Domino reaction of N-(cyanomethyl)-1,3-azolium quaternary salts with o-hydroxybenzaldehydes: Scope and limitations

Article abstract of DOI:10.1039/c4ra14122a

A route towards chromenes, annulated with an imidazo[5,1-c][1,4]thiazine core through a base-promoted domino reaction of thiazolium quaternary salts, has been developed. The synthesised compounds show high cytotoxic activity against human tumour cell line

Full text of DOI:10.1039/c4ra14122a

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Journal Name
RSCPublishing
ARTICLE
Domino reaction of N-(cyanomethyl)-1,3-azolium
quaternary salts with o-hydroxybenzaldehydes: Scope
and limitations
Cite this: DOI: 10.1039/x0xx00000x
a
a
a
L.G. Voskressensky* , A.A. Festa , O.A. Storozhenko , T.A. Le , V.T. Nguyen,
A.V. Varlamov
b
c
a
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
A route towards chromenes, annulated with an imidazo[5,1-c][1,4]thiazine core through a
base-promoted domino reaction of thiazolium quaternary salts, has been developed. The
synthesised compounds show high cytotoxic activity against human tumour cell lines.
www.rsc.org/
Introduction
Synthesis of N-(cyanomethyl)-1,3-azolium salts
Domino reactions, also known as tandem or cascade reactions, have The preparation of the starting thiazolium salts, 1a–c, has
9
emerged as a highly effective strategy for the synthesis of previously been reported. The yields can be significantly
heterocyclic compounds, including bioactive natural products and increased by running the reactions under microwave (MW)
1
pharmaceutical agents. These protocols enable chemists to perform irradiation conditions (Table 1). Imidazolium salt
2 was
complex synthetic conversions with high efficiency using readily prepared with a good yield without employing MW irradiation.
2
available starting materials, often via a biomimetic pathway. Thus, Unfortunately, we did not succeed in preparing the oxazolium
domino reactions contribute exceedingly to synthetic drug design quaternary salts by any means; the use of more facile leaving
strategies, enhance elegant approaches in total synthesis and improve groups (–Br, –I), solvent-free techniques and MW irradiation
1
yields in large-scale syntheses. The advantages of these methods
,2
did not provide positive results.
3
include excellent atom economy, high selectivity and less waste.
Additionally, using these strategies, multiple transformations can be
carried out in a single laboratory operation without the isolation of
4
intermediates, making them prime examples of green chemistry.
Despite the widespread proliferation of domino reactions,
researchers have continued to channel their efforts in this area, as
new heterocyclic structures and novel substitution patterns are
Table 1. The synthesis of quaternary salts 1, 2.
5
required.
Prev.
Rep.
Yield,
%
Pro-
Yield,
%
1
2
The reactivity of N-(cyanomethyl) heterocyclic quaternary salts in
domino reactions are of interest, owing to the structural complexity
generated and the potential biological activity of the resulting
products. Investigations in this field have shown the possibility to
R
R
X
Conditions
duct
MW, 140°C,
30 min,
6
1a
H
H
H
S
S
S
49
33
20
81
79
82
easily transform pyridinium salts to chromenoimidazopyridines,
7
solvent-free
MW, 140°C,
30 min,
isoquinolinium salts to chromeno-
and thiochromeno-
8
imidazoisoquinolines. Moreover, we have had preliminary results
showing a route to the chromenoimidazothiazine core through the
ANRORC transformation of N-(cyanomethyl)-1,3-thiazolium salts
1
b
Me
solvent-free
MW, 140°C,
30 min,
9
under the action of salicylic aldehydes. The optimisation of the
1
c
Me Me
latter reaction conditions, the extension of the methodology to other
solvent-free
MW, 140°C,
30 min,
1
,3-azoles and the biological evaluation of the chromeno-
imidazothiazines are disclosed in the present paper.
1
d
H
H
Me
H
S
65
-
81
78
solvent-free
Results and discussion
2
N-
CH CN,
3
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ART22ICLE
DOI: 10.1039/C4RA141 A
o
50 C, 1 h
Me
and substituted aldehydes in pure water. As far as the products
of the reactions precipitate from the reaction mixture, the
homogeneity of the starting reactants in the solvent is important
for producing the precipitates with the acceptable purity. The
general recommendations for carrying out these reactions are
the avoidance of high temperatures and to minimise the
reaction time when using either an equivalent or excess amount
of base.
Reaction of thiazolium salts with o-hydroxybenzaldehydes:
Optimisation and scope
9
Owing to preliminary studies, the reaction of thiazolium salts
1
with
proceeded as a domino process, involving an ANRORC step,
and led to the formation of chromenoimidazothiazines
Scheme 1).
o-hydroxybenzaldehydes under base-promoted conditions
3
(
Table 2. Optimisation of the model reaction conditions.
o
T, C
Yield,
%
Entry
t, h
1
Solvent
MeOH-
Promoter
NH OAc
(100 mol%)
Prod.
