salt 3a),
and 30 h (salts 3c,d). After cooling, the precipitate formed of the corresponding bromide 4 was filtered off and
washed with acetone.
11-(4-Chlorophenyl)pyrido[1,2-b]isoquinolinium-1-olate (5). A solution of salt 4c (0.39 g, 1 mmol)
in a mixture of Et3N (0.5 ml, 3.6 mmol) and methanol (20 ml) was stirred at room temperature for 30 min. The
solvent was evaporated in vacuum. Then, 2-propanol (15 ml) was added to the residue. The mixture was heated
to reflux. After cooling, the precipitate of product 5 was filtered off and washed with 2-propanol.
1-(Acetoxy)-11-(4-chlorophenyl)pyrido[1,2-b]isoquinolinium bromide (6). A mixture of salt 4c
(0.3 g, 0.8 mmol) and acetic anhydride (10 ml) was heated at reflux for 20 min. After cooling, diethyl ether (50
ml) was added. The precipitate of bromide 6 was filtered off and washed with 2-propanol.
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