4
1
reflux
reflux
3b
10
H
2
O
MeOH-
O-
THF
t-BuOK
2
3
H
2
3a
trace
trace
(
20 mol%)
-Proline
(10 mol%)
-Proline
(120 mol%)
Et
MeOH-
L
3
4
5
6
7
8
9
r.t.
reflux
r.t.
12
3a
3a
3a
3a
3b
3a
3b
3b
3a
3a
3a
3a
3a
3b
3b
3a
2
H O
MeOH-
L
3
3
trace
7
2
H O
MeOH-
3
N
H
2
O
MeOH-
(100 mol%)
DMAP
(100 mol%)
reflux
reflux
reflux
reflux
reflux
reflux
40
3
trace
18
H
2
O
MeOH-
K
2
CO
(20 mol%)
CO
(20 mol%)
CO
(60 mol%)
CO
(100 mol%)
CO
(100 mol%)
CO
(100 mol%)
CO
3
3
2
H O
MeOH-
K
2
3
1
19
2
H O
MeOH-
K
2
3
3
38
2
H O
MeOH-
K
2
3
1
1
1
0
1
2
0.1
0.1
1
48
2
H O
Scheme 1. Plausible scheme of chromenoimidazothiazine formation.
MeOH-
K
2
3
trace
37
2
H O
The initial optimisation of the reaction conditions showed that
the use of 20 mol% sodium carbonate as a base and MeOH–
MeOH-
K
2
3
2
H O
K
2
3
H O as a solvent was optimal. Still, the yields of the tetracyclic
2
13
80
1
DMF
DMF
trace
trace
10
(
20 mol%)
K CO3
products were satisfactory, but the reaction failed to produce
2
1
4
80
1
3
4
5
(
100 mol%)
CO
target compounds with salicylic aldehyde (R , R , R =H). To
overcome these problems, a more thorough study of the
reaction conditions was initiated. The reactions of thiazolium
salts 1b and 1c with salicylic aldehyde were chosen as the
model, and the results of the optimisation process are
summarised in Table 2. It has been shown that the use of
promoters such as ammonium acetate, potassium tert-butoxide,
K
2
3
15
reflux
reflux
r.t.
0.1
1
TFE
(100 mol%)
DBU
MeOH-
1
6
43
H
2
O
MeOH-
(100 mol%)
DBU
(110 mol%)
DBU
(110 mol%)
17
18
18
61
H
2
O
MeOH-
1
8
r.t
62
H
2
O
L
-proline, triethylamine or dimethylaminopyridine resulted in To show the advantages of the newly selected conditions,
the formation of only trace amounts of products 3a and 3b previously reported compounds were obtained by a modified
Table 2, entries 1–6). The use of potassium carbonate (20 protocol. Thus, the yields of compounds 3d 3e 3g and 3h were
(
,
,
mol%) provided compound 3b in 18% yield in refluxing significantly improved (Table 3, entries 4–7 and 9–12). The
MeOH–H O for 3 h. The use of 60 mol% K CO raised the reaction worked well for aldehydes bearing both electron-
2
2
3
yield to 38% with 3 h reflux. A further increase in the amount donating and electron-withdrawing groups, giving target
of K CO (100 mol%) provided compound 3b in 48% yield compounds with satisfactory-to-good yields (Table 3).
3
2
3
after 10 min reflux, but resulted in complex-mixture formation
Reactions of imidazolium salt with o-hydroxybenzaldehydes
with
improvements (Table 2, entries 13–15). DBU was found to be hydroxybenzaldehydes were anticipated to proceed in a similar
the most suitable base, as compound 3b was obtained in 61% way. Despite the expectations, the reaction of and salicylic
yield and 3a in 62% yield. Further studies failed to improve aldehyde in MeOH–H O, using K CO as a base, produced no
in the case of 3a (Table 2, entries 10 and 11). The employment
of TFE or DMF as solvents did not result in any yield The reactions of imidazolium salt
2
o-
2
2
2
3
these yields. The methanol and water were not used separately mobile spots on the TLC plate. The resulting product 4a
due to the poor solubility of the quaternary salts in pure alcohol precipitated from the reaction mixture after the addition of
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ART22ICLE
Table 3. The scope of chromenoimidazothiazines 3.
1
2
3
4
5
Entry
R
R
R
R
R
Conditions
DBU (110 mol%), r.t., 18 h
DBU (110 mol%), r.t., 18 h
Product
3a
3b
3c
3d
3d
3e
Yield, %
1
2
3
4
5
6
7
8
9
Me
Me
H
Me
Me
Me
Me
H
Me
Me
Me
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Br
Br
Br
Br
Br
NO
NO
NO
NO
NO
H
H
H
H
H
H
H
H
H
H
H
H
H
62
61
34
28
61
12
61
46
27
81
12
76
34
30
37
54
72
58
43
Me
Me
H
K
Na
2
CO
3
(110 mol%), 40 °C, 1h
(20 mol%), reflux, 1h
2
CO
3
H
DBU (110 mol%), r.t., 18 h
Na CO (20 mol%), reflux, 1h
Me
Me
Me
H
2
3
DBU (110 mol%), r.t., 18 h
DBU (110 mol%), r.t., 12 h
3e
3f
2
2
2
2
2
Na
DBU (110 mol%), r.t., 18 h
Na CO (20 mol%), reflux, 1h
2
CO
3
(20 mol%), reflux, 1h
3g
3g
3h
3h
3i
3j
3k
3l
1
1
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
8
9
H
Me
Me
Me
Me
Me
H
Me
Me
Me
2
3
DBU (110 mol%), r.t., 18 h
DBU (110 mol%), r.t., 12 h
Me
H
Me
Me
H
-CH-(CH)2-CH-
-CH-(CH)2-CH-
OMe
OMe
OMe
K
2
CO
CO
3
(20 mol%), reflux, 45 min
(20 mol%), reflux, 45 min
K
2
3
H
H
H
H
K
2
CO
CO
CO
3
3
3
(110 mol%), 40 °C, 1h
(110 mol%), 40 °C, 1h
(110 mol%), 40 °C, 1h
K
2
3m
3n
3o
H
OMe
K
2
Me
NO
2
DBU (110 mol%), r.t., 18 h
picric acid, making it possible to characterise the products by imine bond in zwitter-ion
A (Scheme 2). The similar product,
1
X-ray analysis. The formation of this coumaryl-substituted 4b, was obtained from nitro-substituted salicylic aldehyde with
0
imidazolium picrate may be explained by the hydrolysis of the
4
2% yield. To avoid hydrolysis, the reaction was carried out in exhibited potent cytotoxicity against the KB cell line with IC50
water-free conditions, but the exploitation of dry DMF or = 4 and 6.32 µg/mL, respectively. Meanwhile, analoguess 3e
MeOH led to the formation of inseparable mixtures.
and 3l inhibited the Hep-G cell line with IC values in the 80–
2 50
1
17.5 µg/mL range. Derivative 3m displayed cytotoxic activity
against LU cell lines, with an IC50 value of 99.76 µg/mL.
Concerning the last cell line, MCF7, the
R1
O
O
CN
Cl
1) K CO
O N
NO2
2
2
3
chromenoimidazothiazines analogues showed weak activities,
with IC50 values above 128 µg/mL. It is noteworthy to mention
that two derivatives, 3m and 3l, present a cytotoxicity activity
against the cancer cell line KB that is comparable with
ellipticine.
N
N
OH
MeOH-H2O
O
R1
2) picric
acid
O
NO2
N
Me
1
4
4
a R =H; 48%
2
N
1
b R =NO2; 42%
Me
-
-
H2O
HCl
Table 4. Cytotoxic activity of compounds 3b, 3e, 3l, 3m and 5.
picric acid
H O
2
Compound
Cell line, IC50 ꢀg/mL
R1
R1
KB
HepG
2
Lu
MCF-7
0.71
Ellipticin
0
.25
0.29
1.18
>128
>128
3
b
32
>128
117.5
>128
O
O
N
3e
68.0
> 128
CN
3l
4
80
>128
>128
>128
>128
3m
6.32
99.76
N
N
N
N
A
Me
Me
Scheme 2. Coumaryl-substituted imidazolium picrate
4
formation.
> 128
> 128
> 128
> 128
Biological evaluation of chromenoimidazothiazines
9
Compounds 3b, 3e, 3l, 3m and
5
were evaluated in vitro for
their cytotoxic activity against four human tumour cell lines
KB, Hep-G , LU and MCF-7), and the results are summarised Conclusions
(
2
in Table 4. These particular compounds have been selected due
to their better water solubility. Four chromeno-imidazothiazine
derivatives showed strong activity against the KB cell line with
an IC50 value below 100 µg/mL. Analogues 3m and 3l
A number of 10bH-6-oxa-1-thia-3a,5-diazaacephenanthrylenes
have been synthesised through the ANRORC domino reaction
of -(cyanomethyl)-1,3-thiazolium salts with salicylic
N
aldehydes. It has been shown that 3-(cyanomethyl)-1-
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methylimidazolium chloride reacts with salicylic aldehydes
differently to expected, forming coumaryl-substituted
imidazolium salts. It has been also reported that the 1,3-oxazole
failed to give the
N-cyanomethyl quaternary salt. Some of the
synthesised compounds were tested in vitro and showed high
cytotoxic activity against human tumour cells.
Acknowledgements
This work was financially supported by the Russian Foundation
for Basic Research (grants 14-03-31140-mol_a and 14-03-
9
3001), the Ministry of education and science of Russian
Federation (project 2042) and VAST (grant
VAST.HTQT.NGA.06/14-15).
Notes and references
a
Organic Chemistry Department, Peoples’ Friendship University of
Russia, Miklukho-Maklaya st., 6., 117198, Moscow, Russian Federation.
b
Department of Chemistry, Vietnam National University, 144 Xuan
Thuy, Cau Giay, Hanoi, Vietnam.
c
Institute of Chemistry, Vietnam Academy of Science & Technology, 18
Hoang Quoc Viet, Cau Giay, Hanoi, Vietnam.
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1 13
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